Some complications of the therapy of hemorrhagic disorders

SOME

COMPLICATIONS OF HEMORRHAGIC

OF THE THERAPY DISORDERS

ABSTRACT.-The principal mode for treating disorders of hemostasis is correction of the patient’s hmctional defect by transfusions of appropriate fractions of normal plasma or transfusions of platelets. Two major complications of such therapy are the transmission of infectious diseases, particularly hepatitis and the acquired immune deficiency syndrome (AIDS), and the development of antibodies against clotting factors that are deficient in the patient’s plasma. Measures that reduce the occurrence of infection include careful selection of donors, fractionation of plasma with the help of monoclonal antibodies, and treatment of plasma or its fractions with heat or with virus-inactivating organic solvents. No technique of preparing or administering blood or its components can prevent the emergence of antibodies against clotting factors. Desensitization by repeated infusions of antigen, for example, antihemophilic factor, however, appears to result in remission in some patients. IN BBIEF The evolution of current methods of controlling bleeding in patients with hemostatic defects is a tale of alloyed success. This review focuses on some side effects encountered in the treatment of such patients. The control of bleeding includes local measures that promote hemostasis; correction of deficiencies of plasma clotting factors, platelets, or both; and, in some situations, prevention of the dissolution of clots. Correction of hereditary or acquired deficiencies of clotting factors visually requires transfusion of plasma or appropriate fractions of plasma but exposes the patient to a variety of adverse complications. The most dire of these, only partially resolved, are the transmission of infectious diseases, particularly hepatitis and the acquired im-

mune deficiency syndrome (AIDS), and the development of antibodies (circulating anticoagulants) against the patient’s missing factor. By the end of August 1991, about 10% of individuals in the United States with hereditary clotting disorders had acquired AIDS, and over a thousand patients had died of AIDS or AIDS-related illnesses, including opportunistic infections and lymphomas of B-cell origin, for example, Burkitt’s lymphoma. Other striking complications of AIDS include syndromes resembling idiopathic (autoimmune) thrombocytopenic purpura and primary pulmonary hypertension. Whole plasma, originally the only available agent for correcting hemostatic defects other than those associated with platelet disorders, is still the only practical source of plasma thromboplastin antecedent (factor XI), proaccelerin (factor V), fibrin-stabilizing factor (factor XIII), and in some situations, Christmas factor (factor IX). The plasma used should be from individual donors rather than pooled and should be type-specific or from an AB donor; if the patient is Rh negative, the plasma should be from an Rh-negative donor. The utility of plasma infusions is limited by the possibility that large volumes will overload the circulation. Patients may experience the same acute allergic symptoms that are commonplace when whole blood or packed red cells are transfused. A serious problem is induction of the adult respiratory distress syndrome, presumably the consequence of antileukocytic antibodies in the infused plasma. Another complication is induction of antibodies against antihemophilic factor. Treatment of bleeding episodes in patients with classic hemophilia (factor VIII deficiency) is now more effectively carried out by the use of appropriate fractions of normal human plasma. The first to gain widespread use, cryoprecipitates, can be administered without significant symptoms in most patients, but a few have reactions not unlike those induced by plasma. Cryoprecipitates must be stored in frozen condition, a problem obviated by the development of lyophilized concentrates of antihemophilic factor. The use of these lyophilized concentrates may occasionally be accompanied by symptoms characteristic of reactions to infusions of plasma, but their biggest drawback has been in the transmission of viral diseases. To address these problems, more care has been used in selection of donors; plasmas have been tested for evidence of hepatitis and human immunodeficiency virus infection; the concentrates have been heat treated; and both antihemophilic factor (factor VIII) and Christmas factor (factor IX) have been separated through the use of monoclonal antibodies. Concentrates of the vitamin K-dependent clotting factors have been used particularly in the treatment of Christmas disease (factor IX deficiency). Their efficacy has been marred by transmission of viruses of hepatitis and AIDS, the emergence of circulating anticoagulants against Christmas factor, and the induction of thrombosis. In mild classic hemophilia and in von Willebrand’s disease, the ad-

ministration of desmopressin (DDAVP, Stimate) may increase the titers of coagulant factor VIII and von Willebrand factor to hemostatic levels. Besides minor symptoms such as facial flushing, headache, nausea, and so forth, the patient may experience hyponatremia, with its accompanying symptoms, and peripheral venous thrombosis or myocardial infarction. Antifibrinolytic agents such as l -aminocaproic acid and tranexamic acid are principally useful to inhibit bleeding after dental extraction. Their use is complicated by nausea and vomiting, diarrhea, abdominal distress, light-headedness, hypotension, and syncope. Treatment of circulating anticoagulants has taken a new turn. Attempts to eradicate antibodies against antihemophilic factor by treatment with prednisone and immunosuppressive drugs have usually been disappointing. More recently, however, desensitization by repeated infusions of antihemophilic factor concentrate appears to result in remission in some patients. The future of therapy will undoubtedly be the correction of the basic defects of hereditary hemostatic disorders through molecular biologic techniques. Whether these procedures will have serious side effects is yet to be learned.

Oscar Ratnofi M.D., was born in New York City in 1926, the son of a school teacher and a pediatrician, who was one of the first in Brooklyn. He was educated in the public schools of Brooklyn, going to a high school whose graduates included Walter Stroud, Professor of Mathematics at Columbia University; Aaron Copland; Norman Mailer; and several distinguished hematologists, among them Samuel Charache and Aaron Marcus. He went to Columbia College, where he had his first taste of research with Gardner Murphy of the Psychology Department. He then attended Columbia University’s College of Physicians and Surgeons, where he had the good fortune to work with a number of faculty persons, including Beatrice Seegal and her husband, David, and Arthur J. Patek, Jr., whoprst described the defect in classic hemophilia. Dr. Ratnofiinterned on the medical service at the Johns Hopkins Hospital and then went to Harvard Medical School as a teaching fellow in Physiologv, carrying out research in neurophysiology. He returned to New York, first as an assistant resident in Medicine at Montehore Hospital for Chronic Diseases and then as a resident on the Research Service for Chronic 3ot4

Diseases at Goldwater Memorial Hospital. After 3 years in the Army Air Corps, he returned to Johns Hopkins as a fellow and then instructor in Medicine. There, by coincidence, he did research on$brinolysis in the very laboratory where Dr. William Tillett had discovered streptokinase. His mentor in Baltimore was Dr. George Mirick, and the director of the department, Dr. A. McGehee Harvey. In 1950, Dr. Ratnofl moved to Cleveland as an Assistant Professor of Medicine at Western Reserve University School of Medicine, and Associate in Medicine at Mt. Sinai Hospital of Cleveland. In 1952, he moved to University Hospitals of Cleveland where he has been ever since. Between 1960 and 1986, Dr. Ratnojjwas a Career lnvestigator of the American Heart Association. He was promoted to Professor of Medicine in 1961. Between 1970 and 1982, he was Director and then Codirector of the Division of Hematology/Oncologv of the Department qf Medicine at University Hospitals of Cleveland. Dr. Ratnofls research activities have been supported over the years by the National Institutes of Health and by the American Heart Association and its Northeast Ohio affiliate. He has been elected to various societies, among them the Central Society for Clinical Research iof which he was President in 1970 and 1971), the American Society of Hematology (of which he was President in 1974 and 1975), the American Society for Clinical Investigation, the Association of American Physicians, and the National Academy of Sciences. He is additionally a Master of the American College of Physicians, and an Honorary Fellow of the Royal College of Physicians and Surgeons of Glasgow; he holds an Honorary Doctor of Laws from the University of Aberdeen. His laboratory’s work has been recognized by a number of awards. His career has been abetted by a succession of supportive chiefs and by his family: his wife, Marian, a lawyer; his son, William, a rheumatologist at Emory University; and his daughter, Martha Fleisher, an attorney.

SOME

COMPLICATIONS OF HEMORRHAGIC

OF THE THERAPY DISORDERS

The evolution of current methods of controlling bleeding in patients with hemostatic defects is a tale of alloyed success. This review focuses on some of the side effects encountered in the treatment of patients with hemorrhagic disorders. Although sometimes to be forewarned is to be forearmed, not all complications of therapy are avoidable. The control of bleeding in patients with hemostatic abnormalities includes local measures to promote hemostasis; correction of deficiencies of plasma clotting factors, platelets, or both; and in some situations, prevention of the dissolution of the clots. Scurvy is cured rapidly by providing vitamin C. When deficiencies of the vitamin K-dependent clotting factors (prothrombin [factor 111,Stuart factor [factor Xl, proconvertin [factor VIII, and Christmas factor [factor IX]) are due to inadequate absorption or utilization of vitamin K, the defect can often be corrected by supplying this vitamin. Correction of hereditary or acquired deficiencies of these and other clotting factors usually requires transfusion of plasma or appropriate fractions of plasma but exposes the patient to a variety of adverse complications. The most dire of these, which are only partially resolved, are the transmission of infectious disease, particularly hepatitis and the acquired immune deficiency syndrome (AIDS), and the development of antibodies (circulating anticoagulants1 against the patient’s missing factor. These complications have had a devastating effect. By the end of August 1991, of the approximately 15,000 to 20,000 individuals in the United States with hereditary clotting disorders, 1698 had AIDS, including about one of every 10 patients with classic hemophilia (factor VIII deficiency) (S. Wiley, personal communication, 19911. There were 173 cases among patients with Christmas disease (factor IX deficiency) and 64 in patients with other hemostatic disorders. As of the same date, 1168 patients with bleeding disorders had died of AIDS or AIDS-related illnesses, including opportunistic infections and lymphomas of B-cell origin, for example, Burkitt’s lymphoma. The microcosm of northeast Ohio provides similarly grim data. Since January 1982, among 108 patients with classic hemophilia enrolled in a home therapy program, 19 have died of opportunistic 310

infections, two died of Burkitt’s lymphoma, five died of non-Hodgkin’s iymphoma, and one died of primary pulmonary hypertension-all disorders that have been associated with AIDS. Additionally, four died of hepatic disease, three died as a consequence of bleeding, two died of unknown causes, and one death was a suicide. of the 108 patients, at least 11 have had significant “idiopathic” thrombocytopenic purpura, 23 are alive with AIDS-related symptoms, and four other patients have overt AIDS. These data are similar to those reported by other centers. PLASMA AND PLASMA

