Pulmonary thromboembolic disease

PULMONARY THROMBOEMBOLIC DISEASE* WILLIAM R. BELL, M.D. JOHN R. BARTHOLOMEW, M.D.

*Supported the National The Whitehall

in part by research grants HL01601, HL24898, Institutes of Health, National Heart, Lung, Foundation, and The Hazel Dell Foundation.

and HL07377 from and Blood Institute,

0146-2806/85/09-OOl-070-$9.95

01985,

Year Book Medical

Publishers,

Inc.

completed, his house staff training in internal medicine at The Johns Hopkins Hospital, Baltimore, and the Peter Bent Brigham Hospital, Boston. He served as a clinical associate at the National Institutes of Health in the National Cancer Institute, a visiting investigator at the Royal Postgraduate Medical School-Hammersmith Hospital of the University of London, and as a member of the Advisory committee to the Director of the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Bell joined The Johns Hopkins University School of Medicine faculty in 1970. He is now Professor of Medicine and Radiology in the Division of Hematology at The Johns Hopkins University School of Medicine and The Johns Hopkins Hospital.

is currently of Medicine, Hospital.

a Senior Clinical Fellow in the Department Hematology Division, at The Johns Hopkins

MEDICAL historians relate that the disorder of pulmonary embolism initially was designated “sudden breathless sleep.” For years, the etiology of the sudden breathlessness was obscure. With the advent of autopsy studies, first performed at the end of the 11th century, endogenously formed thrombi were recognized to be the cause of the pulmonary symptomatology that was often followed by death. Not until nearly 400 years later were the pathophysiologic consequences of thrombi in the pulmonary arteries first described by Virch0w.l More than 50 years later, suggestions for therapy first appeared.‘, 3 For the next 100 years, various surgical techniques were the major, if not the only, form of therapy employed. Up until 1924, the mortality rate from the most frequently employed surgical procedure, as initially devised by Trendelenburg,2 was 100%. From the time of the first successful survivor of this procedure, performed by Kirschner,* to 1932, a total of 123 operations were performed, with only nine complete recoveries5 The tenth successful embolectomy reported in the world was in 1936,6 in Rome. The first successful report in the United States was in 1958.7 The difficulties surrounding surgical attack on pulmonary embolism prompted the use of some nonsurgical (medical) forms of 5

therapy. The initial results were not dramatic, but success was reported employing oxygen’ in 1891. Although an anticoagulant (heparin) was discovered in 1916,9 its use clinically as an antithrombotic agent was not tried until 1935.r’ During the next 40 years, several studies repeatedly demonstrated that medical therapy, including anticoagulants, is the initial treatment of choice. During this time, the utilization of many different surgical techniques has declined progressively in the management of pulmonary thromboembolic disease. Although this disease has been recognized in considerable detail for several centuries, it remains one of the most common and most difficult problems in the clinical practice of medicine. Pulmonary thromboembolic disease is a universal problem that crosses all traditional compartments, specialties, and subspecialties of medical practice. Although there are numerous reasons that make this disease difficult to manage, the major source of difficulty to the physician is how to establish the diagnosis. This pathologic process affects an estimated 650,000 patients annually in the United States, with over 200,000 fatalities. Numerous autopsy studies reported over the past 15 years indicate that pulmonary thromboembolism is perhaps the most commonly missed diagnosis that is directly responsible for patient mortality. Thoughtfully designed necropsy studies reveal that 40% to 60% of patients who died because of pulmonary emboli arrived at postmortem examination without correct diagnosis and treatment.l” I2 Recent studies have shown that only 30% of anatomically major pulmonary emboli are correctly diagnosed clinically,13 and this may reflect the nonspecificity of the histoIy, physical examination, and noninvasive laboratory studies. The only definitive means to diagnose pulmonary embolus before death is with pulmonary angiography, although a normal lung scan will exclude the diagnosis. Once the diagnosis is suspected, therapy should begin immediately. Thrombolytic therapy has replaced heparin as the initial treatment of choice in many centers. Pulmonary embolism continues to be one of the most difficult diagnostic problems that confronts all physicians. PATHOLOGY

Pulmonary emboli commonly result from venous thrombi that have migrated to the pulmonary vasculature. Arterial thrombi and nonthrombotic processes can also cause pulmonary embolism. These conditions result in partially or totally occluded pulmonary vessels and may be accompanied by pulmonary infarction. Thrombi are usually of two kinds, venous or arterial, and are .generally composed of platelets, red cells, leukocytes, and other plasma proteins enmeshed in fibrin. Arterial thrombi usu6

ally occur in association with a damaged vessel wall and platelets may play a major role in their origin. Venous thrombi usually occur in the absence of vascular injury and are more dependent on reduced blood flow and activated components of the intrinsic clotting system.i5 Venous thrombi are either inflammatory or noninflammatory and generally not seen in the free-floating circulation. A thrombus may vary greatly in size and grows by deposition of successive layers of platelets, red cells, and fibrin that may break loose to form an embolus. Most venous thrombi originate within the valve pockets of the lower extremities. There are three fundamental factors responsible for most thrombi formation, which are collectively known as Virchow’s triad. They include stasis or decreased blood flow, changes in or injury to the vessel wall, and alteration in the coagulability of blood. Venous stasis appears to be the most important factor in the formation of thrombi. Stasis alters the physical properties of blood that facilitate fibrin formation.16 ’ It also promotes the accumulation of activated clotting factors in areas such as the venous valve pockets by slowing their clearance in the liver and preventing dissolution by fibrinolysis. Injury to vessels is a less common cause of thrombosis, but is seen during surgery of the hipi or fractures of the lower extremities. Intraoperative damage to the femoral vein due to manipulation during surgery and venous stasis are probably the thrombogenic stimuli. Another factor that predisposes to venous thrombosis is hypercoagulability, which may be defined as hemostatic overactivity. In this process, activation of coagulation factors by collagen, endotoxin, procoagnlant material from malignant tissue, or release of thromboplastin into the circulation during childbirth, surgery, or trauma. may incite thrombus formation.lg, 2o Platelets may play a role in venous thrombosis because of increased adhesiveness and due to a release of procoagulant materia1.21-23 Platelet hyperaggregability has also been described.= Other factors that are elevated but not specific in thrombosis include fibrinopeptides A and B, circulating fibrin monomer, and fibrinfibrinogen split products.ig7 25 Abnormalities of antithrombin III, which is physiologically important in neutralizing thrombin and preventin~~oagulation ef the blood, may contribute to thrombus formation. Pulmonary emboli originate from many sources, including deep venous thrombi, thrombi in the right atrium, septic foci related to drug abuse, pelvic thrombophlebitis, dental infection, suppurative phlebitis from intravenous (IV) catheters, infected pacemakers, infected arterial venous shunts, and direct injection of iufected material into the vein.277 28 Other sources include turnoqm, 29 amniotic fluid, fat, air, artheroemboli, e.g., from an 7

abdominal aortic aneurysm,“’ bone marrow, parasites, cardiac catheters, and brain tissue, often related to trauma. The origin of pulmonary embolism is not always embolic. In situ pulmonary thrombosis can occur from trauma to the chest, congenital cardiac anomalies, vegetations, (e.g., subacute bacterial endocarditis) and with reduced blood flow as in tetralogy of Fallot or pulmonary stenosis. Sickle cell anemia28 may also predispose to pulmonary thrombosis. The major source of pulmonary embolism is the deep venous system of the legs and pelvis. According to some authors, approximately 50% of deep venous thrombi in the iliofemoral venous system will embolize,31 while others estimate this at 15% to 20%. Still other studies have found a 10% to 50% frequency of embolization in the iliofemoral system.32 The incidence of embolism from thrombosis below the popliteal vein is reported around 30%.33, 34 Most figures remain controversial, and there is still disagreement not only to the extent that thrombi embolize from the legs, but also their source, either from above the calf or below it. A study of 132 consecutive patients investigated after sugery for deep venous thrombosis found evidence for thrombosis in 30% of the patients. Pulmonary embolism was only found in four patients and all had proximal extension of calf vein thrombosis.35 A more recent autopsy study showed embolization in over 60% of cases with deep venous thrombosis. The most common sites of origin for emboli were from veins of calf, plantar, and common femoral and superficial femoral areas. Of the more serious emboli, one third had their most proximal originating thrombi in the calf and plantar veins, and two thirds were in the calf-iliofemoral segments of the leg veins. In less serious emboli, the majority of thrombi were from a calf vein source.36 Another study found that calf deep venous thrombosis posed a low risk of embolization, while thigh thrombosis posed a much greater risk. 37 This conclusion was supported by a surgical group who believed that propagation from distal to proximal sites is not a significant pathogenetic mechanism. They thought that only small emboli came from distal sites, while thrombosis above the knee was the source for most life-threatening embolism.38, 3g It appears that thrombi embolize about 15% to 20% of the time and that major emboli are more likely to come from thrombosis proximal to the knee, but can occur from calf vein sources. Thrombi may arise in the iliofemoral veins but more commonly propagate proximally from calf veins. M. H. CRAWFORD: The right ventricle occasionally may be the site of material that embolize to the pulmonary circulation. This is especially true in patients with right ventricular infarction-a frequent accompaniment of inferior left ventricular myocardial infarction-and severe biventricular failure. Both conditions may also

origin of thrombotic

8

result in decreased extremity blood flow, so that the source cannot automatically be assumed to be from the right ventricle. However, this source should be considered before deciding against anti-coagulant therapy or for peripheral venous surgery in the appropriate clinical setting. Two-dimensional echocardiographic imaging may document this source of thrombotic material.

PATHOGENESIS

OF EMBOLISM

Vasoconstriction and bronchoconstriction occur as a result of pulmonary embolism,40, 41 and can lead to ventilation-perfusion abnormalities.42 Bronchoconstriction is due to a decrease in or loss of blood flow, as well as a slow loss of surface active material in segments of lung without perfusion, and release of substances like histamine and serotonin. Increased dead space is also found.31 The cardiovascular system’s response to the reduced arterial flow in the lung is a decline in systemic blood pressure and a rise in the pulmonary arterial pressure. The right cardiac chamber dilates and cardiac output decreases. This results in hypoxemia, increases in both right atria1 mean pressure and mean pulmonary artery pressure, as well as in increased right ventricular systolic pressure. These findings are due to constriction of pulmonary vascular beds,43 except for hypoxemia, which is due to perfusion of underventilated areas of the lung. Pulmonary infarction may accompany pulmonary embolism, and recent studies have found the frequency to be as high as 31% in autopsyproved cases,44 while others believe the frequency to be around 1O%.31 Pulmonary infarction occurs most commonly in subjects with cardiovascular disease or malignancy. Infarction is reported to be uncommon when emboli obstruct the central arteries but more frequent when emboli obstruct more distal arteries. 45 An example of a massive pulmonary embolism is seen in Figure 1. Pulmonary emboli resolve primarily by progressive fibrinolysis. Resolution even of massive emboli can occur in as little as 30 hours.46, 47 In one series, spontaneous resolution was complete in six patients within seven to 19 days, and almost complete in one patient within 16 days.48 Generally, resolution depends on the severity of the embolism as well as coexisting states and treatment used. COEXISTING

CONDITIONS

Recognition of clinical conditions that can coexist with pulmonary embolism may facilitate early diagnosis. These clinical conditions are often present immediately before and at the time of the embolic event and may be termed coexisting conditions. Some authors refer to these coexisting conditions as predispos9

Fig 1 .-Massive through pulmonary causing complete

pulmonary embolus with thrombus extending from right valve and outflow tract into right and left pulmonary blockage of blood flow.

ventricle arteries

ing factors in the development of thrombosis. However, since these conditions are nonspecific, and the frequency of these conditions in people who do not experience pulmonary emboli is not known, it is erroneous to use the term predisposing. They include immobilization, age and sex, cardiac disease, trauma, obesity, neoplasms, pregnancy and the puerperium, drugs, and hematologic disorders.

Immobilization is the most common coexisting condition that leads to pulmonary embolism. It may be due to disabling problems such as leg fractures, the postoperative period, incapacitating cardiac or pulmonary disease, nervous system paralysis, general disability, or inappropriate, extended bed rest in healthy persons. Immobilization removes the repetitive muscular massaging activity of the deep and superficial veins of the lower extremities and loss of this movement promotes stasis.4g This retardation of blood flow is superimposed on the focal sluggish flow around the venous valves and explains why the valve pockets are the most common sites of thrombus formation in the lower extremities.50-52 The soleus and gastrocnemius muscles are the sites of the slowest blood flow where most of these of the lower exthrombi originate.53-57 Prolonged immobility tremities in healthy persons is also associated with deep vein thrombosis.58-61 There is a progressive increase in the frequency 10

of dse..eEZ-xTin thrombosis that parallels the length of bed rest. ’ Venous stasis is a pathologic common denominator for venous thrombosis that, in turn, precedes most pulmonary embolism. It ties together the medical and surgical illnesses that confer “risk” for the development of thromboembolic events.65-70 Other than immobilization, no abnormalities have been identified to account for the changes. AGE AND SEX

The frequency of pulmonary embolism is greatest in patients between the ages of 50 to 65 years71 and one report indicated that 90% of fatal pulmonary embolism occurred in patients older than 50 years.72 Age distribution in patients does not represent an independent risk factor. A 10% frequency of ulmonary embolism is reported in the pediatric population.73-7 F No significant difference has been found in sex distribution.68* 71,78, 7g An association has been identified in females taking oral contraceptiveseO CARDIAC DISEASE

Heart disease is one of the ma&r risk factors for the development of thromboembolic disease. Atria1 fibrillation and congestive heart failure are the diseases with the highest incidence, followed by patients with rheumatic, arteriosclerotic, bacterial, and hypertensive heart disease.683 ‘OPe2 TRAUMA

A frequency of 15% ofzulmonary emboli is noted in patients with accidental trauma.6 Frequency does not vary with the site of trauma, except for fractures of the hip or pelvis.64* 83-85 Burns are associated with a high frequency of pulmonary embolism. 68*‘6-e’ The duration of survival after burns or trauma was the major influence on the risk of pulmonary embolism.68 OBESITY

An increased frequency of thromboembolism is noted in patients who weigh more than 20% above the standard amount for their age, sex and frame size; however, no mechanism has been identified ‘8, Sb,“,89-94 Long-term risk factors in subjects from the Framingham Heart Study indicated that an increase in weight is an important risk factor for major pulmonary embolism only among women.g5 As the degree of obesity increases beyond 20% more than the standard weight, there is no significant increase in embolic disease. 11

NEOPLASM An increased frequency of pulmonary emboli is found in patients with cancer, and is greatest for neoplasms of the lung, pancreas, and alimentary and genitourinary tracts. Thromboembolic disease may be the presenting sign of neoplasm.g6-g8 Trousseau first reported an association between migratory and recurrent thromboembolic disease and neoplasms.” It has been postulated in malignant diseases that mucin-producing cells are related to thrombus formation, but no definite relationship has been proved.g7 The hemostatic mechanisms can be abnormal in patients with malignancy. ‘g-10’ A shortened bleeding and clotting time and decreased prothrombin and partial thromboplastin times suggest the presence of a circulating thromboplastin. This substance has not been characterized. It has been recognized that neoplastic cells can produce a variety of other substances including histones, cathepsins, and proteases, which are capable of activating the coagulation system.lo2 Plasma cell dyscrasias, which produce abnormal proteins, may also play a role.lo3 PREGNANCYANDTHEPUERPERIUM The risk of thromboembolic disease increases during pregnancy and may be seven times greater than in age-matched nonpregnant females81, lo4-lo7; however, the overall incidence is low. Thrombosis is more common during the third trimester but the greatest incidence occurs in the postpartum period. A greater incidence is suspected in patients who undergo a caesarean sectionlo and the incidence of death is reported as increasing.l” Venous thrombosis is also more common in patients who are bedridden for complications of pregnancy including threatened abortion, rupture of membranes, and preeclampsia.110-120 Studies performed on the coagulation and fibrin01 tic states to idenH’ have found that tify the etiology of this increased frequency’ many of the coagulation factors and platelets were increased. The activity of the plasminogen-plasmin proteolytic system is decreased. Although these changes suggest predisposition for thrombosis, there is no absolute difference in these changes in pregnant women who do not experience thrombosis compared with those who do. DRUGS A definite relationship appears to exist between thromboembolism and oral contraceptives.803 122-125 They include changes in coagulation factors, platelets, activity of the fibrinolytic system, plasma lipoproteins, triglycerides, and cholesterol.llg, 126-132 Although the precise mechanism for thrombus formation is not known, it is generally advised that these agents be avoided, es12

pecially if other risks such as obesity, immobilization tension coexist.

or hyper-

HEMATOLOGIC DISEASE Thromboembolism in the hematologic disorders is uncomembolism is rare in sickle cell disease,133-134 mon. *’ Pulmonary but in paroxysmal nocturnal hemoglobinuria, thrombus formation is the most common cause of death.135-141 Some authors believe thromboembolic disease is common in polycythemia Vera, ‘6x 142 but in a large series of patients studied with pulmonary embolism, not one patient with polycythemia rubra vera had thromboembolic disease.80 Thrombocytosis does not appear to predispose patients to thromboembolism; however, there are reports of development of thrombocytosis in splenectomized patients who have had embolic events.143 This has been attributed to an increase in&&elet stickiness,144 although this is not confirmed by others. In several groups studied with a severe degree of thrombocytosis, an increased incidence of thromboembolic disease was not found.21, 146 An increased frequency of thromboembolic disease has been reported in families deficient in antithrombin 111147-153 and in one family with abnormal plasminogen.154 A high percenta e of patients with blood group A have thromboembolic disease gl, 155-162 while the frequency in blood group 0 is relatively rare. A connection between red cell antigens and thrombus formation has not been identified. Homocystinuria, an inborn error of metabolism characterized by an absence of cystathione synthetase, has an unusual incidence of thromboembolic disease.163-170 Homocystine appears to induce vascular endothelial damage that facilitates plug formation and thrombosis,171 while others have re orted platelet abnormalities as the cause of thrombosis.167’ i 8 Thromboembolic disease has been reported in 25% of patients with Behcet’s syndrome, a multisystem disease characterized by recurrent oralgenital ulcerations.172-177 Increased levels of fibrinogen, abnormal platelet function and decreased activity of the fibrinolytic system may be related to the thrombotic events.178-1s2 A 20% incidence of emboli has been reported in patients with diabetes mellitus6* and an increased frequency of emboli has been observed in patients with chronic pulmonary disease.183 SIGNS AND SYMPTOMS The initial presentation of pulmonary embolism may be quite variable. Pulmonary embolism may be seen in patients with recent surgery, trauma, phlebitis, congestive heart failure, atria1 fibrillation, malignancies, or in patients who are receiving oral contraceptives, experiencing prolonged bed rest, the postpartum 13

state, or respiratory failure.ls4 It may present in previously healthy persons or as complications of a chronic illness, such as chronic cardiopulmonary problems. It may present as a fever of unknown origin. 185 The onset may be abrupt, such as an overwhelming catastrophic event, or it may be insidious. The differential diagnosis suggests a wide array of illnesses, including pneumonia, myocardial infarction, congestive heart failure, chronic obstructive pulmonarys3disease, angina pectoris, pleurisy, or carcinoma of the lung. Clinical signs and symptoms are important in leading one to suspect the diagnosis of pulmonary embolism. Studies have demonstrated, however, that no clinical findings are specific for pulmonary embolism.80 Clinical features closely related to the pathophysiology include wheezing, tachypnea, hypoxia, and signs of pulmonary hypertension. Pleuritic pain may accompany infarction.72’ 7 The classic pictures of hypotension, elevated jugular venous pressure, and right ventricular gallop in massive embolism, or pleuritic chest pain, hemoptysis, and fever in subacute cases, appear with many variations. The frequency of various symptoms and signs observed in the largest series of patients with angiographically documented pulmonary emboli are listed in Table 1.80 The most frequent complaint was chest pain, which was generally pleuritic in nature (74%), and was often noted three to four days before the diagnosis. The pain may also be dull or crushing in nature and mimic coronary artery disease. Similarly, although not well recognized, patients with massive embolization may have chest pain caused by coronary insufficiency and a failure to recognize this gyts the patient at increased risk for further embolization. Most patients will complain of shortness of breath, and dyspnea has been reported in 85% of patients with documented pulmonary embolism.” It is frequently sudden in onset and may last briefly or for several hours. Often, this is the patient’s only complaint31 The intensity and duration of dyF$nea generally correspond to the extent of embolic obstruction. More than half of patients studied experience apprehension and cough. The cough is frequently nonspecific and nonproductive. Other symptoms may include leg cramps, syncope, palpitations, nausea, vomiting, chills, hemoptysis, and diaphoresis. Syncope may occur in more than 10% ofgatients and generally implies massive pulmonary embolism.” These symptoms are frequently present 24 to 36 hours before the diagnosis is made. Up to one fourth of patients may give a history of previous thromboembolism. Physical examination results commonly reveal tachypnea, rales, and an increase in intensity of the pulmonic component of 14

the second heart sound. A respiratory rate approaching 40 to 50 breaths per minute is not uncommon, in more severe cases. In at least half of the patients with documented pulmonary emboli, the pulse rate is within the normal range.” In the remainder, the pulse was between 100 to 120 beats per minute, and in a small segment of patients, the pulse was greater than 120 beats per minute. Hypotension leading to shock occurred in about 10% of the patients and was almost always associated with massive emboli. An elevated temperature should not be a deterrent to the diagnosis of pulmonary embolism, as 43% of the patients with angiographically proved pulmonary emboli had a temperature greater than 37.8” C. Temperatures above 39” C due to pulmonary thromboembolism may occur early in the course of the illness and a low-grade fever may last for a week or longer.‘s’ The combination of rales, rhonchi, wheezes, and a pleural friction rub are present in the majority of patients. Cardiac signs often present include an S3 or S4 gallop, cardiac murmur (most frequently in the pulmonic valve area), peripheral edema, cyanosis, hepatic enlargement, jugular venous distension, and a pericarTABLE

l.-SYMPTOMS ANGI~GRAPHICALLY

AND SIGNS OBSERVED IN 327 PATIENTS DOCUMENTED PULMONARY EMBOLI*

(N SYMPTOMS

Symptoms Chest Pain Pleuritic Nonpleuritic Dyspnea Apprehension Cough Hemoptysis Sweats Syncope Signs Respirations Rales + SzPt Pulse >lOO Temperature Diaphoresis Gallop Phlebitis Edema Murmur Cyanosis

=%327)

(N

AND SIGNS

> 16/min

beats per >37.8”C

MASSIVE EMBOLISM,

min

=

197)

%

WITH

SUBMASSIVE EMBOLISM, %

(N

=

130)

88 74 14 85 59 53

85 64 6 85 65 53

82 85 8 82 50 56

30 27 13

23

29

40 23 6

92

95

58 53 44 43 36 34 32 24 23

57 58 48 43 42

19

20

39 36 28 27 25

*Courtesy of Bell W. R. et al.: Am. Heart J. 103:244, 1982. t + S2P indicates increase in intensity of the pulmonic component second heart sound.

