Hemophilia: Current Concepts in Management

Symposium on Hemorrhagic Disorders

Hemophilia Current Concepts in Management

David Green, M.D.,* and Nathan J. Smith**

Our current concepts of the management of hemophilia have their origins in the proscription of the ancient Talmud against ritual circumcision in a child whose siblings had bled excessively with this procedure. 39 The often dramatic hemorrhages in those afflicted have challenged the inventiveness and ingenuity of generations of therapists. The earliest remedies consisted of the topical use of astringents, strong styptics, healing herbs, opiates, and even bleeding with leeches! Ott031 reported the "sulphate of soda ... to be completely curative of hemorrhages." However, by 1872, it was recognized that the use of ice combined with compression of the bleeding site offered a reasonable method of controlling bleeding. 25 The local introduction of ice was even recommended for rectal bleeding! For internal bleeding, any of the following were administered: lead acetate, alum, mineral acids, oil of turpentine, tannin, gallic acid, strychnine, creosote, arnich, opium, and the tincture of the common shepherd's purse. A more rational therapy consisted of ergot,5 to 10 grains every hour. Legg,25 to whom we are indebted for this compendium of agents employed by his contemporaries, felt that the tincture of the perchloride of iron was most beneficial, especially when accompanied by purging with magnesium sulfate. He also emphasized the waters of Harrowgate, "especially as the air there is dry and bracing." The use of hypnosis has been found to have remarkable and salutary effects. The well-documented relief afforded to Alexis the Czarevitch by Rasputin indicates the potent analgesic effect of hypnosis. 29 In recent times, Lucas and Tocantins 26 reported that hypnosis of hemophilic subjects prior to dental extraction resulted in freedom from pain and a decrease in blood loss. The modern treatment of hemophilia began in 1840, when Lane23 described the successful transfusion of blood from a "stout, healthy *Assistant Professor of Medicine, Northwestern University Medical School, Chicago, Illinois *':'Executive Director, Midwest Chapter, National Hemophilia Society, Chicago, Illinois

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young woman" to an 11 year old hemophiliac exsanguinating following a surgical operation to correct a squint. The blood was collected into a funnel, drawn into a syringe, and injected into the patient. The patient was apparently moribund at the outset, but following infusion of 5 1/2 ounces of blood, was able to sit up and drink" a glass of wine and water from his own hand." However, transfusion fell into disfavor when operators employed animal blood or permitted air to be injected into the recipientY Safe blood transfusions did not become possible until Landsteiner discovered the blood groups in 1901. 22 In 1938, Macfarlane27 emphasized that rational treatment of hemophilia could be realized only by first understanding the physiology of normal clotting and hemostasis. From the evidence available at that time, he concluded that "there is in normal blood a factor ... that is essential for the rapid activation of prothrombin and that this factor is at fault in haemophilia." This factor was identified as "antihemophilic globulin" by Patek and Taylor. 33 It was not until 1955, however, that a test was devised which could rather specifically measure the coagulant activity associated with the antihemophilic factor: the modified thromboplastin generation test of Biggs, Eveling, and Richards. 6 In Oxford, the development of this assay procedure and the preparation of animal antihemophilic globulin were undertaken simultaneously, and in 1954 the use of this animal material to control bleeding in hemophilic patients was first reported. 28 Human concentrate became available in 1957 and 1958, but the amounts of starting material required for the preparation of this material greatly limited its availability. Infusions of fresh frozen plasma were the mainstay of therapy. With increasing clinical experience and the use of specific assay techniques, it soon became apparent that the volumes of plasma required to effect hemostasis after major trauma or surgery were in excess of what the cardiovascular system of the patient could reasonably tolerate. A major breakthrough came in 1965, when Pool and Shannon34 described a simple method of concentrating antihemophilic factor by employing the technique of cryoprecipitation. Human factor VIII concentrates are now available from commercial sources and from blood banks throughout the world.

