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Disseminated Intravascular Coagulation in the Urologic Patient
Ta:s ,Jocr-:NAL OF UR01-cGv Copyright© 1976 ';_'he VVilliams
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DISSEMINATED INTRAVASCULAR COAGULATION IN THE UROLOGIC PATIENT MICHAEL L. PERGAMENT, * WILLIAM R. SWAIM
AND
CLYDE E. BLACKARD
From the Departments of Urologic Surgery, Laboratory Medicine and Pathology, and Medicine, University of lvlinnesota Health Sciences Center and the Veterans Administration Hospital, Minneapolis, l\1innesota
ABSTRACT
Gram-negative septicemia and metastatic prostatic cancer are frequent causes of disseminated intravascular coagulation, The clinical manifestations of this condition as well as the laboratory data vary considerably, depending on the patient's compensatory mechanisms in relation to the magnitude and duration of the thromboplastin or endotoxin release. Treatment centers primarily on correcting the underlying disorder. Secondly, deficient clotting factors and platelets should be replaced in the appropriate patient, Heparinization is often unnecessary, The use of drugs that inhibit the ~v,~Tnnh,,a mechanism is contraindicated in disseminated intravascular
Disseminated intravascular coagulation is an acquired coagulopathy occurring as a complicating event during the course of another disease process. McKay aptly termed disseminated intravascular coagulation as an intermediary mechanism of disease. 1 It is not a separate disease entity but rather a pathophysiologic response to an underlying disorder that activates the clotting mechanism with capabilities of thron1botic as well as hemorrhagic manifestations. The term disseminated intravascular coagulation may be misleading in that the clotting process often is not disseminated but rather localized to 1 or a few organs. 2 The products of the subsequent local fibrinolytic reaction are then disseminated the circulation. The entities shown capable of resulting in intravascular coagulation cover the complete spectrum of human disease with new causes continually being identified. 3 Two diseases shown to be common causes of disseminated intravascular coagulation are encountered often in the practice. Bacterial a of urinary tract instrumentation, almost half of the with acute disseminated intravascu.lar Colman and associates. 4 In Straub's review of chronic disseminated intravascular cancer. 5 be familiar with the various aspects of this pathologic process. Unfortunately, the pathogenesis of disseminated intravascular coagulation has been understood in the past and even today many mechanisms resulting in the clinical and laboratory findings are unknown, 6 Consequently, treatment of these patients often has been unsatisfactory. We herein review the current literature regarding pathogenesis, clinical spectrum, laboratory methods and treatment of disseminated intravascular coagulation, which are of importance to the clinical urologist, Several approaches to therapy will be illustrated by 4 patients with common urologic problems and Accepted for publication December 5, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * Requests for reprints: Department of Urologic Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.
clinical manifestations to be related to an associated disseminated intravascular coagulation state, CASE REPORTS
Case 1. H. a 63-year-old man, was hospitalized with complaints of abdominal pain associated with a weight loss during the previous 8 months. The patient described a weak stream, nocturia and urinary urgency. Physical examination was normal except for an enlarged, nodular, firm prostate. A chest radiogram revealed lesions involving multiple ribs, Open rib biopsy showed differentiated, clear cell adenocarcinoma. Afterward, the patient had slow bc1t persistent bleeding from the biopsy site, An excretory urogram (IVP) showed partial right ureterovesical obstruction. Total acid phosphatase was 53 international units per liter (LU. !.-normal Oto 9) with a fraction of 41 I.U. per l. 0 to 2). The alkaline was 175 I.U, per l. (normal 24 to 96). revealed an prostate with extension of The next the and the onset of tract. At this time the clinical picture was data were to be compatiwith acute disseminated intra.vascular (see table). A significant growth of Escherichia coli was cultured from the urine the day after cystoscopy. A treatment program was which included antibiotics, fresh frozen plasma, 1,500 units sodium heparint intravenously every 4 hours for 7 days and high dose estrogen administration. The patient eventually recovered with complete correction of the coagulation studies. Comment: This case illustrates a common pattern of presentation of disseminated intravascular coagulation in the urologic patient. The clinical and laboratory findings were consistent with a pre-existing, low grade, chronic disseminated intravascular coagulation associated with stage IV prostatic
t Lipo-hepin,
Riker Laboratories, Inc., Northridge, California 91324.
2
PERGAMENT, SWAIM AND BLACKARD
Laboratory data Pt.
HK
Day After Admission 0 13 19 25 26
29 33
Event/freatment
Platelet Count (No.Imm.')
PT* (12-13 sec.)
PTTt (35-45 sec.)
TT:j: (12-17 sec.)
Fibrinogen (200-400 mg./dl.)
Factor V (%normal)
Staphylococcal Clump Titer ( < 10 µg./ml.)
SDPS§ (-24 hrs.)
198,000
16
159,000
17
66
19
152
92
128
+½
83,000
18
56
29
91
43
260
+½
77,000 181,000
13 13
44 37
17 16
168 242
105 150
260 64
+½
Rib biopsy Cystoscopy Sepsis, antibiotics, heparin, fresh frozen plasma Estrogen
-½ +24
CR
0 2
3 7
Decompressive laminectomy Fresh frozen plasma, platelet concentrates, fresh whole blood Same as day 2
11 27,000
19
66
21
45
25
660
+½
23,000 35,000
13 11
34 29
15 15
166 272
50 94
266 32
+½ -1/2
-24 GR
RB
0 3
4 7 0
Prostatectomy, cryoprecipitate, fresh frozen plasma, fresh whole blood
Urethral false passage, suprapubic cystostomy, antibiotics, fresh frozen plasma
1 3
103,000
10 17
35 Unmeasurable
17 39
11 12
16 17 49
34 11
85,000 90,000 150,000
18
38 32 72
102,000 93,000
13 11
41 36
27
52 100
400
323 10
* PT-prothrombin time.
t PTT-partial thromboplastin time. :j: TT-thrombin time. § SOPS-serial dilution protamine sulfate.
cancer that had advanced to an acute bleeding diathesis after a septic episode related to urinary tract instrumentation. The underlying disorders were treated with antibiotics and estrogen therapy. Heparinization and clotting factor replacement also were used in the management of this patient. A rapid improvement in his clinical condition occurred and, therefore, plasma administration was stopped after 1 unit. Anticoagulation was initially believed to be necessary because of the fulminant nature of the bleeding diathesis and was continued until the degradation products returned toward normal. Case 2. C. R., a 53-year-old man with known stage IV adenocarcinoma of the prostate, was hospitalized with acute paraplegia. He denied a bleeding tendency. A lumbar myelogram showed an incomplete epidural block. During decompressive laminectomy tumor tissue was found around the spinal canal with complete replacement of the third vertebral body, and infiltration into the paraspinal muscles and retroperitoneal space. A large amount of this metastatic tissue was removed. Despite receiving 3 units of blood intraoperatively and 4 more during the next 24 hours, the hematocrit decreased from 34 to 16 per cent. During this time bleeding continued from the operative site. Coagulation studies 36 hours postoperatively showed values compatible with acute disseminated intravascular coagulation (see table). The patient was treated with 7 units of fresh frozen plasma and 16 platelet concentrates with correction of clotting studies during the next 24 hours. Renal failure resolved during the following 2 weeks with conservative fluid and electrolyte management. During the next month neurologic function in the lower extremities partially returned. The coagulation studies have remained normal. Case 3. G. R., a 65-year-old man, was hospitalized with a 4-month history of obstructive voiding symptoms. Physical
examination was normal except for an enlarged, hard, right prostatic lobe. Laboratory data including acid phosphatase were normal. The IVP, metastatic bone survey and bone marrow biopsy were all normal. Open perinea! prostatic biopsy revealed adenocarcinoma and the patient underwent radical perineal prostatectomy. Immediately after the operative procedure excessive hematuria was noted. Coagulation studies were all abnormal, being compatible with acute disseminated intravascular coagulation (see table). The laboratory values returned to normal during the next 12 hours, while 20 units of cryoprecipitate and 2 units of fresh frozen plasma were being administered. Convalescence was uneventful. Pathologic examination showed carcinoma involving the prostatic capsule and both seminal vesicles. Comment: Manipulation of prostatic tumor tissue at the metastatic site during decompressive laminectomy (case 2) and at the primary site during radical perinea! prostatectomy (case 3) possibly resulted in the bleeding diathesis in these patients. These episodes were presumed to be owing to the sudden release of thromboplastic material into the circulation. Neither patient had a bleeding tendency, nor abnormal clotting studies prior to the operation. The onset of bleeding in both cases correlated best with the surgical event that involved considerable manipulation of tumor tissue. No other apparent causes of disseminated intravascular coagulation, such as infection, shock or acidosis, could be documented. Both episodes resolved spontaneously, requiring only clotting factor and platelet replacement. Case 4. R. B., a 67-year-old man, was initially seen for evaluation of obstructive voiding symptoms. Urethral false passage occurred while obtaining a voiding cystourethrogram. The patient had a clinical picture suggestive of sepsis and characterized by chills, fever to 102F, cyanosis and shock. After
3
DISSEJ\1HNATED INT'RA\li':.SCUL/:,Jl COAGULATION
resuscitation with grrL nate* intravenously and cystostomy was nP'rtnrm without unusual bleeding, Postopthe preoperative coagulation studies showed results consistent with acute disseminated intravascular (see table) - The patient was believed to be in eminent bleeding and was treated with fresh frozen plasma, Coagulation tests returned to normal the day - Preoperative blood and urine cultures were sterile, Comment: This case illustrates the unusual finding of laboratory evidence suggesting acute disseminated intravascular coagulation after an acute shock state in a patient who did not clinically decompensate even during the operation, Correction of the shock state, high dose steroids and clotting factor replacement were believed to be important factors in maintaining adequate hemostasis, HISTORICAL BACKGROUND