87 60 45 38 42 27 25 26 25 16

9 of the

15

dial friction rub. Clinically evident thrombophlebitis of the lower extremities is not frequently present at the time of diagnosis, but tortuous varicosities, venous insufficiency with mild edema, and skin changes of stasis were commonly observed. As defined by angiography, submassive embolism are those involving less than the equivalent of two lobar arteries with significant filling defects or obstruction. Massive emboli are those with si ificant defects or obstruction of two or more lobar arteries. l@ Pleuritic chest pain and hemoptysis are significantly more common in submassive embolism, while apprehension, syncope, an increase in intensity of the pulmonic component of the second heart sound, gallop, and murmur are more common with massive embolism. Previously described popular triads such as an increase in pulse rate, respiration, and fever; cough, chest pain, and syncope; chest pain, fever, and hemoptysis; tachycardia, hemoptysis, and shock were not commonly observed as triads in patients documented to have pulmonary thromboembolic disease. Clinical signs are often very abrupt and more than half of the patients who die from pulmonary embolism will die within one hour and three fourths within two hours.‘g1 The history and physical examination remain invaluable as the initial step in the detection of pulmonary embolism, although most of the aforementioned signs and symptoms can be found in a wide variety of diseases. However, if the patient under suspicion for pulmonary embolism lacks the complaint of shortness of breath or chest pain and is not tachypneic at the time of physical examination, the diagnosis is unlikely. M. H. CRAWFORD: A rare but dramatic Sian attributed to massive embolus occluding the main pulmonary artery has been referred to in the German literature as “die rote blutwelle.” The initial occlusion induces a shock state in which the patient has marked pallor. If the embolus subsequently breaks apart and travels distally, pulmonary blood flow is transiently restored resulting in blushing of the skin which is then followed by progressive pallor and cyanosis again. Hence, “the red blood wave.” Unfortunately, there are no reports of this observation in which the diagnosis of pulmonary embolism was established with certainty. The increase in the pulmonic component of the second heart sound may be accompanied by a palpable pulmonary artery segment in the left second intercostal space adjacent to the sternum. Characteristically the right heart gallop sounds and murmurs will increase in intensity during inspiration, which helps distinguish them from left-sided sounds. There are two types of murmurs associated with pulmonary embolus. First are murmurs such as pulmonic and tricuspid regurgitation due to the resultant pulmonary hypertension. Second, are murmurs originating from the proximal pulmonary vasculature due to partial occlusion by the thrombi. The latter are much less common and can be distinguished from the former by their tendency to be louder in the interscapular and axillary areas. 16

DIAGNOSIS A definite diagnosis of pulmonary embolism is based on a variety of results from general laboratory tests and specific diagnostic maneuvers once clinical suspicion has been aroused. Immediate tests should include an arterial blood gas, chest x-ray, and electrocardiogram (ECG). Although these tests are not specific for the diagnosis of pulmonary embolism, they often provide additional supportive information for making this diagnosis, If normal, they do not exclude pulmonary embolism. Other more definitive studies include a ventilation-perfusion lung scan and pulmonary angiography. Arterial blood gases represent one of the most readily available tests. Arterial hypoxemia is expected with a severe perfusion abnormality of the lungs secondary to pulmonary embolism. If present, the degree of hypoxemia may correlate with the severity of obstruction to pulmonary flow. A normal PO, on room air has been reported to be rare in the presence of recent pulmonar embolism.1g2-1g3 In a large series of patients studied, 71SJ’ 10% had PO, values greater than 80 mm Hg, and three patients actually had a Pot greater than 90 mm Hg. The mean PO, value among these patients was 62 mm Hg. Another series noted a slightly higher mean value of PO, at 72.4 mm Hg.lg4 Arterial Pco2 is less useful, although hypoxemia in pulmonary embolism is usually accompanied by a low Pco~. Arterial blood gases remain nonspecific because there are multiple other causes for arterial hypoxemia, including pneumonia and congestive heart failure. One should not exclude the diagnosis of pulmonary embolism on the basis of a normal arterial blood gas alone. Although the chest x-ray is often nonspecific as a method of diagnosing pulmonary embolism, some abnormality is seen in over 85% to 90% of patients.lg5’ lg6 An elevated diaphragm, pleural effusion, infiltrate, or consolidation, atelectasis, or pulmonary vessel changes are among the most common findin s seen on chest x-ray in the setting of pulmonary embolism. 51 Most abnormalities are seen in the lower lobes and are usually bilateral. A wedge shaped infiltrate is seen in only a minority of cases. Many patients with angiographically proved pulmonary embolism have normal chest x-rays. In some patients changes in the ECG may be one of the first signs that the patient has developed a pulmonary embolism. The ECG is frequently abnormal but is usually nonspecific, demonstrating sinus tachycardia or nonspecific ST-T changes. These findings are frequently encountered in many other cardiopulmonary diseases and, in fact, the ECG in this setting is helpful to exclude other disorders. The ECG’s greatest value is in massive embolism, where it is reported to be abnormal in 87% of the cases and in submassive embolism, where abnormal ECGs are found in 77% of the cases. Axis changes, such as an acute right 17

shift, T wave changes, and elevated RST se ents are significantly more common in massive embolism.1g P-igg Right ventricular strain patterns are also suggestive of the diagnosis. The much heralded Si, Qs, T3 findings on ECGs are quite uncommon and found in only about 10% of patients with proved pulmonary embolism. Arrhythmias are associated with pulmonary embolism 20% to 25% of the time and include premature atria1 contractions, premature ventricular contractions, atria1 fibrillation, and other conduction disturbances. Arrhythmias, however, are common in patients with underlying heart or lung disease and, therefore, are nonspecific. A number of biochemical and coagulation tests have been proposed as being helpful in the diagnosis of pulmonary embolism. Enzyme tests such as lactic dehydrogenase (LDH), serum glutamic oxaloacetic transaminase @GOT) and bilirubin, ori&nally reported as a “triad” diagnostic for pulmonary embolism, have subsequently proved to be of little value. In the original report, an elevated level of serum LDH, a normal SGOT value, and augmentation of the serum bilirubin levels were considered diagnostic for pulmonary embolism. Lactic dehydrogenase values in this report were elevated in 97% of the cases and frequent elevations had been confirmed by others.lg3 Subsequent reports have shown that increases in levels of serum LDH in pulmonary embolism depend primarily on its release from extra pulmonary sources. These sources are mainly LDHi and LDHB isozymes from hemolysis and liver congestion.“i In the largest trials, increases in levels of LDH and bilirubin with a normal SGOT value were seen in only 4% of the patient”;i and 50% of the patients actually had a normal level of LDH. These enzymes are actually of little aid in the diagnosis of pulmonary embolism. The routine white blood cell count may be slightly elevated in the setting of gutgyonary embolism, with an average count of 11,000 cu mm. 7 With pulmonary infarction, the white blood cell count may rise to 20,000 cu mm. The platelet count is usually normal, with a mean count of 265,000 cu mm.lg3 The erythrocyte sedimentation rate was elevated in 40% of patients in these studies.71 Coagulation tests in pulmonary embolism have not been helpfu1.71 An increase in fibrinogen, as an acute phase reactant, and a slight decrease in plasminogen, probably related to acceleration of in vivo fibrinolysis resulting from pulmonary embolism, have been noted.71 The detection of fibrinogen-fibrin degradation products (FDPfdp) have been proposed as a laboratory technique for diagnosis of pulmonary embolism.202-205 Studies in dogs have documented an early rise in FDP-fdp levels with experimentally induced emboli.206-20’ In 1966, one study noted a definite increase in FDPfdp in five patients with acute pulmonary embolism.208 In a recent series of 40 clinically ill patients with suspected pulmonary embolism, 28 of 29 patients with a positive pulmonay &erio18

gram had significantly higher concentrations of FDP-fdp.20g Highest levels are reported to occur in the first three days after embolism is diagnosed.210 Usefulness of this assay has not been confirmed by others,211, 212 and limitations of this test include its specificity. High levels of FDP-fdp are found in other diseases including liver illness, obstetrical conditions, acute myocardial infarction, disseminated intravascular coagulation, and pancreatitis. Fibrinopeptide A, a peptide that is formed by the proteolytic action of thrombin on fibrinogen, has been proposed as a laboratory test useful for the diagnosis of thrombophlebitis or pulmonary emoblism. Fibrinopeptide A levels have been reported elevated in all patients with either deep venous thrombosis or pulmonary embolism, with the more recent onset of symptoms associated with higher levels. Some authors feel that when the fibrinopeptide A level is normal, the existence of acute deep venous thrombosis or pulmonary embolism may be safely excluded.‘13 Others have noted elevations of fibrinopeptide A in patients with cellulitis and normal venography, as well as other conditions.214 Its main usefulness as a clinical test may be in symptomatic patients when used in addition to other diagnostic methods.215 Plasma and serum concentrations of DNA have been proposed as a rapid, simple, and inexpensive screening test for pulmonary embolism.216, 2 7 Others have found that circulating DNA concentrations do not discriminate between patients with pulmonary embolism and other forms of lung disease218 and that routine use of plasma DNA for pulmonary embolic screening is not to be recommended.21g Other noninvasive studies, including: B-thromboglobulm~~2; 221 antifibrin antibody,222 &atelet coagulant activities, various degradation products of fiplatelet hperaggregability, brin 215*2 isotopically labeled proteins to image a thrombus,22g231 activated factor X (Xa),232-233 and the use of chromogenic substrates to detect activated factors234 may be helpful in recognizing in vivo thrombus formation, but their ultimate diagnostic value remains to be established. Pulmonary function tests and hemodynamics have been used to diagnose pulmonary embolism. In patients without cardiopulmonary disease, pulmonary hypertension is proportional to the amount of obstruction’ seen on angiography, and is generally seen only with a 25% to 30% vascular obstruction.235-23 Cardiac index may be depressed in pulmonary embolism. An increase in mean pulmonary arterial pressure requires an obstruction of greater than 25% of the arterial vasculature, although if other cardiopulmonary abnormalities exist it can be seen with much less obstruction. The severity of hemodynamic derangement is often related to the extent of the embolism, with higher right ventricular end diastolic pressures and pulmonary artery pressures, lower arterial PO,, and cardiac index seen more in mas19

sive embolism than in submassive embolism. The age of patients and previous evidence of cardiopulmonary disease also influences the hemodynamic response. Hemodynamic derangements are also more severe in those patients with shock. A history of pulmonary embolism reportedly had a lesser effect on hemodynamic abnormalities.71 Pulmonary infarction leads to further pulmonary dysfunction due to the loss of lung volume for gas exchange and may be associated with 70% of lethal emboli and about 30% of all cases.36 Hemodynamic data may be of some importance in planning therapy and predicting prognosis, but are rarely critical to diagnosis since they are obtained at the time of angiography. Pulmonary function tests are of limited benefit in the diagnosis of pulmonary embolus,lg4 with a decrease in vital capacity found in one half of the patients. Accurate diagnosis of pulmonary embolism is not only necessary to insure treatment of patients with this disease, but also to prevent inappropriate anticoagulation or surgery. Most of the previously listed diagnostic studies are of only limited help in diagnosing pulmonary embolism. Some recent studies have suggested that ultrasound may be another reliable noninvasive method for diagnosis of pulmonary embolism.238 Ventilation and perfusion lung scanning and pulmonary angiography remain the procedures of choice. A normal perfusion lung scan (in six views) is specific in ruling out the diagnosis of pulmonary embolism,23g and has the same value in excluding embolism as a normal arteriogram.240 An abnormal lung scan, however, is not helpful. Pulmonary arteriography remains the definite diagnostic procedure of choice. The lung scan provides a safe, simple, sensitive, and precise method to define the status of pulmonary blood flow, and has been used frequently to evaluate patients suspected of having pulmonary embolism.241-247 Blood flow is determined by imaging the movement of radioactively tagged particles (20 to 40 k in diameter) as their passage is retarded in precapillary arterioles and capillaries of the lung, after injection of these particles in a peripheral vein. Images are obtained in four to six views (anterior, posterior, right and left lateral, and right and left posterior obliques). The currently used radiopharmaceuticals for perfusion lung scanning are technetium Tc 99m-labeled particles, either macroaggregated albumin or albumin microspheres.248 This procedure can be performed safely in seriously ill patients in 30 minutes. An example of normal perfusion scan and one in a patient with pulmonary embolism is seen in Figures 2 and 3. Although the perfusion lung scan is sensitive, providing information about blood flow in vessels as small as 7 to 10 l.~ in diameter, it lacks specificity. Many disease entities can alter blood flow and cause an abnormal perfusion lung scan, including ob20

Ant

RPO

Rt.Lat

Lt. tat

Fig 2.-Normal perfusion lung following injection of technetium Tc 99m microspheres. Six standard views include: anterior (Ant), posterior (Post), right posterior oblique @PO), left posterior oblique &PO), right lateral (Rr. Lat) and left lateral (Lf. Lat) are shown. (From Wagner H.N. Jr., et al.: Nuclear Medicine Case Studies, in press. New York, Medical Examination Publishing Co. Used by permission.)

structive airway disease, bronchogenic carcinoma, congestive heart failure, pneumonia, vasculitis, radiation therapy, diseases associated with mediastinal lymphadenopathy, and others

196,249-255

In the urokinase/streptokinase Pulmonary Embolism Trial study where lung perfusion scanning was used as a screening procedure, 906 patientshad scans consistent with embolism and all had angiography. In 754 of these patients, pulmonary angiografhy did not confirm the diagnosis of pulmonary embolism.’ In a similar study of 157 pulmonary angiograms based on clinically suspected pulmonary embolism and a positive perfusion scan, 114 failed to show pulmonary embolism at angiography.256 Because of the nonspecificity of perfusion defects and the controversy regarding diagnosing and treating patients for pulmo21

nary embolism based on this alone, the use of radiolabeled gas xenon Xe 133 to examine the ventilatory compartments has been used in combination with perfusion scanning.257-261 A ventilation study is not necessary if the perfusion scan is normal. The perfusion and ventilation compartments can be examined separately. The defects observed in these scans can be attributed to lesions that exist either in the perfusing blood vessels or the ventilating compartments, or both. The utility of combining these two techniques is based on the premise that a reduction or alteration in lung perfusion (blood flow) does not cause a corresponding alteration in ventilation. Thus in the presence of pulmonary emboli, a defect will be visible on perfusion scan, not on ventilation scan. In the presence of normal blood flow, disturbances within the ventilation compartments should not cause defects on the perfusion scan. Early studies performed combining perfusion and ventilation scans in evaluating patients suspected of having pulmonary embolismZ60,261-265 reported a significant improvement in diagnostic accuracy. In two studies evaluating combined perfusionventilation scans in patients suspected of having pulmonary embolism and employing angiography,266-267 the diagnostic accuracy of emboli was significantly improved when xenon ventilation was used. Experience from a third group indicates that 92%

Ant

Post Fig 3.-Abnormal perfusion defects terior (Post), right (Rt Lat), and left Case Studies, in permission.) 22

Lt. Lat

RPO

LPO

Ftt. Lat

perfusion lung scan demonstrating multiple large segmental in both lung fields. Six standard views include: anterior (Ant), posposterior oblique (RPO), left posterior oblique &PO), right lateral lateral (Lt. Laf). (From Wagner H.N. Jr., et al.: Nuclear Medicine press. New York, Medical Examination Publishing Co. Used by

Fig 4.-Normal ventilation lung scan employing xenon Xe 133 gas is seen in posterior view. Image is obtained after a single breath (S.B.) of gas is taken; this represents ventilation of larger airways. Equilibrium image (Equip) is obtained after three minutes of breathing an oxygen-xenon Xe 133 mixture and is a measurement of alveolar air space. Images are also obtained at -5 seconds, 15 seconds, and two and four minutes. The image at -5 seconds is taken before the patient starts to breathe room air. Washout images are then shown at 15 seconds and two and four minutes. In a normal study, all of the xenon Xe 133 gas L expired within one or two minutes. (From Wagner H.N. Jr., et al.: Nuclear Medicine Case Studies, in press. New York, Medical Examination Publishing Co. Used by permission.)

of patients with characteristic ventilatory-perfusion mismatches will have emboli.268 St@ another study indicates that perfusion defects segmental or larger in size that ventilate normally are associated with a high Frequency of venous thromboembolism (91%).26g A pattern of diagnostic significance emerged that observed perfusion defects without ventilatory abnormalities (ventilation perfusion [V/Q]); and these findings were not possible with perfusion studies alone,261Z 263-2652270- ’ and allowed documentation of pulmonary embolism.272-275 Pulmonary angiography was not used to confirm the findings reported in these ventilation-perfusion studies. Examples of a normal ventilation scan and one in a patient with pulmonary embolism can be seen in Figures 4 and 5. 23

Additional studies employing angiography to verify the results of the combined scanning techniques need to be performed. A large multicenter study under the sponsorship of the National Heart, Lung, and Blood Institute is currently in progress to answer these questions. Pulmonary imaging has become the most widely used screening test for pulmonary embolism and, although the technique is clearly of additional help in accurately making the diagnosis of pulmonary embolism, it cannot be substituted for pulmonary angiography. Concern about the overdiagnosis and subsequent treatment with anticoagulant therapy based on V/$ scan results have arisen,256 despite its apparent usefulness.27 There are a considerable number of patients with nonspecific abnormalities on lung scan whose risk of complication from empiric treatment with anticoagulation drugs is probably greater than the risk of complications of pulmonary angiography.276

Fig 5.-Ventilation lung scan of patient with abnormal perfusion scan as shown in Figure 3 is seen. This is a normal ventilation scan and, although a small amount of retention of xenon Xe 133 gas is seen at 25 seconds and two minutes, this area clears at five minutes. S.B. indicates image obtained after a single breath of gas is taken; and Equil, equilibrium image obtained after three minutes of breathing an oxygen-xenon Xe 133 mixture and is a measurement of alveolar air space. (From Wagner H.N. Jr., et al.: Nuclear Medicine Case Studies, in press. New York, Medical Examination Publishing Co. Used by permission.) 24

PULMONARYANGIOGRAPHY Pulmonary angiography remains the most highly sensitive and specific test for the diagnosis of pulmonary emboli.277-280 It is the standard test with which all new tests281 must be compared to evaluate their potential efficacy in making the diagnosis of pulmonary embolism.71, 282 In a study of over 800 ulmonary angiograms in patients with pulmonary emboli,71, B83 the morbidity was less than 1% and the mortality was 0%. Generally, it is recommended that angiography be performed within 24 to 72 hours of the suspected pulmonary embolism to avoid resolution of the clots and to make interpretation of the angiogram less difficult.284 An abrupt cutoff of a major vessel or an intraluminal filling defect are the most common angiographic defects noted. An example of massive pulmonary embolism diagnosed by arteriography is seen in Figure 6. The hemodynamics of pulmonary and cardiac function can also be measured when doing angiography using a catheter in the pulmonary artery. Complications of pulmonary angiography were reviewed in a large series of 1,350 patients. There were three deaths reported, with cardiac perforation in 14 patients, and endocardial or myocardial injury in six patients, 11 significant arrhythmias, five cardiac arrests, and 11 reactions to contrast materia1.285 Other undesirable features of angiography include (1) its invasiveness, (2) it requires professional medical and paramedical personnel, (3) it requires sophisticated equipment, (4) it may be uncomfortable, and (5) it is expensive. Although it is recognized that angiography is the best available technique to objectively establish the presence of emboli in the pulmonary arterial vessels, it is not without error. Two false negatives were reported in the UrokinaseStreptokinase Pulmonary Embolism Trial study283 and angiography is also subject to interpretative limitations. These limitations include an inability to demonstrate obstruction in smaller vessels and failure to recognize certain less specific angiographic abnormalities as being characteristic of embolism.31 Sufficient data to indicate how often the angiogram actually provides erroneous information about the presence of pulmonary embolism are not available except at autopsy or surgery. In a study of 180 patients followed up carefully for six months, who were clinically suspected of having pulmonary embolism but who had a normal angiogram, none of the atients had additional clinical events suggestive of embolism.28 IF Angiography is generally performed in the patient suspected of having a pulmonary embolism after the clinical history, physical examination, chest x-ray, ECG, arterial blood gas measurements, and ventilation perfusion scan are performed. If a normal lung scan is observed, angiography need not be performed. If the patient has significant pulmonary pathology, congestive heart 25

Fig 6.-Pulmonary angiography with dye injected into main pulmonary veals a large thrombus in left main pulmonary artery, resulting in nearly obstruction of blood flow to left lung.

artery recomplete

failure, infiltrates, atelectasis, or emphysema, a scan should not be done and angiography performed directly. If the scan is inconclusive and does not point to another diagnosis, then angiography should also be performed. If, however, any type of surgical procedure (i.e., pulmonary embolectomy, plication, ligation, or placement of a filter device, umbrella, or balloon) is considered, it is mandatory that the diagnosis of pulmonary embolism be established with angiography. Other indications for angiography include: if the patient is allergic to heparin or warfarin drugs, has a contraindication to anticoagulants, or thrombolytic therapy, or has a history of bleeding while being treated with anticoagulants or recurring emboli while being treated with heparin. In addition, if the patient has guaiac-positive stool, the diagnosis must be confirmed if anticoagulation therapy is contemplated. The risks of employing anticoagulation in such a situation may be justifiable, but only after the diagnosis is secure with angiography. Many authors feel that digital-subtraction angiography is both a sensitive and useful tool for the diagnosis of pulmonary embolism.287 The contrast material can be injected into a peripheral vein, thus avoiding the risks of transcardiac catheterization. It is reportedly easier, faster, and safer in patients with hemodynamic instability.2877 288 It is also less expensive. Additionally, it allows smaller volumes of contrast material to be used. Subsequent studies have demonstrated that digital-subtrac26

tion angiography’s use in diagnosing pulmonary emboli is more limited. It is not recommended by some authors in patients who might have multiple small emboli.288 A major problem is that in the chest, the heart and lungs are always in motion and this prevents accurate and detailed images, especially in patients who cannot hold their breath.287-2s0 OTHER DIAGNOSTIC STUDIES Positive venograms of the lower extremities may be helpful and provide an indication for institution of anticoagulant or thrombolytic therapy. Unfortunately, venograms of the lower extremities may be normal because all thrombi have embolized to the lungs or because the source of the embolus is elsewhere. Additionally, the test may be difficult to perform and is painful, but does give immediate information about the size and location of the clot. Observer variation has also been reported to be a problem.2g1 It remains the procedure of choice for diagnosis of deep venous thrombosis but does not establish the diagnosis of pulmonary emboli. Impedance plethysmography of the deep venous system has been examined as a noninvasive diagnostic aid in pulmonary embolism. A measurement of the changes in blood volumes of the two lower extremities during and after cuff occlusion at two points are compared. When the venous thrombosis is located above the knee, good correlation with contrast venography is reported, but not for venous thrombosis below the knee. Impedance plethysmography has been found helpful by some because it has a 90% positive and negative correlation with angiographJ in patients who are being evaluated for pulmonary embolism.2 2 In the diagnosis of deep venous thrombosis, however, it has been found to lack both sensitivity and specifici$ and is not recognized as a screening test for distal thrombi.2 3 The use of Iodine I 125-fibrinogen injected IV appears to be less reliable2g4 for the diagnosis of pulmonary embolism. Its use is limited because of a delay of 12 to 36 hours before the counts are diagnostic. Anticoagulant therapy must be delayed to avoid invalidating the test. Iodine I 125fibrinogen is expensive, not readily available, and presents difficulty in obtaining and storing the isotope. Another noninvasive test used to detect deep vein thrombosis is Doppler ultrasound. In a study of 80 patients, comparing the use of Doppler ultrasound with venography, a 94% accuracy rate with one false negative study was noted using ultrasound in the diagnosis of deep vein thrombosis.2g5 Ultrasound’s main advantages include availability, price, and noninvasiveness. Caution is indicated before depending on studies of the legs to make a clinical decision about disease in the lung. A summary of helpful 27

diagnostic plans that may aid the physician in correctly fying a pulmonary embolism is seen in Figure 7.

identi-

M. H. CRAWFORD: The diagnostic value of the sudden onset of atria1 fibrillation in pulmonary embolus has been highly overrated. Although atria1 arrhythmias may occur in patients with pulmonary hypertension due to pulmonary embolus, atria1 fibrillation is rarely the initial manifestation of pulmonary emboli. In the absence of other features pointing to this diagnosis, I would not order a V/Q scan as part of the workup of new onset atria1 fibrillation. The presence of a pulmonary density at the phrenic angle that is convex toward the mediastinum on chest xray has been touted as a sign of pulmonary infarction (Hampton’s hump). This is a rare finding that I have observed a few times in the setting of pulmonary infarction caused by a pulmonary artery catheter that has migrated to a wedge position for several hours.