CLOTTING FACTOR CONCENTRATES The control of hemorrhage in patients with factor VIII (antihemophilic factor) deficiency is now ordinarily achieved by the administration of a suitable factor VIII concentrate. The characteristics of several varieties of concentrates are shown in Table 1. The factor VIII activity of the therapeutic material is measured as ml. of plasma equivalent-l unit of activity is equivalent to 1 ml. of fresh normal plasma. An initial dose of 30 units per kg. of body weight will raise factor VIII levels to roughly 50 per cent of normal. Levels of 25 to 50 per cent may then be maintained by giving 15 units per kg. every 12 hours (the half-life of factor VIII). The factor VIII level in the patient should be measured after a

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dose to insure that the expected levels of the factor have actually been achieved. Rizza and Biggs37 recG.nmend 12-hourly doses of 10 to 15 units per kg. of body weight for the treatment of spontaneous bleeding, up to 30 units per kg. for dangerous hematomas or to cover dental extractions, and 50 to 100 units per kg. for serious trauma or in those undergoing major surgery. Surgical procedures should not be undertaken until (a) one is certain that adequate levels of plasma factor VIII can be achieved-Le., the patient does not have factor VIII antibodies (see page 145)-and (b) sufficient factor VIII is available to cover the entire period of wound healing, even if this is prolonged by infection. Although patients with hemophilia B (Christmas disease, factor IX deficiency) are clinically indistinguishable from those with classical hemophilia, they do not respond to cryoprecipitate or factor VIII concentrates. They also respond less well to plasma, perhaps because the factor they are lacking, factor IX, has a larger area of distribution than factor VIIJ.7 Factor IX has been concentrated from normal plasma, however, and a potent factor IX concentrate is available for the treatment of these patients (Konyne, Cutter Laboratories). The principles of treatment are similar to those for classic hemophilia, with the exception that the doses are usually slightly larger (a standard dose would be 20 units per kg. of body weight) and the infusions are given less frequently (once per 24 hours). It is well recognized that the prompt institution of replacement therapy for bleeding episodes leads to a more rapid resolution of hemorrhages along with a significant reduction in pain, disability, and time lost from school or job. Therefore, three alternative methods for providing such prompt care have been proposed. 1. A prophylactic program of replacement therapy either daily or every other day, irrespective of whether there is bleeding. 2. A home treatment program, with the patient or family administering the therapeutic material when needed. 3. Home storage of the therapeutic material, which is administered by a locally based physician or hospital when required. Prophylactic therapy has been described from at least four treatment centers. 16 • 19, 24, 38 In carefully selected cases, it was found that either the daily or every other day intravenous infusion of factor VIII concentrate obviated the need for frequent hospital admissions and reduced the risk of serious hemorrhage. Home treatment programs have been enthusiastically recommended by Rabiner and co-workers at Michael Reese Medical Center,36 and by Lazerson at Stanford. 24 Patients or families are instructed in the techniques necessary for administration of therapeutic material. In the Michael Reese program, when a patient experiences a bleeding episode, he contacts a physician at the hospital, who decides whether the hemorrhage can be safely managed at home. If it is a minor bleed, the :patient is instructed to "treat" himself. The patient subsequently report's results of the therapy and, based on his report, a decision is made as to whether further care is indicated. After approximately 2 years of experience with this program, it has been observed that

Stable, dried preparations of antihemophilic factor derived from human plasma.

Factor VIII deficiency, especially in life-threatening situations where a dose of known potency must be administered. Reconstitute dried concentrate with supplied diluent. Agitate gently until dissolved (more rapid at 37° C.). Administer with a plastic syringe through tubing containing an in-line filter.

Concentrated portion of the plasma containing factor VIII and fibrinogen. Plasma is quickfrozen and thawed in refrigerator slowly. When thawed plasma is drawn off, factor VIII and fibrinogen remain.

Hemophilia A (factor VIII or AHF deficiency), von Willebrand's disease, hypofibrinogenemia. Mainly for situations where bleeding is not immediately life-threatening.