Intravascular clotting produced by the infusion of thromboplastic material has been recognized in experimental animals for almost 100 years, 7 - 9 Although acute intravascular coagulation syndromes were induced occasionally in animals during the early 1900s, no obvious clinical situation was published until the late 1940s, 10 At that time it was shown that a remarkable parallel existed between induced intravascular coagulation in animals and certain bleeding states associated with obstetric complications, especially abruptio placenta and dead fetus syndrome, In 1930 attention was first turned to a coagulation defect as a cause of the bleeding diathesis in patients with prostatic cancer, 11 and Trautwein's patient had widespread cancer of the prostate associated with a severe bleeding diathesis and hypofibrinogenemia, They incorrectly ascribed the depressed fibrinogen level to impaired synthesis by the bone marrow, In 1953 Tagnon and associates demonstrated that low fibrinogen levels were associated with marked fibrinoin the blood and tumor cells of these patients, postulating release of a fibrinolytic enzyme directly into the circulation from the tumor cells, 12 Their theory and subsequent confirming reports during the next 15 years 13 - 14 formed the basis of a notion still prevalent today, that is that bleeding diathesis is owing to the release of fibrinolysins or fibrinoactivators into the circulation with subsequent enzymatic breakdown of fibrinogen and other clotting factors, The concept of the hemostatic defect being caused by intravascular coagulation arose in 1959, Rapaport and Chapman with metastatic prostatic cancer and hypofibrinogenernia coexisted fibrinolysis, 15 In 1967 Straub and associates on a patient with metastatic carcinorna of the prostate, decreased levels and systemic fibrinolysis, 16 The was repeatedly abolished after suggesting that this was These reports and others 17 - 19 attested to fibrinolysis as a ,-e,cu,C1u,,uv physiologic, mechanism in patients with disseminated intravascular to prostatic cancer, Primary fibrinolysis rarely has been documented during the last decade, 20
, gro~p of
disorders, clinical Ln&.nifestations and data, Acute disseminated intravascular coaguiation is most commonly seen secondary to septicemia,• although it may occur following other sudden catastrophic events such as trauma, shock, burns, abruptio ,-, ..~v,,rn,~, amniotic fluid embolism and others, The initiating or triggering event may involve either the rapid release of thromboplastic materials or endotoxin and then be perpetuated by hypoxia and acidosis if shock is present- Chronic disseminated intravascular coagulation is often assumed to be associated with the gradual release of thromboplastic substances as in widespread malignancies, 21 • 22 This hypothesis has been supported in part by the induction of a chronic disseminated intravascular coagulation state in dogs with intravenous thromboplastin infusions, 23 The release of thromboplastic materials from tumor cells and the exposure of subendothelial collagen by endotoxin result in disseminated intravascular coagulation through activation of the clotting mechanism and platelet consumption (see figure) - O'Meara showed that prostatic tumor cells are rich in thromboplastin, 24 Through the presumed release of this material directly into the circulation activation of the extrinsic system of coagulation occurs with thrombin formation, Endotoxin liberation during sepsis also is capable of thrombin production but this se'1uence is initiated through the intrinsic system of coagulation, 25 In addition, endotoxin causes aggregation of platelets with local deposition at sites of exposed collagen, 26 Thrombin plays a central role in the clotting sequence and fibrin clot lysis, It activates clotting factors V and VIII as well as resulting in platelet aggregation with release of an important procoagulant platelet factor HL In addition, thrombin directly converts fibrinogen to fibrin monomer and through activation of fibrin stabilizing factor (factor XIII) stable fibrin polymers are formed, Lastly, thrombin is capable of activating the fibrinolytic system, The presence of fibrin polymers in the microcirculation is of grave consequence to the patient because of the potential Pros totic Cancer
Gram-negat1ve
Sepsis
I
\
Thromboploslm Release
Plate/el Aggregolron
Endotoxm Release
t::"1bnnolys1s Ac!wat1on
Clot/mg Depie Iron
Formation
PATHOGENESIS
The pathogenesis of disseminated intravascular coagulation is complicated and not well understood, 6 Most concepts are based on in vitro and animal experiments with their relevance to the clinical disease in man not yet clearly established, Disseminated intravascular coagulation has been recognized in acute and chronic forms, each with its own characteristic
* Solu-Medrol, The Upjohn Co,, Kalamazoo, Michigan 49001.
! Voscoloc
Ocdosio0
r Hemorrhage
J
Theoretic scheme for pathogenesis of disseminated intravascular coagulation in urologic patient,
4
PERGAMENT, SWAIM AND BLACKARD
vascular occlusion and resultant ischemic tissue damage. The degree of deposition depends on the effectiveness of the body's defense mechanisms, including the continued blood flow through the microvasculature, and the reticuloendothelial system and hepatic clearance mechanisms. It also relies on the level of fibrinolytic activity in the area. If the available fibrinolytic system is insufficient in quantity then defective fibrin removal with obstruction of the vasculature will result. The mechanism(s) by which clots are endowed with a lytic potential is (are) unclear. It has been suggested that when suitably stimulated the endothelium releases an activator of the fibrinolytic system, which is then absorbed onto the fibrin microthrombi along with plasminogen (the proenzyme of the active fibrinolytic enzyme plasmin). 27 Plasmin is then formed within the fibrin clot and lysis of the fibrin polymers occurs, resulting in the release of fibrin degradation products. These act as anticoagulants through their antithrombin action and their ability to form complexes with fibrin monomers interfering with subsequent fibrin polymerization. Any depletion of clotting factors and platelets further enhances the bleeding potential. The capability of the patient to counteract the effects of intravascular clotting is relative to the magnitude and duration of the triggering mechanism. This relationship further involves the interplay between consumption and production of clotting factors and platelets, the deposition and lysis of fibrin, and the formation and clearance of degradation products of fibrinogen and fibrin.2 1 In acute disseminated intravascular coagulation, where massive infusion of endotoxin or thromboplastic material occurs, the body's compensatory mechanisms are rapidly overwhelmed. However, in chronic disseminated intravascular coagulation with a slow continuous release the body's response may vary from overcompensation with elevated levels of clotting factors and platelets to decompensation with deficiencies of the hemostatic elements. 28 This concept might explain the varied clinical manifestations and laboratory results noted in patients with disseminated intravascular coagulation. Some patients with widespread malignancy have elevated levels of clotting factors and platelets as well as increased platelet stickiness and other hemostatic abnormalities conducive to thrombosis or development of disseminated intravascular coagulation. 29 In fact, 13 per cent of patients with metastatic cancer have chronic disseminated intravascular coagulation demonstrable at any one time. 29- 31 Other patients with cancer may have subclinical intravascular coagulation with rapid turnover of clotting factors and platelets, although these conditions also have been noted in non-malignant states and may be non-specific. 29 In either case, the coagulation mechanism in patients with widespread malignancy is in varying degrees of compensation and may be tipped into an acute decompensated hemorrhagic diathesis by stimuli such as sepsis, radiation or chemotherapy, 30 or may be associated with a thrombotic tendency. 32
thrombosis. The ecchymoses or other mild bleeding manifestations may be intermittent with non-bleeding intervals or may persist for months with varying degrees of compensation. Thromboembolic phenomena with phlebitis occurring at unusual sites may be a recurrent problem. Some patients have few bleeding symptoms but they may have findings of vascular obstruction with organ dysfunction such as impaired renal clearance or transient neurologic signs. A sudden worsening of the hemorrhagic or thrombotic episodes may indicate acute decompensated disseminated intravascular coagulation. There are numerous laboratory tests that can be used to characterize the hemostatic abnormality in disseminated intravascular coagulation but only a few of these are necessary to establish the diagnosis. Those tests shown to be the most reliable when used together and usually obtainable at any time in most laboratories include platelet count or platelet estimate from a blood smear, plasma fibrinogen level, prothrombin time and partial thromboplastin time.•. 33 In an appropriate clinical setting, when the platelet count and plasma fibrinogen level are below normal and the prothrombin time and partial thromboplastin time are prolonged, then treatment for disseminated intravascular coagulation may be started. Evaluation of erythrocytes on a routine blood smear occasionally provides evidence for disseminated intravascular coagulation. It has been shown that red blood cells are subjected to shearing forces that fragment the cell while passing through the fibrin meshwork laid down in the microvasculature. 34 The resultant abnormal forms have been termed helmet cells or schistocytes. Tests for determining the presence of degradation products of fibrinogen and fibrin are now available in most hospitals. The staphylococcal clumping test 35 uses a strain of staphylococcus that aggregates in the presence of degradation products of fibrinogen and/or fibrin. It is highly sensitive as is the tanned red cell hemagglutination inhibition assay, 36 in which clumping of fibrinogen-coated red blood cells by unneutralized antifibrinogen antibody added to the patient's serum indicates the presence of degradation products of fibrinogen and fibrin. Both tests are equally sensitive in detecting the early, high molecular weight degradation products of fibrin known as X and Y. However, the tanned red cell hemagglutination inhibition assay is more sensitive in detecting late, low molecular weight degradation products known as D and E. The presence of antibodies against staphylococci may give a falsely positive result in the staphylococcal clumping system. This problem can be resolved by heating an aliquot of serum converting a positive test to negative if degradation products are present or remaining positive in the presence of staphylococcal antibody. Neither the staphylococcal clumping test nor the tanned red cell hemagglutination inhibition assay is able to differentiate degradation products of fibrinogen from fibrin, that is primary from secondary fibrinolysis. The paracoagulation tests do make this theoretic distinction. 