PRODUCTS

USED IN TREATMENT

A preview of the way patients with hereditary clotting defects are now treated occurred in the early 19th century when a Mr. Samuel Lane’ reported that he was able to halt bleeding in a patient who probably had hemophilia by transfusion of whole blood. He did not describe any symptoms suggestive of a possible mismatch between the patient’s blood and that of the donor. Transfusion of whole blood did not achieve popularity for the treatment of bleeding disorders undoubtedly because of ignorance about the need to transfuse compatible blood: In the care of patients with hemostatic defects, transfusion of whole blood or, nowadays, packed red blood cells is indicated only to compensate for blood loss; the volume of whole blood needed to provide sufficient plasma for hemostasis would overload the circulation and induce congestive heart failure. PLAASkt4 Infusion of whole plasma, a logical next step that was championed by Feisslef in the 192Os, had several virtues. Plasma contains all of the blood elements needed for hemostasis except platelets, and transfusion reactions due to incompatibility between donor and recipient are usually minimal. Indeed, plasma is still the only practical source of plasma thromboplastin antecedent (factor XI), proaccelerin (factor V), and fibrin-stabilizing factor (factor XIII) and in some situations is the treatment of choice in the care of patients with Christmas disease (factor IX deficiency). Plasma is also useful in the emergency care of patients whose bleeding is attributable to acquired multiple clotting factor deficiencies, which are found in some patients with hepatic disease and in patients with deficiencies of the vitamin K-dependent clotting factors associated with treatment with coumarinlike anticoagulants such as warfarin. The infusion of plasma, or plasma exchange transfusion, is a major way to treat patients with thrombotic thrombocytopenic purpura and the hemolytic uremic s.yndrome. Plasma exchange has also been suggested as a wa.y to de11M, May

1993

311

crease the titer of circulating anticoagulants, principally against the antihemophilic factor (factor VIII), temporarily in an attempt to control bleeding in patients with this complication; the reduction in the concentration of the anticoagulants thus achieved, however, is not clinically helpful. Plasma needed for treatment of bleeding in hereditary or acquired clotting disorders can be stored for some weeks in the frozen state.3 To minimize the chance of transmitting infectious agents, plasma prepared from the blood of individual donors should be stored in separate containers; pooling plasma increases the statistical risk that any batch of plasma may contain an infectious agent. To forestall hemolytic reactions due to mismatch between the patient and the plasma to be infused, the plasma should be type-specific or from an AB donor; if the patient is Rh negative, the plasma should be from an Rh-negative donor to prevent sensitization to any Rhpositive cells that might contaminate the plasma. A useful dosage schedule in the adult is 1000 mL of plasma intravenously, followed by 500 mL every 6 to 12 hours, depending on the severity of the bleeding and the biologic half-life of the factor that the patient lacks. In patients with hereditary clotting deficiencies, the effectiveness of plasma infusions can be monitored by specific assays for the clotting factor in question. This is cumbersome, however, and a simpler clinical guide is to assay the activated partial thromboplastin time; the degree of shortening of an abnormally long partial thromboplastin time by transfusion of plasma is a rough measure of the degree to which the patient’s specific abnormality has been corrected. A handy nomogram has been published.4 A number of complications, both minor and major, limit the efficacy of plasma infusions in the care of patients with clotting factor deficiencies. As is true of whole blood, large volumes of plasma may overload the circulation, whereas lesser volumes may not be adequate to raise the titer of deficient factors to hemostatic levels.5J6 To some extent, this problem can be obviated by simultaneous administration of diuretics such as furosemide. When plasma is the only therapy available, as in the case of pamhemophilia (hereditary factor V deficiency), plasmapheresis has been used to provide adequate hemostasis7 Other complications of the use of plasma are not unique to hemorrhagic disorders. The patient may experience the same acute allergic symptoms that are commonplace when whole blood is transfused. These symptoms may be treated with antihistaminic agents such as diphenhydramine (Benadryl), 50 mg orally to adult patients. If the patient has a history of earlier allergic reactions to plasma, diphenhydramine should be given 30 minutes before the start of a plasma infusion. Rarely, the patient may experience a more formidable reaction, such as chills, fever, or an anaphylactoid response with 312

DM, May 1993

severe dyspnea, “allergic” pulmonary edema, or hypotension.’ These last responses may be related to a most serious problem, induction of the adult respiratory distress syndrome, presumably the consequence of the presence of antileukocytic antibodies in the infused plasma.’ Patients with adult respiratory distress syndrome may have fever, dyspnea, hypotension, and radiographically demonstrable pulmonary infiltratesS8’” Although this reaction is usually self-limiting, at least one death has been recorded.8 If the reaction occurs before the infusion of plasma is completed, the infusion should be stopped. When the patient has recovered, future plasma infusions should be given only with the greatest care. That plasma therapy carried the risk of transmitting hepatitis was recognized early, but the tilluency with which liver disease actually occurred was probably low. Other complications of the transfusion of plasma to patients with classic hemophilia include the induction of antibodies against factor VIII that vitiate further therapy with this agent. Additionally, transfusion of plasma, like that of whole blood, can induce hepatitis in the recipient. This possibility has been a major spur to the development, over the last half century, of techniques of fractionating plasma. Fractionation has made therapy more specific, as exemplified by the current use of fractions of plasma to promote hemostasis in patients with classic hemophilia or Christmas disease, but until recently did not have a major impact on the transmission of hepatitis.

PLASMA FRACTIONS To my knowledge, Patek and Taylo?’ were the first to use a fraction of plasma to correct the clotting defect of a patient with classic hemophilia. They precipitated the euglobulin fraction of normal plasma by dilution and acidification. This fraction, dried at room temperature in a vacuum desiccator, shortened the clotting time of hemophilic plasma in vitro, whereas the corresponding fraction of hemophilic plasma was inert. Moreover, intravenous injection of the fraction of normal plasma into each of three hemophiliacs shortened the clotting time, an effect that lasted at least 4 hours. Patek and Taylor related that the patients experienced a sensation of slight fullness in the head, and two of the three patients experienced brief chills and headache. Cohn Fraction 1 The studies of Patek and Taylor were extended by Taylor and his colleagues,” who localized the antihemophilic property of normal plasma to Cohn fraction I, that is, the fraction precipitated by addition of ethanol to a concentration of 8% This fraction was infused

intravenously to control bleeding in patients with classic hemophilia,13 but its use was abandoned because its content of factor VIII appeared to vary widely from batch to batch and because the patients who were transfused with this agent had a high incidence of hepatitis.14 Because Cohn fraction I was prepared from pooled plasma, the assumption was made that a hepatitis virus, presumably similar to that responsible for many cases of “homologous serum jaundice,” was present in one or more plasmas composing the po01.~’ Other reported complications of the use of Cohn fraction I include hemolytic anemia,13 apneic episodes,15 chills, dyspnea, abdominal distreSS,‘6 itching, urticaria, and facial edema.14 Cohn fraction I is rich in fibrinogen and was used in the treatment of hypofibrinogenemia, particularly that associated with acute disseminated intravascular coto induce hepatitis led to its loss of agulation, l7 but its propensity Food and Drug Administration approval.

Cryoprecipitated

Factor VI11

Because these early clotting factor concentrates were impractical for the management of classic hemophilia, plasma remained the agent of choice for the treatment of bleeding episodes until the mid 1960s. Then, two agents became availablecryoprecipitated and lyophilized concentrates of factor VIII. Pool, Hershgold, and Pappenhagen” made the striking discovery that, when fresh frozen plasma was allowed to thaw overnight at refrigerator temperatures, a small insoluble precipitate remained undissolved that could be concentrated by centrifugation at cold temperatures. The cold-precipitated fraction, which they called a cryoprecipitate (cry0 meaning cold), had clot-promoting activity that, they demonstrated, was due to the presence of the bulk of the factor VIII from the original plasma. The concentrated cryoprecipitates could be stored in the freezer and then thawed when needed, pooling the number of units needed for the care of the patient.” Although the amount of factor VIII varies as widely from bag to bag as it varies among normal individuals, on the average, a bag of cryoprecipitate contains about 100 units of factor VIII, one unit being the amount in 1 mL of a standard pool of plasmas derived from the blood of normal adults.” With the exception of infants, for whom a single bag of cryoprecipitate may provide hemostasis, treatment usually requires the pooling of cryoprecipitates from more than one donor, so that differences in the titer of factor VIII from bag to bag are evened out. The availability of cryoprecipitates made it possible to treat episodes of bleeding in patients with classic hemophilia effectively and to administer the large amounts of factor VIII needed to provide hemostasis, even during major surgical procedures, without vascular overload. Cryoprecipitates proved useful in the treatment of von Willebrand’s disease, as they are a rich