PREVENTION Prevention remains a controversial area in discussion of pulmonary embolism. On the basis of autopsy studies, the majority of significant emboli originate from thrombi forming in the deep venous system of the pelvis and thighs. Prevention, therefore, is centered on this concept and the importance of this is evident by the high incidence of sudden death and clinically unsuspected pulmonary emboli found at autopsy. A number of high-risk Emboll ruled out $$a

+

: :::%ip:smbol~ 3 Surgcol treatment

Treatment OSoer DlOr!

Emboll ruled cut

POSITIVE SCAN High probobiMy

f NORMAL

SCAN No further WOIk-Up

TWUtIlWlt

OtherwIse healthy pts + Treatment

e”iOt”‘e wpnrt PE t No change ,R

. .’ Low orobobllltv

oiembolt ’

Because of other disease

Lo* ,,bh pt 1 otherwse healthy Lo* probobtltty of repeated embol~ No therapy cost/btnet~t too high

s”~Bc’on h’ph I I

ICHF, CDPD,etc)

4 Small PE possible

,Jr,h pt high susp~c~o” h nnglo @/ \\o Nofurther Treutnwnt WOhUP

Cll”lCOl s”splclM lOuI \/ “rnography I PG Doppler

I

t

I &peat lung S‘O”

1 *peclol 1 PfS

I / %e:5P

@for venous daeov

four to seven days / Treatment

i Chaqmg SW” evidence for PE

1 No further WXhP

4 CCKltlflUt ,reo,mtnt

I NO further WflWp

Fig I.--Reasonable diagnostic plan to follow once clinical embolism (PI.) is entertained. Angie indicates angiography; congestive heart failure; COPD, chronic obstructive pulmonary ance plethysmography; and Doppler, Doppler ultrasound. 28

stop ,reo,ment

suspicion of pulmonary pts., patients; C/-/F, disease: IPG, imped-

groups, including patients with myocardial infarction, hip fractures, and other surgical procedures, have been studied for the benefits of prevention. Currently, there are many methods used to prevent thrombosis, and most are based on physical or chemical means. These methods are aimed at decreasing venous stasis, preventing endothelial injury, and correcting hypercoagulability. Physical methods to decrease venous stasis in the leg veins include the following: early postoperative ambulation, leg elevation, elastic compression stockings, active and passive leg exercises, and a semi-Fowler’s bed position. While a combination of ambulation and elastic stockings may be more helpful, they still may not be adequate2g6, 2g7 in the prevention of venous thromboembolism. Only a $rysiologic basis has been demonand two studies, one randomized strated for elastic stockings, and one not, showed benefit, while another randomized study did not. 2gg-301 The use of a combination of these methods may reduce the risk of thrombosis in certain patients302 although definite proof of significant protection is lacking.303’ 304 Other physical methods, including external pneumatic compression, may be of benefit in the prevention of deep venous thrombosis. In one study of 107 patients undergoing major surgery for gynecologic malignancy, external pneumatic calf compression was applied intraoperatively and found to significant1 reduce the incidence of postoperative venous thrombosis.30B Studies in patients with neurologic and urologic problems have shown similar benefits.306T 307 By using a venous flow stimulator, another group reported a 75% to 95% reduction in postoperative deep venous thrombosis.308 Electrical calf-muscle stimulation has also been proved effective in prevention of thrombus formation in patients undergoi;gg laparotomy for benign disease, but not mali 3qant disease. Failure with this and pain limits this method to method has been reported anesthetized patients3’* Chemical or pharmacologic prophylaxis began with the use of heparin and followed with oral anticoagulant drugs of the coumarin and phenindione group. Phenindione used in a controlled trial in 1959 in patients with fractured femurs, reduced thrombosis from 28.7% in a control group of 2.7% in the treated group and at autopsy, a reduction in thromboembolism from 83% to 14% was noted.83 Similar benefits in a large group of patients treated with warfarin before hip reconstruction has been demonstrated,311-313 although another study found no benefit.314 A 1976 trial confirmed the reduction of deep venous thrombosis and pulmonary embolism both clinically and postmortem in a trial using warfarin in elderly patients with a fractured femur, although no difference in mortality could be shown. The need for some form of prophylaxis in orthopedic patients is consistently emphasized315 and selective use of anticoagulants in patients 29

with high-risk features deep venous thrombosis, tis is recommended316 in data continue to support in orthopedic patients, it

including obesity, leg edema, history of varicose veins, and severe osteoarthridouble hip replacement. Although most the need for some form of prophylaxis surgeons still are reluctant to use

317,318

‘Other high-risk groups have been studied extensively, including patients with myocardial infarctions. In many studies a significantly lower rate of thromboembolism has been reported in the anticoagulated group~.~~’ Two retrospective studies have shown reduced mortality in patients receiving anticoagulants compared with those not receiving anticoagulant therapy.320-321 A large veterans’ hospital study showed benefit from the use of anticoagulants in the acute stage of myocardial infarction that was felt to be due to a reduction in thromboembolic conditions, rather an effect on the underlying coronary disease.322 Other studies have found that while anticoagulation reduces the frequency of calf vein thrombosis, early mobilization is equally effective in prevention.323 Controversy over the advantages of long-term anticoagulation to prevent thromboembolism persist. Of over 12 trials, the larger trials favored anticoagulant therapy while the small trials showed no benefit.324 Other forms of prevention against pulmonary embolism include the use of low-dose heparin, antiplatelet agents, and dextran. Low-dose heparin is given as 5,000 units, subcutaneously, every 12 hours, and is based on a naturally occurring inhibitor to activated factor X. This inhibitor is increased by trace amounts of heparin that inactivate factor X and decrease thrombogenicity. Low-dose heparin lowers blood viscosity325 and does not induce a hypocoagulable state* therefore, it should not be associated with increased bleeding. !326 Low-dose heparin has been used since 1960.32’ Early studies showed that older patients undergoing major surgery had a reduced risk for the development of deep venous thrombosis when given heparin subcutaneously before surgery. This was continued after surgery every eight or 12 hours, and the results were compared with a control grou~.~~* Other studies also demonstrated a decrease in presumed pulmonary embolism based on lung scans in patients receiving low-dose heparin after surgery. 32g-331 Numerous other trials have shown similar benefits in patients after surgery, with most studies using Iodine I 125 fibrinogen as the end point for diagnosing thrombosis.332-341 Benefits have also been seen in an;;ologic surgery,342’ 343 in patients undergoing neurosurgery and in transurethral prostatectomy.34 Low-dose heparin has also been reported effective in protecting4,against deep venous thrombosis in victims with acute stroke and in pregnant patients.348P 34g In patients undergoing total hip replacement, low-dose hepa30

rin has been shown beneficial in some studies,350-355 but not protective in others.356-360 Another study found low-dose heparin ineffective in atients with fractured hips,361 while others reported benefit. g62, 363 In major orthopedic surgery or trauma, it app;tdrs a convincing case cannot be made for low-dose heparin. In an international study of over 4,000 patients undergoing major surgery who were given low-dose heparin, significant reductions in the frequency of pulmonary embolism were noted. Recommendations based on this study established that patients over 40 years of age and undergoing major thoracic, abdominal, and pelvic surgery can be protected against pulmonary embolism by the use of low-dose heparin. This was given two hours before surgery and continued every eight hours for seven days.365 In the United States, because of differences in the heparin preparation, the heparin is given every 12 hours.364 Other studies supported the claim that low-dose heparin is beneficial in Frevention of fatal pulmonary embolism diagnosed 36 Still others have shown less benefit and more side $f~gT6Y. Because of the low incidence of fatal postoperative pulmonary embolism reported in a survey of 25 teaching institutions,368 it is suggested that low-dose heparin only be used in patients who have a risk factor for thromboembolism other than the surgery itself (e.g., obesity, congestive heart failure, venous stasis). In other high-risk groups, such as patients with myocardial infarction, data is controversial,335’ 36g-371 and disappointing results have been obtained in colorectal surgery of the pelvis.372 Studies have shown low-dose heparin equal to full warfarin anticoagulation, 373 more potent than electrical stimulation of the calf,3 4 and more effective than external pneumatic compression.375 Laboratory monitoring of low-dose heparin is not required according to some authors376 and another study found low-dose heparin prophylaxis safe without need for monitoring in a general hospital situation.377 Other reports advocate monitoring because of variations in heparin levels with high values associated with bleeding and low values with absence of protection.378-383 A frequent complication of low-dose heparin is wound hematoma noted after hip surgery,384 prostatectomy,385 and in surgical patients in generaP,38 Massive hematoma in the abdominal wall following injection387 and thrombocytopenia3887 38g have been noted. One study combining dihydroergotamine mesylate with lowdose heparin found a low incidence of wound hematoma with protection against thrombosis.3g0 A more recent multicenter investigation involving patients undergoing elective abdominal, pelvic, and thoracic surgery found that 0.5 mg of dihydroergotamine mesylate plus 5,000 units of heparin reduced the risk of 31

develoxgent of deep vein thrombosis in patients over 40 years Patients were given the medications two hours before of age. surgery and every 12 hours after surgery for five to seven days. Dihydroergotamine is felt to have a synergistic effect with subcutaneously administered heparin and is believed to alter Virchow’s triad by decreasing stasis and vein wall injury and altering the hypercoagulable state.3g2 Another agent, dextran, is also used as an antithrombotic agent. Dextran’s antithrombotic effects relate both nonspecifically to hemodilution and specifically to alterations in factor VIII, fibrin polymerization, decrease in platelet aggregability, and thrombus stabilization. Dextran is available in two preparations, dextran 70 and dextran 40. Major side effects include anaphylaxis, excessive bleeding, renal failure, and volume overload.3g3 It has been shown effective in reducing venous thrombosis after elective surgery of the hip.3g4 In patients undergoing total hip replacement, dextran 40 appeared as effective and safe as warfarin.3g5 Others found it less effective.3g6 Dextran 70 has been found as effective as low-dose heparin in one study3g7 but not in others.3g8 Another study found a lower frequency of thrombosis after hip surgery in patients receiving dextran 70, while low-dose heparin diminished the frequency after elective hip surgery. Both agents were equally effective in prophylaxis of pulmonary embolism.3gg Dextran has also been combined with aspirin or warfarin in prophylaxis and found satisfactory.400 Platelet suppressive therapy has also been studied in prophylaxis of pulmonary embolism. One study involving aspirin found it effective in prevention of thromboembolism in atients undergoing total hip replacement, but only in men.40 P Other studies eneral surgical patients have found only minimal with benefit 5 O2and two others found aspirin of no benefit in patients after surgery.403, 404 Other studies have not found impressive results with aspirin and dipyridamole added.405 In a large series of 528 patients, an extremely low incidence of thromboembolic complications was found in atients undergoing total hip replacement while on aspirin.4 B6 Thromboembolic disease is also reported reduced in patients undergoing total knee replacement while taking aspirin regularly.407 In hip fracture, two major studies using aspirin have reported benefit, while two have not,405 and, in eneral, platelet suppressive drugs have not been proven useful. 42 Other studies aimed at preventing pulmonary embolism have included phenformin and ethyloestrenol.408 Subcutaneous ancrod has also been used.40g Prophylactic treatment of patients who might experience pulmonary embolism remains controversial. Low-dose heparin appears to be effective in preventing deep venous thrombosis and pulmonary embolism in patients who are immobilized, have congestive heart failure, are obese, have chronic pulmonary dis32

ease, venous insufficiency, or a previous history of thromboembolism. It does not appear effective in orthopedic surgery or patients with thrombosis and neoplasms. The benefits of antiplatelet agents have not been established and oral anticoagulants may be as effective as low-dose heparin, but require more monitoring and are not easily terminated.14 Mechanical devices are encouraging, but need further evaluation, while early mobilization appears to be the most important form of prophylaxis.14 TREATMENT The treatment of pulmonary embolism should begin as soon as the diagnosis is suspected. Vital signs must be maintained. A large bore needle should be inserted for vascular access and IV fluids and oxygen supplied as needed. Antiarrhythmic agents, vasopressors, and inotropic agents may be indicated. Shock should be aggresively treated. The most significant advance in the management of thromboembolic disease has been in the area of therapy.14 Because heparin and warfarin therapy at best only prevent further thrombus formation and embolization, the advent of thrombolytic therapy has for the first time made it possible not only to induce the dissolution of thrombi, but also to return cardiopulmonary and eripheral vascular hemodynamics rapidly back to norma1.410-41 F Ideally, the embolus or thrombus should be less than 5 days old, although recent studies suggest benefits in subacute and chronic embolism.413-414 Patients selection must be careful because of the potency and expense of this therapy and the lack of proof that ultimate prognosis is changed. The majority of reviews show no agreement in patient selection415-421 and the clinician must decide the importance of reversing the hemodynamic and perfusion abnormalities caused by acute embolism. Two pharmacologic agents currently available that induce thrombolytic activity are: streptokinase and ‘urokinase. The Food and Drug Administration (FDA) has approved the use of urokinase for therapy of pulmonary embolism and the use of streptokinase in deep venous thrombosis and pulmonary embolism. Streptokinase was discovered in 1933, by Tillet and Garner.422 It is a nonenzymatic protein which is secreted by group C phemolytic streptococci. Streptokinase activates fibrinolysis by combining with plasminogen and the streptokinase-plasminogen complex changes the conformation of plasminogen-yielding plasmin. Urokinase, described by Williams423 in 1951, is an enzymatic protein produced from human fetal kidney cells. Fetal kidney cells yield much larger quantities of urokinase than adult renal parenchymal cells. It activates plasminogen directly by peptidebond cleavage in the plasminogen molecule. 33

Both drugs are rapidly cleared from the circulation after IV injection. Streptokinase has two half-lives,424 the first is 18 minutes and represents clearance after binding with antistreptokinase antibodies, and the second is 83 minutes. Urokinase is expected to have a half-life of about 16 minutes.425 Thrombolytic therapy must be followed by conventional heparin and warfarin therapy to prevent further thrombosis or embolization. The diagnosis should be objectively established before thrombolytic agents are used. At times this will be possible to do clinically because the evidence will be overwhelming. On other occasions, angiography may be necessary, and the arm is the preferred site for this procedure411 in this situation. There have been multiple reports of more dramatic improvement with thrombolytic therapy in pulmonary embolism than with heparin alone. 426-433 The Urokinase-Streptokinase National Cooperative Study showed a marked acceleration in angiographic resolution, improved perfusion by lung scan, lowering of pulmonary artery pressure, and improvement of both right and left heart hemodynamic measurements in patients treated within five days of the presumed embolus, compared with patients treated with heparin alone.71’ 410 Although results in initial treatment using thrombolytic agents on massive and submassive embolism to rapidly dissolve thrombi and emboli are well known, the effects on small, peripheral pulmonary clots are not well understood. A recent study of the pulmonary capillary blood volume and diffusing capacity in patients with pulmonary embolism found that there is more complete resolution of thromboemboli with thrombolytic agents than with heparin and that capillary perfusion and diffusion are improved. 434 Other reports limited to lifethreatening pulmonary embolism have indicated an angiographically improved resolution in patients treated with stre tokinase, compared with patients treated with heparin alone. g5-436 Striking results after 24 hours of thrombolytic therapy in a patient with pulmonary embolism are demonstrated with both angiography and perfusion lung scan in Figure 8. In acute deep venous thrombosis, streptokinase is used to dissolve the thrombus and preserve the valves of the venous system. Several reports have indicated a higher frequency of preserved valve cusp function in legs that were treated with streptokinase, which may have long-term implications in preventin chronic venous hypertension and venous insufficiency. 5 37, 438 Patients with more acute symptoms of under seven days’ duration have shown greater improvement than did those with more chronic symptoms. A prospective study of streptokinase and heparin noted that 71.4% of the streptokinase-treated patients showed phlebographical thrombolysis as compared with 23.8% of the heparin group. 43g A follow-up study of the same group done 6% years later found avoidance of late post-thrombotic changes, in addition to significant initial thrombolysis at 34

i-i.-

I

.

Fig 8.-Pulmonary arteriogram and lung perfusion can be shown before (upper panel) and after (lower panel) thrombolytic therapy. Before therapy there is striking obstruction of blood flow to left lung seen on both lung perfusion scan and angiogram (top). After 24 hours of thrombolytic therapy near normal perfusion of left lung is now demonstrated (bottom).

the time of treatment.440 Other studies support this concept.441 Visible improvement after thrombolytic therapy employed for deep venous thrombosis is seen in Figure 9. The recommended loading dose for streptokinase in pulmonary embolism or deep venous thrombosis is 250,000 units in normal saline, or 5% of dextrose (or combinations thereof) administered over 30 minutes. This is followed by maintenance therapy of 100,000 units per hour. For pulmonary embolism, 24 to 36 hours of therapy is considered adequate, but for deep venous thrombosis, 48 to 72 hours is preferred. At times, an increased loading dose of this agent may be needed to overcome a high titer of antistreptokinase antibodies, In patients who do not demonstrate a lytic state because of this, urokinase may be substituted.442 Urokinase is given in dosages of 4,400 international units CIU per kg loading dose and 4,400 III/kg/hour for 12 to 24 hours in pulmonary embolism. ..Both agents are given by continuous infusion (Table 2).443 There has also been some data suggesting that bolus infusions of thrombolytic agents directly into the pulmonary arteryM4’ 445 with plasminogen,446 or combinations of low-dose streptokinase with heparin447’ 448 may be alternative approaches. Obtaining baseline information is suggested before thrombolytic therapy is started and should include: hematocrit, white blood cell count, platelet count, prothrombin time, activated partial thromboplastin time, and a thrombin time. This will allow confidence that the hemostatic mechanism is intact while 35

screening for coagulation subsequent heparin and lytic therapy, the thrombin between 1.5 to five times time is not available, the

disorders and obtaining guidelines for warfarin therapy.44g During thrombotime should be elevated in seconds to the preinfusion value. If a thrombin activated partial thromboplastin time

Fig 9.-Deep venous thrombosis is demonstrated by venography before (right) and after (left) thrombolytic therapy. Note cessation of blood flow proximal to the popliteal vein (right) and immediately following thrombolytic therapy there is reconstitution of blood flow in superficial and deep femoral vessels (left). Deep venous valves are also identified and their function is preserved.

36

TABLE

S.--TREATMENT

PROGRAMSIN

PULMONARYEMBOLISM

Submassive Heparin, 70 units/kg IV* simultaneously with infusion of 20-25 unitsikglhr IV regulated to keep APTTt between 60-80 set or Lee-White CT+ between 20-35 min for 7-10 days; or Heparin, 55-70 units/kg every 4 hr IV 7-10 days. Massive Streptokinase, 250,000 units IV for 30 min followed by 100,000 unit&r for 24 hr, or urokinase, 4,400 units/kg for 10 min followed by 4,400 units/kg& for 12-24 hr. During thrombolytic therapy, the thrombin time should be 1.5-5 x baseline. At completion of thrombolytic infusion when thrombin time less than 2 x baseline (2 hr later), start heparin therapy without a loading dose. If thrombolytics and anticoagulants contraindicated; vena caval ligation, umbrella, or balloon or embolectomy, for life-threatening embolus should be considered. Long-term Therapy Warfarin to keep prothrombin time between 18-25 set, overlap 3-5 days with heparin and continue at least 12 wk; further therapy guided by status of predisposing conditions; or Heparin, 5,000 units every 8-12 hr subcutaneously for a minimum of 12 wk. *IV indicates intravenously. tAPIT indicates activated $CT indicates whole blood

partial thromboplastin Lee-White clotting

time. time.

may be substituted and during therapy should be prolonged to between two and five times the preinfusion value. A thrombin time should be checked three to four hours after initiation of therapy to determine if there is adequate activation of the plasminogen-plasmin system. If streptokinase is used, a thrombin time should be checked every 12 hours throughout treatment. With urokinase (for a 12-hour infusion), a thrombin time should be repeated after eight hours of therapy. Following the discontinuation of thrombolytic agents, heparin should be used. No loading dose is given and before beginning the heparin, the thrombin time should be less than twice the initial baseline value. This generally takes two to three hours after discontinuation of the thrombolytic agent. Although benefits of the use of thrombolytic agents are well documented, there is still reluctance in some centers to use these agents.450 Initially there was concern about the frequency of hemorrhage associated with thrombolytic therapy; however, this has now been attributed directly to the number of invasive procedures used. Avoiding invasive procedures has greatly reduced the risk of hemorrhage.44g Venipuncture, arterial puncture, cutdowns, and surgical procedures are complicated by profuse bleeding if followed by thrombolytic agents and therefore should be avoided. Since FDA approval, the incidence of serious hemorrhage with thrombolytic therapy has been about 51%~~~In addition to avoiding invasive 37

procedures, care should be taken to avoid moving the patient. Bed rest must be enforced and parenteral injections discontinued. Also, avoidance of aspirin, aspirin-containing compounds, antiplatelet agents, dextran, or other anticoagulant agents is recommended. Minor bleeding can be controlled by local pressure. If major bleeding does occur or an emergency surgical procedure must be performed, the lytic state can be rapidly reversed by discontinuation of the thrombolytic agent and administration of epsilon aminocaproic acid. Additionally, cryoprecipitate or fresh frozen plasma may be helpful to replace diminished coagulation factors. In addition to hemorrhage, other adverse reactions to thrombolytic therapy are well recognized. Streptokinase is antigenic, and minor allergic reactions such as urticaria, itching, flushing, nausea, headaches, and muscular pains may occur. Mild fever may be observed in up to one third of patients on streptokinase. Abdominal pain, an acute hepatitis-like reaction, delirium, and depression have been reported. Serum sickness has been described.451 Most of these minor reactions can be treated with acetominophen or antihistamines. An IV infusion of 100 mg of hydrocortisone administered before beginning streptokinase therapy and continued every 12 to 24 hours for the duration of treatment may be helpful,4 2 but is not necessary and not advised. Contraindications to the use of thrombolytic agents are listed (Table 3) in patients with massive pulmonary embolism. Some of these contraindications are relative and the risks of thrombolytic therapy must be weighed against its benefits. If it appears clinically important to have a more rapid reversal of the hemodynamic and perfusion abnormalities, thrombolytic therapy should be considered. HEPARIN Despite the advent of thrombolytic therapy, heparin may be the initial anticoagulant drug of choice for less severe pulmonary emboli. l4 This agent is also used in many patients with deep venous thrombosis.453 Heparin is an acid mucopolysaccharide that is widely distributed in animal tissues.364 Commercially available heparin is prepared from lung and intestinal mucosa from a variety of animals including bovine, porcine, and caprine species. Heparin is metabolized in the liver and excreted in the urine. The indications for the use of heparin result from the ability of this agent to retard endogenous blood coagulation. Heparin acts by inhibition of the enzymatic steps of the coagulation system by combining with antithrombin III, a naturally occurring circulating heparin cofactor.454-457 38