37 They use either ethanol or protamine sulfate to separate the complexes formed in the circulation. In primary fibrinolysis (fibrinogenolysis) the freed fibrinogen and related degradation products are not able DIAGNOSIS to gel, while in disseminated intravascular coagulation with The clinical manifestations of acute and chronic dis- secondary fibrinolysis the liberated fibrin monomers and the seminated intravascular coagulation are highly variable al- degradation product from fibrin are able to form a gel giving a though 2 general patterns can be defined. In acute dis- positive test. The paracoagulation tests in contrast to the seminated intravascular coagulation spontaneous bleeding is tanned red cell hemagglutination inhibition assay or staphylothe most common finding usually presenting as cutaneous coccal clumping tests are less time consuming, simple to petechiae or ecchymoses. Bleeding from venipuncture sites, the perform and highly specific, making them suitable as a gastrointestinal tract, incisions and the urinary tract also is screening test for disseminated intravascular coagulation. common.• Large areas of skin necrosis, respiratory distress, However, these tests are less sensitive than the tanned red cell pulmonary infiltrates, hypotension, convulsions and coma may hemagglutination inhibition assay or staphylococcal clumping be present. When oliguria is accompanied by hematuria, renal tests in detecting degradation products of fibrinogen and damage exists varying from acute tubular necrosis to diffuse fibrin. Because of the difference in sensitivity a negative bilateral renal cortical necrosis. In contrast, the clinical paracoagulation test does not rule out a disseminated intravaspattern of chronic disseminated intravascular coagulation is cular coagulation state since it is possible to have an elevation usually a low grade bleeding tendency with or without venous of degradation products of fibrinogen and fibrin and yet have
DISSEMINATED INTRAVASCULAR COAGULATION IN UROLOGIC PATIENT
insufficient concentrations of fibrin monomers and/or the high molecular weight X degradation product of fibrin to form a gel. Other laboratory tests may be useful but are limited by their availability. The thrombin time measures the interval for formation of fibrin after thrombin is added to the patient's plasma. It is prolonged when either the fibrinogen level is sufficiently decreased (less than 130 mg. per dl.) or when degradation products of fibrinogen and fibrin are present in sufficient quantities to interfere with polymerization of fibrin monomers. The thrombin time has been advocated as a screening test for disseminated intra vascular coagulation 30 but it may be normal in milder disseminated intravascular coagulation states because of its intermediate sensitivity. Determining clotting factor V level may be valuable in the diagnosis of disseminated intravascular coagulation but it is assayed only in larger coagulation laboratories. There are several cautions in the interpretation of laboratory results in patients suspected of having disseminated intravascular coagulation. Test results may reflect other abnormalities such as liver disease, congenital factor deficiencies, heparin administration and other drug effects, faulty blood drawing, inflammation and many other disease processes. These may affect the levels and/or activity of hemostatic components independently of (or associated with) an intravascular coagulation process. For example fibrinogen levels may be elevated in association with inflammation and factor VIII levels may rise rapidly under stressful situations such as operation or fever. 33 If disseminated intravascular coagulation is suspected in these patients normal coagulation studies may be obtained during the early phase of disseminated intravascular coagulation because clotting factors and platelets, although being consumed, are still adequate for normal test results. Repetition of these tests several hours later including degradation products of fibrinogen and fibrin determination may then support the clinical suspicion of disseminated intravascular coagulation. Appropriate treatment should then be started. TREATMENT
The most important principle in the management of patients with disseminated intravascular coagulation is control or elimination of the underlying disease sometimes referred to as the triggering event. 4 • 19 • 30• 33 ' 38 Many of the acute forms of disseminated intravascular coagulation are initiated by events that are either brief and self-limited or readily treatable so that spontaneous cure is usually the rule. When septicemia is the triggering mechanism administration of appropriate antibiotics and surgical drainage of the source of infection help prevent the further release of endotoxin. Correction of coexisting shock limits the severity of disseminated intravascular coagulation. 39 In those patients with widespread malignancy and chronic disseminated intravascular coagulation the underlying disease is not readily controlled. In fact, chemotherapy and radiation therapy have precipitated acute bleeding episodes. 3 °For example testosterone administration in a few patients with metastatic prostatic carcinoma has resulted in an acute hemorrhagic diathesis. 40 However, estrogen treatment has been shown in prostatic cancer patients to be beneficial in ameliorating or preventing disseminated intravascular coagulation recurrences. 38 Its administration though is associated with increased platelet aggregation and adhesiveness as well as enhanced clot formation. 41 Thromboembolic phenomena have been well documented with its use. 42 The full clinical significance of these observations relative to the causation of disseminated intravascular coagulation in estrogen-treated patients with prostatic cancer has not been determined. While attempts are being made to control the underlying disease we believe that deficient hemostatic elements should be restored although a controlled study involving this aspect of treatment has not been reported. The substances available are cryoprecipitate, fresh frozen plasma, fresh whole blood and
5
platelet concentrates. Cryoprecipitate contains high concentrations of fibrinogen without the incidence of hepatitis associated with other fibrinogen preparations. Fresh whole blood not only provides red cell mass but also platelets and clotting factors. When the underlying disease cannot be controlled and replacement of depleted hemostatic elements fails to improve the patient's clinical findings and laboratory tests, then anticoagulation with heparin is recommended. 4 • 19 The rationale lies in its interruption of the coagulation sequence preventing fibrin formation. The dose required to adequately heparinize a patient with disseminated intravascular coagulation will vary but is usually recommended as 5,000 to 10,000 units intravenously every 4 to 6 hours or a continuous intravenous infusion of 1,000 to 1,500 units every hour. 21 An adequate response is judged by improvement in the clinical picture and laboratory data. After 12 to 24 hours of heparin therapy the clotting studies and degradation products of fibrinogen and fibrin level should begin to improve. 38 The platelet count is not a valid indicator of response to treatment frequently requiring a week or more before correction occurs. Prolonged thrombocytopenia may be owing to the limited productive capacity of the megakaryocyte or to bone marrow suppression from sepsis, drugs or tumor involvement. Although oral anticoagulants have been advocated for use in chronic disseminated intravascular coagulation on the basis of experimental and clinical trials, in other studies they have not been shown effective. 38 The use of heparin in the treatment of disseminated intravascular coagulation has become controversial in recent years"· 43 -• 7 despite reports supporting its effectiveness. 4 • 18 If the activating stimulus is transitory or rapidly corrected, it is likely that a spontaneous cure through normal physiologic mechanisms will be seen even if heparin had not been used. In addition, heparin has worsened the course of several patients with disseminated intravascular coagulation resulting in fatal hemorrhage. 6 • 43 Furthermore, disseminated intravascular coagulation actually occurred in patients who were already heparinized as part of the treatment program for pulmonary em bolus.•• Heparin not only failed to prevent disseminated intravascular coagulation in these patients but may have contributed to their fatal outcome. Lastly, when heparin was used to treat disseminated intravascular coagulation owing to septic shock, no improvement in survival was noted although the coagulation defects were improved in half of the patients studied. 45 These reports and others••. 47 emphasize the need for initiation of controlled studies to more adequately determine the role of heparin in the treatment of disseminated intravascular coagulation states. In addition to treatment of the underlying disease, correction of shock, replacement of hemostatic elements and the use of heparin, the administration of drugs inhibitory to the fibrinolytic system is often considered. Epsilon aminocaproic acid* prevents the conversion of plasminogen to plasmin primarily through inhibition of circulating plasminogen activators. Its popularity in the past arose from the favorable results reported in correcting the bleeding diathesis and clotting studies in patients with cancer of the prostate and excessive fibrinolysis. "· 48 The continued use of epsilon aminocaproic acid has been occasionally associated with generalized, fatal, thrombotic states. 49 By blocking the protective fibrinolytic mechanism the thrombotic process was allowed to progress. Epsilon aminocaproic acid in conjunction with heparin has been recommended 50 but its effectiveness under these circumstances is difficult to determine. Furthermore, in recent years it has become evident that primary fibrinolysis is extremely rare and fibrinolysis may not even occur without pre-existing intravascular coagulation. 4 • 20 • 33 Therefore, epsilon aminocaproic acid
* Amicar, Lederle Laboratories, Pearl River, New York 10965.