source of von Willebrand factor.z1 They are the only available source of fibrinogen for treatment of hypofibrinogenemia or afibrinogenemia; on the average, each unit contains about 300 mg of fibrinogen, but individual units, like their donors, vary considerably.” Cryoprecipitates have also been used to control the bleeding tendency in uremia. Moreover, the supernatant plasma that remains after cryoprecipitates have been separated can be saved for use in nonhemophilic patients or can be processed to prepare other useful fractions.23 That similar cryoprecipitates were clot promoting was recognized many years earlier by Wooldridge et a12’ and others.25,26 Pool et all8 provided insight into the therapeutic usefulness of the cryoprecipitates. It is a sad footnote of history that Remigy,27 a medical student, described that cryoprecipitates contained factor VIII in his doctoral thesis in 1955. Like Pool et al., he found that cryoprecipitates were useful in the treatment of classic hemophilia, but before he could publish the results of his studies in a medical journal, he was killed in an automobile accident. The administration of cryoprecipitates is not usually associated with acute reactions, but may result in untoward effects like those induced by plasma. The patient may experience headache, chills, fever, urticarial reactions, or frank anaphylaxis.28-30 Another, fortunately rare, acute response of interest, described by Reese et al.,31 is an acute pulmonary reaction characterized by cough, headache, lightheadedness, chill, and difficulty breathing. Radiographic studies demonstrated diffuse patchy alveolar infiltrates throughout both lung fields. Significantly, no evidence for leukoagglutinins or lymphotoxic, antiplatelet or anti-Gm antibodies were found. The condition of the patient reported by Reese et al. improved coincident with therapy with oxygen and methylprednisolone. The use of cryoprecipitates was discontinued, and the patient was then treated with lyophilized concentrates of factor VIII without incident. Whether such reactions are due to the presence in cryoprecipitates of particulate matter derived from platelets is not clear.32 Other reactions of importance after the transfusion of cryoprecipitates are the appearance of anticoagulants against factor VIII33 and infection with the viruses of hepatitis34’“” and AIDS, as will be discussed separately below.

Lyophilized

Concentrates of Factor VIII Soon after the introduction of cryoprecipitates for the treatment of classic hemophilia, other concentrates of factor VIII became available. Wagner et al.36 and Webster and coworkers37 at the University of North Carolina precipitated factor VIII from plasma by addition of neutral amino acids such as glycine; solutions of the resultant pre-

cipitate could be lyophilized, allowing storage of factor VIII without the deep freezes needed for cryoprecipitates. Commercial adaptations were soon available; in general, methods for preparing factor VIII use cryoprecipitates as starting material, but the details of preparation vary among manufacturers and may include such steps as precipitation of factor VIII from redissolved cryoprecipitates, chromatography on resins such as ECTEOLA-cellulose, or adsorption of cryoprecipitates with aluminum hydroxide to reduce contamination with the vitamin K- dependent clotting factors. The final product, factor VIII purified to a varying degree, is lyophilized in lots suitable for treatment of individual episodes of bleeding. The lyophilized products contain variable amounts of contaminating proteins, including, among others, isohemagglutinins, albumin, fibrinogen, and fibronectin. Most factor VIII preparations are poor in von Willebrand’s factor; Koate HS (Cutter, Berkeley, CA) and Humate-P IArmour, Blue Bell, PA) are exceptions to this generalization. At first, the availability of lyophilized preparations seemed an unalloyed advance in therapy, for it allowed administration of large amounts of factor VIII with no significant change in the patient’s plasma volume. Further, the lyophilized preparations were suitable for self-administration of factor VIII, providing patients with a new independence from the physician and hospital and improving their morale. Improved attendance at school and job performance provided objective evidence of the value of self-administration of factor VIII. Less clear is whether self-treatment reduced joint damage. The use of lyophylized preparations of factor VIII may be complicated by the same anaphylactoid symptoms characteristic of reactions to infusions of plasma. Patients may also experience headache, abdominal pain, and flushing. Like those treated with plasma, patients infused with lyophilized concentrates of factor VIII may develop antibodies (circulating anticoagulants) to this protein. Until recent years, the biggest drawback from the use of lyophilized factor VIII preparations was their transmission of viral diseases, including hepatitis and AIDS; the risk of AIDS has been essentially eliminated, but whether this is true of hepatitis is not yet clear. Monoclonal

Antibody-Purified

Factor VI11

The next significant improvement in factor VIII preparations was the use of insolubilized monoclonal antibodies to separate factor VIII from other plasma proteins, a principle introduced by Zimmerman.“8 In general, two techniques have been used. In one, cryoprecipitates rich in antihemophilic factor are filtered through a column of agarose to which murine monoclonal antibodies against von Willebrand factor have been attached. The column is then washed with saline

solution to remove extraneous plasma proteins (and presumably, viruses as well). A solution of calcium salts is then filtered through the column, dissociating coagulant factor VIII from the von Willebrand factor that is adherent to the murine antibody. The coagulant factor VIII is collected and lyophilized. Originally, inactivation of viruses was carried out by subjecting the lyophilized preparations to dry heating. More recently, the preparations have been heated at 60°C for 10 hours while in solution but before adsorption to the insolubilized monoclonal antibody. In an alternative scheme of purification, cryoprecipitates containing factor VIII are mixed with an organic solvent and a detergent to inactivate viruses. The cryoprecipitates are then adsorbed to an insolubilized murine antibody against factor VIII itself and, in this way, are separated born contaminating plasma proteins . Hecombinant Factor VZZZ The limited supply of factor VIII derived from plasma and the difficulty in assuring that plasma-derived fractions are free of contaminating viruses has spurred commercial development of recombinant factor VIII. Preparations that have been studied extensively have been manufactured by Cutter Biological and by Baxter-Hyland. In preliminary studies, a few immediate reactions have been described-an unusual taste in the mouth, oral dryness, erythema at the infusion site, and more worrisome, “dizziness” and mild transient hypotension.3g-41 Much more troublesome are reports that patients treated with recombinant factor VIII may develop antibodies to factor VIII.42 Concentrates of the Vitamin K-Dependent Clotting Factors At least six plasma proteins participating in hemostasis require vitamin K for completion of their synthesis-prothrombin, factors VII, IX, and X and proteins C and S. Each of these proteins is synthesized in nonfunctional, precursor form in hepatocytes. Vitamin K serves as a cofactor to a carboxylase that directs the insertion of a molecule of carbon dioxide into the -y-carbon of glutamic acid residues in these protein precursors. The tricarboxylic glutamic acid residues formed in this way are the sites of attachment of the calcium ions essential for the functional behavior of these proteins. Concentrates of the vitamin K-dependent clotting factors have been prepared by taking advantage of their adsorption to calcium phosphate and to diethylaminoethyl cellulose. The clotting factors are eluted from these adsorbents, further purified to some degree, and then lyophilized for storage. They have found usage in three situations. The concentrates have been infused to control bleeding in patients with hereditary deficiencies of one or another of the vitamin

K-dependent clotting factors, particularly factor IX, deficiency of which is called Christmas disease, hemophilia B, or hereditary factor IX deficiency. They have also been used for the more frequent acquired deficiencies of the vitamin K-dependent clotting factors, that are seen in patients undergoing treatment with oral anticoagulants such as warfarin, in patients with malabsorption syndromes such as obstructive jaundice or nontropical sprue, and in patients with the multiple clotting defects of hepatic disease. They have also been used with varying success in treatment of bleeding in patients who have circulating anticoagulants against factor VIII and whose bleeding cannot be readily controlled by transfusion of plasma or its fractions, as described in subsequent paragraphs. Four major complications have tempered enthusiasm for the use of concentrates of the vitamin K-dependent clotting factors, namely, transmission of the viruses of hepatitis and AIDS, the emergence of circulating anticoagulants against factor IX, an anamnestic rise in the titer of anticoagulants against factor VIII,4”,44 and induction of thrombosis. Thromboembolism, disseminated intravascular coagulation, myocardial infarction, and stroke have all been described?5-51 At autopsy, patients with acute myocardial infarcts may have patchy myocardial necrosis without obstructive coronary hemorrhages5”; this suggests arterial lesion,5z or massive transmural that the pathologly of the infarcts is altered by the patient’s basic hemorrhagic disorder.

Monoclonal

Antibody-Purified

Christmas

factor

(Factor IX)

Little experience has been published concerning the use of monoclonal antibody-purified Christmas factor, which is prepared by techniques analogous to those used to prepare monoclonal antibody-purified factor VIII and treated to inactivate viruses.54855 I am unfamiliar with any unusual complications of its use.