The rationale behind treatment with heparin, unless there is a strong contraindication to its use, was demonstrated in a study of 516 patients with pulmonary emboli. In this study, survival after diagnosis was noted in 92% of the anticoagulated patients vs. 42% survival in patients in whom anticoagulants were withheld because of a medical contraindication. Additionally, recurrence of pulmonary embolism decreased from 55% to 16%.456 Others have noted that untreated pulmonary embolism has a mortality rate in the range of 15% to 30%, while anticoagulation with heparin causes hemorrhage in 5% and death in 0.5% of patients.457 In addition to reducing the risks of further thrombus growth, heparin may facilitate restoration of patent veins.453 Its only effect on thrombi already formed are stabilization and prevention of distal propagation. Its main function remains, however, in preventing additional accretion of thrombus.458 For established thromboembolism, heparin should be given IV either continuously or intermittently for at least seven to ten days. This should be followed by long-term therapy with oral anticoagulants. The efficacy of this regimen was demonstrated in a controlled tria1.45g Heparin should be given for at least seven to ten days, followed by warfarin anticoagulation suffiTABLE

3.-CONTRAINDICATIONSTO

THROMBOLYTIC

THERAPY

GENERAL

1. Surgical procedures within the past 10 days, including invasive biopsy, thoracentesis, or paracentesis. 2. Intraarterial diagnostic procedures within the past 10 days (excluding arterial blood gas studies employing a 22-gauge or smaller needle, that have been uncomplicated). 3. Active gastrointestinal tract bleeding or conditions such as ulcerative colitis or diverticulosis with a high potential for bleeding. 4. Defective hemostasis, including coagulation factor deficiency or thrombocytopenia. 5. Recent (within 2 mo) stroke or conditions such as atria1 fibrillation with subacute bacterial endocarditis, with potential for central nervous system embolism. 6. Recent trauma with possible internal injuries, or external cardiac massage. 7. Intracranial malignancy-primary or metastatic. 8. Severe hypertension (diastolic BP > 125 mm Hg). 9. Active and progressive cavitating lung disease. 10. Acute or chronic hepatic or renal insufficiency. 11. Ulcerative cutaneous or mucous membrane lesions. 12. A history of severe allergic reaction to the agent. 13. Pregnancy or first 10 days post partum. ABSOLUTE

The two absolute contraindications 1. Active bleeding-any site. 2. Central nervous system damage surgery, primary or metastatic

to the use of thrombolytic (recent neoplastic

infarction, disease).

agents

hemorrhage,

are: trauma, 39

cientbi;4E;duce prothrombin activity to the range of 18% to 29%. ’ For continuous infusion, therapy should be started by an initial bolus of 5,000 units of heparin, followed by constant administration through an infusion pump463 of 400 to 500 units per kg of body weight every 24 hours. If intermittent heparin therapy is to be employed, the recommended dose is 5,000 units given IV, every four hours. After approximately 48 hours, oral anticoagulant therapy can be started, using at least a two- to threeday overlap with the two anticoagulants. In massive pulmonary embolism, larger doses are recommended at least for the first 24 hours of treatment (approximately 10,000 units every four hours).364, 464 This technique may be associated with striking hemorrhage. The need for laboratory monitoring of dosage is unresolved. Monitoring heparin therapy by coagulation tests was not shown to be effective when intermittent heparin was used.465 However, there have been two studies suggesting benefit when continuous infusion has been used.‘l’ *IX The Lee-White clotting time done as a bedside test works well, but is difficult to standardize and is time consuming.71 The whole blood recalcification time, an adaption of the Lee-White clotting time has been found reproducible and sensitive by some authors.467-470 The thrombin clotting time with or without dilution has been used successfully by several groups to control heparin therapy.471-473 The activated partial thromboplastin time has become the most common test used, with a value of between 1.5 to 2.5 times the baseline value generally recommended for appropriate anticoagulation. The partial thrombo$astin time can be done on either whole blood or plasma.474-4 There is variability in reagents and results with fluctuating facamong different subjects477 and variations tor VIII levels in the patient.478 Additionally, a baseline hematocrit value, white blood count, prothrombin time, and platelet count should be done. Patients receiving heparin should have daily examinations for abnormal bleeding, including tests of stool for occult blood. Invasive procedures such as lumbar punctures, intramuscular injections, and arterial punctures should be avoided. Special problems have been noted with heparin therapy. Arguments that hemorrhagic complications particularly in high-risk patients are reduced by continuous infusion, as opposed to intermittent therapy have been s;Egcn$ed by two controlled trials,465, 47g but not by two others. Increased frequency of recurrent thromboembolism in patients receiving continuous heparin vs. intermittent therapy has been described by some.482 Although controversy remains, complications can probably be reduced by continuous IV heparin infusion, since the total dose of the drug used per day is generally less with continuous infusion than with intermittent therapy. Heparin remains one of the drugs most commonly associated 40

with death.483 Many of its complications are well noted in the literature, especially the risk of bleeding with this agent in women older than age 60 years.484 In a study of 280 patients treated for deep venous thrombosis, women older than 70 years were found more prone to bleeding complications.453 In patients with artificial heart valves who are receiving anticoagulant therapy, intracranial hemorrhage is a hazard, especially with coexistent endocarditis.485 Bleedin in the retroperitoneal space can cause femoral neuropathy4 8s-48g and is often not suspected.453 Arterial puncture is a hazard in patients receiving anticoagulant therapy, resulting in neuropathies, muscle ischemia, and skin infections as complications.4g0-4g3 Other adverse effects include heparin-induced hypoaldosteronism,4g1 heparin-induced skin necrosis,4g2 and massive hemothorax.4g4 Other cases of hemorrhage have been reported, including ovarian hematoma4g5 and subconjunctival hemorrhage.4g6 Heparin appears to have a minimal delaying effect on wound healing.4g7 Allergic reactions have also been note&i$uding necrosis of involved areas of subcutaneous tissues. Additional well-known complications include osteoporosis and thrombocytopenia. Heparin-associated thrombocytopenia can occur in from 5%500 to as many as 18% of patients who receive this drug.5o1 A higher frequency of thrombocytopenia is associated with bovine lung heparin as compared with the intestinal mucosal source of this agent.502 The mechanism for thrombocytopenia is unknown, although, complement mediated platelet injury has been suggested.503 Reports that there may be more than one type of thrombocytopenia associated with heparin therapy have been mentioned; a severe form, probably immunologic, and a symptom-free mild form due to a direct action of heparin on the plateleL504 Multiple other reports have appeared most of which stress the likelihood of an antibody mechanism. 5b5-513 There is also evidence that heparin can induce a consumption coagulopathy with hypofibrinogenemia and increased FDP-fdp, as well as thrombocytopenia. 5013514,515 While heparin has some effects on platelet function516 a platelet functional defect is not demonstrable except at very high doses.517 Arterial embolism518-51g has also occurred during systemic heparin therapy. Heparin-associated thrombocytopenia with arterial thrombosis, while a less frequent complication than thrombocytopenia alone, can cause major complications including stroke, heart attack, and death.500 Because of the uncertain frequency of heparin-induced thrombocytopenia, platelet counts should be obtained before and frequently (every third and fourth day) during heparin therapy. If thrombocytopenia develops rapidly, discontinuation of heparin therapy should be considered. Although many problems do exist with heparin therapy, generally treatment is safe when patients are carefully screened for 41

preexisting hemostatic defects. Contraindications to its use include active bleeding, malignant hypertension, cerebrovascular hemorrhage, acute bacterial endocarditis, and unsatisfactory patient cooperation.

ANTICOAGULANTTHERAPYIN

PREGNANCY

The incidence of deep venous thrombosis and pulmonary embolism in pregnancy is low,520 but there are special considerations that must be taken for the patient receiving anticoagulant therapy. In both vaginal delivery and caesarean section, there may be maternal bleeding and fetal damage. Heparin does not cross the placenta and may be rapidly reversed with protamine sulfate if there is clinical evidence of hemorrhage. If stopped sufficiently before delivery and not restarted until proper postpartum hemostasis has been obtained, heparin can be used safely. There are reports, however, that indicate there is a significant risk of infants who are stillborn or premature.521 Coumarin drugs cross the placenta and can cause fetal damage including abortion or stillbirth, a sr2Fcific embryopathy, and Some authors recomcentral nervous system abnormalities. mend termination of the pregnancy if anticoagulation therapy is needed,521 while other reports sag2it52iay be safe if stopped at least three weeks before delivery.

WARFARIN Warfarin is used for long-term management of deep venous thrombosis and pulmonary embolism. It is a derivative of coumarinic acid that inhibits the action of vitamin K (fat-soluble vitamin) and alters the synthesis of primary procoa giants, factors II, VII, IX, and X, and proteins C, S, and Z. More recently, the action of warfarin has been found to be due to the formation of a “false protein” unable to bind calcium.525 In addition, a delayed antithrombin-potentiating effect has been postulated.526 Warfarin prevents the formation and extension of stasis thrombi in the venous system. It is generally used after heparin therapy because of its delayed onset of action. This prevention of thrombosis is related to the depression of factors IX and X. Warfarin has been compared with low-dose subcutaneous heparin, and one study found the two equal in protection.527 Another small trial found low-dose heparin less effective than warfarin but associated with less risk of bleeding.528 Warfarin therapy is initiated by the daily administration of doses of 10 to 15 mg in an average-size adult until therapeutic prolongation of the prothrombin time to between 1.5 and 2.5 that of control is obtained. This may be preferable to using a loading dose in which precipitous depression of factor VII may

42

cause hemorrhage. The dose is either increased or decreased depending on the prothrombin time until the dose is found that maintains the prothrombin time at the desired value. Warfarin therapy is usually started five to seven days after heparin is instituted for the treatment of pulmonary emboli. There are no data, however, to support this technique, contrasted to starting warfarin therapy 48 to 72 hours after institution of heparin and discontinuing heparin when war-far-in is therapeutic. Therapy with warfarin is complicated by the lar&: number of drugs that either potentiate or retard its actions. The duration of therapy with warfarin depends on coexisting factors. Warfarin administration is generally given for three to six months for initial episodes of deep venous thrombosis or pulmonary embolism and up to 12 months or longer for recurrent episodes of venous thromboembolism.52g Absolute contraindications to the use of oral anticoagulants are similar to those with thrombolytic therapy and heparin. Because of its use, mainly on an outpatient basis, patient compliance and cooperation is essential. A major limitation of warfarin is hemorrhage. Significant bleeding complicates at least 5% of all patients receiving warfarin therapy.530 The frequency of bleeding increases with the intensity of treatment, as reflected in daily prothrombin times, as well as associated conditions such as advanced age, urologic disorders, gynecologic problems, postpartum state, and the initiation of therapy with large doses of the anticoagulant. If bleeding is a problem, small doses of vitamin K will promptly reverse warfarin’s effects. SURGERY Most patients with documented pulmonary embolism can be adequately managed medically, utilizing thrombolytic therapy or with anticoagulant therapy using heparin. Surgical procedures, used more often in the past, are now less frequently employed. There are two major approaches to surgical intervention. The first method employs interruption of the vena cava, and the second approach is pulmonary embolectomy. Vena caval interruption interferes with the propagation of an embolus to the lungs and is recommended for any of the following conditions: anticoagulant or thrombolytic failures, contraindications to anticoagulants, chronic embolization, uncontrolled septic thrombophlebitis from the lower extremities, and with pulmonary embolectomy. 531 Extensive review of this procedure at two major teaching hospitals (Northwestern University, Chicago, and Duke University, Durham, NC) indicated that with adequate anticoagulation, the procedure is rarely justified.531-532 The methods used for vena cava interruption include clips,531 43

intraluminal devices (an umbrella or filter),533-537 transvenous balloon occ1usion,538 and ligation. Intraluminal devices can be inserted underlocal anesthesia through the internal jugular vein or femoral vein. In many centers, transvenous placement of a Kim-Ray Greenfield filter device has become the approach of choice for all patients who require mechanical protection.53g The major advantages of the transvenous approach are the avoidance of general anesthesia and less morbidity and mortality.540 Other advantages include safety, speed, minimal cost, and shortened hospital stay. In addition, some authors feel that elderly patients with recurrent deep venous thrombosis may be more safely protected from a pulmonary embolism by a Kim-Ray Greenfield filter device rather than with long-term anticoagulation therapy.541 Longterm patency in a study of 119 patients with this device was found to be 95% by veno am, and no deaths due to recurrent embolism were reported.5 !F’ The Mobin-Uddin umbrella also has been used exensively for transvenous interruption of the inferior vena cava, but the Kim-Ray Greenfield filter has been shown to have a superior long-term patency.541 In addition, there has been a greater frequency of recurrent m&monary embolism reported with the Mobin-Uddin umbrella. Complications of the filter devices include migration, perforation, recurrent emboli, venous stasis, and occasional death. It is important to note that if not contraindicated, anticoagulation therapy should be continued after placement.284 Partial caval occlusion by clips has been used to prevent large emboli but maintain caval patency, with the hopes of avoiding swelling of the leg, venous stasis, and ulceration described in vena caval ligation. Continued protection from fatal emboli has been afforded this grou~.~*~ The transvenous catheter embolectomy, a concept based on femoral venous access with passage of a balloon-tipped catheter and cup device, has been used in some centers.54 A mortality rate of 27% has been noted.545 Because beneficial hemodynamic effects have been seen, the further development of this method may allow emergency management of major pulmonary embolism even in centers that do not have the capability for cardiopulmonary bypass.546 Inferior vena caval interruption is being used less frequently because of several developments. This includes a better understanding of heparin kinetics, the development of continuous-infusion pumps, and a better and earlier method of diagnosing pulmonary embolism by arteriography. Also contributing are a better understanding of the frequency and management of complications of anticoagulation therapy, and the increased use of thrombolytic therapy.540 Other surgical methods have been used, particularly with cardiopulmonary arrest in acute ulmonary embolism. Support with the membrane 1ung547* 8*’ and hypothermia5*’ have been used. 44

Pulmonary Embolectomy Trendelenburg originally described the direct removal of a massive life-threatening embolism as a method of treatment and this has been used with cardiopulmonary bypass. Despite a mortality rate of greater than 50%, some success with the procedure has been reported.550-557 Surgical treatment of pulmonary embolism is indicated when anticoagulant therapy is absolutely contraindicated and in the patient with cardiopulmonary arrest.558 Additionally, if there is a failure of optimal medical treatment, pulmonary embolectomy may be lifesaving. Some authors list criteria for pulmonary embolectomy as including refractory hypotension and b,h,oxemia in a patient with documented pulmonary embolism. Other criteria include: systolic blood pressure of less than 90 mm Hg, Pao2 below 60 mm Hg, signs of peripheral vasomotor collapse, and urine out ut below 20 mg/hour after one hour of nonsurgical management. F6o A marginal role for surgical management in severe chronic embolism has also been claimed.561 In general, surgery is not the initial treatment of choice, and the frequency for surgery is extremely rare, but it may be lifesaving in those who need it. Medical progress has improved and changed the prognosis for thousands of patients who suffer a pulmonary embolus. In a study of 72 patients, some followed up for up to nine years and treated with different modalities, those who suffered either subacute massive or minor embolism had no late deaths due to thromboembolic disease and hemodynamics were not significantly impaired.562X 563 Poor prognosis was related to chronic or Normal Scan-No PE

Paoy

’

IPG Doppler Isotope Venography

Chest Med-Low

History-Physical Examination for Suspicion of PE Fluid Volume High Probability Lesion \ Thrombolytic Followed Fig lO.-Concise, monary embolism; sound.

direct approach IPG, impedance

from diagnosis plethysmography;

Pulmonary Angiography J Positive I Therapy by Heparin

I Positive J/

to treatment. PE indicates and Doppler, Doppler

pulultra45

recurrent thromboembolic disease with subsequent pulmonary hypertension. There is little long-term mortality or morbidity associated with a single, acute, nonfatal embolism.75, 562-570 A mortality rate of 8% was found in an American series of 144 patients, and no deaths occurred in a group of British patients who were receiving adequate anticoagulant therapy.5 ‘, 572 In summary, the prognosis of pulmonary embolism appears to depend on the outlook of any underlying disease that may be present, as well as the rapidity with which therapy is initiated. An immediate direct plan of action from suspicion to treatment (Fig 10) is helpful in providing the maximum potential benefit to the patient. ACKNOWLEDGMENT

The authors thank Nuclear Medicine Case Studies and Medical Examination Publishing Company for permission to print Figures 2, 3, 4, and 5. The authors express their utmost appreciation for the excellent skills and patience of Kimberly Pruitt who technically prepared this manuscript. REFERENCES 1. Virchow R.L.K.: Gesammelte abhandlungen zur wissenschaftlichen, in Thrombose and Emboli, Berlin, G. Hamm-Grotesche Buchhandlung, 1862, vol. 4, p. 219. Trendelenburg F.: Ueber die operative behandlung der embolie der lungenarterie. Arch. Klin. Chir. 86:686, 1908. Nystrom G.: Experiences with the Trendelenberg operation for pulmonary embolus. Ann. Surg. 92:498, 1930. Kirschner M.: Ein durch die Trendelenburgsche operation geheilter fall von embolie der art. pulmonalis. Arch. Klin. Chir. 133:312, 1924. Matas R.: Postoperative thrombosis and pulmonary embolism before and after Lister: A retrospect and prospect. Univ. Toronto Med. Bull. lO:l, 1932. 6. Valdoni P.: Un case di embolia dell arterio polmonare quarito con L’Embolectomio. Policlinico 14:1, 1936. 7. Steenberg R.W., Wilson R., Wilson R.E., Rudulf, L.E.: A new look at pulmonary embolectomy. Surg. Gyrwcol. Obstet. 107:214, 1958. 8. Fell G.E.: Embolism of a branch of the pulmonary artery: Patient sustained by oxygen gas: Recovery. JA.MA. 17:90, 1891. 9. McLean J.: The discovery of heparin. Circulation 19:75, 1959. 10. Griffith G.C., Silverglade A.: Symposium on heparin. Am. J. Cardiol. 14:1, 1964. L.W.: A study of pulmonary embolism. Arch. Intern. Med. 108:418, 11. Gorham 1961. 12. Freiman D.G., Suyemoto J., Wessler S.: Frequency of pulmonary thromboembolism in man. N. EngZ. J. Med. 272:1270, 1965. 13. Goldhaber S.Z., Hennekens C.H., Evans D.A., Newton E.C., Godleski J.J.: Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am. J. Med. 73:822, 1982. 14. Bell W.R.: Pulmonary embolism: Progress and problems. Am. J. Med. 72:181, 1982. 15. Sherry S.: Acute pulmonary embolism. Geriatrics 22:150, 1967. 46

16. 17.

18.

19. 20.

21.

22. 23.

24. 25.

26. 27.

28. 29. 30. 31. 32.

33.

34. 35. 36. 37. 38. 39. 40.

41.

Wessler S.: Thrombosis in the presence of vascular stasis. Am. J. Med. 33:648, 1962. Wessler S.: The role of stasis in thrombosis, in Sherry S., Brinkhouse K.M., Genton E., Stengle J.M. (eds.): Thrombosis. Washington, D.C., National Academy of Science, 1969, p. 461. Stamatakis J.D, Kakkar V.V., Sagar S., Lawrence D., Nairn D., Bentley P.G.: Femoral vein thrombosis and total hip replacement. Br. Med. J. 2:223, 1977. Hirsh J.: Hypercoagulability. Semin. Hematol. 14:409, 1977. Davies J.A., McNicol G.P.: Blood coagulation in pathological thrombus formation and the detection in blood of a thrombotic tendency. Br. Med. Bull. 34:113, 1978. Walsh P.N., Murphy S., Barry W.E.: The role of platelets in the pathogenesis of thrombosis and hemorrhage in patients with thrombocytosis. Thromb. Haemost. 38:1085, 1977. Steele P.L., Weily H.S., Genton E.: Platelet survival and adhesiveness in recurrent venous thrombosis. N. Engl. J. Med. 288:1148, 1973. Harker L.A., Slichter S.J.: Arterial and venous thromboembolism: Kinetic characterization and evaluation of therapy. Thromb. Diath. Haemorrh. 31:188, 1974. Wu K.K., Barnes R.W., Hoak J.C.: Platelet hyperaggregability in idiopathic recurrent deep vein thrombosis. Circulation 53:687, 1976. Collins G.J., Rich N.M., Scialla S., Anderson C.A., McDonald P.T.: Coagulation abnormalities in patients with arterial, venous and combined arterial and venous thrombosis. Arch. Surg. 112:1347, 1977. Stewart G.J.: The role of hypercoagulability in thrombosis. Br. J. Haematol. 40:395, 1978. MacMillan J.C., Milstein S.H., Samson P.C.: Clinical spectrum of septic pulmonary embolism and infarction. J. Thorac. Cardiouasc. Surg. 75670, 1978. Spencer H.: Pathology of the Lung-Excluding Pulmonary Tuberculosis, ed. 3. Oxford, England, Pergamon Press, 1977, vol. 2, p. 543. Levine R.H. Airhart R.A.: Renal carcinoma presenting with pulmonary embolism: A review of two cases. Br. J. Ural. 49:447, 1977. Weigent C.E.: Pulmonary atheroembolism complicating repair of an arteriosclerotic abdominal aneurysm. Minn. Med. 61:15, 1978. Moser K.M.: Pulmonary embolism. Am. Reu. Respir. Dis. 115829, 1977. Gallus A.S.: IlZ5 fibrinogen leg scanning, in Fratantoni J., Wessler S., (eds.): Prophylactic Therapy of Deep Vein Thrombosis and Pulmonary Embolism. Dept. of Health, Education, and Welfare publication 76-866. National Institutes of Health, 1975, p. 77. Kistner R.L.. Ball J.J.. Nordvke R.A.. Freeman B.C.: Incidence of nulmonary embolism in the course of thrombophlebitis of the lower extre-mities. Am. J. Surg. 124:169, 1977. Moreno-Cabral R.. Kistner R.L.. Nordvke R.A.: Imnortance of calf-vein thrombophlebitis. Surgery 80:735; 1976.” Kakkar V.V., Howe C.T., Flanc C., Clarke M.B.: Natural history of postoperative deep-vein thrombosis. Lancet 2:230, 1969. Havig 0.: Deep vein thrombosis and pulmonary embolism. Acta Chir. Stand. 478 (suppl.):l, 1977. Moser K.M., LeMoine J.R.: Is embolic risk conditioned by location of deep venous thrombosis? Ann. Intern. Med. 94:439, 1981. Mavor G.E., Galloway J.M.A.: Iliofemoral venous thrombosis. Br. J. Surg. 56:45, 1969. LeQuesne L.P.: Relation between deep vein thrombosis and pulmonary embolism in surgical patients. N. Engl. J. Med. 291:1292, 1974. Dalen J.E., Haynes F.W., Hoppin F.G., Evans G.L., Bhardwaj O.P., Dexter L.: Cardiovascular responses to experimental pulmonary embolism. Am. J. Cardiol. 20:3, 1967. Thomas D., Stein M., Tanabe G., Rege V., Wessler S.: Mechanism of bron47 I

”

42.

43. 44. 45.

46. 47.

48. 49. 50. 51. 52. 53. 54.

55. 56. 57. 58.

59. 60. 61. 62. 63. 64.