6
PERGAMENT, SWAIM AND BLACKARD
is not a recommended or acceptable agent in the treatment of disseminated intravascular coagulation. CONCLUSIONS
Although the true incidence of disseminated intravascular coagulation is unknown it appears that the urologic patient is at high risk for development of this complication with bacterial sepsis and metastatic prostatic cancer being 2 of the most common causes. The manifestations of each vary from an acute fulminant bleeding diathesis to a chronic low grade bleeding tendency depending on the characteristics of the initiating event relative to the patient's compensatory mechanisms. The laboratory evaluation centers on the blood smear, prothrombin time, partial thromboplastin time, platelet count and plasma fibrinogen level. All are readily available in most hospitals at any time. The thrombin time, serial dilution protamine sulfate, staphylococcal clumping test and tanned red cell hemagglutination inhibition assay, if available, would also be helpful. Clotting factor assays, with the exception of fibrinogen and factor V, are of limited value. Treatment in previous years has been confusing because of uncertainty regarding the pathogenesis of the bleeding diathesis in these patients. It is now realized that primary fibrinolysis rarely, if ever, occurs. The fibrinolytic mechanism has been shown to be a normal physiologic response secondary to intravascular coagulation, generally protective in function, and, therefore, antifibrinolysins are contraindicated. Heparin has been popularized as an important adjuvant in the treatment of disseminated intravascular coagulation but even this may be unnecessary in most patients. Treatment of the underlying disorder is the most important aspect of management. REFERENCES
1. McKay, D. G.: Disseminated Intravascular Coagulation. An Intermediary Mechanism of Disease. New York: Harper & Row, Publishers, Inc., 1964. 2. Bowie, E. J. W. and Owen, C. A., Jr.: Introduction. Symposium on the diagnosis and treatment of intravascular coagulationfibrinolysis (ICF) syndrome, with special emphasis on this syndrome in patients with cancer. Mayo Clin. Proc., 49: 635, 1974. 3. Vaisrub, S.: Disseminated intravascular coagulation-a color of different horses. J.A.M.A., 231: 180, 1975. 4. Colman, R. W., Robboy, S. J. and Minna, J. D.: Disseminated intravascular coagulation (DIC): an approach. Amer. J. Med., 52: 679, 1972. 5. Straub, P. W.: Chronic intravascular coagulation. Clinical spectrum and diagnostic criteria, with special emphasis on metabolism, distribution and localization ofl 131-fibrinogen. Acta Med. Scand., suppl. 526, p. 1, 1971. 6. Merskey, C.: Defibrination syndrome or ... ? Blood, 41: 599, 1973. 7. Naunyn, B.: Untersuchungen iiber Blutgerinnung im lebenden Thiere und ihre Folgen. Arch. Exp. Path. Pharmakol., 1: 1, 1873. 8. Schaffer, J.: Ueber die angebliche Gerinnung des Bluts im lebenden Thier nach Injection freier fibrinoplastischer substanz in die Gefassbahn. Chi. f. d. med. Wissensch., 10: 145, 1872. 9. Bordet, J. and Delange, L.: Injections intraveineuses de cytoszyme et coagulabilite du sang. Compt. rend. Soc. de Biol., 75: 168, 1913. 10. Schneider, C. L.: The active principle of placental toxin: thromboplastin; its inactivator in blood: antithromboplastin. Amer. J. Physiol., 149: 123, 1947. 11. Jurgens, R. and Trautwein, H.: Ueber Fibrinopenie (Fibrinogenopenie) beim Erwachsener, nebst Bermerkungen iiber die Herkwas des Fibrinogens. Deutsch. Arch. Klin. Med., 169: 28, 1930. 12. Tagnon, H. J., Whitmore, W. F., Jr., Schulman, P. and Kravitz, S. C.: The significance of fibrinolysis occurring in patients with metastatic cancer of the prostate. Cancer, 6: 63, 1953. 13. Andersson, L.: Fibrinolysis in patients with prostatic cancer. Acta Chir. Scand., 126: 172, 1963.
14. Pellman, C. M., Ridlon, H. C. and Phillips, L. L.: Manifestation and management of hypofibrinogenemia and fibrinolysis in patients with carcinoma of the prostate. J. Urol., 96: 375, 1966. 15. Rapaport, S. I. and Chapman, C. G.: Coexistent hypercoagulability and acute hypofibrinogenemia in a patient with prostatic carcinoma. Amer. J. Med., 27: 144, 1959. 16. Straub, P. W., Riedler, G. and Frick, P. G.: Hypofibrinogenaemia in metastatic carcinoma of the prostate: suppression of systemic fibrinolysis by heparin. J. Clin. Path., 20: 152, 1967. 17. Rodriguez-Erdmann, F.: Bleeding due to increased intravascular blood coagulation, hemorrhagic syndrome caused by consumption of blood clotting factors (consumption-coagulopathies). New Engl. J. Med., 273: 1370, 1965. 18. Merskey, C., Johnson, A. J., Kleiner, G. J. and Wohl, H.: The defibrination syndrome: clinical features and laboratory diagnosis. Brit. J. Haematol., 13: 528, 1967. 19. Samaha, R. J., Bruns, N. C. and Ross, G. J., Jr.: Chronic intravascular coagulation in metastatic prostate cancer. Arch. Surg., 106: 295, 1973. 20. Gans, H.: Is primary fibrinolysis a real entity? Surg., Gynec. & Obst., 136: 975, 1973. 21. Wintrobe, M. M.: Clinical Hematology, 7th ed. Philadelphia: Lea & Febiger, pp. 1211-1224, 1974. 22. Williams, W. J., Beutler, E., Erslev, A. J. and Rundles, R. W.: Hematology. New York: McGraw-Hill Book Co., p. 1236, 1972. 23. Cooper, H. A., Bowie, E. J. and Owen, C. A., Jr.: Chronic induced intravascular coagulation in dogs. Amer. J. Physiol., 225: 1355, 1973. 24. O'Meara, R. A. Q.: Coagulative properties of cancers. IrishJ. Med. Sci., series 6, p. 474, 1958. 25. Deykin, D.: The clinical challenge of disseminated intravascular coagulation. New Engl. J. Med., 283: 636, 1970. 26. McGrath, J. M. and Stewart, G. J.: The effects of endotoxin on vascular endothelium. J. Exp. Med., 129: 833, 1969. 27. Sherry, S.: Fibrinolysis. Ann. Rev. Med., 19: 247, 1968. 28. Cooper, H. A., Bowie, E. J. W., Didisheim, P. and Owen, C. A., Jr.: Paradoxic changes in platelets and fibrinogen in chronically induced intravascular coagulation. Mayo Clin. Proc., 46: 521, 1971. 29. Davis, R. B., Theologides, A. and Kennedy, B. J.: Comparative studies of blood coagulation and platelet aggregation in patients with cancer and nonmalignant diseases. Ann. Intern. Med., 71: 67, 1969. 30. Peck, S. D. and Reiquam, C. W.: Disseminated intravascular coagulation in cancer patients: supportive evidence. Cancer, 31: 1114, 1973. 31. Miller, S. P., Sanchez-Avalos, J., Stefanski, T. and Zuckerman, L.: Coagulation disorders in cancer. I. Clinical and laboratory studies. Cancer, 20: 1452, 1967. 32. Sun, N. C. J., Bowie, E. J. W., Kazmier, F. J., Elveback, L. R. and Owen, C. A., Jr.: Blood coagulation studies in patients with cancer. Mayo Clin. Proc., 49: 636, 1974. 33. Rodriguez-Erdmann, F.: The syndrome of intravascular coagulation. Postgrad. Med., 55: 91, 1974. 34. Bull, B. S., Rubenberg, M. L., Dacie, J. V. and Brain, M. C.: Microangiopathic haemolytic anaemia: mechanisms of red-cell fragmentation: in vitro studies. Brit. J. Haematol., 14: 643, 1968. 35. Niewiarowski, S. and Thomas, D. P.: Measurement of the level of fibrinogen degradation products (FDP) in serum by staphylococcal clumping test. Thromb. Diath. Haemorrh., suppl. 45, p. 373, 1971. 36. Merskey, C., Kleiner, G. J. and Johnson, A. J.: Quantitative estimation of split products of fibrinogen in human serum, relation to diagnosis and treatment. Blood, 28: 1, 1966. 37. Seabaugh, D. R., Pappas, J., Seaman, A. and Hodges, C. V.: Disseminated intravascular coagulation and the urologist. J. Urol., 106: 267, 1971. 38. Vreeken, J.: Diffuse intravascular coagulation (DIC): a basic mechanism of disease in internal medicine. A survey of recent developments. Neth. J. Med., 16: 237, 1973. 39. Hardaway, R. M., III: Disseminated intravascular coagulation (DIC). J.A.M.A., 227: 657, 1974. 40. Ellman, L.: Generalized bleeding following the treatment of prostatic carcinoma with testosterone and radioactive phosphorus. J. Urol., HO: 331, 1973.
D13SEJ:vn:N.ATBD lNT}i,1--":_\lASCUi:AR COAGULATION
41. Dugdale, M. and Masi, A. T.: Hormonal contraception and thrornboembolic disease: effects of the oral contraceptives on hemostatic mechanisms. A review. J. Chron. Dis., 23: 775, 1971. 42. Blackard, C. E., Doe, R. P., Iviellinger, G. T. and Byar, D. P.: Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer, 26: 249, 1970. 43. Green, D., Seeler, R. A., Allen, N. and Alavi, I. A.: The role of heparin in the management of consumption coagulopathy. Med. Clin. N. Amer., 56: 193, 1972. 44. Klein, H. G. and Bell, W.R.: Disseminated intravascular coagulation during heparin therapy. Ann. Intern. Med., 80: 477, 1974. 45. Corrigan, J. J., Jr. and Jordan, C. M.: Heparin therapy in septicemia with disseminated intravascular coagulation. Effect on mortality and on correction of hemostatic defects. New Engl. J. Med., 283: 778, 1970.