Antithrombin

111

Antithrombin III has had limited use in the prophylaxis and treatment of thromboembolism in hereditary or acquired deficiency of this anticoagulant protein. The commercially available, plasmaderived preparation (KabiVitrum AB, Stockholm) is heat treated, and I am unaware of instances of hepatitis or human immunodeficiency virus (HIV) infection related to its use. Lightheadedness, perhaps coincidental, has been described in association with the treatment of antithrombin III deficiency,“6 and two instances of “diuretic and vasodilatory effects” were reported by the manufacturer in patients with disseminated intravascular coagulation treated with this fraction. No other ill effects are described.

pHAFUWACOLOGIC

AGENTS

DESMOPRESSIN In mild classic hemophilia and von Willebrand’s disease, the administration of desmopressin (l-desamino-8-o-arginine vasopressin, DDAVP, Stirnate) may increase the titers of coagulant factor VIII and von Willebrand factor to hemostatic levels.57 This ingenious therapy derives from early observations of Ingram and Vaughn Jones5’ and others5’ that certain vasoactive substances increase the plasma titer of factor VIII. Administration of intravenous, subcutaneous, or intranasal desmopressin to normal individuals and to those with mild classic hemophilia or von Willebrand’s disease raises the titers of factor VIII and von Willebrand factor, which reach a peak in about 3 hours and then gradually fall over the succeeding hours.“7,60,61 Desmopressin is administered intravenously at a dosage of 0.3 kg/kg of body weight, given over a span of 15 to 30 minutes in a volume of 50 mL, or intranasally at a dosage in adults of 300 kg into one or both nostrils. Coincident with the rise in von Willebrand titer, the bleeding time may shorten. Thereafter, a period of tachyphylaxis ensues, so that satisfactory responses may not be seen for another day. The mechanism of action of desmopressin is not clear. The assumption has been made that this agent releases coagulant factor VIII and von Willebrand factor from vascular endothelial stores, but the situation may be more complex because this hypothesis could not be sustained in studies of cultured human umbilical vein endothelial cells.62 The titers of factor VIII and von Willebrand factor do not rise in patients with severe classic hemophilia or von Willebrand’s disease, and no benefit is seen when desmopressin is given to individuals with other clotting factor deficiencies. Desmopressin is suitable for the prevention of bleeding during and after minor surgical or dental procedures. It does not provide sure enough hemostasis for more formidable challenges, but I have used it as an adjunct to plasma or clotting factor infusions in patients undergoing major surgery. Experience with the use of desmopressin, particularly in relationship to surgeiy, has been summarized recently by Kodeghiero et al.63 Patients treated with desmopressin may experience facial flushing (although this is said not to occur in those with von Willebrand’s disease64). The patients may also have headache, nausea, mild abdominal cramping, vulval pain, tachycardia, and transient increases or decreases in blood pressure. One patient suffered facial angioedema and bilateral wheezing.6” Much more serious is the occurrence of hyponatremia, as would This may be maximal as late as 20 hours after infube anticipated.“” sion of desmopressin and is probably responsible for grand mal seizures that have occurred in infants under the age of 5 years.“7,68 Other

major symptoms that may be related to hyponatremia include fusion, obtundation, and as in one of our own patients, transient pressive aphasia. Several patients have been described in whom ripheral venous thrombosis or myocardial or cerebral infarction these complications of desmopressin occurred.6s-74 Although apy are minimized by some,“” they are a formidable obstacle to apy in patients thought to be at risk for thrombosis. ANTIFIBRINOLYTZC

conexpehave thertherF

AGENTS

e-Aminocaproic acid (Amicar) and tranexamic acid (Cyclocapron) have been suggested repeatedly for the treatment of bleeding in patients with hemostatic disorders. These two substances inhibit the conversion of plasminogen to plasmin and thereby retard the dissolution of clots. Their principal value has been in preventing rebleeding after dental extraction.75 Rebleeding occurs in patients with hemorrhagic disorders about 5 days after extraction and is presumably due to reliquefaction of the clot, perhaps induced by the plasminogen activator properties of saliva. A useful dosage of e-aminocaproic acid is 4 g every 4 hours morning and night for 10 days, beginning as soon after extraction as the patient can swallow. The comparable dosage of tranexamic acid is 0.5 g every 8 hours. Concentrates of the vitamin K-dependent clotting factors are contraindicated during therapy with oral antifibrinolytic agents lest they foster thrombosis.76 Other complications of the use of antifibrinolytic agents include nausea and vomiting, diarrhea, abdominal distress, lightheadedness, hypotension and syncope, rash, myalgia, muscle weakness, myoglobinuria, and rarely, grand mal seizures or transient delirium. Particularly troublesome to young hemophiliacs is failure of ejaculation.77 Other indications for the use of oral antifibrinolytic agents were summarized in recent reviews.77’78 INFECTIOUS

COMPLICATIONS

OF THERAPY

f ZEPATZTZS

A major problem posed by the infusion of blood, plasma, or fractions of plasma and not yet entirely solved is the transmission of infectious agents, particularly those of hepatitis and AIDS. The fact that blood and plasma transmitted viruses of hepatitis became evident during World War II when a major epidemic occurred after the immunization of soldiers with yellow fever vaccine that had been stabilized by the addition of pooled human plasma.7s It was recognized that hepatitis could be transmitted by parenteral injection of very small quantities of plasma, presumably explaining the infectious na-

ture of the pooled plasma from many supposedly normal donors, Studies after World War II identified two forms of viral hepatitis, now called hepatitis A and B. Hepatitis A is transmitted orally, has an incubation period after exposure of about 2 to 5 weeks, is self-limited, rarely has significant sequelae, and confers immunity to subsequent infection with the same virus. Transmission of hepatitis A virus by blood or its fractions is rare, the usual route being enteral. Virtually none of the hepatitis that occurs in patients with clotting disorders is due to the virus of hepatitis A. Hepatitis B, by contrast, is transmitted by parenteral injection of blood or fractions of blood infected with hepatitis B virus (HBV), has an incubation period that varies from about 1 month to as long as 7 months, may result in chronic changes in hepatic structure and function that lead to cirrhosis and carcinoma of the liver, and confers immunity to the same virus. Also in contrast to hepatitis A, viremia may Last indefinitely and may foster transmission of the disease to anyone exposed to the patient’s blood. HBV can also be spread via household and sexual contacts.““1”’ Infection with HBV accounts for much but not all of the hepatitis seen in patients with classic hemophilia, von Willebrand’s disease, or Christmas disease. Serologic evidence of past or present hepatitis B infection has been detected in more than 90% of hemophiliacs8’ Among those patients who are not carriers of hepatitis B surface antigen (HBsAg), about one third had antibodies to hepatitis B core antigen (HBcAg) and were more likely to have elevated aminotransferases .” Only a small proportion of patients have clinical hepatitis.83J84 The diagnosis is more often made by serologic studies demonstrating infection with the virus or by evidence of impaired hepatic function, criteria that do not separate hepatitis B from non-A, non-B hepatitis, that is, hepatitis C. Among those who were not carriers of HBsAg, about one third had antibodies to HBcAg; those with antibodies to HBcAg were more likely to have elevated aminotransferases than those who lacked these antibodies8’ Death as a consequence of acute infection due to HBV is rare.” In some patients, HBV infection may be complicated by a coincident infection with hepatitis D virus that may compound the chronic@ of hepatitis due to HBV. Whether coinfection of hepatitis B and D accounted for the extraordinarily high case fatality rate of “homologous serum jaundice” after transfusion of whole blood during the 1940s is not known to me.86J87 Not all cases of hepatitis found in patients with hemorrhagic disorders can be identified as being due to HBV, either by demonstration of antibodies to HBV or by the presence in plasma of HBcAg. A small proportion of patients with hemorrhagic disease carry HBsAg and are presumably still actively infected.88 HBV infection can also he recognized in some cases by detecting HBV DNA in serum.“’ Only rarely is immunologic evidence of hepatitis A found,“’ Much more

often, the existence of hepatitis has been predicated not upon the results of serologic testing but on clinical evidence of this syndrome or by the detection of abnormal liver function.s1-s3 In many patients, whether or not they have hemorrhagic disorders, evidence for neither hepatitis A nor B can be found.s4 The arguments that indicated that hepatitis in these individuals was due to yet another virus, ten-, tatively described as non-A, non-B, were well summarized by Dienstag”: More than two episodes of acute hepatitis may occur in drug addicts and hemophiliacs; the incubation period of non-A, non-B hepatitis seems to fall between those of hepatitis A and B; there is failure to detect HBsAg in almost all cases of posttransfusion hepatitis; screening donors for HBsAg has only a limited effect on the frequency of hepatitis in blood recipients; the presence of HBs antibodies in blood recipients does not protect them against blood-borne hepatitis; and elimination of commercially obtained donor blood reduces the frequency not only of hepatitis B but also non-B hepatitis after transfusion. In patients with non-A, non-B hepatitis, hepatic dysfunction is usually reflected by elevation of the concentration of serum enzymes such as aspartate aminotransferase (serum glutamic-oxaloacetic transaminase, SGOT) or alanine aminotransferase (serum glutamicpyruvic transaminase, ALT, SGFFU.Abnormal liver function tests may persist for many monthsy3 In patients with classic hemophilia, I have observed recurrent episodes of clinically overt hepatitis after transfusion of blood products, and this has been recognized by others.s3,s6 The etiology of non-A, non-B hepatitis was clarified by a remarkable tour de force in which viral protein was generated from the plasma of infected persons by molecular biologic techniquesy7 This protein served as the antigen to identify the specific antibody to what was named hepatitis C virus (HCV) in human serum.s8 With this anthat more than half of transfused tigen, Alter et al.” demonstrated patients who had non-A, non-B hepatitis had antibodies against HCV. Similarly, Lim et aLloo found that of 28 patients with non-A, non-B hepatitis, 27 had antibodies to HCV. In 10 of their patients, it was thought possible to date the first exposure to blood products and the time of seroconversion. On the average, non-A, non-B hepatitis was detected in 4 weeks (range, 1 to 7 weeks), and the time to seroconversion to antibodies to hepatitis averaged 11 weeks (range, 7.5 to 14.5 weeks). As I have emphasized, hepatitis was recognized early as a complication of the use of plasma and its fractions in patients with hemorrhagic disorders. Supposedly normal American individualsthe donors of blood that serves as the starting material for cryoprecipitates or commercial Iyophilized concentrates of clotting factors-have a carrier rate for HBV of 0.3% to l.O%, and for HCV, a rate of 0.3% to 1.5%. Thus, the statistical odds are very high that commercial conXL2