65. 66. 67. 68. 48

choconstriction produced by thromboemboli in dogs. Am. J. Physiol. 206:1207, 1964. Robin E.D.: Ventilation-perfusion abnormalities in pulmonary embolism, in Sasahara A.A., Stein M. (eds.): Pulmonary Embolic Disease. New York, Grune & Stratton, 1964, p. 149. Caldin P.: Pulmonary hemodynamics and arterial oxygen saturation in pulmonary embolism. J. Appl. Physiol. 20:184, 1965. Tsao M.S., Schraufnagel D., Wang N.S.: Pathogenesis of pulmonary infarction. Am. J. Med. 72:599, 1982. Dalen J.E., Haffajee C.L., Alpert J.S., et al: Pulmonary embolism, pulmonary hemorrhage and pulmonary infarction. N. Engl. J. Med. 296:1431, 1977. Sauter R.D., Fletcher F.E., Ousley J.L., Wenzel F.J.: Rapid resolution of a pulmonary embolus. Dis. Chest 52:825, 1967. Sautter R.D., Fletcher F.W., Emanuel D.A., Lawton B.R., Olsen T.G.: Complete resolution of massive pulmonary thromboembolism. J.A .M.A 189:948, 1964. Fred H.L., Axelrad M.A., Lewis J.M., Alexander J.K.: Rapid resolution of pulmonary thromboembolism in man. J.A.MA. 196:1137,1966. Almen T., Nylander G.: Serial phlebography of the normal lower leg during muscular contraction and relaxation. Acta Radiol. 57:264, 1962. Diemer L.: Intraosseous phlebography of the lower limb. Acta Radial. (Suppl.) Stochh. 3304, 1971. McLachlin A.D., McLachlin J.A., Jory T.A., Rawling E.G.: Venous stasis in the lower extremities. Ann. Surg. 152:678, 1960. Hodgson D.C.: Venous stasis during surgery. Anaesthesia 19:96, 1964. Flanc C., Kakkar V.V., Clarke M.B.: The detection of venous thrombosis of the legs using “‘I-labelled fibrinogen. Br. J. Surg. 55742, 1968. Negus D., Pinto D.J., LeQuesne L.P., Brown N., Chapman M.: ‘“‘I-labelled fibrinogen in the diagnosis of deep-vein thrombosis and its correlation with phlebography. BF. J. Surg. 55:835, 1968. Nicolaides A.N., Kakkar V.V., Field ES., Fish P.: Venous stasis and deepvein thrombosis. Br. J. Surg. 59:714, 1972. Nicolaides A.N., Kakkar V.V., Field ES., Renney J.T.G.: The origin of deep-vein thrombosis: A venographic study. Br. J. Radiol. 44:653, 1971. Nicolaides A.N., Kakkar V.V., Renney J.T.G.: The soleal sinuses: Origin of deep-vein thrombosis. Br. J. Surg. 57:860, 1970. Clark C., Cotton L.T.: Blood flow in deep veins of the legs: Recording techniques and evaluation of methods to increase flow during operation. Br. J. Surg. 55:211, 1968. Simpson K.: Shelter deaths from pulmonary embolism. Lancet 2:744, 1940. Homans J.: Thrombosis of deep leg veins due to prolonged sitting. N. Engl. J. Med. 250:148, 1954. Maide M.: Prolonged television viewing as a cause of venous and arterial thrombosis in legs. J.A.M.A. 165:681, 1957. Gibbs N.M.: Venous thrombosis of the lower limbs with particular reference to bedrest. Br. J. Surg. 45:209, 1957. Roberts G.H.: Venous thrombosis in hospital patients: A post-mortem study. Scott. Med. J. 8:11, 1963. Sevitt S., Gallagher N.: Venous thrombosis and pulmonary embolism: A clinico-pathological study in injured and burned patients. Br. J. Surg. 48:495, 1961. Silver J.R., Moulton A.: Prophylactic anticoagulant therapy against pulmonary emboli in acute paraplegia. Br. Med. J. 2:338, 1970. Walsh J.J., Tribe C.R.: Phlebo-thrombosis and pulmonary embolism in paraplegia. Paraplegia 3:209, 1965. Watson N.: Venous thrombosis and pulmonary embolism in spinal cord injury. Paraplegia 6:113, 1968. Coon W.W.: Risk factors in pulmonary embolism. Surg. Gynecol. Obstet. 143:385, 1976.

69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

84. 85.

86. 87. 88. 89. 90.

91. 92.

93. 94. 95.

Cope C., Reyes T.M., Skversky, N.J.: Phlebographic analysis of the incidence of thrombosis in hemiplegia. Radiology 109581, 1973. Frykholm R.: The pathogenesis and mechanical prophylaxis of venous thrombosis. Surg. Gynecol. Obstet. 71:306, 1940. The Urokinase Pulmonary Embolism Trial. Circulation 47(suppl.):II-I, 1973. Parker B.M., Smith J.R.: Pulmonary embolism and infarction. Am. J. Med. 24:402, 1958. Emery J.L.: Pulmonary embolism in children. Arch. Dis. Child. 37591, 1962. Haber S.L.. Bennington J.L.: Pulmonary embolism in an infant. J. Pediutr. 61:759, 1962. Jones D.R.B., MacIntyre I.M.C.: Venous thromboembolism in infancy and childhood. Arch. Dis. Child. 50:X3. 1975. Jones R.H., Sabiston D.C.: Pulmonary embolism in childhood. Monogr. Surg. Sci. 3:35, 1966. Stevenson G.F., Stevenson F.L.: Pulmonary embolism in childhood. J. Pediatr. 34:62, 1949. Soloff L.A., Rodman T.: Acute pulmonary embolism. I. Review. Am. Heart J. 74:710, 1967. Soloff L.A., Rodman T.: Acute pulmonary embolism. II. Clinical. Am. Heart J. 74:829, 1967. Bell W.R., Simon T.L., DeMets D.L.: The clinical features of submassive and massive pulmonary emboli. Am. J. Med. 62:355, 1977. Morrell M.T., Truelove SC., Barr A.V.: Pulmonary embolism. Br. Med. J. 2:830, 1963. Israel H.L., Goldstein F.: The varied clinical manifestations of pulmonary embolism. Ann. Intern. Med. 47:202. 1957. Sevitt S., Gallagher N.G.: Prevention of venous thrombosis and pulmonary embolism in injured patients: A trial of anticoagulant prophylaxis with phenindione in middle-aged and elderly patients with fractured necks of femur. Lancet 2:981, 1959. Neu L.T., Waterfield J.R., Ash C.J.: Prophylactic anticoagulant therapy in the orthopedic patient. Ann. Intern. Med. 62:463, 1965. Salzman E.W., Harris W.H., DeSanctis R.W.: Anticoagulation for prevention of thromboembolism following fracture of the hip. N. Engl. J. Med. 275:112, 1966. Coon W.W., Coller F.A.: Clinicopathologic correlation in thromboembolism. Surg. Gynecol. Obstet. 109:259, 1959. Coon W.W., Coller F.A.: Some epidemiologic considerations of thromboembolism. Surg. Gynecol. Obstet. 109:259, 1959. Coon W.W.: The spectrum of pulmonary embolism: Twenty years later. Arch. Surg. 111:398, 1976. Snell A.M.: The relation of obesity to fatal postoperative pulmonary embolism. Arch. Surg. 15:237, 1927. Barker N.W., Nygaard K.K., Walters W., Priestly J.T.: A statistical study of postoperative venous thrombosis and pulmonary embolism: Predisposing factors. Mayo Clin. Proc. 16:117, 1941. Sandritter W.: Die pathologische anatomic der tbrombose and lung embolic. Sonderdruck Benzinghnerke - Mitteil. 41:37, 1962. Turnbull A.C.: Prophylaxis by anticoagulants after gynaecological, operation, in Walker W., Dundee D., Thompson C. (eds.): Thrombosis and Anticoagulant Therapy. London, Livingstone Co., 1960, p. 60. Kent D.C., Reid D.: Pulmonary embolism in active duty service men. Arch. Environ. Health 12:509, 1966. Bennett N.B., Ogston C.M., McAndrew G.M., Ogston D.: Studies on the fibrinolytic enzyme system in obesity. J. Clin. Z’athol. 19:241, 1966. Goldhaber S.Z., Savage D.D., Garrison R.J., Castelli W.P., Kannel W.B., McNamara P.M., Gheradi G., Feinleib W.: Risk factors for pulmonary embolism. Am. J. Med. 74:1023, 1983. 49

96.

Perlow S. Daniels J.L.: Venous thrombosis and obscure visceral carcinoma. Arch. Intern. Med. 97:184, 1956. Lafler C.J., Hinerman D.L.: A morphologic study of pancreatic carcinoma with reference to multiple thrombi. Cancer 14:944, 1961. Lieberman J.S., Borrero J., Urdaneta E., Wright I.S.: Thrombophlebitis and cancer. JAMA. 177542, 1961. Sack G.H. Jr., Levin J., Bell W.R.: Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: Clinical, pathophysiologic, and therapeutic features. Medicine 56:1, 1977. Miller S.P., Sanchez-Avalos J., Stefanski T., Zuckerman L.: Coagulation disorders in cancer: I. Clinical and laboratory studies. Cancer 20:1452, 1967. Duckert F., Streuli F.: Role of coagulation in thrombosis. Thromb. Diath. Huemorrh. 21 (suppl.):185, 1966. Mersky C.: Defibrination syndrome or .? Blood 41:599, 1973. Catovsky D., Ikoku N.B., Pitney W.R., Gatton D.A.G.: Thromboembolic complications in myelomatosis. Br. Med. J. 3:438, 1970. Massey T.N.: Pulmonary embolism. N. C. Med. J. 27:63, 1966. Daniel D.G., Campbell M., Tumball A.C.: Puerperal thromboembolism and suppression of lactation. Lancet 2:287, 1967. Husni E.A., Pena L.I., Lenhert A.E.: Thrombophlebitis in pregnancy. Am. J. Obstet. Gynecol. 97:901, 1967. McDevitt E. Smith B.: Thrombophlebitis during pregnancy and the puerperium, in Sherry S., Brinkhouse K.M., Genton E., Stengle J.M. (eds.): Thrombosis. Washington, D.C., 1969, National Academy of Sciences, p. 55. Arthure H., Tomlinson J., Organe G., Adelstein A.M., Weatherall J.A.: Thromboembolism, in Humphrey A.L. (ed.): Report on Confidentinl Enquiries Into Maternal Deaths in England and Wales, 1961-1969. London, H.M.S.O., 1972, p. 30. Henderson S.R., Lund C.J., Greasman W.T.: Antepartum pulmonary embolism. Am. J. Obstet. Gynecol. 112:476, 1972. Bonnar J., McNicol G.P., Douglas A.S.: Fibrinolytic enzyme system and pregnancy. Br. Med. J. 3:387, 1969. Bonnar J., McNicol G.P., Douglas A.S.: The blood coagulation and fibrinolytic systems in the newborn and the mother at birth. J. Obstet. Gynaecol. BF. Commonw. 4:355, 1971. Bonnar J., McNicol G.P., Douglas A.S.: Coagulation and fibrinolytic mechanisms durine and after normal childbirth. BF. Med. J. 2:200. 1970. Bonnar J., Prentice C.R.M., McNicol G.P., Douglas A.S.:’ Haemostatic mechanisms in the uterine circulation during placental separation. Br. Med. J. 2564, 1970. Bonnar J., Walsh J.: Prevention of thrombosis after pelvic surgery by British dextran 70. Lancet 1:614, 1972. Phillips L.L., Gladstone W., van de Wille R.: Studies of the coagulation and fibrinolytic systems in hyperstimulation syndrome after administration of human gonadotropins. J. Reprod. Med. 14:138, 1975. Strauss H.S., Diamond L.K.: Elevation of factor VIII during pregnancy in normal persons and in a patient with von Willebrand’s disease. N. Engl. J. Med. 269:1251, 1963. Rutherford R.N., Hougie C., Banks A.L., Coburn W.A.: Effects of sex steroids and pregnancy on blood coagulation factors. Obstet. Gynecol. 24:886, 1964. Todd M.E., Thompson J.G., Bowie E.J.W., Owen CA.: Changes in blood coagulation during pregnancy. Mayo Clin. PFOC. 40:370, 1965. Ygge J.: Changes in blood coagulation and fibrinolysis during the puerperium. Am. J. Obstet. Gynecol. 104:2, 1969. Villasanta V.: Thromboembolic disease in pregnancy. Am. J. Obstet. Gynecol. 93:142, 1965.

97. 98. 99.

100.

101. 102. 103. 104. 105. 106. 107.

108.

109. 110. 111.

112. 113.

114. 115.

116.

117.

118. 119. 120. 50

121. 122. 123.

124.

125. 126. 127.

128.

129. 130.

131. 132. 133.

134. 135. 136.

137. 138.

139. 140. 141.

142.

143.

144.

Wardle E.N., Menon I.S.: Fibrinolysis in pre-eclampsia toxemia of pregnancy. Br. Med. J. 2:625, 1969. Vessey M.P., Doll R.: Investigation of relation between use of oral contraceptives and thromboembolic disease. Br. Med. J. 2:199, 1968. Vessey M.P., Doll R.: Investigation of relation between use of oral contraceptives and thromboembolic disease: A further report. Br. Med. J. 2:651, 1969. Sartwell P.E., Masi A.T., Arthes F.G., Greene G.R., Smith H.E.: Thromboembolism and oral contraceptives: An epidemiological case control study. Am. J. Epidemiol. 90:365, 1969. Atkinson E.A., Fariburn B., Heathsfield K.W.G.: Intracranial venous thrombosis as complication of oral contraception. Lancet 1:914, 1970. Poller L., Tabiowo A., Thompson J.M.: Effects of low-dose oral contraceptives on blood coagulation. Br. Med. J. 3:218, 1968. Ambrus J.L., Niswander K.R., Courey N.G., Wamsteker E.F., Mink I.B.: Progestational agents and blood coagulation. II. Am. J. Obstet. Gynecol. 103:994, 1969. Peterson R.A., Krull P.E., Finley P., Ettinger M.G.: Changes in antithrombin III and plasminogen induced by oral contraceptives. Am. J. Clin. Pathol. 53:468, 1970. von Kaulla E., von Kaulla K.N.: Oral contraceptives and low antithrombin III activity. Luncet 1:36, 1970. Horne C.H.W., Howie P.W., Weir R.J., Goudie R.B.: Effect of combined oestrogen-progestogen oral contraceptives on serum levels of alphaa-macroglobulin, transferrin, albumin, and IgG. Luncet 1:49, 1970. Bolton C.H., Hampton J.R., Mitchell J.R.A.: Effect of oral contraceptives agents on platelets and plasma phospholipids. Lancet 1:1336, 1968. Doar J.W.H., Wynn V.: Serum lipid levels during oral contraceptive and glucocorticoid administration. J. Clin. Puthol. 23 (suppl.):55, 1970. Penick G.D.: Blood states that predispose to thrombosis, in Sherry S., Brinkhouse K.M.. Genton E.. Stenele J.M. (eds.): in Thrombosis. Washineton, D.C., National Academy’ of S&me, 1969, p. 553. Edington G.M., Gillies H.M.: Pathology in the Tropics. London, Edward Arnold, 1969, p. 388. Dacie J.V.: The Huemolytic Anuemias: Congenital and Acquired, London, Churchill Ltd., 1967, part 4, p. 1134. Horler A.R.. Shaw M.T.. Thomnson R.B.: Budd-Chiari svndrome as a complication of paroxysmal nocturnal haemoglobinuria. Postgrad. Med. J. 46:618, 1970. Amris C.J., Hansen N.E.: Coagulation and fibrinolytic studies in paroxysmal nocturnal haemoglobinuria. Actu Med. Scund. 184~551, 1968. Aster R.H., Enright S.E.: A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria: usefulness for the detection of platelet antibodies. J. Clin. Invest. 48:1199, 1969. Sirchia G., Lewis S.M.: Paroxysmal nocturnal hemoglobinuria. Clin. Huem&01. 4:199, 1975. Hartmann R.C., Arnold A.B.: Paroxysmal nocturnal hemoglobinuria (PNH) as a clonal disorder. Annu. Rev. Med. 28:187, 1977. Peytremann R, Rhodes .R.C., Hartmann R.C.: Thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) with particular reference to progressive diffuse hepatic venous thrombosis. Semin. Hemutol. 5:115, 1972. Perkins J., Israels M.C.G., Wilkinson J.F.: Polycythemia Vera: Clinical studies on a series of 127 patients managed without radiation therapy. Q. J. Med. 33:499, 1964. Hirsh J., McBride J.A., Dacie J.V.: Thrombo-embolism and increased platelet adhesiveness in post-splenectomy thrombocytosis. Aust. Ann. Med. 15:212, 1966. Hirsh J., Dacie J.V.: Persistent post-splenectomy thrombocytosis and thrombo-embolism: A consequence of continuing anaemia. Br. J. Huemutol. 12:44, 1966. 51

145.

Negus D., Pinto D.J., Brown N.: Platelet adhesiveness in postoperative deep-vein thrombosis. Lancet 1:220, 1969. Levin J., Conley C.L.: Thrombocvtosis associated with malignant disease. Arch. Intern. Mid. 114:497, 1964: Egeberg 0.: Inherited antithrombin deficiency causing thrombophilia. Thromb. Diath. Haemorrh. 13:516, 1965. Sas G., Blasko G., Banhegyi D., Jako J., Palos L.A.: Abnormal antithrombin III (antithrombin III ‘Budanest’) as a cause of a familial thrombonhilia. Thromb. Diath. Haemorrh. 32:iO5, 1974. Marciniak C., Farley S.H., DeSimone P.A.: Familial thrombosis due to antithrombin III deficiency. Blood 43:219, 1974. von Kaulla E., von Kaulla K.N.: Antithrombin III and diseases. Am. J. Clin. Pathol. 48:69, 1967. Carvalho A., Ellman L.: Hereditary antithrombin III deficiency: Effect of antithrombin III deficiency on platelet function. Am. J. Med. 61:179, 1976. Filip D.J., Eckstein J.D., Veltkamp J.J.: Hereditary antithrombin III deficiency and thromboembolic disease. Am. J. Hematol. 2~343, 1976. van der Meer J., Stoepman-van Dalen E.A., Jansen J.M.S.: Antithrombin III deficiency in a Dutch family. J. Clin. Pathol. 26:532, 1973. Aoki N., Moroi M., Sakata Y., Yoshida N.: Abnormal plasminogen: A hereditary molecular abnormality found in a patient with recurrent thrombosis. J. Clin. Invest. 61:1186, 1978. Jick H., Slone D., Westerholm B., Inman W.H.W., Vessey M.P., Shapiro S., Lewis G.P., Worcester J.: Venous thromboembolic disease and ABO blood group: A cooperative study. Lancet 1:539, 1969. MacAndrew R.: Venous thromboembolism and blood group. Lancet 1:1263, 1969. Nefzger M.D., Hrubec Z., Chalmers T.C.: Venous thromboembolism and blood group. Lancet 1:887, 1969. Talbot S., Wakley E.J., Ryrie D., Langman M.J.S.: ABO blood groups and venous thromboembolic disease. Lancet 1:1257, 1970. Allan T.M., Stewart K.S.: ABO blood groups and superficial puerperal thrombophlebitis. Lancet 1:1125, 1971. Bates M.M.: Venous thromboembolic disease and ABO blood type. Lancet 1:239, 1971. Mourant A.E., Kopec A.C., Domaniewska-Sobczak K.: Blood groups and blood clotting. Lancet 1:223, 1971. Westerholm B., Wiechel B., Eklund G.: Oral contraceptives, venous thromboembolic disease, and ABO blood type. Lancet 2:664, 1971. Carson N.A.J., Cusworth D.C., Dent C.E., Field C.M.B., Neil1 D.W., Westall R.G.: Homocystinuria: A new inborn error of metabolism associated with mental deficiency. Arch. Dis. Child. 38:425, 1963. Carson N.A.J., Dent C.E., Field C.M.B., Gaul1 G.E.: Homocystinuria: Clinical and pathological review of ten cases. J. Pediatr. 66:656, 1965. Gerritsen T. Waisman H.A.: Homocystinuria: Absence of cystathionine in the brain. Science 145588, 1964. Gibson J.B., Carson N.A.J., Neil1 D.W.: Pathological findings in homocystinuria. J. Clin. Pathol. 17:427, 1964. McDonald L., Bray C., Field C., Love F., Davies B.: Homocystinuria, thrombosis, and the blood platelets. Lancet 1:745, 1964. Schimke R.N., McKusick V.A., Huang T., Pollack A.D.: Homocystinuria: Studies of 20 families with 38 affected members. J.A.M.A. 193:711, 1965. Uhlendorf B.W., Mudd S.H.: Cystathionine synthase in tissue culture derived from human skin: Enzyme defect in homocystinuria. Science 160:1007, 1968. McCully K.S.: Vascular pathology of homocystinemia: Implications for the pathogenesis of arteriosclerosis. Am. J. Pathol. 56:111, 1969. Harker L.A., Slichter S.J., Scott C.R., Ross R.: Homocystinemia. N. EngZ. J. Med. 2911577, 1974. Pallis C.A., Fudge B.J.: The neurological complications of Behcet’s syndrome. Arch. Neural. Psych&r. 75:1, 1956.

146. 147. 148.

149. 150. 151. 152. 153. 154.

155.

156. 157. 158. 159. 160. 161. 162. 163.

164. 165. 166. 167. 168. 169.

170. 171. 172. 52

173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183.

184. 185. 186. 187. 188. 189. 190. 191.

192.

193.

194. 195. 196.

197.

198. 199.

Boe J., Dalgaard J., Scott D.: Mucocutaneous-ocular syndrome with intestinal involvement. Am. J. Med. 25~857, 1958. O’Duffy J.D., Carney J.A., Deodhar S.: Behcet’s disease. Ann. Intern. Med. 75561, 1971. Chajek T., Fainaru M.: Behcet’s disease: Report of 41 cases and review of literature. Medicine 54:179, 1975. Rapidis A.D., Langdon J., Pate1 M.F.: Recurrent oral and oculogenital ulcerations (Behcet’s syndrome). Oral Surg. 41:451, 1976. Kansu E., Deglin S., Cantor I., Burke J.F., Cho S.Y., Cathart R.T.: The expanding spectrum of Behcet’s syndrome. J.A.M.A. 237:1855, 1977. Chajek T., Aronowski E., Izak G.: Decreased fibrinolysis in Behcet’s disease. Thromb. Diath. Haemorrh. 20:610, 1973. Chaiek T.. Fainaru M.: Behcet’s disease with decreased fibrinolvsis and superior vena caval occlusion. Br. Med. J. 1:782, 1973. Cadman E.C., Lundberg W.B., Mitchell M.S.: Pulmonary manifestations in Behcet’s syndrome. Arch. Intern. Med. 136:944, 1976. Asbeck F., Meyer-Boernecke D., Vandeloo J.: Inhibition of the fibrinolytic system in Behcet’s disease? Haemostasis 6:303, 1977. Economopoulos T.C., Papayannis A.G., Thomopoulos D.: Platelet function, blood coagulation and fibrinolysis in Behcet’s syndrome. Blut 34:215, 1977. Sasahara A., Cannilia J.E., Morse R.L., Sidd J.J., Tremblay G.M.: Clinical and physiologic studies in pulmonary thromboembolism. Am. J. Cardiol. 20:10, 1967. Viamonte M., Koolpe H., Janowitz W., Hildner F.: Pulmonary thromboembolism-uodate. J.A.M.A. 243:2229. 1980. Esposito-A.L., Glechman R.A.: A diagnostic approach to the adult with fever of unknown origin. Arch. Intern. Med. 139:575, 1979. Shaw R.A., Schonfeld S.A., Whitcomb M.E.: Pulmonary embolism presenting as coronary insufficiency. Arch. Intern. Med. 141:651, 1981. Moser K.M.: Diagnosis and management of pulmonary embolism. Hosp. Pratt. 15:57, 1980. Simpson R.J., Podolak R., Mangano C.A., Foster J.R., Dalldorf F.G.: Vagal syncope during recurrent pulmonary embolism. J.A.M.A. 249:390,1983. Murray H.W., Ellis G.C., Blumenthal D.S., SOS T.A.: Fever and pulmonary thromboembolism. Am. J. Med. 67:239, 1979. Sasahara A.A., Stein M., Simon, M., et al.: Pulmonary angiography in the diagnosis of thromboembolic disease. N. En&. J. Med. 270:2075, 1965. Dexter L.: Natural history of pulmonary embolism, in Sherry S., Brinkhouse K.M., Genton E., Stengle J.M. (eds.): Thrombosis. Washington, D.C., National Academv of Science, 1969, p. 85. McIntyre K.M., Sasahara A.: Determinants of cardiovascular response to pulmonary embolism, in Moser K.M., Stein M. (eds.): Pulmonary Th.romboembolism. Chicago, Year Book Medical Publishers, 1973, p. 144. Szucs M.M., Brooks H.L., Grossman W., Banas J.S. Jr., Meister S.G., Dexter L., Dalen J.E.: Diagnostic sensitivity of laboratory findings in acute pulmonary embolism. Ann. Intern. Med. 74:161, 1971. Kafer F.R.: Respiratory function in pulmonary thromboembolic disease. Am. J. Med. 47:904, 1969. Goodall R.J.R., Greenfield L.J.: Clinical correlations in the diagnosis of pulmonary embolism. Ann. Surg. 191:219, 1980. Kelly M.J., Elliot L.P.: The radiologic evaluation of the patient with suspected pulmonary thromboembolic disease. Med. Clin. North Am. 59:3, 1974. McIntyre K.M., Sasahara A.A., Littman D.: Relation of the electrocardiogram to hemodynamic alterations in pulmonary embolism. Am. J. Cardiol. 30:205, 1972. Spodich D.H.: Electrocardiographic response to pulmonary embolism. Am. J. Cardiol. 30:695, 1972. Stein P.D., Dalen J.E., McIntyre K.M., Sasahara A.A., Wenger N.K., Willis P.W.: The electrocardiogram in acute pulmonary embolism. Prog. Cardiouasc. Dis. 171247. 1974. 53

200.