n~
UROLOG!(:: PATIENT
7
46. Lasch, H. G. and Heene, D. H.: Heparin of diffuse intravascular coagulation (DIC). Thromb. Haernorrh. 33: 105, 1974. 47. Straub, P. W.: A case against heparin therapy of intravascular coagulation. Thromb. Diath. Haemorrh., 33: 107, 1974. 48. Nilsson, I. M., Andersson, L. and Bjorkman, S. E.: Epsilonaminocaprnic acid (E-ACA) as a therapeutic agent based on 5 year's clinical experience. Acta Med. Scand., suppl. 448, p. 1, 1966. 49. Naeye, R. L.: Thrombotic state after hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood, 19: 694, 1962. 50. Bergin, J. J., Crosby, W. H. and Jahnke, E. J.: Massive bleeding with fibrinolysis: management with heparin and epsilon aminocaproic acid. Milit. Med., 131: 340, 1966. 1
Vi/ilkins
R
A
DISSEMINATED INTRAVASCULAR COAGULATION IN THE UROLOGIC PATIENT MICHAEL L. PERGAMENT, * WILLIAM R. SWAIM
AND
CLYDE E. BLACKARD
From the Departments of Urologic Surgery, Laboratory Medicine and Pathology, and Medicine, University of lvlinnesota Health Sciences Center and the Veterans Administration Hospital, Minneapolis, l\1innesota
ABSTRACT
Gram-negative septicemia and metastatic prostatic cancer are frequent causes of disseminated intravascular coagulation, The clinical manifestations of this condition as well as the laboratory data vary considerably, depending on the patient's compensatory mechanisms in relation to the magnitude and duration of the thromboplastin or endotoxin release. Treatment centers primarily on correcting the underlying disorder. Secondly, deficient clotting factors and platelets should be replaced in the appropriate patient, Heparinization is often unnecessary, The use of drugs that inhibit the ~v,~Tnnh,,a mechanism is contraindicated in disseminated intravascular
Disseminated intravascular coagulation is an acquired coagulopathy occurring as a complicating event during the course of another disease process. McKay aptly termed disseminated intravascular coagulation as an intermediary mechanism of disease. 1 It is not a separate disease entity but rather a pathophysiologic response to an underlying disorder that activates the clotting mechanism with capabilities of thron1botic as well as hemorrhagic manifestations. The term disseminated intravascular coagulation may be misleading in that the clotting process often is not disseminated but rather localized to 1 or a few organs. 2 The products of the subsequent local fibrinolytic reaction are then disseminated the circulation. The entities shown capable of resulting in intravascular coagulation cover the complete spectrum of human disease with new causes continually being identified. 3 Two diseases shown to be common causes of disseminated intravascular coagulation are encountered often in the practice. Bacterial a of urinary tract instrumentation, almost half of the with acute disseminated intravascu.lar Colman and associates. 4 In Straub's review of chronic disseminated intravascular cancer. 5 be familiar with the various aspects of this pathologic process. Unfortunately, the pathogenesis of disseminated intravascular coagulation has been understood in the past and even today many mechanisms resulting in the clinical and laboratory findings are unknown, 6 Consequently, treatment of these patients often has been unsatisfactory. We herein review the current literature regarding pathogenesis, clinical spectrum, laboratory methods and treatment of disseminated intravascular coagulation, which are of importance to the clinical urologist, Several approaches to therapy will be illustrated by 4 patients with common urologic problems and Accepted for publication December 5, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * Requests for reprints: Department of Urologic Surgery, University of Minnesota Health Sciences Center, Minneapolis, Minnesota 55455.
clinical manifestations to be related to an associated disseminated intravascular coagulation state, CASE REPORTS
Case 1. H. a 63-year-old man, was hospitalized with complaints of abdominal pain associated with a weight loss during the previous 8 months. The patient described a weak stream, nocturia and urinary urgency. Physical examination was normal except for an enlarged, nodular, firm prostate. A chest radiogram revealed lesions involving multiple ribs, Open rib biopsy showed differentiated, clear cell adenocarcinoma. Afterward, the patient had slow bc1t persistent bleeding from the biopsy site, An excretory urogram (IVP) showed partial right ureterovesical obstruction. Total acid phosphatase was 53 international units per liter (LU. !.-normal Oto 9) with a fraction of 41 I.U. per l. 0 to 2). The alkaline was 175 I.U, per l. (normal 24 to 96). revealed an prostate with extension of The next the and the onset of tract. At this time the clinical picture was data were to be compatiwith acute disseminated intra.vascular (see table). A significant growth of Escherichia coli was cultured from the urine the day after cystoscopy. A treatment program was which included antibiotics, fresh frozen plasma, 1,500 units sodium heparint intravenously every 4 hours for 7 days and high dose estrogen administration. The patient eventually recovered with complete correction of the coagulation studies. Comment: This case illustrates a common pattern of presentation of disseminated intravascular coagulation in the urologic patient. The clinical and laboratory findings were consistent with a pre-existing, low grade, chronic disseminated intravascular coagulation associated with stage IV prostatic
t Lipo-hepin,
Riker Laboratories, Inc., Northridge, California 91324.
2
PERGAMENT, SWAIM AND BLACKARD
Laboratory data Pt.
HK
Day After Admission 0 13 19 25 26
29 33
Event/freatment
Platelet Count (No.Imm.')
PT* (12-13 sec.)
PTTt (35-45 sec.)
TT:j: (12-17 sec.)
Fibrinogen (200-400 mg./dl.)
Factor V (%normal)
Staphylococcal Clump Titer ( < 10 µg./ml.)
SDPS§ (-24 hrs.)
198,000
16
159,000
17
66
19
152
92
128
+½
83,000
18
56
29
91
43
260
+½
77,000 181,000
13 13
44 37
17 16
168 242
105 150
260 64
+½
Rib biopsy Cystoscopy Sepsis, antibiotics, heparin, fresh frozen plasma Estrogen
-½ +24
CR
0 2
3 7
Decompressive laminectomy Fresh frozen plasma, platelet concentrates, fresh whole blood Same as day 2
11 27,000
19
66
21
45
25
660
+½
23,000 35,000
13 11
34 29
15 15
166 272
50 94
266 32
+½ -1/2
-24 GR
RB
0 3
4 7 0
Prostatectomy, cryoprecipitate, fresh frozen plasma, fresh whole blood
Urethral false passage, suprapubic cystostomy, antibiotics, fresh frozen plasma
1 3
103,000
10 17
35 Unmeasurable
17 39
11 12
16 17 49
34 11
85,000 90,000 150,000
18
38 32 72
102,000 93,000
13 11
41 36
27
52 100
400
323 10
* PT-prothrombin time.
t PTT-partial thromboplastin time. :j: TT-thrombin time. § SOPS-serial dilution protamine sulfate.
cancer that had advanced to an acute bleeding diathesis after a septic episode related to urinary tract instrumentation. The underlying disorders were treated with antibiotics and estrogen therapy. Heparinization and clotting factor replacement also were used in the management of this patient. A rapid improvement in his clinical condition occurred and, therefore, plasma administration was stopped after 1 unit. Anticoagulation was initially believed to be necessary because of the fulminant nature of the bleeding diathesis and was continued until the degradation products returned toward normal. Case 2. C. R., a 53-year-old man with known stage IV adenocarcinoma of the prostate, was hospitalized with acute paraplegia. He denied a bleeding tendency. A lumbar myelogram showed an incomplete epidural block. During decompressive laminectomy tumor tissue was found around the spinal canal with complete replacement of the third vertebral body, and infiltration into the paraspinal muscles and retroperitoneal space. A large amount of this metastatic tissue was removed. Despite receiving 3 units of blood intraoperatively and 4 more during the next 24 hours, the hematocrit decreased from 34 to 16 per cent. During this time bleeding continued from the operative site. Coagulation studies 36 hours postoperatively showed values compatible with acute disseminated intravascular coagulation (see table). The patient was treated with 7 units of fresh frozen plasma and 16 platelet concentrates with correction of clotting studies during the next 24 hours. Renal failure resolved during the following 2 weeks with conservative fluid and electrolyte management. During the next month neurologic function in the lower extremities partially returned. The coagulation studies have remained normal. Case 3. G. R., a 65-year-old man, was hospitalized with a 4-month history of obstructive voiding symptoms. Physical
examination was normal except for an enlarged, hard, right prostatic lobe. Laboratory data including acid phosphatase were normal. The IVP, metastatic bone survey and bone marrow biopsy were all normal. Open perinea! prostatic biopsy revealed adenocarcinoma and the patient underwent radical perineal prostatectomy. Immediately after the operative procedure excessive hematuria was noted. Coagulation studies were all abnormal, being compatible with acute disseminated intravascular coagulation (see table). The laboratory values returned to normal during the next 12 hours, while 20 units of cryoprecipitate and 2 units of fresh frozen plasma were being administered. Convalescence was uneventful. Pathologic examination showed carcinoma involving the prostatic capsule and both seminal vesicles. Comment: Manipulation of prostatic tumor tissue at the metastatic site during decompressive laminectomy (case 2) and at the primary site during radical perinea! prostatectomy (case 3) possibly resulted in the bleeding diathesis in these patients. These episodes were presumed to be owing to the sudden release of thromboplastic material into the circulation. Neither patient had a bleeding tendency, nor abnormal clotting studies prior to the operation. The onset of bleeding in both cases correlated best with the surgical event that involved considerable manipulation of tumor tissue. No other apparent causes of disseminated intravascular coagulation, such as infection, shock or acidosis, could be documented. Both episodes resolved spontaneously, requiring only clotting factor and platelet replacement. Case 4. R. B., a 67-year-old man, was initially seen for evaluation of obstructive voiding symptoms. Urethral false passage occurred while obtaining a voiding cystourethrogram. The patient had a clinical picture suggestive of sepsis and characterized by chills, fever to 102F, cyanosis and shock. After
3
DISSEJ\1HNATED INT'RA\li':.SCUL/:,Jl COAGULATION