Bags are thawed in 37" C. water bath. Administer immediately with a plastic syringe and tubing containing an in-line filter, or with a blood administration set. Administer at a rate of approximately 10 m!. per minute.

Description

Indications

Administration

FACTOR VIII CONCENTRATES

COMMERCIALLY PREPARED

Reconstitute with supplied diluent. Agitate slowly until dissolved (2 to 5 minutes). Administer with plastic syringe.

Hemophilia B (factor IX deficiency), and factor II, VII, and X deficiencies.

Stable, dried, purified plasma fraction comprising coagulation factors II, VII, IX, and X with minimal amount of protein.

FACTOR IX CONCENTRATE

COMMERCIALLY PREPARED

Plasma Products Used in the Treatment of Hemophilia

BLOOD BANK CRYOPRECIPITATE

Table 1.

:=

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z>

:=

Z > ..,

Ij

Z

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to to Z

PO

GJ

El

tI > <

00

.... Q

Hepatitis virus may be present.

Refrigerate concentrate. Cutter (Konyne): 14 cents per IX unit.

Hepatitis virus may be present. Occasionally fibrin precipitates in Courtland material.

Refrigerate concentrate. Courtland: 10 cents per VUI unit. Hyland: 16 cents per VIII unit. Parke, Davis: 12 cents per VIII unit.

Hepatitis virus may be present although chance is less than with commercial products because each bag of "cryo" is from a single donor. Potency may be quite variable from bag to bag. Precipitated fibrin may clog filter.

Freeze: -20" C. or below.

7 cents per VIII unit.

Disadvantages

Storage

Cost

"Modified from a table prepared by the Regional Hemophilia Rehabilitation Center, Orthopaedic Hospital, Los Angeles.

Flushing, chills, headache, tingling if administered too rapidly.

Rare; occasional flushing. Hemolysis may occur when large doses are given to patients of blood groups A, B, or AB.

"Allergic reaction" as hives, itching. Antihistamines should be given to counteract. With large doses of ABO-Rh incompatible material, hemolysis may occur.

Side Effects

250 factor IX units per vial.

Varies with company, but potency always indicated on label.

90 to 100 VIII units per bag. Usually processed as double-units or in a syringe containing approximately 200 to 250 units. Potency of individual bags is not furnished.

Potency

.... o 1.0

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DAVID GREEN AND NATHAN

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patients are receiving more frequent treatment, suffering less disability, and spending much less time in the hospital. Prophylactic treatment is probably not warranted if the patient has infrequent bleeding episodes, if the cost of therapeutic materials is particularly high in a given geographical area, or if home treatment is not acceptable to either the patient or his family. In such situations, it would seem prudent to encourage the patient to maintain a supply of either factor VIII or factor IX concentrate in his home freezer or refrigerator. The reason for this is that many local dispensaries do not stock this material. The authors have occasionally observed instances where, following a fall at home or an automobile accident, the patient is brought to an institution where concentrate is not available. The family arrives on the scene, requests that concentrate be given, and is told that the patient will have to be transported to a medical center for such therapy. This leads to cOlisiderable delay in institution of specific treatment, often with dire consequences for the patient.!4 Although infusions of materials containing factor VIII or factor IX are specific for the treatment of hemophilia, there are a number of adjunctive measures which may be of value either in preventing serious hemorrhage, in potentiating transfusion therapy, or in treating the deformities resulting from previous bleeding.