ml,

May

11333

centrates of clotting factors made from the pooled plasmas of as many as 20,000 or more donors would be contaminated with hepatitis viruses. Mannucci et allo and Dane and Cameron,102 for example, reported that HBsAg was demonstrable in commercial factor VIII preparations. In contrast, recipients of blood products derived from single donors, for example, plasma or cryoprecipitates, would be expected to be at much lower risk. Published data support this supposition. Thus, although patients treated with cryoprecipitates may contract clinical hepatitis, their risk appears to be less than that of hemophiliacs treated with lyophilized preparations of factor VIII. 103-106 Among 558 patients with classic hemophilia, Christmas disease, or von Willebrand’s disease, Hasiba et allo found antibodies against HBsAg in 90% of those treated with lyophilized factor concentrates, but in only 49% of those treated with fresh frozen plasma or cryoprecipitates. Similarly, persistently abnormal transaminase levels were found in 31% of hemophiliacs treated with commercial products but in only 2% of those treated with cryoprecipitates, a difference that persisted until patients had been treated with at least 50,000 units of factor VIII. Gomperts et allo observed that of 11 patients treated with products prepared from plasma that had been from donors who did not carry HBsAg, only one developed immunologic evidence of exposure to hepatitis B. More than half of their patients, however, had abnormal liver function tests, suggesting that they had had non-A, non-B hepatitis. A curious observation may reflect the nature of the purification process of different clotting factors or, possibly, subtle differences among patients with different hereditary clotting disorders. Lewis et al.35 reported that 22% of her patients with hereditary clotting disorders who were treated with concentrates derived from pooled plasma had overt hepatitis, and that concentrates used to treat Christmas disease were more likely to induce hepatitis than concentrates of factor VIII. Similar data were also recorded by Kunst et allo As might be anticipated, antibodies against HCV have been detected in the serum of 60% to 90% of patients with classic hemophilia or Christmas disease who had been infused with lyophilized concentrates of factor VIII or factor IX that had not been treated to reduce the titer of contaminating viruses.10s-1’3 Using the polymerase chain reaction to amplify viral RNA, Simmonds et al.“” and Garson et al.“” detected specific HCV RNA sequences in the plasma of patients with hemophilia. HCV RNA was also found in all batches of commercial factor VIII that had not been heat treated, whereas lots of factors VIII and IX that had been gathered from volunteer donors were negative. Whether some patients are infected with yet another hepatitisinducing virus is unclear; those who are HCV negative nonetheless often have elevated levels of aminotransferase.“l In contrast, hemophiliacs who were infused only with virus-inactivated clotting factors nnr, May 1393

323

or with cryoprecipitates were usually anti-HCV negative. Most disturbing was evidence correlating the presence of anti-HCV antibodies in serum and the development of hepatocellular carcinoma.ll’ Although hepatitis in patients with coagulative disorders is clearly transmitted parenterally, evidence not dissimilar to that accumulated after World War II supports the view that the virus can be spread!by the fecal-oral route from infected hemophiliacs to their household contacts. Not surprisingly, both hepatitis B and C that have been acquired parenterally can apparently be transmitted to household contacts and specifically by sexual intercourse.81~1*7-11s Studies of hepatic histology in patients who were treated with plasma fractions has demonstrated a wide spectrum of pathologic changes, including chronic active hepatitis, chronic persistent hepatitis, fatty infiltration of the liver, cirrhosis, and even carcinoma of the liver. 120-123 This last observation is anticipated because the relationship between hepatocellular carcinoma and the sequelae of infectious hepatitis is well known. Colombo et al.l*‘j assembled 10 instances of hepatic carcinoma in cases of hepatitis. In the nine patients for whom information was available, antibodies to HCV were demonstrated in four of five cases tested, and HBsAg was present in five. Similar observations have been recorded by Bruiz et al.lz4 and Nishioka et alTz5 As in other forms of cirrhosis, portal hypertension may bring about variceal bleeding, a complication of special peril in the light of the patient’s underlying hemostatic defect.l” In patients with hepatitis B, both the nucleus and cytoplasm of hepatocytes contain immunologically demonstrable hepatitis B surface and core antigensF2’ Schimpf et al.12’ made the disturbing observation that of 26 unselected patients with classic hemophilia or Christmas disease, none had normal hepatic histology and that even asymptomatic patients with normal hepatic enzymes had histologic hepatic abnormalities. In an extensive review, Aledort et al.“’ found evidence of severe liver disease in 22% of the biopsy and autopsy specimens they examined, including cirrhosis in 15% of cases and chronic active hepatitis in 7%. Aledort and coworkers thought that the chronic hepatitis often appeared to reflect infection with non-A, non-B hepatitis virus rather than hepatitis B. He believed, in contrast to data I reviewed in an earlier paragraph, that severe liver disease was found no more often in those patients treated with lyophilized products than in those treated with cryoprecipitates or plasma. As in patients with chronic hepatitis unassociated with hemophilia, consideration must be given to treatment with alpha interferon. In nonhemophilic patients with chronic hepatitis due to hepatitis B and C viruses, treatment with alpha interferon results in improvement in the level of serum aminotransferases and disappearance of the respective viral HNA in some but not all patients,lZRJ’“” Lee and her col324

ml.

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19m

reduced the elevated titer of asleagues130 reported that interferon partate transaminase in a symptomatic carrier of classic hemophilia and in a patient with this disease. There was improvement in the patients’ well-being, but on withdrawal of therapy, the hepatic functional defects appeared to relapse. Notably, while receiving interferon therapy, the patients experienced malaise, fatigue, aching, rigors, and back pain; other complications of interferon therapy include thrombocytopenia and neutropenia. Whether interferon therapy is truly efficacious in patients with hemostatic disorders who suffer the consequences of hepatitis is not yet certain. Prophylaxis against hepatitis B is widely practiced in the care of patients with classic hemophilia or Christmas disease. Buchanan et al.8l recommend immunization of hemophiliacs with hepatitis B vaccine, giving the necessary amount in three doses. In their experience, 31 of 32 patients responded with development of antibodies against HBsAg, and none had clinically recognized hepatitis over a 30-month period. We have not made it a practice to immunize family members of patients with coagulative disorders, but this sound idea has been proposed by Zuckerman. 13’ A usual immunization course in children up to the age of 10 years is 10 pg intramuscularly, repeated 1 month and 6 months after the initial dose, and for those over 10 years of age, 20 pg at the same intervals. Surprisingly, bleeding at the site of injection is seldom a problem in patients with hemorrhagic disorders. Additionally, in health care workers (or family members) who may be inadvertently exposed to HBV through a needle stick or otherwise, hepatitis B immune globulin (0.06 mL per kg of body weight) should be administered intramuscularly as soon as possible.

ACQUIRED

IMMUNE

DEFICIENCY

SYNDROME

A second and much more devastating infectious complication of the treatment of classic hemophilia and other hereditary disorders of coagulation is AIDS. AIDS was first recognized as a complication of classic hemophilia when three patients who were under treatment with lyophilized concentrates of factor VIII contracted Pneumocystis carinii pneumonia; two of the patients had died.13’ Two of the three patients also had oral candidiasis, and one, infection with Mycobacterium avium-intracellufare. Immunologic studies, performed in two of the patients, demonstrated impaired cell-mediated immunity. Coming in the midst of the beginning of the current epidemic of AIDS in nonhemophiliacs, these observations suggested that the blood from which the lyophilized concentrates had been prepared might be infected with what was later called human immunodeficiency virus. Several groups soon demonstrated that immunologic changes similar to those seen in patients with AIDS were prevalent among D\4,

May 1393

325

patients with classic hemophilia or Christmas disease who had been treated with lyophilized concentrates of factor VIII or IX. In contrast, patients with classic hemophilia who had been treated e&usively with cryoprecipitates did not have impaired cellular immunity. 133-136 In general, the difference in the infectivity of lyophilized preparations of plasma compared to cryoprecipitates has been observed elsewhere .l 37.y3R The impaired cell-mediated immunity found in patients treated with lyophilized clotting factors predictably set the stage for clinical AIDS. This disorder has been a major scourge of the hemophilic community. The manifestation of AIDS among hemophiliacs differ little from those of nonhemophilic individuals, but Kaposi’s sarcoma is most unusual, as is also true of AIDS in drug users.13y Non-Hodgkin’s lymphomas, including Burkitt’s lymphoma, are common complications and are usually, but not always, of B-cell origin.‘4”“41 In young hemophilic boys with HIV infection, growth retardation may be striking,14’ and impaired responses to the usual immunization routines of childhood are the rule.143 Some evidence suggests that in hemophiliacs, the tendency to develop AIDS in the face of HIV infection is familial.lM The hemophilic siblings of patients with classic hemophilia complicated by AIDS had a 75% chance of having AIDS, AIDS-related complex, or thrombocytopenia. In contrast, there was an 11% risk of these manifestations among siblings of patients who did not have AIDS or AIDS-related complex. The epidemic of AIDS among hemophiliacs has been met with great anxiety by patients and their families, and this was first manifest by a large element of denial.145 Such simple measures as the use of condoms to reduce the risk of transmitting the AIDS virus to spouses were avoided.146,147 The spouses of two of our own hemophiliacs have now died of AIDS, and this is by no means unusual; as of August 1991, there have been 97 cases of AIDS in the sexual partners of patients with clotting disorders reported in the United States, of which 57 were fatal 6. Wiley, personal communication, 1991). Development of a serologic test for antibodies against HIV made it possible to examine stored plasmas that had been collected over the years from patients with classic hemophilia.14’ Antibodies against HIV were not detected in any samples collected before 1980. Among patients who had been treated with lyophilized concentrates, the prevalence of antibodies against HIV rose from 25% in 1980 to 78% in 1984. In contrast, among those treated exclusively with cryoprecipitates, none had detectable antibodies through 1984. Seropositive patients who were still asymptomatic had fewer CD4 lymphocytes than normal individuals, impaired lymphoproliferative responses to phytohemagglutinin, and decreased natural killer cell activity when compared to seronegative patients. Similar data were reported from other 326