Wacker W.E.C., Rosenthal M., Snodgrass P.J., Amador E.: Diagnosis of pulmonary embolism and infarction. JAMA. 178:8, 1961. Konttinen A., Somer H., Auvinen S.: Serum enzymes and isoenxymes. Arch. Intern. Med. 133:243, 1974. Bynum L.J., Crotty C.M., Wilson J.E.: Diagnostic value of tests of fibrin metabolism in patients predisposed by pulmonary embolism. Arch. Intern. Med. 139:283, 1979. Ruckley C.V., Das P.C., Leitch A.G., Donaldson A.A., Copland W.A., Redpath A.T., Scott P., Cash J.D.: Serum fibrin-fibrinogen degradation products associated with post-operative pulmonary embolism and venous thrombosis. Br. Med. J. 4395, 1970. Wilson J.E. III, Frenkel E.P., Pierce A.K., Johnson R.L. Jr., Winga E.R., Curry G.C., Mierzwiak D.S.: Spontaneous fibrinolysis in pulmonary embolism. J. CEin. Znuest. 50:474, 1971. Gurewich V., Hume M., Patrick M.: The laboratory diagnosis of venous thromboembolic disease by measurement of fibrinogen-fibrin degradation products and fibrin monomer. Chest 64:585, 1973. Jones D.R.B., Ruckley C.V., Owens R., Cash J.D.: Serum fibrin-fibrinogen degradation products after experimental pulmonary embolism. Br. J. Surg. 61:811, 1974. Cade J., Hirsh J., Regoeczi E.: Mechanisms for elevated fibrin-fibrinogen degradation products in acute experimental pulmonary embolism. Blood 45:563, 1975. Merskey C., Kleiner G.J., Johnson A.J.: Quantitative estimation of split products of fibrinogen in human serum: Relation to diagnosis and treatment. Blood 28:1, 1966. Jareno A.J., Delaserna J.L., Corral E.E., Gallego J., Patino R.: Fibrinogen/ fibrin degradation products in the diagnosis of pulmonary embolism in critically ill patients. &-it. Cure Med. 8:646, 1980. Rickman F.D., Handin R., Howe J.P., Alpert J.S., Dexter L., Dalen J.E.: Fibrin split products in acute pulmonary embolism. Ann. Intern. Med. 79:664, 1973. Light R.W., Bell W.R.: LDH and fibrinogen-fibrin degradation products in pulmonary embolism. Arch Intern. Med. 133:372, 1974. Wood E.H., Prentice C.R.M., McNicoI G.P.: Association of fibrinogen-fibrin related antigen with post-operative deep vein thrombosis and systemic complications. Lancet 1:166, 1972. Hulsteijn H., Briet E., Kock C., Hermans J., Bertina R.: Diagnostic value of fibrinopeptide A and beta-thromboglobulin in acute deep venous thrombosis and pulmonary embolism. Acta Med. Stand. 211:323, 1982. Nossel H.L.: Radioimmunoassay of fibrinonentides in relation to intravascular coagulation and thrombosis. N. Engl: 2 Med. 295:428, 1976. Yudelman I.M.. Nossel H.L.. Kaolan K.L.. Hirsh J.: Plasma fibrinooeutide A levels in symptomatic venous ihromboembolism. Blood 51:1189, iSiS. Sipes J.N., Suratt P.M., Teams C.D., Barada F.A., Davis J.S., Tegtmeyer C.J.: A prospective study of plasma DNA in the diagnosis of pulmonary embolism. Am. Rev. Respir. Dis. 118:475, 1978. Barada F.A., Soratt P.M., Davis J.S. IV, et al.: Free plasma DNA in patients with nulmonarv embolism. South. Med. J. 73:345, 1980. Lippman M.L., Morgan L., Fein A., Shapiro B., Leon’ S.A.: Plasma and serum concentrations of DNA in pulmonary thromboembolism. Am. Rev. Respir. Dis. 125:416, 1982. Goldhaber S.Z., Hennekens C.H., Mar& J.A., McNeil B.J., Glynn M.A., Bettman M.A., Schur P.A.: Low sensitivity of plasma DNA in screening for nulmonarv embolism. Am. Rev. Resoir. Dis. 126360. 1982. Moore S.,“Pepper D.S., Cash J.D.: The isolation and characterization of a platelet-specific B-globulin (B-thromboglobulin) and the detection of antiurokinase and antiplasmin released from thrombin-aggregated washed human platelets. B&hem. Biophys. Actu 379:360,1975. Ludlin C.A., Moore S., Bolton A.E., Pepper D.S., Cash J.D.: The release of

201. 202.

203.

204.

205.

206.

207.

208.

209.

210.

211. 212.

213.

214. 215. 216.

217. 218.

219.

220.

221. 54

222.

223.

224. 225. 226.

227.

228.

229. 230.

231.

232. 233.

234. 235.

236.

237.

238.

239. 240.

241. 242. 243.

a human platelet specific protein measured by a radioimmunoassay. Thromb. Res. 6543, 1975. Bosnjakovic V.B., Jankovic B.D., Horvat J., Cvoric J.: Radiolabelled antihuman fibrin antibody: A new thrombusdetecting agent. Lancet 1:452, 1977. Walsh P.N.: The effect of dilution of plasma on coagulation. The significance of the dilution-activation phenomenon for the study of platelet coagulant activities. Br. J. Haematol. 22:219, 1972. Walsh P.N.: The role of platelets in the contact phase of blood coagulation. Br. J. Hoemntol. 22~237, 1972. Walsh P.N.: Platelet coagulant activities and hemostasis: a hvnothesis. -_ Blood 43:597, 1974. King J.B., Joffe, S.N.: The prediction of post-operative deep vein thrombosis, using a newly described test of platelet function. Thromb. Diath. Haemorrh. 32502, 1974. Walsh P.N., Rogers P.H., Marder V.J., Gognatelli G., Escovits ES., Sherry S.: The relationship of platelet coagulant activities to venous thrombosis. Br. J. Haematol. 32~421, 1976. Dechavanne J.M., Ville D., Clermont N., Pouillaude J.M., Clermont A., Viala J.J., de Mourgues G.: The radioimmunological assay of fibrinogen breakdown products with E. antigen during post-operative venous thrombosis. Nouv. Presse. Med. 6:3721, 1977. Webber M.M.: Labeled albumin aggregates for detection of clots. Semin. Nucl. Med. 7~253, 1977. Krohn K.A., Knight L.C.: Radiopharmaceuticals for thrombus detection: Selection, preparation and critical evaluation. Semin. Nucl. Med. 7:219, 1977. Harwig J.F., Harwig S.S.L., Eichling J.O., Coleman R.E., Welch M.J.: lz31labeled soluble fibrin: Preparation and comparison with other thrombus imaging agents. Znt. J. Appl. Radiat. Zsot. 28157, 1977. Yin E.T., Wessler S., St011 P.J.: Biological properties of the naturally occurring plasma inhibitor to activated factor X. J. Biol. Chem. 246:3703, 1971. Yin E.T., Wessler S., St011 P.J.: Identity of plasma-activated factor X inhibitor with antithrombin III and heparin cofactor. J. Biol. Chem. 246:3712, 1971. Pepper D.S., Preston F.E., Mibashon R.S.: Newer techniques in the study of hemostatis disorders. Semin. Hemutol. 15:73, 1978. Moses D.C., Silver T.M., Bookstein J.T.: The complementary roles of chest radiography, lung scanning, and selective pulmonary angiography in the diagnosis of pulmonary embolism. Circulation 49179, 1974. Simon M.: Plain film and angiographic aspects of pulmonary embolism, in Moser K.M., Stein M. feds.): Pulmonary Thromboembolism. Chicago, Year Book Medical Publishers, 1973, p. 197. McIntyre K.M., Sasahara A.A.: The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am. J. Curdiol. 28:285, 1971. Sagar K.B., Rhyne T.L., Greenfield L.J.: Echocardiographic tissue characterization and range-gated Doppler ultrasound for the diagnosis of pulmonary embolism. Circulutiorv 67:365,1983. Greenspan R.H.: Does a normal isotope perfusion scan exclude pulmonary embolism? Invest. Radial. 8:97, 1973. Kipper M.S., Moser K.M., Kortman K.E., Ashbum W.L.: Longterm followup of patients with suspected pulmonary embolism and a normal lung scan. Chest 82:411, 1982. Quinn J.C., Head L.R.: Radioisotope photoscanning in pulmonary disease. J. Nucl. Med. 7:1, 1966. Wagner H.N. Jr.: Lung scanning in pulmonary embolism. Bull. Physiopathol. Respir. 6:65, 1970. Seeker-Walker R.H., Siegel B.A.: The use of nuclear medicine in the diagnosis of lung disease. Radiol. Clin. North Am. 11:215, 1973. 55

244. 245. 246. 247.

248. 249. 250. 251.

252.

253. 254. 255. 256. 257.

258.

259.

260.

261.

262.

263.

264.

265.

266.

267. 56

Mishkin F.S., Johnson P.M.: The role of lung imaging in pulmonary embolism. Postgrad. Med. J. 49:487, 1973. Seriff N.S., Khan F., Lazo B.J.: Acute respiratory failure: Current concepts of pathophysiology and management. Med. Clin. North Am. 57:1539, 1973. Schorn D.: Aids in the diagnosis of pulmonary embolism. S. Afr. Med. J. 47:1951, 1973. Anderson T. McD. Jr., Mall J.C., Hoffer P.B., Tetalman M.R., Hendrix R.W.: Efficacy of emergency radionuclide perfusion lung studies. Radiology 120:125, 1976. Spies W.G., Spies S.M., Mintzer R.A.: Radionuclide imaging in diseases of the chest: Part 1. Chest 83:122, 1983. Friedman W.F., Braunwald E.: Alterations in regional pulmonary blood flow in mitral valve disease by radioisotope scanning. Circulation 34:363, 1966. Gluck M.C., Moser K.M.: Pulmonary artery agenesis: Diagnosis with ventilation and perfusion scintiphotography. Circulation 41:859, 1970. Poulose K.P., Reba R.C., Gilday D.L., Deland F.H., Wagner H.N. Jr.: Diagnosis of pulmonary embolism: A correlative study of the clinical, scan, and angiographic findings. Br. Med. J. 3:67, 1970. James A.E., Jr., Cooper M., White R.I., Wagner H.N. Jr.: Perfusion changes on lung scans in patients with congestive heart failure. Radiology 100:99, 1971. Moser K.M., Longo A.M., Ashburn W.L., Guisan M.: Spurious scintiphotographic recurrence of pulmonary emboli. Am. J. Med. 55:434, 1973. Haynie T.P., Hendrick C.K., Schreiber M.H.: Diagnosis of pulmonary embolism and infarction by photoscanning. J. Nucl. Med. 6:613, 1965. Shoop J.D.: Why do a lung scan? J.A.M.A. 229:567, 1974. Robin E.D.: Overdiagnosis and overtreatment of pulmonary embolism: The emperor may have no clothes. Ann. Intern. Med. 87:775, 1977. Loken M.K., Westgate H.D.: Evaluation of pulmonary function using xenon-133 and the scintillation camera. Am. J. Roentgenol. Radium Ther. Nucl. Med. 4:835, 1967. Haddon R.W.T., Wood D.E., Woolfe C.R.: The measurement of ventilation/ perfusion relationships using multiple crystal retilinear scanner. Can. Med. Assoc. J. 99:1111, 1968. Marks A., Chervony I., Lankford R., Smith E.M., Gilson A.J., Smoak W.: Ventilation-perfusion relationships in humans measured by scintillation scanning. J. Nucl. Med. 9:450, 1968. Newhouse M.T., Wright F.J., Ingham G.K., Archer N.P., Hughes L.B., and Hopkins O.L.: Use of scintillation camera and ‘s3-xenon for study of topographic pulmonary function. Respir. Physiol. 4:141, 1968. Moser K.M., Guisan M., Cuomo A., and Ashburn W.L.: Differentiation of pulmonary vascular from parenchymal disease by ventilation/perfusion scintiphotography. Ann. Intern. Med. 75:597, 1971. Stjernholm M.R., Landis G.A., Marcus F.I., Miale A. Jr., Moser K.M., and Walsh B.: Perfusion and ventilation radioisotope lung scans in stenosis of the pulmonary arteries and their branches. Am. Heart J. 78137, 1969. Wagner H.N. Jr., Lopez-Majano V., Langan J.K., and Joshi R.C.: Radioactive xenon in the differential diagnosis of pulmonary embolism. Radiology 91:1168, 1968. Medina J.R., Lillehei J.P., Loken M.K., and Ebert R.V.: Use of the scintillation anger camera and xenon Xe 133 in the study of chronic obstructive lung disease. J.A.M.A. 208:985, 1969. DeNardo G.L., Goodwin D.A., Ravasini R., Dietrich P.A.: The ventilatory lung scan in the diagnosis of pulmonary embolism. N. Engl. J. Med. 282:1334, 1970. Alderson P.O., Rujanavech N., Seeker-Walker R.H., McKnight R.C.: The role of 133Xe ventilation studies in the scintigraphic detection of pulmonary embolism. Radiology 120:633, 1976. McNeil B.J.: A diagnostic strategy using ventilation-perfusion studies in patients suspect for pulmonary embolism. J. Nucl. Med. 17:613, 1976.

268. 269.

270. 271.

272. 273. 274.

275. 276.

277. 278. 279.

280. 281. 282.

283. 284. 285.

286.

287. 288.

289.

290.

291. 292.

Biello D.: Clinicopathologic conference. Am. J. Med. 67:105, 1979. Hull R.D.. Hirsh J.. Carter C.J.. Jav R.M.. Dodd P.E.. et al.: Pulmonarv angiography, ventilation lung scanning and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann. Zntern. Med. 98891, 1983. Jacobstein J.G.: ‘a3Xe ventilation scanning immediately following the 99mTC perfusion scan. J. Nucl. Med. 15:964, 1974. Epstein J., Taylor A., Alasraki N., Coel M.: Acute pulmonary embolus associated with transient ventilatory defect: Case report. J. Nucl. Med. 16:1017, 1975. Yao J.S.T., Henkin R.E., Conn J. Jr., Quinn J.L., Bergan J.J.: Combined isotope venography and lung scanning. Arch. Surg. 107:146, 1973. Williams O., Lyall J., Vernon M., Croft D.N.: Ventilation-perfusion lung scanning for pulmonary emboli. Br. Med. J. 1:600, 1974. Wagner H.N. Jr., Sabiston D.C., McAfee J.G., Tow D., Stern H.S.: Diagnosis of massive pulmonary embolism in man by radioisotopic scanning. N. Engl. J. Med. 2711377, 1964. Browse N.L., Clemenson G., Croft D.N.: Fibrinogen-detectable thrombosis in the legs and pulmonary embolism. Br. Med. J. 1:603,1974. Cheely R., McCartney W.H., Perry J.R., Delany D.J., Bustad L., Wynia V.H., Griggs T.R.: The role of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism. Am. J. Med. 70:17, 1981. Bookstein J.J.: Segmental arteriography in pulmonary embolism. Radiology 93:1007, 1969. Bookstein J.J.: Pulmonary thromboembolism with emphasis on angiographic-pathologic correlation. Semin. Roentgenol. 5:291, 1970. Dalen J.E., Brooks H.L., Johnson L.W., Meister S.G., Szucs M.M., Dexter L.: Pulmonary angiography in acute pulmonary embolism: Indications, techniques, and results in 367 patients. Am. Heart J. 81:175, 1971. Bookstein J.J., Silver T.M.: The angiographic differential diagnosis of acute pulmonary embolism. Radiology 110:25, 1974. Tow D.E.: Thrombus detection: Here and now. J. Nucl. Med. 18:90, 1977. Gilday D.L., Poulse K.P., Deland F.H.: Accuracy of detection of pulmonary embolism by lung scanning correlated with pulmonary angiography. Am. J. Roentgenol. 115732, 1972. Bell W.R., Simon T.L.: A comparative analysis of pulmonary perfusion scans with pulmonary angiograms. Am. Heart J. 92:700, 1976. Rosenow E.C., Osmundson P.J., Brown M.L., Pulmonary embolism. Mayo Clin. Proc. 56:161, 1981. Mills S.R., Jackson D.C., Older R.A., Heaston D.K., Moore A.V.: The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Radiology 136:295, 1980. Novelline R.A., Baltarowich O.H., Athanasoulis C.A., Waltman A.C., Greenfield A.J., McKusick K.A.: The clinical course of patients with suspected pulmonary embolism and a negative pulmonary arteriogram. Radiology 126:561, 1978. Goodman P.C., Brant-Zawadzki M.: Digital subtraction pulmonary angiography. Am. J. Roentgenol. 139:305, 1982. Pond G.D., Ovitt T.W., Cap-p M.P.: Comparison of conventional pulmonary angiography with intravenous digital subtraction angiography for pulmonary embolic disease. Radiology 147:345, 1983. Meaney T.F., Weinstein M.A., Buonocore E., Pavlicek W., Borkowski G.P., Gallagher J.H., Sufka B., MacIntyre W.J.: Digital subtraction angiography of the human cardiovascular system. Am. J. Roentgenol. 135:1153, 1980. Ludwig J.W., Verhoeven L.A., Kersbergen J.J., Overtoom T.T.: Digital subtraction angiography of the pulmonary arteries for the diagnosis of pulmonary embolism. Radiology 147:639, 1983. Sachett D.L.: Observer variation in the interpretation of lower limb venograms. Am. J. Roentgenol. 132~227, 1979. Sasahara A.A., Sharma G.V.R.K., Parisi A.F.: New developments in the 57

detection and prevention of venous thromboembolism. Am. J. Cardiol. 43:124, 1979. Olsson C.G., Albrechtsson U.: A modified ‘z51-fibrinogen technique in suspected deep vein thrombosis. Actu Med. Stand. 207:461, 1980. Sautter R.D., Larson D.E., Bhattacharyya S.K., Chen H.M., Treuhaft P.S., Milbauer J.P., Mazza J.J., Emanuel D.A., Koch E.L., Lolley D.M., Myers W.O., Ray J.F., Plotka E .D., Nyez G.R., Wenzel F. J.: The limited utility of fibrinogen Iiz5 leg scanning. Arch. Znt. Med. 139:148, 1979. Dosick SM., Blakemore W.S., Navarre J.R.: The role of Doppler ultrasound in acute deep vein thrombosis. Circulation Bl(supp1 2):9, 1975. Wilkins R.W.. Mixter G.. Stanton J.R.. Litter J.: Elastic stockinas in the prevention of pulmonary embolism: A preliminary report. N. Engl J. Med. 246:360, 1952. Wilkins R.W., Stanton J.R.: Elastic stockings in the prevention of pulmonary embolism: II. A progress report. N. Engl. J. Med. 2481087, 1953. Sigel G., Edelstein A.L., Felix W.R., Memhardt C.R.: Compression of the deep venous system of the lower leg during inactive recumbency. Arch. Surg. 106:38, 1973. Flanc C., Kakkar V.V., Clarke M.B.: Postoperative deep-vein thrombosis: Effect of intensive prophylaxis. Lancet 1:477, 1969. Tsapogas M.J., Goussous H., Peabody R.A., Karmody A.M., Echert C.: Postoperative venous thrombosis and the effectiveness of prophylactic measures. Arch. Surg. 103:561, 1971. Rosengarten D.S., Laird J., Jeyasingh K., Martin P.: The failure of compression stockings (Tubigrips) to prevent deep venous thrombosis after surgery. Br. J. Surg. 57:296, 1970. Skillman J.J.: Postoperative deep vein thrombosis and pulmonary embolism: A selective review and personal viewpoint. Surgery 75:114, 1974. Clagett G.P., Salzman E.W.: Prevention of venous thromboembolism. Prog. Cardiovasc. Dis. 17:345, 1975. Collins R.E.C.: Physical methods of prophylaxis against deep vein thrombosis, in Frantantoni J., Wessler S. (eds.): Prophylactic Therapy of Deep Vein Thrombosis and Pulmonary Embolism. Dept. of Health, Education, and Welfare publication 78-866. National Institutes of Health, 1975, pp. 158-169. Clarke-Pearson D.L., Synan I.S., Hinshaw W.M., Coleman R.E., Creasman W.T.: Prevention of postoperative venous thromboembolism by external pneumatic calf compression in patients with gynecologic malignancy. Obstet. Gynecol. 63:92, 1984. Skillman J.J., Collins R.E.C., Coe N.P., Goldstein B.S., Shapiro R.M., Zervas N.T., Bettmann M.A., Salzman E.W.: Prevention of deep vein thrombosis in neurosurgical patients: A controlled randomized trial of external pneumatic compression boots. Surgery 83:354, 1978. Coe N.P., Collins R.E.C., Klein LA., Bettman M.A., Skillman J.J., Shapiro R.M.. Salzman E.W.: Prevention of deep vein thrombosis in urological natients: A controlled, randomized trial-of low-dose heparin and external pneumatic compression boots. Surgery 83:230, 1978. Roberts V.C., Cotton L.T.: Prevention of postoperative deep vein thrombosis in patients with malignant disease. Br. Med. -J. 1:358, 1974. Rosenburg I.L., Evans M., Pollack A.V.: Prophylaxis of postoperative leg vein thrombosis by low dose subcutaneous heparin or preoperative calf muscle stimulation: A controlled clinical trial. Br. Med. J. 1:649, 1975. Dejode L.R., Kurshid M., Walther W.W.: The influence of electrical stimulation of the leg during surgical operations on the subsequent development of deep-vein thrombosis. Br. J. Surg. 60:31, 1973. Harris W.H., Salzman E.W., DeSanctis R.W.: The prevention of thromboembolic disease by prophylactic anticoagulation, abstracted. J. Bone Joint Surg. 4981, 1967. Harris W.H., Salzman E.W., DeSanctis R.W., Coutts R.D.: Prevention of

293. 294.