HORMONAL AGENTS ADRENAL CORTICOIDS. Factor VIII levels are elevated in patients with Cushing's syndrome and in nonhemophilic patients receiving corticosteroid therapy.32 A controlled trial of steroids in a group of hemophilic children resulted in slight increases in factor VIII levels but no alterations in the severity of bleeding or disability.s The hazardous side effects of long-term steroid therapy are well known and do not justify the chronic use of these agents. 5 However, steroids may be a useful adjunct to factor VIII infusions when acute bleeding problems are encountered. Beneficial results were reportee! by Trieger and McGovern45 in patients undergoing dental extraction, and by Abildgaard et al.! in patients with hematuria. Kisker and Burke,2! in a double-blind study, noted that significantly less replacement therapy was required to relieve the pain of acute hem arthroses if steroids were given concomitantly. The question of whether the relief of pain was due to an actual decrease in the extent of bleeding, or to the nonspecific anti-inflammatory effect of the steroids, was unanswered. Long-term follow-up of these cases is not yet available. CONTRACEPTIVES. Patients with von Willebrand's disease and carriers of hemophilia often have decreased levels of factor VIII. Normal factor VIII activity has been observed when these patients take oral contraceptives. 40 , 4;) Interpretation of these findings is made difficult by the fact that these agents increase the levels of several clotting factors, factor VII and X in particular. Increased levels of these latter factors may masquerade as increased factor VIII activity when factor VIII is assayed by a one-stage technique. That this is so in patients taking oral con-

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traceptives has recently been confirmed by Crowell et al. IO In addition, a controlled trial of oral contraceptives in patients with hemophilia showed that these agent~ were no more effective than a placebo. 4 THYROXINE AND TRI-IODOTHYRONINE. These agents produce slight increases in factor VIII levels, but the associated metabolic side effects of the preparations outweigh the beneficial effects on the hemorrhagic disorder.I7 VASOPRESSIN AND ESTROGENS. These appear to affect hemostasis through their actions on platelets or vessels rather than factor VIII. The use of these agents as an adjunct to factor VIII therapy in patients with hemophilia has not been reported.

ANTIFIBRINOLYTIC AGENTS Several years ago peanuts were thought to be of value in controlling the number and severity of hemorrhages in patients with hemophilia. The active principle is a protease inhibitor with an antifibrinolytic activity similar to that of epsilon-aminocaproic acid CEACA).2 Antifibrinolytic agents may protect formed clots from the physiological fibrinolytic activity of plasma. Where fibrin formation is delayed, as in hemophilia, these substances permit the formation of a firmer clot. However, double-blind trials employing either peanut extract47 or EACN4 in prophylactic regimens have not demonstrated a substantial beneficial effect. On the other hand, these agents, like the corticosteroids, may be of value as adjuncts in the treatment of specific bleeding episodes. EACA seems particularly valuable in the management of dental extractions in hemophiliacs. When combined with an initial infusion of factor VIII to control operative bleeding, and careful surgical technique, EACA administration can markedly reduce the need for factor VIII infusions. 48 With this regimen, it has been possible to perform dental extractions in the outpatient department, with considerable savings in expense and factor VIII concentrate. Although EACA has been used to control hematuria in hemophiliacs,3 in a few instances clots forming in the excretory pathways led to obstructive uropathy with loss of renal function 42 and death in one patientP

MANAGEMENT OF HEMARTHROSES A good long-term study comparing joint aspiration and replacement therapy with replacement therapy alone has not been reported; therefore, the value of aspiration in preventing joint deformity cannot be ascertained. Following the experimental studies of Trueta,46 it is clear that blood, in itself, is damaging to the articular cartilage. An example of the effect of repeated hemC?rrhages in the shoulder joint over a period of 1 year is shown in Figure '1. Although aspiration will certainly not remove all of the blood in the joint, it will relieve increased pressure within the joint. While aspiration is routinely performed by a few centers, the

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Figure 1. Effect of repeated hemarthroses in the left shoulder joint of a 24 year old man with severe factor IX deficiency. Above, initial radiograph showing a few areas of cystic change in the humeral head and neck. Below, 1 year later, now showing multiple cystic areas in the humeral head and neck and also in the scapula.

majority aspirate only severely distended joints. However, all investigators emphasize that prompt, adequate replacement therapy is probably the most important factor in treatment. If adequate factor VIII levels are achieved (above 10 per cent), then there would seem to be little reason for immobilization of the affected joint. Without immobilization, there is less chance for muscle atrophy, and less absenteeism from work or school.