OAL May

13%

laboratories14g-152; that concentrates remained whem.137,153

hemophiliacs seronegative

not treated was also

with lyophilized confirmed else-

Several factors appear to account for the greater infectivity of lyophilized preparations of factor VIII compared to cryoprecipitates. Perhaps most important is that lyophilized preparations are separated from the pooled cryoprecipitates of as many as 22,000 individual donors. In contrast, far fewer donors are needed to furnish the number of individual cryoprecipitates needed to treat most hemorrhagic episodes in patients with classic hemophilia or to prevent bleeding during surgical procedures. Additionally, at the time HIV infection appeared to be spreading in the hemophilic community, lyophilized preparations were derived at least in part from the plasma of commercial donors and prison inmates, whereas cryoprecipitates were separated almost exclusively horn the plasmas of volunteer donors. Before the infectious nature of AIDS was established, concern was expressed that in some way proteins present in clotting factor preparations impaired the immune defenses of treated patients. Indeed, Froebel et al.154 reported that factor VIII concentrates of intermediate purity impaired phytohemagglutinin-induced lymphocyte proliferation in vitro. We, too, observed that both lyophilized factor VIII and cryoprecipitates inhibited phytohemagglutinin-induced lymphocyte proliferative responses in vitro.155 Further, lyophilized factor VIII inhibited production of interleukin-2 by human lymphocytes. Gel filtration studies indicated that at least part of these inhibitory activities could be dissociated from factor VIII itself. In agreement with these experiments, higher-purity factor VIII prepared by monoclonal antibody techniques was without inhibitory activity.‘56 A syndrome resembling idiopathic thrombocytopenic purpura is well known in patients infected with HIV. Not surprisingly, this complication was also seen by several investigators in patients with classic hemophilia or Christmas disease treated with commercial lyophilized clotting factor concentrates.‘57-162 Bedall et al.,163 like ourselves, pointed out that those hemophiliacs treated exclusively with cryoprecipitates have not developed thrombocytopenia. Although at first unrecognized, the relationship between thrombocytopenia and HIV infection became clear when three of four patients tested had a decreased relative number of CD4 (helper) lymphocytes and an increased relative number of CD8 (suppressor) lymnatural killer cell activity and lymphocyte phocytes.161 Additionally, responses to mitogens were decreased in the two patients tested.“’ With the development of serologic testing for antibodies against HIV, the relationship between thrombocytopenia and HIV infection in hemophilia became clear. The incidence of thrombocytopenia as a complication of classic hrLAM, May

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mophilia or Christmas disease is substantial among those who have antibodies against HIV; thus Ragni et al.164 observed platelet counts below lOO,OOO/~L in 30 (36% 1 of 87 patients who were seropositive for HIV, of whom 11 had platelet counts less than 5O,OOO/kL. A similar prevalence was reported by others.165-16g Finazzi et al.165 detected platelet counts below lOO,OOO/~L in 11% of patients with “hemophilia” who were HIV antibody positive. In the series of Ragni et al.,lfi4 of nine patients for whom the time of seroconversion could be measured with some degree of accuracy, the interval between this event and the appearance of thrombocytopenia ranged from 24 to 73 months. Similarly, Kim et al.16’ noted that all five of their patients developed antibodies to HIV 6 to 60 months before thrombocytopenia was recognized. Surprisingly, the coincidence of thrombocytopenia, sometimes of considerable severity (e.g., 8OOO/pL), and hemophilia or Christmas disease is often unassociated with any significant increase in bleeding symptoms. Thrombocytopenia did not seem to have a significant impact on the occurrence of bleeding in our own experience or in that of other observers.1”5 In contrast, Ragni et al.‘“4 reported that nine of 11 patients with classic hemophilia or Christmas disease who were HIV positive and had significant thrombocytopenia had bleeding complications, including four instances of intracranial hemorrhage, three fatal. Others have also reported a high incidence of central nervous system hemorrhage in hemophiliacs with thrombocytopenia. 168~170But the more usual experience is that of Finazzi et al.,165 who observed an average of 1.82 episodes of major bleeding per year in hemophiliacs, not significantly different from that observed in patients with “idiopathic” thrombocytopenic purpura. These authors did not count the incidence of hemarthrosis or hematomas, because “these bleeding episodes were not considered related to thrombocytopenia.” The pathogenesis of thrombocytopenia in patients with classic hemophilia and HIV infection is not clearly understood. As in nonhemophilic patients with thrombocytopenia and evidence of HIV infection, bone marrow aspirates do not differ from those seen in idiopathic or autoimmune thrombocytopenic purpura, with plentiful megakavocytes that are usually depleted of cytoplasm. Platelet life span is shorter than normal’“‘; platelet-bound immunoglobulin G (IgG) or M (IgM), C3, C4, and plasma circulating immune complexes may be detectedl”‘; and plasma immunoglobulins (especially IgG) may be increased in concentration.161’171”72 Karpatkin171 also noted that antiplatelet IgG was detectable in 14 of 16 serums of HIVseropositive hemophiliacs with thrombocytopenia and that antiplatelet IgG could be eluted from their platelets. Non-HIV seropositive, nonthromboqtopenic hemophiliacs had normal control values. When the first case of thrombocytopenia in a patient with classit>

hemophilia was recognized at University Hospitals of Cleveland, these laboratory findings led to the initial thought that this was mere coincidence.lfi’ The patient was therefore treated as if he had idiopathic thrombocytopenic purpura, first with prednisone and then, Lvhen lie relapsed as the dosage of steroids was decreased, by sllle,,ectom~. under cover of cryoprecipitatr infusion 7’1~ l~ntic-~l~tLll,l)f:;lr,ril t;! ;;r* -~,qc.*.c*~tfj~]?-cr’nr’F”~ .-..,. ~.. il,rt, .XliC IyLII.cI J’ rlO,II .i.. .~.fn,. .~__ 10 -. c7!‘-tli??Prl ...I _I ti L.L.,. \I<,‘,~‘ *jc* tients described in this early report were trezttmj +y attII~inistr~ati!,I, r,f glucocortiroids but not by splenectoni~y anfi tc; I~II’ IcIwI~~P~~~ none had serious bleeding problems %lbsrqllcntl\. I\-+ !?;I\ $1i‘r+crr,tcdc! to splenectomy in only one other thrnrnl-,oc..vtop~~ll~r patirnl h~(~;~~lsr~ his persistently low platelet count did not respond to ~)l‘t?rltlist)rlr~ rherapy

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pura in nonhemophiliacs, therapy with intravenously administered Iligh-dose IgG or anti-D immunoglobulins may tide the patient over a hemorrhagic episode or raise the platelet count before splenecto“1lY.185.170.173panzer et al~17:’ Infused IgC; at frequent intervals for at least 6 months to avoid splenectomy, but this regimen did not obviate such surgery in three of his five patients. In an instructive patient of Boughton et al.,174 treatment with 0.5 mg of anti-Rh (D) immunoglobulin administered intravenously over 2 hours brought about remission of thrombocytopenia that lasted between 10 days and 3 weeks; there was no evidence that this treatment induced hemolytic anemia. Another form of therapy that is sometimes successful in banal idiopathic thrombocytopenic purpura is the administration of danazol. It is perhaps important to note that while receiving danazol, an HIVpositive, thrombocytopenic hemophilic patient of Kim et al.lfi8 sustained a spontaneous subarachnoid hemorrhage, and two of three others were thought to have increased frequency of bleeding. A reasonable question is whether splenectomy may adversely affect individuals who carry antibodies to HIV. In a review of published studies of nonhemophiliacs, Barbui et al.17” found that AIDS developed in nine of 36 patients subjected to splenectomy, compared to five of 65 patients treated conservatively. Similarly, that all three hemophiliacs who had C;oldsmith et al.“” reported undergone splenectomy developed AIDS. Whether this means that those patients selected for splenectomy are those more likely to develop AIDS is not clear. Others have taken a conservative approach, avoiding splenectomy.‘77 Zidovudine therapy has been proposed for treatment of thrombocytopenia in AIDS patients the literature, FinIlllrelated tu h~?r~~ophilia,“H~‘7R but in reviewing il:ZI, May