295. 296.

297.

298.

299. 300.

301.

302. 303. 304.

305.

306.

307.

308. 309.

310.

311.

312. 58

313.

314.

315.

316. 317. 318. 319.

320.

321.

322. 323. 324. 325. 326. 327.

330

331.

332. 333.

334.

venous thromboembolism following total hip replacement. J.A.M.A. 220:1319, 1972. Harris W.H., Salzman E.W., Athanasoulis C., Waltman A.C., Baum S., DeSanctis R.W.: Comparison of warfarin, low-molecular-weight dextran, aspirin, and subcutaneous heparin in prevention of venous thromboembolism following total hip replacement, abstracted. J. Bone Joint Surg. 56:1552, 1974. D’Ambrosia R.D., Lipscomb P.R., McClain E.J., Wissnger H.A., McDowell J.A.: Prophylactic anticoagulation in total hip replacement. Surg. Gynecol. O&et. 140:523, 1975. Johnson R., Green J.R., Charnley J.: Pulmonary embolism and its prophylaxis following the Charnley total hip replacement. Clin. Orthop. 127:123, 1977. Kelsev J.L., Wood P.H.M., Charnley J.: Prediction of thromboembolism following total hip replacement. CkOrthop. 114:247, 1976. Morris G.K.. Mitchell J.R.A.: Prevention and diaanosis of venous thrombosis in patients with hip fractures. Lancet 2:867, i976. Simon T.L., Stengle J.M.: Antithrombotic practice in orthopedic surgery: Results of a survey. Clin. Orthop. 102:181, 1974. Chalmers T.C., Matta R.J., Smith H., Kunzler A.M.: Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N. Engl. J. Med. 297:1091, 1977. Modan B., Shani M., Schor S., Modan N.L.: Reduction of hospital mortality from acute myocardial infarction by anticoagulant therapy. N. Engl. J. Med. 292:1359, 1975. Tonascia J., Gordis L., Schmerler H.: Retrospective evidence favoring use of anticoagulants for myocardial infarction. N. EngZ. J. Med. 292:1362, 1975. Results of a cooperative clinical trial: Anticoagulants in acute myocardial infarction. J.A.M.A. 2251724, 1973. Wray R., Maurer B., Shillingford J.: Anticoagulants to prevent calf-vein thrombosis after myocardial infarction. N. Engl. J. Med. 288:815, 1973. Douglas A.S.: Management of thrombotic disease. Semin. Hematol. 8:95, 1971. Erdi A., Kakkar V.V., Thomas D.P., Lane D.A.: Effect of low-dose subcutaneous heparin on whole-blood viscosity. Lancet 2:342, 1976. Wessler S., Yin E.T.: Theory and practice of minidose heparin in surgical patients. Circulation 47:671; 1973.Sharnoff J.G.. Rosen R.. Sadler A.H.. Ibarra-Isunza G.C.: Prevention of fatal pulmonary thromboembolism by heparin prophylaxis after surgery for hip fractures. J. Bone Joint Swg. 58-A913, 1976. Kakkar V.V., Corrigan T., Spindler J., Fossard D.P., Flute P.T., Crellin R.O., Wessler S.. Yin E.T.: Efficacy of low doses of heparin in prevention of deeplvein thrombosis after major surgery. Lancet 2:161, 1972.Lahnborg G.. Friman G.. Bergstrom K.. Lawrareen H.: Effect of low-dose heparin in incidence of’ post-operative’ pulmonary embolism detected by photoscanning. Lancet 1:329, 1974. Abernathy E.A., Hartsuck J.M.: Postoperative pulmonary embolism: A prospective study utilizing low-dose heparin. Am. J. Surg. 128:739, 1974. Kill J., Kill J., Axelson F., Anderson D.: Prophylaxis against postoperative pulmonary embolism and deep vein thrombosis by low-dose heparin. Lancet 1:1115, 1978. Williams H.T.: Prevention of postoperative deep vein thrombosis with perioperative subcutaneous heparin. Lancet 2:950, 1972. Nicolaides A.N., DuPont P.A., Desai S., Lewis J.D., Douglas J.N., Dodsworth H., Fourides G., Luck R.J., Jamieson C.W.: Small doses of subcutaneous sodium heparin in preventing deep venous thrombosis after major surgery. Lancet 2:890, 1972. Gordon-Smith I.C., Grundy D.J., LeQuesne L.P., Newcombe J.F., Bramble 59

F.J.: Controlled trial of two regimens of subcutaneous heparin in prevention of postoperative deep venous thrombosis. Lancet 1:1133, 1972. Gallus A.S., Hirsh J., Tuttle R.J., Trebilcock R., O’Brien S.E., Carroll J.J., Minden J.H., Hudecki S.M.: Small subcutaneous doses of heparin in prevention of venous thrombosis. N. Engl. J. Med. 288:545,1973. van Vroohoven T.J., van Zijl J., Muller H.: Low-dose subcutaneous heparin versus oral anticoagulants in the prevention of postoperative deep-venous thrombosis: A controlled clinical trial. Lancet 2:375, 1974. Propsting J., Williams O., Stathis M., McCaffrey J.F.: The prophylaxis of deep vein thrombosis with low-dose heparin: A trial. Aust. N.Z. J. Surg. 44:289, 1974. Covey T.H., Sherman L., Baue A.E.: Low-dose heparin in postoperative patients. Arch. Surg. 110:1021, 1975. Strand L., Bank-Mikkelson O.K., Lindewald J.: Small heparin doses as prophylaxis against deep-vein thrombosis in major surgery. Acta Chir. Stand. 141:624, 1975. Gallus A.S., Hirsh J., O’Brien S.E., McBride J.A., Tuttle T., Gent M.: Prevention of venous thrombosis with small subcutaneous doses of heparin. J.A.M.A. 235:1980, 1976. Joffe S.: Drum nrevention of oostonerative deen vein thrombosis. Arch. _ _ Surg. 111:37,-!I976. Ballard R.M.. Bradlev-Watson P.J.. Johnson F.D.. Kennev A.. McCarthv T.G., Campbell S., Weston J.: Low’ doses of subcutaneous” heparin in the prevention of deep vein thrombosis after gynecological surgery. J. Obstet. Gynecol. Br. Commonw. 80:469, 1973. McCarthy T.G., McQueen J., Johnstone F.D., Weston J., Campbell S.: A comparison of low-dose subcutaneous heparin and intravenous dextran-70 in the prophylaxis of deep venous thrombosis after gynecological surgery. J. Obstet. Gynecol. Br. Commonw. 81:486, 1974. Casas R.E., Sanchez M.P., Arias C.R., Masip J.P.: Prophylaxis of venous thrombosis and pulmonary embolism in patients with acute traumatic spinal cord lesions. Paraplegia 15:209, 1977-78. Cerrato D., Arianc C., Fiacchino F.: Deep vein thrombosis and low dose heparin prophylaxis in neurological patients. J. Neurosurg. 49:378, 1978. Kass E.J., Sonda P., Gershon C., Fisher C.P.: The use of prophylactic low dose heparin in transurethral prostatectomy. J. Ural. 120:186, 1978. McCarthy S.T., Turner J.J., Robertson D., Hawkey C.J.: Low-dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet 2:800, 1976. Spearing G., Fraser I., Turner G., Dixon G.: Long-term self-administered subcutaneous heparin in pregnancy. Br. Med. J. 1:1457,1978. Bannar J.: Long-term self-administered heparin therapy for prevention and treatment of thromboembolic complications in pregnancy, in Kakkar V.V., Thomas D.P. (eds.): Hepurin Chemistry and Clinical Usage. London, Academic Press, 1976, pp. 247-260. Venous Thrombosis Clinical Study Group: Small doses of subcutaneous heparin in the prevention of deep vein thrombosis after elective hip operations. Br. J. Surg. 62:348, 1975. Sagar S., Nairn D., Stamatakis J.D., Maffei F.H., Higgins A.F., Thomas D.P., Kakkar V.V.: Efficacy of low-dose heparin in prevention of extensive deep-vein thrombosis in patients undergoing total-hip replacement. Lancet 1:1151, 1976. Mannucci P.M., Citterio L.E., Panajotopoulos N.: Low-dose heparin and deep-vein thrombosis after total hip replacement. Thromb. Huemost. 36:157, 1976. Schondorf T.H., Hey D.: Modified “low-dose” heparin prophylaxis to reduce thrombosis after hip joint operation. Thromb. Res. 12:155, 1977. Dechavanne M., Ville D., Viala J.J., Kher A., Faivre J., Pousset M.B., Dejour H.: Prevention of deep vein thrombosis following total hip arthroplasty: A controlled trial of heparin versus aspirin and dipyridamole, in

335.

336.

337.

338. 339.

340.

341. 342.

343.

344.

345. 346. 347.

348. 349.

350.

351.

352.

353. 354.

60

355.

356.

357.

358. 359.

360.

361. 362.

363.

364. 365. 366. 367.

368.

369. 370. 371.

372.

373.

374.

Kakkar V.V., Thomas D.P. (eds.1: Heparin: Chemistry and Clinical Usage. London, Academic Press, 1976, pp. 337-348. Scondorf T.H., Hey D.: Effectiveness of subcutaneous heparin in the prevention of thromboembolism after major hip operations. Dtsch. Med. Wochenschr. 100:2014, 1975. Morris G.K., Mitchell J.R.A.: Warfarin sodium in prevention of deep venous thrombosis and pulmonary embolism in patients with fractured neck of femur. Lancet 2:869, 1976. Hampson W.G.J., Harris F.C., Lucas H.K., Roberts P.H., McCall I.W., Jackson P.C., Powell N.L., Staddon G.E.: Failure of low-dose heparin to prevent deep-vein thrombosis after hip replacement arthroplasty. Lancer 2:795, 1974. Eva& C.M., Alfidi R.J.: Thromboembolism after total hip reconstruction. J.A.M.A. 225:515, 1973. Rogers P.H., Walsh P.N., Marder V.J., Bosake G.C., Lachman J.W., Ritchie W.G.M., Oppenheire L., Sherry S.: Controlled trial of low-dose heparin and sulfurpyrazone to prevent venous thromboembolism after operation of the hip. J. Bone Joint Surg. 60-A:758, 1970. Williams J.W., Eikman S.A., Greenberg S.H., Hewitt J.C., Lopez-Cuenca E., Jones B.P., Madden J.P.: Failure of low dose heparin to prevent pulmonary embolism after hip surgery or after the knee replacement. Ann. Sure. 188468. 1978. Cheiketts R.G., Bradley J.G.: Low-dose heparin in femoral neck fractures. Injury 542, 1974. Galasko C.S. B., Edwards D.H., Fearn D.A., Barber H.M.: The value of low dosage heparin for the prophylaxis of thromboembolism in patients with transcervical and intertrochanteric femoral fractures. Acta Orthop. &and. 47~276, 1976. Xabregas A., Gray L., Ham J.M.: Heparin prophylaxis of deep vein thrombosis in patients with a fractured neck of the femur. Med. J. Aust. 1:620, 1978. Wessler S., Gitel S.N.: Heparin: New concepts relevant to clinical use. Blood 53:525, 1979. An International Multicentre Trial: Prevention of fatal postoperative pulmonary embolism by low-doses of heparin. Lancet 2:45, 1975. Sagar S., Massey J., Sanderson J.M.: Low-dose heparin prophylaxis against fatal pulmonary embolism. Br. Med. J. 4:257, 1975. Gruber U.G., Duchert F., Fridich R., Torhorst J., Rem J.: Prevention of postoperative thromboembolism by dextran 40, low doses of heparin and xantinol nicotinate. Lancet 1:207, 1977. Bell W.R., Zuidema G.D.: Low dose heparin: Concern and perspectives. Surgery 85:469, 1979. Handley A.J.: Low-dose heparin after myocardial infarction. Lancet 2:623, 1972. Steffensen K.A.: Coronary occlusion treated with small doses of heparin. Actu Med. Stand. 186:519, 1969. Warlow C., Beattie A.G., Terry G., Ogston D., Kenmure A.C.F., Douglas A.S.: A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet 2:934, 1973. Stuart J., Failes D.G., Killingboch M.J., DeLuca C.: Prophylactic administration of low dose heparin in colorectal surgery. Dis. Colon Rectum 21:487, 1978. Taberner D.A., Pollen L., Burslem R.W., Jones J.B.: Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis. Br. Med. J. 1:272, 1978. Pollack A.V., Rosenberg I.L., Evans M.: Prevention of postoperative leg vein-thrombosis: A comparison of low-dose heparin and electrical calf stimulation, in Kakkar V.V., Thomas D.P. teds.): Heparin Chemistry and Clinical Usage. New York, Academic Press, 1976, pp. 349-360. 61

375.

Coe N.P., Collins R.E.C., Klein L.A., Bettman M.A., Shillman J.J., Shapiro R.M., Salzman E.W.: Prevention of deep vein thrombosis in urological patients: A controlled randomized trial of low-dose heparin and external pneumatic compression boots. Surgery 83:230, 1978. Sherry S.: Monitoring during low-dosage heparin prophylaxis. N. Engl. J. Med. 295:776, 1975. Rock0 J.M., Mikhail F., Trilles F., Timmes J.J.: The safety of low dose heparin prophylaxis. Am. J. Surg. 135:798, 1978. Brozovic M., Stirling Y., Abbosh J.: Plasma heparin levels after low-dose subcutaneous heparin in patients undergoing hip replacement. BF. J. Haematol. 31:461, 1975. Corrigan T.P., Kakkar V.V., Fassard D.P.: Low-dose subcutaneous heparinoptimal dose regimen. BF. J. Surg. 61:320, 1974. Kruse-Blinkenberg H.O., BechJansen P., Gormsen J.: Plasma heparin concentrations in thoracic surgery: Low dose heparin prophylaxis. &and. J. Thorac. Cardiovasc. Surg. 11:229, 1977. Gurenwich V., Nunn T., Kuriahose T., Hume M.: Hemostatic effects of uniform, low dose subcutaneous heparin in surgical patients. Arch. Intern. Med. 138:41, 1978. Stamatakis J., Sagar S., Higgins A.F., Thomas D.P., Kakkar V.V.: Heparin levels in patients undergoing hip surgery. BF. J. Surg. 63:158, 1976. String S.T., Barcia P.: Complications of small dose prophylactic heparinization. Am. J. Surg. 130:570, 1975. Hume M.T., Kuriakose T., Zuch L., Turner R.H.: ix51 fibrinogen and the prevention of venous thrombosis. AFC~. Surg. 107803, 1973. Allen N.H., Jenkins J.D., Smart C.J.: Surgical hemorrhage in patients given subcutaneous heparin as prophylaxis against thromboembolism. BF. Med. J. 1:1326, 1978. Pachter H.L., Riles T.S.: Low dose heparin: Bleeding and wound complications in the surgical patient. Ann. S&g. 186669, 1977. Hill J.. Canrini J.A.. Robbins J.L.: An unusual comnlication of minidose heparin therapy. CZii. Otihop. 118:130, 1976. Gallus P.C., Musi H.B., McGraton K.M., Stuart J.J., Hersisley H.D.: Thrombocytopenia in two patients treated with low-dose heparin. Obstet. Gynecol. 52:95, 1978. Hmshesky W.J.: Subcutaneous heparin-induced thrombocytopenia. Arch. Intern. Med. 138:1485, 1978. Kakkar V.V., Stamatakis J.D., Bentley P.G., Lawrence D., deHaas H.A., Ward V.P.: Prophylaxis for postoperative deep-vein thrombosis: Synergistic effect of heparin and dihydroergotamine. J.A.M.A. 241:39, 1979. Multicenter Trial dihydroergotamine-heparin prophylaxis of postoperative deep vein thrombosis. J.A.M.A. 251:2960, 1984. Multicenter Trial Committee: Prophylactic efficacy of low-dose dihydroergotamine and heparin in postoperative deep venous thrombosis following intra-abdominal operations. J. Vast. Surg. 1:608, 1984. Bergentz S-E: Dextran in prophylaxis of pulmonary embolism. World J. ,%Fg. 2:19, 1978. Evarts C.M., Feil E.J.: Prevention of thromboembolism disease after elective surgery of the hip, abstracted. J. Bone Joint Surg. 53:1271, 1971. Harris W.J., Salzman E.W., DeScantis R.W., Coutts R.D.: Prevention of venous thromboembolism following total hip _ replacement. J.A.M.A. _ 220:1319, 1972. Rothermel J.E., Wessinger J.B., Stinchfield F.E.: Dextran 40 and thromboembolism in total hip replacement surgery. Arch. Surg. 106:135,

376. 377. 378.

379. 380.

381.

382. 383. 384. 385.

386. 387. 388.

389. 390.

391. 392.

393. 394. 395.

396.

1973 -_ .-.

397.

McCarthy T.G., McQueen J., Johnstone F.D., Weston J., Campbell S.: A compression of low-dose subcutaneous heparin and intravenous dextran 70 in the prophylactic treatment of deep venous thrombosis after gynecological surgery. J. Gynecol. BF. Commonw. 81:486, 1974. A multi-unit controlled trial: Heparin versus dextran in the prevention of deep-vein thrombosis. Lancet 2:118, 1974.

398. 62

399.

400. 401.

402.

403. 404. 405. 406.

407.

408.

409.

410. 411.

412. 413.

414.

415. 416. 417. 418.

419. 420. 421. 422. 423.

Bergovist D., Efsing H.O.L., Hallbook T., Hedlund T.: Prophylaxis of thromboembolic complications in hip surgery: A controlled trial with lowdose heparin and dextran 70. Thromb. Huemost. 38:238, 1977. Salvati E.A., Lachiewicz P.: Thromboembolism following total hip replacement arthroplasty, abstracted. J. Bone Joint Surg. 58921, 1976. Harris W.H., Salxman E.W., Athanasoulis C.A., Waltman A.C., De&antis R.W.: Aspirin prophylaxis of venous thromboembolism after total hip renlacement. N. Enpl. J. Med. 297:1246, 1977. Clagett G.P.: Bri& K.D.F., Rosoff C.B., Schneider P.B., Salzman E.W.: Effect of aspirm on postoperative platelet kinetics and venous thrombosis. Surg. Forum 25~473, 1974. O’Brien J.R., Tuleriski, V., Ethrington M.: Two in vitro studies comparing high and low aspirin dosage. Lancet 1:399, 1971. Medical Research Council: Report of the steering committee: Effect of aspirin on postoperative venous thrombosis. Lancet 2:441, 1972. Turpie A.G.G., Hirsh J.: Platelet suppressive therapy. Br. Med. Bull. 34:183, 1978. Jennings J.J., Harris W.H., Sarmiento A.: A clinical evaluation of aspirin prophylaxis of thromboembolic disease after total hip arthroplasty. J. Bone Joint Surg. 58-A:926, 1976. McKenna R., Bachmann R., Kaushal S.P., Galante J.O.: Thromboembolic disease in patients undergoing total knee replacement, abstracted. J. Bone Joint Surg. 58:928, 1976. Atkins P, Brown I.K., Dovnie R.J., Haggart B.G., Littler J., Robb P.M., Santer G.J.. Jones I.: The value of nhenformin and ethvloestrenol in the prevention of deep venous thrombosis in patients undergoing surgery. Thromb. Haemost. 39:89, 1978. Lowe G.D.O., Campbell A.F., Meek D.R., Forbes D.C., Prentice C.R.M., Cummings S.W.: Subcutaneous ancrod in prevention of deep vein thrombosis. Lancet 1:51, 1979. A National Cooperative Study: Urokinase-Streptokinase Embolism Trial: Phase 2 results, a cooperative study. JA.MA. 229:1606, 1974. Sherry S., Bell W.R., Ducker F.H., et al. Thrombolytic therapy in thrombosis: A National Institutes of Health consensus development conference. Ann. Intern. Med. 93:141, 1980. Verstraete M.: Biochemical and clinical aspects of thrombolysis. Semin. Hematol. 15:35, 1978. Acar J., Chiche P., Samama M., de Puyfontaine O., Benaim R., Uzan C., Milochevitch R., Fanjoux J.: Thrombolytic treatment of subacute and chronic pulmonary embolism. Couer. Med. Znterne. 16:365, 1977. Acar J., de Puyfontaine O., Fanjoux J., Poisson M., Ramdane D.: Chronic pulmonary arterial emboli: Developmental characteristics and therapeutic possibilities. Couer. Med. Znterne. 16:525, 1977. Fratantoni J.C., Ness P., Simon T.L.: Thrombolytic therapy. N. Engl. J. Med. 293:1073, 1975. Genton E., Hirsh J.: Observations in anticoagulant and thrombolytic therapy in pulmonary embolism. Preg. Cardiouasc. Dis. 17:335, 1975. Simon T.L.: Thrombolytic therapy in pulmonary embolism. Vast. Surg. 11:349, 1977. Miller G.A.H., Hall R.J.C., Paneth M.: Pulmonary embolectomy heparin and streptokinase: Their place in the treatment of acute massive pulmonary embolism. Am. Heart J. 93:568, 1977. Sherry S.: Setting thrombolysis in action. Drug Ther. 2:27, 1977. Porter J.M., Goodnight S.H.: The clinical use of fibrinolytic agents. Am. J. Surg. 134:217, 1977. Kakkar V.V., Scully M.F.: Thrombolytic therapy. Br. Med. Bull. 34:191, 1978. Tillet W.S., Garner R.L.: The fibrinolytic activity of hemolytic streptococci. J. Exp. Med. 58:485, 1933. Williams J.R.B.: The fibrinolytic activity of urine. BF. J. Exp. Pathol. 32:530, 1951. 63

424.