resuscitation with grrL nate* intravenously and cystostomy was nP'rtnrm without unusual bleeding, Postopthe preoperative coagulation studies showed results consistent with acute disseminated intravascular (see table) - The patient was believed to be in eminent bleeding and was treated with fresh frozen plasma, Coagulation tests returned to normal the day - Preoperative blood and urine cultures were sterile, Comment: This case illustrates the unusual finding of laboratory evidence suggesting acute disseminated intravascular coagulation after an acute shock state in a patient who did not clinically decompensate even during the operation, Correction of the shock state, high dose steroids and clotting factor replacement were believed to be important factors in maintaining adequate hemostasis, HISTORICAL BACKGROUND
Intravascular clotting produced by the infusion of thromboplastic material has been recognized in experimental animals for almost 100 years, 7 - 9 Although acute intravascular coagulation syndromes were induced occasionally in animals during the early 1900s, no obvious clinical situation was published until the late 1940s, 10 At that time it was shown that a remarkable parallel existed between induced intravascular coagulation in animals and certain bleeding states associated with obstetric complications, especially abruptio placenta and dead fetus syndrome, In 1930 attention was first turned to a coagulation defect as a cause of the bleeding diathesis in patients with prostatic cancer, 11 and Trautwein's patient had widespread cancer of the prostate associated with a severe bleeding diathesis and hypofibrinogenemia, They incorrectly ascribed the depressed fibrinogen level to impaired synthesis by the bone marrow, In 1953 Tagnon and associates demonstrated that low fibrinogen levels were associated with marked fibrinoin the blood and tumor cells of these patients, postulating release of a fibrinolytic enzyme directly into the circulation from the tumor cells, 12 Their theory and subsequent confirming reports during the next 15 years 13 - 14 formed the basis of a notion still prevalent today, that is that bleeding diathesis is owing to the release of fibrinolysins or fibrinoactivators into the circulation with subsequent enzymatic breakdown of fibrinogen and other clotting factors, The concept of the hemostatic defect being caused by intravascular coagulation arose in 1959, Rapaport and Chapman with metastatic prostatic cancer and hypofibrinogenernia coexisted fibrinolysis, 15 In 1967 Straub and associates on a patient with metastatic carcinorna of the prostate, decreased levels and systemic fibrinolysis, 16 The was repeatedly abolished after suggesting that this was These reports and others 17 - 19 attested to fibrinolysis as a ,-e,cu,C1u,,uv physiologic, mechanism in patients with disseminated intravascular to prostatic cancer, Primary fibrinolysis rarely has been documented during the last decade, 20
, gro~p of
disorders, clinical Ln&.nifestations and data, Acute disseminated intravascular coaguiation is most commonly seen secondary to septicemia,• although it may occur following other sudden catastrophic events such as trauma, shock, burns, abruptio ,-, ..~v,,rn,~, amniotic fluid embolism and others, The initiating or triggering event may involve either the rapid release of thromboplastic materials or endotoxin and then be perpetuated by hypoxia and acidosis if shock is present- Chronic disseminated intravascular coagulation is often assumed to be associated with the gradual release of thromboplastic substances as in widespread malignancies, 21 • 22 This hypothesis has been supported in part by the induction of a chronic disseminated intravascular coagulation state in dogs with intravenous thromboplastin infusions, 23 The release of thromboplastic materials from tumor cells and the exposure of subendothelial collagen by endotoxin result in disseminated intravascular coagulation through activation of the clotting mechanism and platelet consumption (see figure) - O'Meara showed that prostatic tumor cells are rich in thromboplastin, 24 Through the presumed release of this material directly into the circulation activation of the extrinsic system of coagulation occurs with thrombin formation, Endotoxin liberation during sepsis also is capable of thrombin production but this se'1uence is initiated through the intrinsic system of coagulation, 25 In addition, endotoxin causes aggregation of platelets with local deposition at sites of exposed collagen, 26 Thrombin plays a central role in the clotting sequence and fibrin clot lysis, It activates clotting factors V and VIII as well as resulting in platelet aggregation with release of an important procoagulant platelet factor HL In addition, thrombin directly converts fibrinogen to fibrin monomer and through activation of fibrin stabilizing factor (factor XIII) stable fibrin polymers are formed, Lastly, thrombin is capable of activating the fibrinolytic system, The presence of fibrin polymers in the microcirculation is of grave consequence to the patient because of the potential Pros totic Cancer
Gram-negat1ve
Sepsis
I
\
Thromboploslm Release
Plate/el Aggregolron
Endotoxm Release
t::"1bnnolys1s Ac!wat1on
Clot/mg Depie Iron
Formation
PATHOGENESIS
The pathogenesis of disseminated intravascular coagulation is complicated and not well understood, 6 Most concepts are based on in vitro and animal experiments with their relevance to the clinical disease in man not yet clearly established, Disseminated intravascular coagulation has been recognized in acute and chronic forms, each with its own characteristic
* Solu-Medrol, The Upjohn Co,, Kalamazoo, Michigan 49001.
! Voscoloc
Ocdosio0
r Hemorrhage
J
Theoretic scheme for pathogenesis of disseminated intravascular coagulation in urologic patient,
4
PERGAMENT, SWAIM AND BLACKARD
vascular occlusion and resultant ischemic tissue damage. The degree of deposition depends on the effectiveness of the body's defense mechanisms, including the continued blood flow through the microvasculature, and the reticuloendothelial system and hepatic clearance mechanisms. It also relies on the level of fibrinolytic activity in the area. If the available fibrinolytic system is insufficient in quantity then defective fibrin removal with obstruction of the vasculature will result. The mechanism(s) by which clots are endowed with a lytic potential is (are) unclear. It has been suggested that when suitably stimulated the endothelium releases an activator of the fibrinolytic system, which is then absorbed onto the fibrin microthrombi along with plasminogen (the proenzyme of the active fibrinolytic enzyme plasmin). 27 Plasmin is then formed within the fibrin clot and lysis of the fibrin polymers occurs, resulting in the release of fibrin degradation products. These act as anticoagulants through their antithrombin action and their ability to form complexes with fibrin monomers interfering with subsequent fibrin polymerization. Any depletion of clotting factors and platelets further enhances the bleeding potential. The capability of the patient to counteract the effects of intravascular clotting is relative to the magnitude and duration of the triggering mechanism. This relationship further involves the interplay between consumption and production of clotting factors and platelets, the deposition and lysis of fibrin, and the formation and clearance of degradation products of fibrinogen and fibrin.2 1 In acute disseminated intravascular coagulation, where massive infusion of endotoxin or thromboplastic material occurs, the body's compensatory mechanisms are rapidly overwhelmed. However, in chronic disseminated intravascular coagulation with a slow continuous release the body's response may vary from overcompensation with elevated levels of clotting factors and platelets to decompensation with deficiencies of the hemostatic elements. 28 This concept might explain the varied clinical manifestations and laboratory results noted in patients with disseminated intravascular coagulation. Some patients with widespread malignancy have elevated levels of clotting factors and platelets as well as increased platelet stickiness and other hemostatic abnormalities conducive to thrombosis or development of disseminated intravascular coagulation. 29 In fact, 13 per cent of patients with metastatic cancer have chronic disseminated intravascular coagulation demonstrable at any one time. 29- 31 Other patients with cancer may have subclinical intravascular coagulation with rapid turnover of clotting factors and platelets, although these conditions also have been noted in non-malignant states and may be non-specific. 29 In either case, the coagulation mechanism in patients with widespread malignancy is in varying degrees of compensation and may be tipped into an acute decompensated hemorrhagic diathesis by stimuli such as sepsis, radiation or chemotherapy, 30 or may be associated with a thrombotic tendency. 32
thrombosis. The ecchymoses or other mild bleeding manifestations may be intermittent with non-bleeding intervals or may persist for months with varying degrees of compensation. Thromboembolic phenomena with phlebitis occurring at unusual sites may be a recurrent problem. Some patients have few bleeding symptoms but they may have findings of vascular obstruction with organ dysfunction such as impaired renal clearance or transient neurologic signs. A sudden worsening of the hemorrhagic or thrombotic episodes may indicate acute decompensated disseminated intravascular coagulation. There are numerous laboratory tests that can be used to characterize the hemostatic abnormality in disseminated intravascular coagulation but only a few of these are necessary to establish the diagnosis. Those tests shown to be the most reliable when used together and usually obtainable at any time in most laboratories include platelet count or platelet estimate from a blood smear, plasma fibrinogen level, prothrombin time and partial thromboplastin time.•. 33 In an appropriate clinical setting, when the platelet count and plasma fibrinogen level are below normal and the prothrombin time and partial thromboplastin time are prolonged, then treatment for disseminated intravascular coagulation may be started. Evaluation of erythrocytes on a routine blood smear occasionally provides evidence for disseminated intravascular coagulation. It has been shown that red blood cells are subjected to shearing forces that fragment the cell while passing through the fibrin meshwork laid down in the microvasculature. 