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ANALGESIC AGENTS Analgesic agents are extremely important adjuncts in the treatment of patients with hemophilia. However, there are several major problems associated with their use. First, they should not be given intramuscularly unless the patient has already received adequate replacement therapy. Secondly, the use of agents containing aspirin should be avoided. There is no question but that aspirin ingestion increases the bleeding tendency in patients with hemophilia. Mielke and Britten30 demonstrated marked prolongation of the bleeding time in hemophiliacs given 1 gm. of aspirin. Kaneshiro et al.,t8 in a similar study involving 19 patients with severe hemophilia, noted that bleeding times were markedly prolonged by aspirin in eight, and in seven, transfusions were required to stop the bleeding. The mechanism appears to be an inhibitory effect on platelet aggregation, which, combined with the intrinsic defect in the clotting factors, potentiates serious bleeding. Therefore, it is strongly recommended that hemophiliacs never receive aspirin in any form.35 Acetaminophen or propoxyphene are suitable substitutes. 46 Finally, because these patients suffer repeated episodes of painful hemorrhage, the frequent use of potent analgesics (narcotics) may lead to drug addiction. This complication can be avoided if bleeding is controlled by early and adequate replacement therapy.

MANAGEMENT OF OTHER DISORDERS IN PATIENTS WITH HEMOPHILIA Infections Respiratory infections pose three serious threats to the hemophiliac. First, he may inadvertently receive aspirin to control fever, with the attendant dangers described above. Second, epistaxis and hemoptysis may occur secondary to the local inflammatory process. These can be controlled by replacement therapy. Finally, perhaps as a result of coughing, he may develop a sublingual hematoma. As this lesion enlarges, it compresses the pharynx and larynx, leading to progressive dysphagia, hoarseness, and ultimately, airway obstruction. This constitutes a medical emergency, requiring prompt and vigorous replacement therapy, hospitalization, and careful observation for evidence of progression. Hemophiliacs are especially liable to wound infections. Traumatic and surgical wounds are frequently accompanied by hematoma formation, providing a suitable environment for bacterial growth. As with any wound infection, identification of the infecting organism, determination of its antibiotic susceptibility, and the prompt institution of the appropriate agent is essential. A category of infection which is uncommon in the general population, but which should always be considered in patients with hemophilia, is transfusion-transmitted malariaY Malaria should be suspected when one is confronted by a hemophiliac with unexplained fever.

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Disorders of the Nervous System Subdural hematomas commonly occur in hemophilic infants as a result of falling from the crib and in young adults after auto accidents. Prompt therapy with factor VIII and IX concentrates is essential, although many patients nonetheless eventually require craniotomy. Once a decision for surgical intervention has been reached, there should be no delay in preparing the patient. Sufficient replacement therapy should be mobilized so that clotting factor levels can be raised to 100 per cent of normal, and maintained at or near this level until the patient has fully recovered from the operative procedure. Femoral nerve compression occurs when there is hemorrhage under the thick fascia of the iliacus muscleP The presenting symptom is pain in the inguinal area. The hip is held in flexion and there is cutaneous anesthesia over the surface of the thigh, paralysis of the quadriceps, and loss of the patellar tendon reflex. These patients should be treated promptly and vigorously with sufficient amounts of concentrate to raise their factor levels to at least 50 per cent of normal. With adequate replacement therapy, the prognosis for nerve recovery is excellent. Aspiration or other methods of surgical decompression are usually not indicated. Disorders of the Cardiovascular System It has now been amply documented that adult patients with hemophilia are subject to the same incidence of atheromatous vascular disease as nonhemophiliacs. Acute myocardial infarction following thrombosis of the right coronary artery was reported in a 57 year old man with less than 1 per cent factor VIII.15 The vascular occlusions in these patients are on the arterial side, and are due to platelet-fibrin thrombi. Therefore the proper anticoagulant for the treatment of a myocardial infarction in a patient with hemophilia would be an antiplatelet substance such as dipyridamole. There has been no experience with this agent in hemophiliacs with occlusive cardiovascular disease.