1933

329

azzi et al.165 argues against the use of this drug in what is a relatively benign facet of HIV infection. In our original study, we recorded that the direct Coombs test was positive in two of three patients tested and that serum haptoglobin was decreased in one patient.161 Harris et al.“’ observed that two similar patients had evidence of a Coombs-positive hemolytic anemia. The possibility must be considered that this anemia was due to the presence of isohemagglutinins in the transfused factor VIII concentrates and was unrelated to the immunologic disturbance responsible for thrombocytopenia. A rare but instructive complication of HIV infection in patients with hereditary hemorrhagic disease is primary pulmonary hypertension. In 1985, Goldsmith et al.“’ studied a patient with classic hemophilia who had episodic dyspnea and, probably, syncope for about 6 months. At that time, he was evaluated for increasing dyspnea, weakness, and edema, and signs of right-ventricular failure were noted. Cardiac catheterization demonstrated severe pulmonary hypertension. His condition deteriorated rapidly, and he died the next day. At autopsy, there was a markedly enlarged right ventricle. Small pulmonary arteries showed concentric hypertrophy, intimal proliferation, and fibrosis with plexiform lesions. A survey of several major hemophilia treatment centers turned up four additional cases of primary pulmonary hypertension in association with classic hemophilia. No obvious pathogenetic mechanism was discerned, although all patients had been on therapy with lyophilized preparations of factor VIII and all had antibodies to HIV. There was insufficient evidence at the time of the report by Goldsmith et al. to suggest that primary pulmonary hypertension in patients with classic hemophilia was due to HIV. Since then, however, there have been several cases described in patients with AIDS who were not hemophiliacs,1s2 and one can therefore deduce that this was the case in the patients Goldsmith et al. assembled. The treatment of AIDS in patients with disorders of hemostasis is not different from that in other patients. An important, recently published clinical trial examined the question of whether prophylaxis with zidovudine might postpone clinical disease in those individuals who had antibodies against HIV.lB3 All patients were 12 years of age or older and had the presence of HIV antibodies confirmed by Western blot assay. Patients were given 300 mg of zidovudine or a placebo five times daily. The study was stopped before significant endpoints were reached because a similar study in nonbleeders demonstrated the prophylactic benefit of zidovudine. None the less, the data obtained appeared to show that there was a trend toward earlier advancement from the carrier state toward advanced disease in the control group, compared to the treatment group. This difference was particularly impressive in patients who were 30 years of age or older, in 330

1lM

May

lS93

whom there was a significant protective effect in those treated with zidovudine . A matter of grave concern is the transmission of AIDS from patients with hemostatic disorders to their sexual partners.“7 In our own experience, the spouses of two patients with classic hemophilia who are HIV antibody-positive have now died of AIDS. Notably, attempts to educate patients concerning the USC of condoms have met with little success. OTHER VIRAL INFECTIONS In classic hemophilia and Christmas disease, lyophilized concentrates of clotting factors may be contaminated with viruses other than those of hepatitis and AIDS. Levine et al.lm noted high titers of cytomegalovirus antibody in 16 of 19 patients treated with lyophilized clotting factors, and Mortimer et al.“’ reported in 1983 that all but one of 29 children and young adults treated with factor VIII concentrates had antibodies to a parvoviruslike agent. IMPROVING

THE SAFETY OF PLASMA AND ITS FRACTIONS

As I have reviewed in the preceding sections, the principal risk of transfusion of plasma and its fractions is transmission of viral disease. The striking difference in the infectivity of cryoprecipitates and other so-called single-donor products compared to preparations derived from the pooled plasma of many donors is all too apparent. To reduce the patent risk of infection, manufacturers and blood banks now attempt to weed out potential donors who may be in high-risk groups, e.g., homosexual men or intravenous drug users. Various expedients have been used, which include the posting of notices suggesting self-exclusion and allowing potentially infected donors to specify that their blood is “for research only,” so that they are not subjected to the embarrassment of not participating in a donor blood drive. A second form of screening is probably more important. Prison inmates who have high motivation to donate blood but who have a high prevalence of infection with hepatitis viruses and HIV are no longer solicited to be donors. Blood is now subjected to a battery of tests, including a serologic test for syphilis; tests for HBsAg and for antibodies to HIV, human T-cell lymphotropic virus (types I and II), HBcAg, and HCV; and alanine aminotransferase titer.la6 Those bloods that test positive are excluded from the donor pool. A current estimate is that 0.35% of American donors have antibodies to HCV, 2% to HBcAg, and 0.007% to HIV; 0.035% have detectable HBsAg IP. Tomasulo, personal communication, 19911, The screening tests will not 331

eliminate blood that may be drawn between the time the donor is exposed to infection and the time of blood donation. Moreover, if Cleveland, Ohio, can be used as an example, commercial manufacturers of blood fractions still harvest plasma at collection depots sited in skid row areas. If current screening does eliminate some potentially infectious donations, one can only wonder whether we really know whence the next infectious agent will come. Plasma used for the preparation of clotting factor concentrates is similarly screened for the presence of markers of HIV and hepatitis B and C. Unfortunately, this logical step does not insure that the plasma is noninfectious. Clotting factor concentrates prepared from pooled plasma have therefore been further subjected to viral inactivation procedures -either by heat or by addition of detergents and organic solvents that are thought to disrupt viral membranes.187 At first, these measures were only partially effective, and indeed, they may not yet be adequate for the task. Heating lyophilized concentrates at 68°C for 72 hours-so-called dry heating-does not prevent transmission of HIV and does not inactivate hepatitis viruses~88-1s4 More strenuous heating of factor VIII preparations to 80°C for 72 hours may be effective.ls5 Heating solutions of factor VIII-a process described as pasteurization-appears to inactivate HIV, but does not prevent the transmission of hepatitis.1s5-1ss Even monoclonal antibody- purified factor VIII that has been extensively heated has apparently transmitted HCV.2” Nor does subjecting lyophilized preparations to steam rid them of the hepatitis Virus.201 Another technique used to inactivate viruses in plasma or its fractions is exposing them to one or another mixture of organic solvents and detergents aimed at disrupting viral membranes. This procedure does appear to inactivate the AIDS virus, but data about hepatitis viruses are conflicting.202-205 CIRCULATING

ANTICOAGULANTS

Circulating anticoagulants have been defined as abnormal endogenous components of blood that inhibit the coagulation of blood.Z06 In general, circulating anticoagulants in patients who have inherited hemostatic defects are antibodies, and the patients have ordinarily been transfused with plasma or a fraction of plasma containing the agent against which the anticoagulant is directed.‘07 But circulating anticoagulants can arise in patients without hereditary coagulation defects, for example, autoantibodies against factor VIII or so-called lupus anticoagulants. Here, I shall focus attention on those anticoagulants that appear to arise as a complication of the therapy of hereditaT hemostatic disorders.

CIRCULATING

ANTICOAGULANTS

AGAINST

FACTOR

VII1

An often devastating complication of the treatment of classic hemophilia is the emergence of circulating anticoagulants against factor VIII that vitiate the beneficial effects of transfusion of plasma or its fractions. Those that specifically inhibit the function of factor VIII occur both in patients with classic hemophilia and in nonhemophiliacs; among the latter group are women at or after delivery, patients with systemic lupus erythematosus, patients with one or another cutaneous disorder, and patients who have recently ingested penicillinlike compounds or phenytoin, but this is only an incomplete list. The care of these patients does not differ significantly from that of patients with hemophilia complicated by the presence of an anticoagulant . Data concerning the prevalence of circulating anticoagulants among patients with classic hemophilia have varied considerably. In our own survey of the prognosis of classic hemophilia, circulating anticoagulants were found in 33 121%) of 155 patients with severe disease (coagulant titer of factor VIII < 0.01 U/mL) who had been tested for this complication.208 Two other patients were seen among 105 patients with moderately severe disease (factor VIII titer, 0.01 to 0.04 WmL), and none was found among 183 patients with mild disease (factor VIII titer, 0.05 U/mL or higher). The rate of development of inhibitors in patients with classic hemophilia was the subject of a multiinstitutional study.“’ Over a 4-year period, 3.2% of those patients whose coagulant factor VIII titers were I 0.03 U/mL and 0.85% of those with titers of 0.03 U/mL or more developed circulating anticoagulants . Anticoagulants directed against factor VIII are immunoglobulins reacting with epitopes on this plasma protein. Pickering and Gladstone,‘l’ in 1925, may have been the first to recognize the presence of a circulating anticoagulant as a complication of hemophilia, but at that time differentiation among hemophilia-like syndromes was not possible. A firmer diagnosis was apparent in cases reported by Lawrence and Johnson211 and Munro and Jones.2*2 Munro, himself an affected patient, and coworkers212-214 provided a modern view of the nature of circulating anticoagulants. They localized his anticoagulant to a crude y-globulin fraction of plasma and suggested that the anticoagulant was an antibody against factor VIII. In fact, anticoagulants in hemophiliacs appear invariably in those who have been treated with plasma or its fractions.2’5P21fi A reasonable view is that, to the hemophiliac, factor VIII is a foreign protein to which the body responds by the generation of specific antibodies. But a molecular basis for this assumption has yet to be proven,‘07 and this construction begs the question of the origin of anticoagulants in never-transfused, nonhemophilic individuals and fails to exDXI,

May

1993

3’33 .