34 The resultant abnormal forms have been termed helmet cells or schistocytes. Tests for determining the presence of degradation products of fibrinogen and fibrin are now available in most hospitals. The staphylococcal clumping test 35 uses a strain of staphylococcus that aggregates in the presence of degradation products of fibrinogen and/or fibrin. It is highly sensitive as is the tanned red cell hemagglutination inhibition assay, 36 in which clumping of fibrinogen-coated red blood cells by unneutralized antifibrinogen antibody added to the patient's serum indicates the presence of degradation products of fibrinogen and fibrin. Both tests are equally sensitive in detecting the early, high molecular weight degradation products of fibrin known as X and Y. However, the tanned red cell hemagglutination inhibition assay is more sensitive in detecting late, low molecular weight degradation products known as D and E. The presence of antibodies against staphylococci may give a falsely positive result in the staphylococcal clumping system. This problem can be resolved by heating an aliquot of serum converting a positive test to negative if degradation products are present or remaining positive in the presence of staphylococcal antibody. Neither the staphylococcal clumping test nor the tanned red cell hemagglutination inhibition assay is able to differentiate degradation products of fibrinogen from fibrin, that is primary from secondary fibrinolysis. The paracoagulation tests do make this theoretic distinction. 37 They use either ethanol or protamine sulfate to separate the complexes formed in the circulation. In primary fibrinolysis (fibrinogenolysis) the freed fibrinogen and related degradation products are not able DIAGNOSIS to gel, while in disseminated intravascular coagulation with The clinical manifestations of acute and chronic dis- secondary fibrinolysis the liberated fibrin monomers and the seminated intravascular coagulation are highly variable al- degradation product from fibrin are able to form a gel giving a though 2 general patterns can be defined. In acute dis- positive test. The paracoagulation tests in contrast to the seminated intravascular coagulation spontaneous bleeding is tanned red cell hemagglutination inhibition assay or staphylothe most common finding usually presenting as cutaneous coccal clumping tests are less time consuming, simple to petechiae or ecchymoses. Bleeding from venipuncture sites, the perform and highly specific, making them suitable as a gastrointestinal tract, incisions and the urinary tract also is screening test for disseminated intravascular coagulation. common.• Large areas of skin necrosis, respiratory distress, However, these tests are less sensitive than the tanned red cell pulmonary infiltrates, hypotension, convulsions and coma may hemagglutination inhibition assay or staphylococcal clumping be present. When oliguria is accompanied by hematuria, renal tests in detecting degradation products of fibrinogen and damage exists varying from acute tubular necrosis to diffuse fibrin. Because of the difference in sensitivity a negative bilateral renal cortical necrosis. In contrast, the clinical paracoagulation test does not rule out a disseminated intravaspattern of chronic disseminated intravascular coagulation is cular coagulation state since it is possible to have an elevation usually a low grade bleeding tendency with or without venous of degradation products of fibrinogen and fibrin and yet have
DISSEMINATED INTRAVASCULAR COAGULATION IN UROLOGIC PATIENT
insufficient concentrations of fibrin monomers and/or the high molecular weight X degradation product of fibrin to form a gel. Other laboratory tests may be useful but are limited by their availability. The thrombin time measures the interval for formation of fibrin after thrombin is added to the patient's plasma. It is prolonged when either the fibrinogen level is sufficiently decreased (less than 130 mg. per dl.) or when degradation products of fibrinogen and fibrin are present in sufficient quantities to interfere with polymerization of fibrin monomers. The thrombin time has been advocated as a screening test for disseminated intra vascular coagulation 30 but it may be normal in milder disseminated intravascular coagulation states because of its intermediate sensitivity. Determining clotting factor V level may be valuable in the diagnosis of disseminated intravascular coagulation but it is assayed only in larger coagulation laboratories. There are several cautions in the interpretation of laboratory results in patients suspected of having disseminated intravascular coagulation. Test results may reflect other abnormalities such as liver disease, congenital factor deficiencies, heparin administration and other drug effects, faulty blood drawing, inflammation and many other disease processes. These may affect the levels and/or activity of hemostatic components independently of (or associated with) an intravascular coagulation process. For example fibrinogen levels may be elevated in association with inflammation and factor VIII levels may rise rapidly under stressful situations such as operation or fever. 33 If disseminated intravascular coagulation is suspected in these patients normal coagulation studies may be obtained during the early phase of disseminated intravascular coagulation because clotting factors and platelets, although being consumed, are still adequate for normal test results. Repetition of these tests several hours later including degradation products of fibrinogen and fibrin determination may then support the clinical suspicion of disseminated intravascular coagulation. Appropriate treatment should then be started. TREATMENT
The most important principle in the management of patients with disseminated intravascular coagulation is control or elimination of the underlying disease sometimes referred to as the triggering event. 4 • 19 • 30• 33 ' 38 Many of the acute forms of disseminated intravascular coagulation are initiated by events that are either brief and self-limited or readily treatable so that spontaneous cure is usually the rule. When septicemia is the triggering mechanism administration of appropriate antibiotics and surgical drainage of the source of infection help prevent the further release of endotoxin. Correction of coexisting shock limits the severity of disseminated intravascular coagulation. 39 In those patients with widespread malignancy and chronic disseminated intravascular coagulation the underlying disease is not readily controlled. In fact, chemotherapy and radiation therapy have precipitated acute bleeding episodes. 3 °For example testosterone administration in a few patients with metastatic prostatic carcinoma has resulted in an acute hemorrhagic diathesis. 40 However, estrogen treatment has been shown in prostatic cancer patients to be beneficial in ameliorating or preventing disseminated intravascular coagulation recurrences. 38 Its administration though is associated with increased platelet aggregation and adhesiveness as well as enhanced clot formation. 41 Thromboembolic phenomena have been well documented with its use. 42 The full clinical significance of these observations relative to the causation of disseminated intravascular coagulation in estrogen-treated patients with prostatic cancer has not been determined. While attempts are being made to control the underlying disease we believe that deficient hemostatic elements should be restored although a controlled study involving this aspect of treatment has not been reported. The substances available are cryoprecipitate, fresh frozen plasma, fresh whole blood and
5
platelet concentrates. Cryoprecipitate contains high concentrations of fibrinogen without the incidence of hepatitis associated with other fibrinogen preparations. Fresh whole blood not only provides red cell mass but also platelets and clotting factors. When the underlying disease cannot be controlled and replacement of depleted hemostatic elements fails to improve the patient's clinical findings and laboratory tests, then anticoagulation with heparin is recommended. 4 • 19 The rationale lies in its interruption of the coagulation sequence preventing fibrin formation. The dose required to adequately heparinize a patient with disseminated intravascular coagulation will vary but is usually recommended as 5,000 to 10,000 units intravenously every 4 to 6 hours or a continuous intravenous infusion of 1,000 to 1,500 units every hour. 21 An adequate response is judged by improvement in the clinical picture and laboratory data. After 12 to 24 hours of heparin therapy the clotting studies and degradation products of fibrinogen and fibrin level should begin to improve. 38 The platelet count is not a valid indicator of response to treatment frequently requiring a week or more before correction occurs. Prolonged thrombocytopenia may be owing to the limited productive capacity of the megakaryocyte or to bone marrow suppression from sepsis, drugs or tumor involvement. Although oral anticoagulants have been advocated for use in chronic disseminated intravascular coagulation on the basis of experimental and clinical trials, in other studies they have not been shown effective. 38 The use of heparin in the treatment of disseminated intravascular coagulation has become controversial in recent years"· 43 -• 7 despite reports supporting its effectiveness. 4 • 18 If the activating stimulus is transitory or rapidly corrected, it is likely that a spontaneous cure through normal physiologic mechanisms will be seen even if heparin had not been used. In addition, heparin has worsened the course of several patients with disseminated intravascular coagulation resulting in fatal hemorrhage. 6 • 43 Furthermore, disseminated intravascular coagulation actually occurred in patients who were already heparinized as part of the treatment program for pulmonary em bolus.•• Heparin not only failed to prevent disseminated intravascular coagulation in these patients but may have contributed to their fatal outcome. Lastly, when heparin was used to treat disseminated intravascular coagulation owing to septic shock, no improvement in survival was noted although the coagulation defects were improved in half of the patients studied. 45 These reports and others••. 47 emphasize the need for initiation of controlled studies to more adequately determine the role of heparin in the treatment of disseminated intravascular coagulation states. In addition to treatment of the underlying disease, correction of shock, replacement of hemostatic elements and the use of heparin, the administration of drugs inhibitory to the fibrinolytic system is often considered. Epsilon aminocaproic acid* prevents the conversion of plasminogen to plasmin primarily through inhibition of circulating plasminogen activators. Its popularity in the past arose from the favorable results reported in correcting the bleeding diathesis and clotting studies in patients with cancer of the prostate and excessive fibrinolysis. "· 48 The continued use of epsilon aminocaproic acid has been occasionally associated with generalized, fatal, thrombotic states. 49 By blocking the protective fibrinolytic mechanism the thrombotic process was allowed to progress. Epsilon aminocaproic acid in conjunction with heparin has been recommended 50 but its effectiveness under these circumstances is difficult to determine. Furthermore, in recent years it has become evident that primary fibrinolysis is extremely rare and fibrinolysis may not even occur without pre-existing intravascular coagulation. 4 • 20 • 33 Therefore, epsilon aminocaproic acid
* Amicar, Lederle Laboratories, Pearl River, New York 10965.