Disorders of the Gastrointestinal System Gastrointestinal bleeding is very common in severe hemophiliacs and may take the form of hematemesis, melena, or bleeding into the bowel wall. In the latter situation, the picture of an acute bowel obstruction or even appendicitis may be simulated. The patient should be treated with factor VIII or IX replacement and then carefully observed. Surgery should not be undertaken unless it is clear that there has been no response to adequate doses of the concentrates. Duodenal ulcer occurs with some regularity in adults with hemophilia and is associated with repeated episodes of gastrointestinal bleeding. 9 Therefore it has been recommended that elective ulcer surgery be performed in these patients once documented hemorrhage from a duodenal ulcer has occurred. Disorders of the Genitourinary System Hematuria occurs often in hemophiliacs and is best treated by bedrest or, if it is refractory to this measure, then factor replacement.

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The disadvantages of EACA therapy for hematuria have already been mentioned. Disorders of the Muscubskeletal System Cuts of the lips and tongue, as well as epistaxis, are frequent and potentially serious occurrences in young children with hemophilia. These lesions should never be treated by cauterization, which usually causes more tissue destruction, infection, and bleeding. Rather, local compression should be tried first, and if it is ineffective, replacement therapy should be instituted. Protective splints are often helpful in preventing recurrences. The management of acute hem arthrosis has been discussed. The treatment of deforming arthropathy is beyond the scope of this presentation; however, with the availability of replacement therapy, it is now possible to provide adequate factor VIII or IX levels to cover any orthopedic surgery that may be deemed necessary to correct deformities. Social Aspects The modern management of hemophilia stresses the maintenance of a normal home environment. Rabiner et al. 36 indicated that patients on the home transfusion program are capable of leading more normal lives because treatment is so much more accessible. The availability of both commercially and locally prepared clotting factor concentrates has assured that bleeding episodes can be rapidly controlled without the feared sequelae of former years. Therefore, the old idea that a hemophiliac must be protected from even the most minor trauma is no longer tenable. On purely psychological grounds, this concept prevents the development of the individual's character. Repeated frustration leads to rash behavior. Physicians should recognize that these patients are not fragile and that the frequency of bleeding episodes does not correlate with the amount of physical activity-in fact, the opposite may be true. Katz20 has recently analyzed the replies of 1055 hemophiliacs to questions concerning educational achievement, employment, income, social achievement, and attitudes toward hemophilia. The majority of hemophiliacs interviewed emphasize the theme that a child with hemophilia must learn his own limitations through his own experiences. "Encourage him to be independent but sociable and send the child to regular school ... the physical risks are justified by the resulting mental and emotional development." The opportunity to learn by himself his own limitations provides the hemophiliac with the self-confidence necessary to lead a normal life. REFERENCES 1. Abildgaard, C. F., Simone, J. v., and Schulman, I.: Steroid treatment of hemophilic hematuria. J. Pediat., 66:117-119,1965. 2. Astrup T., Brakman, P., Oilendorff, P., and Rasmussen, J.: Haemostasis in haemophilia in relation to the haemostatic balance in the normal organism and the effect of peanuts. Thromb. Diath. Hemorrh., 5:329-340, 1961. 3. Barkhan, P.: Haematuria in a haemophiliac treated with E-aminocaproic acid. Lancet, 2:1061, 1964.