Urokinase Pulmonary Embolism Trial: Phase 1 results, Urokinase Pulmonary Embolism Trial Study Group. J.A.M.A. 214:2163, 1970. Reference manual for abbokinase, North Chicago, Ill., Abbott Laboratories, February 1978. Browse N.L., James D.C.: Streptokinase and pulmonary embolism. Lancet 2:1039, 1964. Chesterman C.N., Biggs J.C., Morgan J., Hickie J.B.: Streptokinase therapy in acute major pulmonary embolism. Med. J. Aust. 2:1096, 1969. Miller G.A.H., Sutton G.C., Kerr I.H., Gibson R.V., Honey M.: Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br. Med. J. 2:681, 1971. Hirsh J., Hale A.G., McDonald I.G., O’Sullivan E.F., Jelniek V.M.: Comparison of the effects of streptokinase and heparin on the early rate of resolution of maior uulmonarv embolism. Can. Med. Assoc. J. 104:488. 1971. Genton E., Wolf P.: Urokinase therapy in pulmonary thromboembolism. Am. Heart J. 76:628, 1968. Tow D.E., Wagner H.N., Holmes R.A.: Urokinase in pulmonary embolism. N. Engl. J. Med. 277:1161, 1967. Sasahara A., Cannilla J.E., Belko J.S., Morse R.L., Criss A.M.: Urokinase therapy in clinical pulmonary embolism. N. Engl. J. Med. 277:1168, 1967. Sautter R.D., Emanuel D.A., Fletcher F.W., Wenzel F.J., Matson J.I.: Urokinase for the treatment of acute pulmonary thromboembolism. J.A.M.A. 202:215, 1967. Sharma G.V.R.K., Burleson V.A., Sasahara A.A.: Effect of thrombolytic therapy on pulmonary-capillary blood volume in patients with pulmonary embolism. N. Engl. J. Med. 303:842, 1980. Tibbutt D.A., Davies J.A., Anderson J.A., Fletcher E.W.L., Hamill J., Holt J.M., Thomas M.L., Lee G.J., Miller G.A.H., Sharp A.A., Sutton G.C.: Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. BF. Med. J. 1:343, 1974. Ly H.O., Arnesen A., Eie H., Ho1 R.: A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med. &and. 203:465, 1978. Kakkar V.V., Howe C.T., Laws J.W., Flanc C.: Late results of treatment of deep vein thrombosis. Br. Med. J. 1:810, 1969. Kakkar V.V.: Results of streotokinase theranv _” in deeo venous thrombosis. Postgrad. Med. J. 49:60, 1973. Arnesen H., Heilo A., Jakobsen E., Ly B., Skaga E.: A prospective study of streptokinase and heparin in the treatment of deep vein thrombosis. Acta Med. Stand. 203:457, 1978. Arnesen H., Hoiseth A., Ly B.: Streptokinase or heparin in the treatment of deep vein thrombosis. Actu Med. Stand. 211:65, 1982. Johnansson L., Nylander G., Hedner U., Nilsson I.M.: Comparison of streptokinase with heparin: Late results in the treatment of deep vein thrombosis. Actu Med. Stand. 206:93, 1979. Marder V.J.: The use of thrombolytic agents: Choice of patient, drug administration, laboratory monitoring. Ann. Intern. Med. 90:802, 1979. Bell W.R., Simon T.L., Stengle J.M., Sherry S.: The Urokinase-streptokinase Pulmonary Embolism Trial (phase II) results. Circulation 50:1070, 1974. Dickie K.J., DeGroot W.J., Cooley R.N., Baird T.P., Guest M.M.: Hemodynamic effects of bolus infusion of urokinase in pulmonary thromboembolism. Am. Rev. Resp. Dis. 109:48, 1974. Barberena J.: Intraarterial infusion of urokinase in the treatment of acute pulmonary thromboembolism: Preliminary observation. Am. J. Roentgenol. 140:883, 1983. Brochier M., Planiol T., Griguer P., Raynaud P., Fauchier J.P., Charbonnier B., Latour F., Pellois A.: Value of lysl-plasminogen-urokinase sequential treatment in thromboembolytic therapy. Coeur. Med. Znterne. 16:513, 1977.

425. 426. 427. 428.

429.

I

430. 431. 432. 433.

434.

435.

436.

437. 438. 439.

440. 441.

442. 443.

444.

445.

446.

64

_

447.

448.

449. 450. 451.

452. 453.

454. 455. 456. 457. 458. 459. 460. 461. 462. 463. 464. 465. 466.

467.

468.

469.

470. 471. 472. 473.

Cade J.F., Hirsh J., Regoeczi R., Gert M., Buchanan M.R., Hynes D.M.: Resolution of experimental pulmonary emboli with heparin and streptokinase in different dosage regimens. J. Clin. Invest. 541782, 1974. Vujic I., Young J.W.R., Gobien R.P., Dawson W.T., Liebscher L., Shelley B.E.: Massive pulmonary embolism: Treatment with full heparinization and topical low dose streptokinase. Radiology 148:671, 1983. Bell W.R., Meek A.G.: Guidelines for the use of thrombolytic agents, N. Engl. J. Med. 301:1266, 1979. Marder V.J.: Are we using fibrinolytic agents often enough? editorial notes. Ann. Intern. Med. 93:136, 1980. Totty W.G., Roman0 T., Benian G.M., Gilula L.A., Sherman L.A.: Serum sickness following streptokinase therapy. Am. J. Roentgenol. 138:143, 1982. Sharma G.V.R.K., Cella G., Parisi A.F., Sasahara A.A.: Thrombolytic therapy. N. Engl. J. Med. 306:1268, 1982. Holm H.A., Finnanger B., Hartmann A., Laerum F., Hren O., Rudd T.E., Stray N., Wolland T.: Heparin treatment of deep venous thrombosis in 280 patients: Symptoms related to dosage. Acta Med. &and. 215:47, 1984. Thomas D.P.: Heparin in the prophylaxis and treatment of venous thromboembolism. Semin. Hematol. 15:1, 1978. Rosenberg R.D.: Heparin, antithrombin, and abnormal clotting. Ann. Rev. Med. 29:367, 1978. Pollak C.W., Sparks F.C., Barker W.F.: Pulmonary embolism: An appraisal __ of therapy in 516 cases. Arch. Surg. 107:66, 1973: Colman R.W., Rubin R.N.: Update on pulmonary embolism: Modern management D.M. 29:1, 1982. Deykin D.: The use of heparin. N. Engl. J. Med. 290:937, 1969. Barritt D.W.. Jordan S.C.: Anticoagulant drugs in the treatment of ~ulmonary embolism. Lancet 1:1309, 1960. Coon W.W., Willis P.W., Symons M.J.: Assessment of anticoagulant treatment of venous thromboembolism. Ann. Surg. 170:559, 1969. Coon W.W., Willis P.W.: Recurrence of venous thromboembolism. Surgery 73:823, 1973. Coon W.W., Willis P.W.: Thromboembolic complications during anticoagulation therapy. Arch. Surg. 105:209, 1972. Genton E.: Guidelines for heparin therapy. Ann. Intern. Med. 80:77, 1974. Wessler S.: Medical management of venous thrombosis. Ann. Rev. Med. 27:313, 1976. Salzman E.W., Deykin D., Shapiro R.M., Rosenberg R.: Management of heparin therapy. N. Engl. J. Med. 292:1046, 1975. Basu D., Gallus A., Hirsh J., Cade J.: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N. Engl. J. Med. 287:324, 1972. Reno W.J., Rotman M., Grumbine F.C., Dennis L.H., Mohler E.R.: Evaluation of the BART test (a modification of the whole-blood activated recalcification time test) as a means of monitoring heparin therapy. Am. J. Clin. Pathol. 61:78, 1974. Ray P.K., Harper T.A.: Comparison of activated recalcification and partial thromboplastin test as controls of heparin therapy. J. Lab. Clin. Med. 77:901, 1971. Gulliani G.L., Hyun G.H., Litten M.B.: Blood recalcification time: A simple and reliable test to monitor heparin therapy. Am. J. Clin. Pathol. 65:390, 1976. Halterslay P.G.: Progress report: The activated coagulation time of whole blood (ACT). Am. J. Clin. Pathol. 66:899, 1976. Penner J.A.: Experience with a thrombin clotting time assay for measuring henarin activity. Am. J. Clin. Pathol. 61:645. 1974. O’Shea M.J., Fiutte P.T., Pannell G.M.: Laboratory control of heparin therapy. J. Clin. Pathol. 24:542, 1971. Stewart C.: The laboratory control of heparin therapy. Med. J. Aust. 1:1160, 1971. 65

474.

Colman R.W., Oxley L., Gannusa P.: Statistical comparison of the automatic activated partial thromboplastin time and the clotting time in the regulation of henarin therapy. Am. J. C&z. Path&. 53904. 1970. M&der V.J.: A-simple technique for the measurement of plasma heparin concentration during anticoagulant therapy. Thromb. Diath. Haemorrah. 24:230, 1970. Handley A.J.: Heparin therapy: A simple test of control. Am. J. Clin. Puthol. 27:250, 1974. Soloway H.B., Bellneau R.R., Grayson J.W., Butler T.J.: The in vitro effect of heparin on the activated partial thromboplastin time. Am. J. Clin. Pathol. 58:405, 1972. Glynn M.F.: Heparin monitoring and thrombosis. Am. J. Clin. Pathol. 71:397, 1979. Glazier R.L., Crowell E.B.: Randomized prospective trial of continuous vs. intermittent heparin therapy. JAMA. 2361365, 1976. Mant J.J., O’Brien B.D., Thong K.L., Hammond G.W., Birthwhistle R.V., Grace M.G.: Hemorrhagic complications of heparin therapy. Lancet 1:1113, 1977. Wilson J.R., Lampman J.: Heparin therapy: A randomized prospective study. Am. Heart J. 97:155, 1979. Wilson J.E., Bynum L.J., Parkey R.W.: Heparin therapy in venous thromboembolism. Am. J. Med. 70:808, 1981. Porter J., Jick H.: Drug-related deaths among medical inpatients. J.A.M.A. 237:879, 1977. Jick H., Slone D., Borda I.T., Shapiro S.: Efficacy and toxicity of heparin in relation to age and sex. N. Engl. J. Med. 2’79:284, 1968. Lieberman A., Hass W.K., Pint R., Isorm W.O., Kupesmith M., Bear G., Chase R.: Intracranial hemorrhage and infarction in anticoagulant patients with prosthetic heart valves. Stroke 9:81, 1978. Willbanks O.L., Fuller C.H.: Femoral neuropathy due to retroperitoneal bleeding. Arch. Intern. Med. 132:83, 1973. Spiegel P.G., Meltsar J.L.: Femoral-nerve neuropathy secondary to anticoagulation, abstracted. J. Bone Joint Surg. 56:425, 1974. Stem M.B., Speigel P.: FemoraI neuropathy as a complication of heparin anticoagulation therapy. Clin. Or&p. 106:140, 1975. Wells J., Templeton J.: Femoral neuropathy associated with anticoagulation therapy. &in. Orthop. 124155, 1975. Neviaser R.J.. Adams J.P.. Mav G.I.: Comnlications or arterial mmcture in anticoagulated patients, abstr&.ed. J. Boie Joint Surg. 58218: 1976. Leehey D., Gant C., Lim V.: Heparin-induced hypoaldosteronism. JAMA. 246:2189, 1981. Levine L.E., Bernstein J.E., Soltani K., Medenica M.M., Yung C.: Heparininduced cutaneous necrosis unrelated to injection sites. Arch. Dermntol. 119:400, 1983. Lute E.A., Futrell J.W., Wilgis F.S., Hoopes J.E.: Compression neuropathy following brachial arterial puncture in anticoagulated patients. J. Trauma 16:717, 1976. Rostand R.A., Feldman R.L., Block E.R.: Massive hemothorax complicating heparin anticoagulation for pulmonary embolus. South. Med. J. 70:1128, 1973. Lee R.A., Kaxmier F.J.: Ovarian hematoma complicating anticoagulant therapy. Mayo Clin. Proc. 5219, 1977. Browne T.R., Wray S.H.: Subco@nctival hemorrhage as a cmnpkation of opthalmodynamometry in anticoagulated patient. Am J. Gp&n!m&. 76:981,1973. Thompson R.C., Ludewig R.M., Wangmr&e n S.L., Rudolf L.M.: Effects of heparin on wound healing. Surg. Gywc& Obstet. 134:22,1972. n L.E., Cervi-Skinner S.I.: AntiPortnay G.I., Vagenakis A.G., Braver-ma coagulant therapy and acute adrenal insufficiency. Ann. Intern. Med. 81:115, 1974.

475.

476. 477.

478. 479. 480.

481. 482. 483. 484. 485.

486. 487. 488. 489. 490. 491. 492.

493.

494.

495. 496.

497. 498.

66

499. 500. 501.

502. 503. 504.

505. 506. 507.

508.

509. 510. 511. 512. 513.

514. 515. 516. 517. 518. 519. 520. 521. 522. 523. 524. 525. 526.

O’Tolle R.D.: Heparin: Adverse reaction. Ann. Intern. Med. 79:759, 1973. King D.J., Kelton J.G.: Heparin associated thrombocytopenia. Ann. Intern. Med. 100535, 1984. Bell W.R., Tomasulo P.A., Alving B.M., Duffy T.P.: Thrombocytopenia occurring during the administration of heparin. Ann. Intern. Med. 85:155, 1976. Bell W.R., Royal1 R.M.: Heparin-associated thrombocytopenia: A comparison of three heparin preparations. N. Engl. J. Med. 303:902, 1980. Cines D.B., Kaywin P., Bina M., Tomaski A., Schreiber A.D.: Heparin-associated thrombocytopenia. N. Engl. J. Med. 303:788, 1980. Chong B.H., Pitney W.R., Castaldi P.A.: Heparin-induced thrombocytopenia: Association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet 2:1246, 1982. Gollub S., Ulin A.W.: Heparin-induced thrombocytopenia in man. J. Lab. Clin. Med. 59:430, 1962. Natelson E.A., Lynch E.C., Alfrey C.P., Gross J.B.: Heparin induced thrombocytopenia. Ann. Intern. Med. 74:1121, 1969. Rhodes G.R., Dixon R.H., Silver D.: Heparin induced thrombocytopenia with thrombotic and hemorrhagic manifestations. Surg. Gynecol. Obstet. 136:409, 1973. Fratantoni J.C., Pollet F., Gralnick H.R.: Heparin-induced thrombocytopenia: Confirmation of diagnosis with in vitro methods. Blood 45:395, 1975. Babock R.B., Dumper C.W., Scharfinan W.B.: Heparin-induced immune thrombocvtonenia. N. ET&. J. Med. 2951237. 1976. Bell W.R:: T‘hrombocytop&ia occurring during heparin therapy. N. Engl. J. Med. 295:276, 1976. Rhodes G.R., Dixon R.H., Silver D.: Heparin induced thrombocytopenia. Ann. Surg. 186:752,1977. Nelson JYC., Lemer R.G., Goldstein R., Cogin N.A.: Heparin induced thrombocvtonenia. Arch. Intern. Med. 138:548. 1978. Green D.: Harris K., Reynolds N., Roberts M., Patterson R.: Heparin immune thrombocytopeniaf Evidence for a heparin-platelet complex as the antigenic determinant. J. Ldb. Clin. Med. 91:167. 1978. Kleii H.G., Bell W.R.: Disseminated intramuscular coagulation during heparin therapy. Ann. Intern. Med. 80:477, 1974. Bell W.R., Anderson N.S., Anderson A.O.: Heparin-induced coagulopathy. J. Lab. Clin. Med. 89:741, 1977. Zucker M.B.: Effect of heparin on platelet function. Thromb. Diath. Huemorrh. 33:63, 1974. Gervin A.: Complications of heparin therapy. Surg. Gynecol. Obstet. 140:789, 1975. Weismann R.E., Tobin R.W.: Arterial embolism occurring during systemic heparin therapy. Arch. Surg. 76:219, 1958. Baird R.A., Convery F.R.: Arterial thromboembolism in patients receiving systemic heparin therapy. J. Bone Joint Surg. 59-A1061, 1977. Aaro L.A., Juergens J.L.: Thrombophlebitis associated with pregnancy. Am. J. Obstet. Gyneco1.,199:1128, 1971. Hall J.G., Pauli R.M., W&son K.A.: Maternal and fetal sequelae of anticoagulation during pregnancy. Am. J. Med. 68:122, 1980. Hirsh J., Cade J.F., Gallus A.S.: Anticoagulants in pregnancy: A review of indications and complications. Am. Heart J. 83:301, 1972. Bissell S.M.: Pulmonary thromboembolism associated with gynecologic surgery and pregnancy. Am. J. Obstet. Gynecol. 128:418, 1977. Deykin D.: War&in therapy. N. Engl. J. Med. 283:691,800, 1970. StenfIo J., Ganrot P.O.: Binding of Ca2+ to normal and dicoumarol induced prothrombin. Bioch.em. Biophys. Res. Commun. 50:98, 1973. Wessler S., Gitel S.N.: Rethrombosiswarfarin or low-dose heparin. N. Engl. J. Med. 301:889, 1979. 67

527.

Bynum L.J., Wilson III J.E.: Low dose heparin therapy in the long-term management of venous thromboembolism. Am. J. Med. 67:553, 1979. Hull R., Delmore T., Genton E., Hirsh J., Gent M., Sackett D., McLaughlin D., Armstrong P.: Warfarin sodium versus low dose heparin in the-long term management of venous thrombosis. N. Ewl. J. Med. 301:855. 1979. Wessler S.,Gitel S.: Warfarin from bedside & bench. N. Engl. ‘J. Med. 311:645, 1984. Deykin D.: Current status of anticoagulant therapy. Am. J. Med. 72:659, 1982. McNarmara M.F., Creasy J.K., Takaki H., Conn J., Yao J.S.T., Bergan J.J.: Vena caval surgery to prevent recurrent pulmonary embolism, in Bergan J.J., Yao J.S.T. (eds.): Venous Problems. Chicago, Year Book Medical Publishers, 1978, pp. 319-331. Silver D., Sabiston D.C.: The role of vena caval interruption in the management of pulmonary embolism. Surgery 77:1, 1975. Gardner A.M.N.: Inferior vena caval interruption in the prevention of fatal pulmonary embolism. Am. Heart J. 95:679, 1978. Greenfield L.J.: Techniques for vena caval interruption and pulmonary embole&my. World J. Surg. 2:45, 1978. Mobin-Uddin K.: The intracaval umbrella in prevention of pulmonary embolism, in Bergan J.J., Yao J.S.T. (eds.1: Venous Problems. Chicago, Year Book Medical Publishers, 1978, pp. 333-346. Cordoba Senties A., Carrera N.F., Gordillo O.G.: Inferior vena cava ligation versus the Mobin-Uddin filter for prevention of recurrent pulmonary embolism. Znt. Surg. 62:420, 1977. Fuller W.D., McDonough J.J., Altemeir W.A.: Clinical experience with vena caval filters. Arch. Surg. 106:582, 1973. Hunter J.A., Dye W.S., Javid J., Najafi H., Goldin M.D., Serry C.: Permanent transvenous balloon occlusion of the inferior vena cava. Arch. Surg. 186:491, 1977. Greenfield L.J., Peyton R., Crute S., Barnes R.: Greenfield vena caval filter experience. Arch. Surg. 116:1451, 1981. Bomalaski J.S., Martin G.J., Hughes R.L., Yao J.S.: Inferior vena cava interruption in the management of pulmonary embolism. Chest 82:767, 1982. Gomez G.A., Cutter B.S., Wheeler H.B.: Transvenous interruption of the inferior vena cava. Surgery 93:612, 1983. Greenfield L.J., Zocco J., Wilk J., Schroeder T.M., Elkins R.C.: Clinical experience with the Kim-Ray greenfield vena caval filter. Ann. Surg. 185:692, 1977. Askew A.R., Gardner A.M.N.: Long-term follow-up of partial caval occlusion by clip. Am. J. Surg. 140:441, 1980. Wilk J.D., Zocco J.J., Crute S.L., Greenfield L.J.: Hemodynamic and respiratory effects of transvenous catheter embolectomy for massive embolism. J. Surg. Res. 231387, 1977. Greenfield L.J., Zocco J.J.: Intraluminal management of acute massive pulmonary thromboembolism. J. Thorucic Cardiouasc. Surg. 77:402, 1979. Stewart J.R., Greenfield L.J.: Transvenous vena caval filtration and pulmonary embolectomy. Surg. Clin. North Am. 62:411, 1982. Krellenstein D.J., Bryan-Brown C.W., Fayemi A.O., Geller S.A., Hanns J., Barron S., Pierce E.C.: Extracorporal membrane oxygenation for massive pulmonary thromboembolism. Ann. Thoruc. Surg. 23:421, 1977. Jardin F., Gurdian F., Blanchet F., Margiaraz A.: Massive pulmonary embolism with circulatory failure. J. Z’horuc. Cardiouasc. Surg. 76:252, 1978. Cleveland J.E.. Lenenson I.M.. Fridman J.: Successful management of massive pulmonary embolism occurring during cardiopulmonary bypass for mitral valve replacement. Chest 73:236, 1978. Donaldson G.A., Williams C., Seannell J.G., Shaw R.A.: A reappraisal of the application of the Trendelenburg operation to massive fatal embolism. N. Engl. J. Med. 268:171, 1963.

528.

529. 530. 531.

532. 533. 534. 535.

536.

537. 538.

539. 540. 541. 542.

543. 544.

545. 546. 547.

548. 549.

550.

68

551. 552. 553. 554.

555. 556. 557.

558.

559.

560. 561.

562. 563.

564. 565. 566.

567. 568. 569. 570. 571. 572.

Sautter R.D.: Massive pulmonary thromboembolism. J.A.M.A. 194:104, 1965. Makey A.F., Bliss B.P.: Pulmonary embolectomy. Lancet 2:1155, 1966. Scannel J.G.: The surgical management of acute massive pulmonary embolism. Prog. Cardiovasc. Dis. 9:488, 1967. Cross F.S., Mowlem A.: A survey of the current status of pulmonary embolectomy for massive pulmonary embolism. Circulation (suppl. 1) 35:86, 1967. Tschirkov A., Krause, E., Elert, O., Satler P.: Surgical management of massive pulmonary embolism. J. Thorac. Cardiovasc. Surg. 75730, 1978. Saylam A., Melo J.Q., Ahanad A., Chapman R.D., Wood J.A., Starr A.: Pulmonary embolectomy. West. J. Med. 128:377, 1978. Berger R.H.: The advantage of embolectomy, in Inglefinger F.G., Ebert R.V., Finland M., Relman A.J. (eds.): Controversies in Internal Medicine II. Philadelphia, W.B. Saunders Co., 1974, pp. 303-310. Sautter R.D.: The effectiveness of thrombolytic therapy, in Inglefinger F.G., Ebert R.V.. Finland M.. Relman A.J. (eds.1: Controversies in Internal Medicine II. Philadelphia, W.B. Saunders Co., 1974, pp. 293-302. Mattox K.L., Feldtman R.W., Beall A.C., DeBakey M.E.: Pulmonary embolectomy for acute massive pulmonary embolism. Ann. Surg. 195:726, 1982. Sasahara A.A., Barsamian E.M.: Another look at pulmonary embolectomy, editorial. Ann. Thoracic. Surg. 16:317, 1973. Sabiston D.C., Wolfe W.G., Gldham H.N., Wechsler A.S., Crawford F.A., Jones K.W., Jones R.H.: Surgical management of chronic pulmonary embolism. Ann. Surg. 185:699, 1977. Hall R.C., Sutton G.C., Kerr I.H.: Long term prognosis of treated acute massive pulmonary embolism. Br. Heart J. 39:1128, 1977. Sutton G.C., Hall R.J.C., Kerr I.H.: Clinical course and late prognosis of treated subacute massive, acute minor and chronic pulmonary thromboembolism. Br. Heart J. 39:1135, 1977. Tow D.E., Wagner H.N.: Recovery of pulmonary arterial blood flow in patients with pulmonary embolism. N. Engl. J. Med. 276:1053, 1967. de Soyza N.D.B., Murphy M.L.: Persistent post-embolic pulmonary hypertension. Chest 62:665, 1972. Paraskos J.A., Adelstein S.J., Smith R.E., Richman F.D., Grossman W., Dexter L., Dalen J.E.: Late prognosis of acute pulmonary embolism. N. Engl. J. Med. 289:55, 1973. Poe N.D., Swanson L.A., Dove E.K., Taplin G.V.: The course of pulmonary embolism. Am. Heart J. 73:582, 1967. Phear D.: Pulmonary embolism: A study of late prognosis. Lancet 2:832, 1960. Duner H., Pernow G., Rigner K.G.: The prognosis of pulmonary embolism. Acta Med. &and. 168:381, 1960. What happens to clots in the lungs? Lancet 1:194, 1978. Barritt D.W., Jordan SC.: Clinical features of pulmonary embolism. Lancet 1:729, 1961. Alpert J.S., Smith R., Carlson J., Ockene I.S., Dexter L., Dalen J.E.: Mortality in patients treated for pulmonary embolism. J.A.M.A. 236:1477, 1976.

SELF-ASSESSMENT

ANSWERS

1. A thrombin time is used to monitor thrombolytic therapy, and if not available, an activated partial thromboplastin time can be used. 2. Active bleeding-at any site or central nervous system dam69