6
PERGAMENT, SWAIM AND BLACKARD
is not a recommended or acceptable agent in the treatment of disseminated intravascular coagulation. CONCLUSIONS
Although the true incidence of disseminated intravascular coagulation is unknown it appears that the urologic patient is at high risk for development of this complication with bacterial sepsis and metastatic prostatic cancer being 2 of the most common causes. The manifestations of each vary from an acute fulminant bleeding diathesis to a chronic low grade bleeding tendency depending on the characteristics of the initiating event relative to the patient's compensatory mechanisms. The laboratory evaluation centers on the blood smear, prothrombin time, partial thromboplastin time, platelet count and plasma fibrinogen level. All are readily available in most hospitals at any time. The thrombin time, serial dilution protamine sulfate, staphylococcal clumping test and tanned red cell hemagglutination inhibition assay, if available, would also be helpful. Clotting factor assays, with the exception of fibrinogen and factor V, are of limited value. Treatment in previous years has been confusing because of uncertainty regarding the pathogenesis of the bleeding diathesis in these patients. It is now realized that primary fibrinolysis rarely, if ever, occurs. The fibrinolytic mechanism has been shown to be a normal physiologic response secondary to intravascular coagulation, generally protective in function, and, therefore, antifibrinolysins are contraindicated. Heparin has been popularized as an important adjuvant in the treatment of disseminated intravascular coagulation but even this may be unnecessary in most patients. Treatment of the underlying disorder is the most important aspect of management. REFERENCES
1. McKay, D. G.: Disseminated Intravascular Coagulation. An Intermediary Mechanism of Disease. New York: Harper & Row, Publishers, Inc., 1964. 2. Bowie, E. J. W. and Owen, C. A., Jr.: Introduction. Symposium on the diagnosis and treatment of intravascular coagulationfibrinolysis (ICF) syndrome, with special emphasis on this syndrome in patients with cancer. Mayo Clin. Proc., 49: 635, 1974. 3. Vaisrub, S.: Disseminated intravascular coagulation-a color of different horses. J.A.M.A., 231: 180, 1975. 4. Colman, R. W., Robboy, S. J. and Minna, J. D.: Disseminated intravascular coagulation (DIC): an approach. Amer. J. Med., 52: 679, 1972. 5. Straub, P. W.: Chronic intravascular coagulation. Clinical spectrum and diagnostic criteria, with special emphasis on metabolism, distribution and localization ofl 131-fibrinogen. Acta Med. Scand., suppl. 526, p. 1, 1971. 6. Merskey, C.: Defibrination syndrome or ... ? Blood, 41: 599, 1973. 7. Naunyn, B.: Untersuchungen iiber Blutgerinnung im lebenden Thiere und ihre Folgen. Arch. Exp. Path. Pharmakol., 1: 1, 1873. 8. Schaffer, J.: Ueber die angebliche Gerinnung des Bluts im lebenden Thier nach Injection freier fibrinoplastischer substanz in die Gefassbahn. Chi. f. d. med. Wissensch., 10: 145, 1872. 9. Bordet, J. and Delange, L.: Injections intraveineuses de cytoszyme et coagulabilite du sang. Compt. rend. Soc. de Biol., 75: 168, 1913. 10. Schneider, C. L.: The active principle of placental toxin: thromboplastin; its inactivator in blood: antithromboplastin. Amer. J. Physiol., 149: 123, 1947. 11. Jurgens, R. and Trautwein, H.: Ueber Fibrinopenie (Fibrinogenopenie) beim Erwachsener, nebst Bermerkungen iiber die Herkwas des Fibrinogens. Deutsch. Arch. Klin. Med., 169: 28, 1930. 12. Tagnon, H. J., Whitmore, W. F., Jr., Schulman, P. and Kravitz, S. C.: The significance of fibrinolysis occurring in patients with metastatic cancer of the prostate. Cancer, 6: 63, 1953. 13. Andersson, L.: Fibrinolysis in patients with prostatic cancer. Acta Chir. Scand., 126: 172, 1963.
14. Pellman, C. M., Ridlon, H. C. and Phillips, L. L.: Manifestation and management of hypofibrinogenemia and fibrinolysis in patients with carcinoma of the prostate. J. Urol., 96: 375, 1966. 15. Rapaport, S. I. and Chapman, C. G.: Coexistent hypercoagulability and acute hypofibrinogenemia in a patient with prostatic carcinoma. Amer. J. Med., 27: 144, 1959. 16. Straub, P. W., Riedler, G. and Frick, P. G.: Hypofibrinogenaemia in metastatic carcinoma of the prostate: suppression of systemic fibrinolysis by heparin. J. Clin. Path., 20: 152, 1967. 17. Rodriguez-Erdmann, F.: Bleeding due to increased intravascular blood coagulation, hemorrhagic syndrome caused by consumption of blood clotting factors (consumption-coagulopathies). New Engl. J. Med., 273: 1370, 1965. 18. Merskey, C., Johnson, A. J., Kleiner, G. J. and Wohl, H.: The defibrination syndrome: clinical features and laboratory diagnosis. Brit. J. Haematol., 13: 528, 1967. 19. Samaha, R. J., Bruns, N. C. and Ross, G. J., Jr.: Chronic intravascular coagulation in metastatic prostate cancer. Arch. Surg., 106: 295, 1973. 20. Gans, H.: Is primary fibrinolysis a real entity? Surg., Gynec. & Obst., 136: 975, 1973. 21. Wintrobe, M. M.: Clinical Hematology, 7th ed. Philadelphia: Lea & Febiger, pp. 1211-1224, 1974. 22. Williams, W. J., Beutler, E., Erslev, A. J. and Rundles, R. W.: Hematology. New York: McGraw-Hill Book Co., p. 1236, 1972. 23. Cooper, H. A., Bowie, E. J. and Owen, C. A., Jr.: Chronic induced intravascular coagulation in dogs. Amer. J. Physiol., 225: 1355, 1973. 24. O'Meara, R. A. Q.: Coagulative properties of cancers. IrishJ. Med. Sci., series 6, p. 474, 1958. 25. Deykin, D.: The clinical challenge of disseminated intravascular coagulation. New Engl. J. Med., 283: 636, 1970. 26. McGrath, J. M. and Stewart, G. J.: The effects of endotoxin on vascular endothelium. J. Exp. Med., 129: 833, 1969. 27. Sherry, S.: Fibrinolysis. Ann. Rev. Med., 19: 247, 1968. 28. Cooper, H. A., Bowie, E. J. W., Didisheim, P. and Owen, C. A., Jr.: Paradoxic changes in platelets and fibrinogen in chronically induced intravascular coagulation. Mayo Clin. Proc., 46: 521, 1971. 29. Davis, R. B., Theologides, A. and Kennedy, B. J.: Comparative studies of blood coagulation and platelet aggregation in patients with cancer and nonmalignant diseases. Ann. Intern. Med., 71: 67, 1969. 30. Peck, S. D. and Reiquam, C. W.: Disseminated intravascular coagulation in cancer patients: supportive evidence. Cancer, 31: 1114, 1973. 31. Miller, S. P., Sanchez-Avalos, J., Stefanski, T. and Zuckerman, L.: Coagulation disorders in cancer. I. Clinical and laboratory studies. Cancer, 20: 1452, 1967. 32. Sun, N. C. J., Bowie, E. J. W., Kazmier, F. J., Elveback, L. R. and Owen, C. A., Jr.: Blood coagulation studies in patients with cancer. Mayo Clin. Proc., 49: 636, 1974. 33. Rodriguez-Erdmann, F.: The syndrome of intravascular coagulation. Postgrad. Med., 55: 91, 1974. 34. Bull, B. S., Rubenberg, M. L., Dacie, J. V. and Brain, M. C.: Microangiopathic haemolytic anaemia: mechanisms of red-cell fragmentation: in vitro studies. Brit. J. Haematol., 14: 643, 1968. 35. Niewiarowski, S. and Thomas, D. P.: Measurement of the level of fibrinogen degradation products (FDP) in serum by staphylococcal clumping test. Thromb. Diath. Haemorrh., suppl. 45, p. 373, 1971. 36. Merskey, C., Kleiner, G. J. and Johnson, A. J.: Quantitative estimation of split products of fibrinogen in human serum, relation to diagnosis and treatment. Blood, 28: 1, 1966. 37. Seabaugh, D. R., Pappas, J., Seaman, A. and Hodges, C. V.: Disseminated intravascular coagulation and the urologist. J. Urol., 106: 267, 1971. 38. Vreeken, J.: Diffuse intravascular coagulation (DIC): a basic mechanism of disease in internal medicine. A survey of recent developments. Neth. J. Med., 16: 237, 1973. 39. Hardaway, R. M., III: Disseminated intravascular coagulation (DIC). J.A.M.A., 227: 657, 1974. 40. Ellman, L.: Generalized bleeding following the treatment of prostatic carcinoma with testosterone and radioactive phosphorus. J. Urol., HO: 331, 1973.
D13SEJ:vn:N.ATBD lNT}i,1--":_\lASCUi:AR COAGULATION
41. Dugdale, M. and Masi, A. T.: Hormonal contraception and thrornboembolic disease: effects of the oral contraceptives on hemostatic mechanisms. A review. J. Chron. Dis., 23: 775, 1971. 42. Blackard, C. E., Doe, R. P., Iviellinger, G. T. and Byar, D. P.: Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer, 26: 249, 1970. 43. Green, D., Seeler, R. A., Allen, N. and Alavi, I. A.: The role of heparin in the management of consumption coagulopathy. Med. Clin. N. Amer., 56: 193, 1972. 44. Klein, H. G. and Bell, W.R.: Disseminated intravascular coagulation during heparin therapy. Ann. Intern. Med., 80: 477, 1974. 45. Corrigan, J. J., Jr. and Jordan, C. M.: Heparin therapy in septicemia with disseminated intravascular coagulation. Effect on mortality and on correction of hemostatic defects. New Engl. J. Med., 283: 778, 1970.
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7
46. Lasch, H. G. and Heene, D. H.: Heparin of diffuse intravascular coagulation (DIC). Thromb. Haernorrh. 33: 105, 1974. 47. Straub, P. W.: A case against heparin therapy of intravascular coagulation. Thromb. Diath. Haemorrh., 33: 107, 1974. 48. Nilsson, I. M., Andersson, L. and Bjorkman, S. E.: Epsilonaminocaprnic acid (E-ACA) as a therapeutic agent based on 5 year's clinical experience. Acta Med. Scand., suppl. 448, p. 1, 1966. 49. Naeye, R. L.: Thrombotic state after hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood, 19: 694, 1962. 50. Bergin, J. J., Crosby, W. H. and Jahnke, E. J.: Massive bleeding with fibrinolysis: management with heparin and epsilon aminocaproic acid. Milit. Med., 131: 340, 1966. 1