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4. Beck, P., Bloom, A. L., Giddings, G. C., and Sweetnam, P. M.: A controlled trial of oral contraceptives in haemophilia. Brit. J. Haemat., 19:667-673,1970. 5. Bennett, A. E., and Ingram, G. I. C.: A controlled trial of long-term steroid treatment in haemophilia. Lancet, 1 :967-970, 1967. 6. Biggs, R, Eveling, J., and Richards, G.: The assay of antihaemophilic-globulin activity. Brit. J. Haemat., 1 :20-34, 1955. 7. Breckenridge, RT., and Ratnoff, O. D.: Therapy of hereditary disorders of blood coagulation. In Ratnoff, O. D., ed.: Treatment of Hemorrhagic Disorders. New York, Harper and Row, 1968, pp. 39-60. 8. Canale, V. C., Hilgartner, M. W., Smith, C. H., et al.: Effect of corticosteroids on factor VIII leveL J. Pediat., 71 :878-880, 1967. 9. Carron, D. B., Boon, T. H., and Walker, F. C.: Peptic ulcer in the haemophiliac and its relation to gastrointestinal bleeding. Lancet, 2:1036-1039,1965. 10. Crowell, E. B., Jr., Clatanoff, D. V., and Kiekhofer, W.: The effect of oral contraceptives on factor VIII levels. J. Lab. Clin. Med., 77:551-557, 1971; Blood, 35: 189-194, 1970; Brit. J. Haemat., 19:667,1970. 11. Dike, A. E.: Two cases of transfusion malaria. Lancet, 1 :72-73,1970. 12. Gobbi, F.: Use and misuse of aminocaproic acid. Lancet, 2:472-473,1967. 13. Goodfellow, J., Fearn, C. B. d'A, and Matthews, J. M.: Iliacus haematoma. J. Bone Joint Surg., 498:748-756,1967. 14. Green, D.: Use of cryoprecipitate. New Eng. J. Med., 278:684, 1968. 15. Green, D., and Rizza, C. R: Myocardial infarction in a patient with a circulating anticoagulant. Lancet, 2:434-436, 1967. 16. Hirschman, R J., Itscoitz, S. B., and Shulman, N. R: Prophylactic treatment of factor VIII deficiency. Blood, 35:189-194,1970. 17. Hoak, J. C., Wilson, W. R., Warner, E. D., et al.: Effects oftriiodothyronine-induced hypermetabolism on factor VIII and fibrinogen in man. J. Clin. Invest., 48:768-774, 1969. 18. Kaneshiro, M. M., Mielke, C. H., Jr., Kasper, C. K., and Rapaport, S. I.: Bleeding time after aspirin in disorders of intrinsic clotting. New Eng. J. Med., 281 :1039-1042, 1969. 19. Kasper, C. K., Dietrich, S. L., and Rapaport, S.I.: Hemophilia prophylaxis with factor VIII concentrate. Arch. Intern. Med., 125:1004-1009, 1970. 20. Katz, A. H.: Hemophilia: A Study in Hope and Reality. Springfield, Charles C Thomas, 1970. 21. Kisker, C. T., and Burke, C.: Double-blind studies on the use of steroids in the treatment of acute hem arthrosis in patients with hemophilia. New Eng. J. Med., 282:639-642,1970. 22. Landsteiner, K.: Uber Agglutinationserscheinungen normalen menschlichen Blutes. Klin. Wschr., 14:1132, 1901. 23. Lane, S.: Hemorrhagic diathesis. Successful transfusion of blood. Lancet, 1 :185-188, 1840. 24. Lazerson, J.: The prophylactic approach to hemophilia A. Hospital Practice, 2:99-109, 1971. 25. Legg, J. W.: A Treatise on Haemophilia. London, H. K. Lewis, 1872, pp. 112-124. 26. Lucas, O. N., and Tocantins, L. M.: Management of dental extractions in hemophilia A and B. In Brinkhous, K. M., ed.: The Hemophilias. Chapel Hill, University of North Carolina Press, 1964, pp. 339-348. 27. Macfarlane, R G., quoted by Biggs, R: Thirty years of haemophilia treatment in Oxford. Brit. J. Haemat., 13:452-463,1967. 28. Macfarlane, R G., Biggs, R, and Bidwell, E.: Bovine antihaemophilic globulin in the treatment of haemophilia. Lancet, 1 :1316-1319,1954. 29. Massey, R K.: Nicholas and Alexandra. New York, Atheneum, 1967. 30. Mielke, C. H., Jr., and Britten, A. F. H.: Use of aspirin or acetaminophen in hemophilia. New Eng. J. Med., 282:1270,1970. 31. Otto, J. C.: An account of an hemorrhagic disposition existing in certain families. Medical Repository, 6:3, 1803 (reprinted in Amer. J. Med., 11 :557-558, 1951). 32. Ozsoylu, S., Strauss, H. S., and Diamond, L. K.: Effect of corticosteroids on coagulation of the blood. Nature, 195:1214,1962. 33. Patek, A. J., and Taylor, F. H. L.: Hemophilia. 11. Some properties of a substance obtained from normal human plasma effective in accelerating the coagulation of hemophilic blood. J. Clin. Invest., 16:113-124,1937. 34. Pool, J. G., and Shannon, A. E.: Production of high potency concentrates of antihemophilic globulin in a closed-bag system. New Eng. J. Med., 273:1443-1447,1965. 35. Quick, A. J.: Hemophilia and aspirin. J.A.M.A., 213:1689, 1970; New Eng. J. Med., 284:218, 1971. 36. Rabiner, S. F., and Telfer, M. C.: Home transfusion for patient's with hemophilia A. New Eng. J. Med., 283:1011-1015, 1970. 37. Rizza, C. R., and Biggs, R: Blood products in the management of haemophilia and Christmas disease. In Poller, L., ed.: Recent Advances in Blood Coagulation. Boston, Little, Brown & Co., 1969, pp. 179-195. .

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38. Robinson, P. M., Tittley, A. R. T., and Smiley, R. F.: Prophylactic treatment in classical hemophilia. Can. Med. Assoc. J., 97:559-561, 1967. 39. Rosner, F.: Hemophilia in the Talmud and rabbinic writings. Ann. Intern. Med., 70:833-837, 1969. 40. Schiffman, S., and Rapaport, S. I.: Increased factor VIII levels in suspected carriers of hemophilia A taking contraceptives by mouth. New Eng. J. Med., 275:599,1967. 41. Schmidt, P. J.: Transfusion in America in the eighteenth and nineteenth centuries. New Eng. J. Med., 279:1319-1320,1968. 42. Stark, S. N., White, J. G., Langer, L., Jr., and Krivit, W.: Epsilon aminocaproic acid therapy as a cause of intrarenal obstruction in haematuria of haemophiliacs. Scand. J. Haemat., 2:99-107, 1965. 43. Strauss, H. S., and Diamond, L. K.: Elevation of factor VIII (antihemophilic factor) during pregnancy in normal persons and in a patient with von Willebrand's disease. New Eng. J. Med., 269:1251-1252, 1963. 44. Strauss, H. S., Kevy, S. V., and Diamond, L. K.: Ineffectiveness of prophylactic epsilonaminocaproic acid in severe hemophilia. New Eng. J. Med., 273:301-304, 1965. 45. Trieger, N., and McGovern, J. J.: Evaluation ofcorticosteroids in hemophilia. New Eng. J. Med., 266:432-437, 1962. 46. Trueta, J.: The orthopaedic management of patients with haemophilia and Christmas disease. In Biggs, R., and Macfariane, R. G., eds.: Treatment of Haemophilia. Philadelphia, F. A. Davis, 1966, p. 282 . .47. Verstraete, M., and Ruys, C. A. J.: Double-blind experiments on the effect of a peanut extract on the bleeding incidence in 92 haemophiliacs. Brit. Med. J., 4:453-456, 1967. 48. Walsh, P. N., Rizza, C. R., Matthews, J. M., et al.: Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease; A double-blind controlled trial. Brit. J. Haemat., 20:463-475, 1971. 303 E. Chicago Avenue Chicago, Illinois 60611