plain the alleged rare occurrence of an anticoagulant arising in an infant with hemophilia who was said never to have been transfL1sed.‘17 Although the bulk of evidence supports the interpretation that circulating anticoagulants are antibodies against factor VIII (antihemophilic factor), these antibodies are unusual in several ways. The in,teraction between antihemophilic factor and circulating anticoagulant is both temperature and time dependent, as if the reaction had characteristics of that between an enzyme and its inhibitor.218~Z1g Usually, the antibodies do not form precipitates with antihemophilic factor, although this may be a matter of technique as Lavergne et al.“” were able to demonstrate that two such anticoagulants were precipitants. If the circulating anticoagulants are indeed specific antibodies to a foreign antigen, they should be polyclonal in nature. Nearly all circulating anticoagulants arising in patients with classic hemophilia have been IgG in nature, and, more specifically, IgGm4.22’, 222 A contrary view, that the anticoagulant IgG is of monoclonal origin, has been expressed,223 but others have provided data supporting the polyclonal hypothesis.224,225 Why only certain patients with classic hemophilia develop circulating anticoagulants is not clear. With few exceptions, those who acquire anticoagulants are severely affected, but of course, these are the very patients who are transfused the most. The question was raised early on whether the tendency to develop circulating anticoagulants was familial,206J226 and this is now well established.“’ Moreover, in an intriguing study by Lubahn and her associates,z27 the anticoagulants in patients from different families reacted with different fragments of the antihemophilic factor molecule, but within a given family there was a high likelihood that the anticoagulants reacted with the same epitope. Evidence that the affected hemophiliacs within a family share the same immunoresponse genes of the histocompatibility complex have been conflicting. These studies by Lubahn et al. underscore the heterogeneous nature of antibodies to antihemophilic factor, and a large body of evidence supports this view. Thus, the kinetic behavior of the reaction between the anticoagulants and their antigen, factor VIII, varies from patient to patient, and the epitopes recognized by the anticoagulant antibodies vary as we11.228 Furthermore, in some patients, the transfusion of agents containing antihemophilic factor is followed by a striking anamnestic rise in anticoagulant (i.e., antibody) titer that lasts for many months. These “high responders” stand in contrast to other patients who do not have a significant anamnestic response and have therefore been called “low responders.” The care of patients with circulating anticoagulants against antiItemophilir !factrw VIII! can be divided into tmw parts, the treatment

of an acute episode of bleeding, and attempts at eradicating the anticoagulant. Neither of these goals has been easy to meet. Spontaneous disappearance of an anticoagulant in patients with classic hemophilia is unusual; three such patients have been observed at University Hospitals of Cleveland. The first was a patient with severe disease, and the other two were moderately affected brothers. Ironically, the intervention of AIDS may bring about disappearance of a circulating anticoagulant.2zs In general, the physician caring for a patient with an anticoagulant should feel considerable reluctance about playing too active a role in controlling hemorrhage. Therefore, immobilization of a joint that is the site of hemarthrosis and application of ice packs may be a safer procedure than more active measures; here, experience is a painfully won guide. When bleeding is more formidable, and the titer of the anticoagulant is relatively low, large amounts of preparations rich in factor VIII may provide hemostasis by neutralizing the anticoagulant so that any excess of factor VIII over antibody may promote coagulation. Control of bleeding by transfusion of blood products may possibly be at the cost of an anamnestic rise in anticoagulant titer-and therefore increased difficulty in the control of a future episode of bleeding.230J231 Of course, the patient should never be allowed to slip into shock from blood loss, but washed packed red cells may provide a minimal level of antigenic stimulation. When the titer of the anticoagulant is too high to be neutralized by transfusion of human factor VIII, other approaches must be considered. One ingenious approach is to transfuse the patient with antihemophilic factor derived from animal plasma. This should afford an essentially limitless supply and at the same time allow the infusion of antihemophilic factor at much higher concentration than is feasible with human preparations. Although human circulating anticoagulants do neutralize the coagulant activity of animal plasmas, the factor VIII of some species is relatively resistant; for example, porcine factor VIII is inactivated less effectively than is human factor VIII.Z3’ One might anticipate a lesser anamnestic response after infusion of animal rather than human factor VIII. Porcine factor VIII does appear to be effective in controlling bleeding in patients with circulating anticoagulants,233’ 234 but the financial cost of porcine factor VIII is unbelievably high. Recently at University Hospitals of Cleveland, a woman with an acquired circulating anticoagulant who had bled under the tongue was treated successfully by intravenous infusion of porcine factor VIII. The cost for 3 days of therapy was $90,000 for the factor VIII alone. The use of porcine factor VIII has been complicated by acute febrile reactions,z35’236 by a rise in the titer of antibodies to human factor VIII, by the appearance of antibodies to porcine factor VIII,2”” and rarely b.y an anaphylacticlike reaction.““’ The fhst porcine factor. VIII concentrates induced DM,

May

WY3

335

thrombocytopenia, but preparations currently in use only occasionally exhibit this complication?33,238 A third way to deal with episodes of bleeding in the patient with a circulating anticoagulant is the intravenous infusion of concentrates of the vitamin K-dependent clotting factors (prothrombin complex) discussed in earlier paragraphs. The logic behind this approach is that activated clotting factors in these preparations will initiate clotting at a point in the clotting mechanism beyond that requiring the participation of antihemophilic factor. 23s9240In this way, the defect in clotting induced by anticoagulants against antihemophilic factor is short-circuited. The effectiveness of therapy with the vitamin Kdependent factors is far from clear,241-245 but the differences in opinion may reflect differences in the preparations tested. A double-blind study of the use of vitamin K-dependent clotting factor concentrates appeared to demonstrate efficacy in patients with hemarthrosis,24G but its value in treatment of more formidable hemorrhages has been may be complidifficult to assess.“44 The use of these concentrates cated by thrombotic episodes, militating strongly against their use. The concentrates have also been implicated in transmission of the AIDS and hepatitis viruses.35,137 The possible benefits of the infusion of prothrombin complex concentrates may be due to their content of the activated forms of Christmas factor (factor IX) and factor VII. However, lots of the prothrombin complex preparations that had high spontaneous activity (marketed as FEIBA [factor VIII inhibitor bypassing activity] or Autoplex) did not seem to be more beneficial than the lots without significant spontaneous activity.243 An extension of this approach to the treatment of bleeding episodes in patients with circulating anticoagulants directed against factors VIII or IX was devised by Hedner and Kisie1.247 They proposed that some of the possible benefit of transfusion of prothrombin complex preparations in patients with such inhibitors was due to their content of activated clotting factors. Activated factor VII (factor VIIa), which might be present in prothrombin complex preparations, could bypass the clotting defect of patients deficient in either factor VIII or IX. They purified factor VII from normal human plasma and converted it to its activated form by limited digestion with activated Hageman factor (factor XIIa). After appropriate sterilization, solutions were stored at -80°C until needed. They treated several patients with classic hemophilia who had antibodies against factor VIII and soft tissue, mucosal, or joint hemorrhage.247J24s In general, hemostasis appeared satisfactory. In one patient, factor VIIa, combined with tranexamic acid (an inhibitor of fibrinolytic activity generation), seemed to control oral mucosal bleeding around deciduous teeth and bleeding after dental extraction. Notably, rebleeding seemed to occur after r:essation of therapy, but they observed “no deleterious side effects.” 336

iH4,

May

IS%+

A major

step forward was the synthesis of recombinant factor obviating fears about transmission of viral diseases by fractions derived from plasma. Recombinant factor VIIa behaved qualitatively like plasma-derived factor Va in vitro.251 It shortened the partial thromboplastin time of dogs with classic hemophilia, Christmas disease, and von Willebrand’s disease. Four of the five dogs studied developed urticaria, but the significance of this is clouded because the factor VIIa used was of human origin. Subsequent to these animal studies, a number of cases of classic hemophilia complicated by the presence of a circulating anticoagulant have been reported in which bleeding has been treated by intravenous injection of recombinant human factor VIIa. The results of treatment have varied from dramatic control of potentially lethal retropharyngeal hemorrhagez5’ and adequate control of hemostasis after dental extractionZ5” to apparent failure in the control of postoperative bleeding.2”4 In most cases in which studies were made, no significant side effects were found, but one patient with a soft-tissue abscess bled after surgical drainage and debridement despite facto1 VIIa therapy, and then died several days after treatment with plasma cryoprecipitates, platelet concentrates, packed red cells, and additional factor VIIa.2”5 In other patients, no laboratory changes suggestive of disseminated intravascular coagulation have been noted. Other ways of promoting hemostasis in the face of circulating anticoagulants against antihemophilic factor have included attempts to reduce the titer of the offending immunoglobulins by exchange transfusion256,257 or by passage of the patient’s blood through an immunoadsorption column composed of protein A (a specific binder of IgG) linked to an insoluble matrix?58 These techniques are probably not yet generally applicable to the care of the patient. The second goal in the treatment of patients with classic hemophilia who have inhibitors is to eradicate the synthesis of the autoantibody. Several techniques have been used. Attempts to eradicate the antibodies by treatment with cyclophosphamide, azathioprine, or prednisone, alone or in combination, have had some success,25g particularly when antihemophilic factor is given as well. The logic of this approach is that the antigen, antihemophilic factor, stimulates cells to synthesize antibody, while cyclophosphamide or other marrow suppressants preferentially attack the expanding clone of plasma cells. This combined attack seems to have been effective in some nonhemophilic patients with acquired inhibitors,Z60 but results in patients with classic hemophilia complicated by the presence of a circulating anticoagulant have been disappointing. Similarly, intravenous administration of immune globulin or anti-D has reduced the titer of anticoagulant in some, but not all, patients, and then, not completely.2”s ~1~,249,250

A ~nwe 1111, Mav

prui~k5il~g IY‘J:J

technique

hah htwn

to attempt

tcl desensitize

the 3:s-i

patient to factor VIII by daily intravenous injections of this antigen, coupled, by some investigators, with various combinations of steroids, immunoglobulins, and cyclophosphamide.261-z64 In some, but not all, patients, this induction of immune tolerance has led to a decrease in the titer of the circulating anticoagulant or to its apparent Thereafter, bleeding episodes in these patotal disappearance.265 tients can be treated with preparations of factor VIII in the usual fashion. The permanence of this benefit has yet to be determined, but remission has lasted as long as 29 months.266 To what extent the presence of a circulating anticoagulant affects the prognosis of patients with classic hemophilia is unclear. Among 155 patients with severe disease who had undergone testing for the presence of a circulating anticoagulant, 40 deaths occurred between 1955 and 1990.2”” Of 33 patients who tested positive, 14 (42%) died within this interval, and of 122 who tested negative, 26 (21%) died, a difference that was not significant. There was, however, a significant inverse relationship between the presence of circulating anticoagulants and death from either AIDS or liver disease, as if the presence of the anticoagulants may have increased the risk of lethal bleeding, but this statistic was balanced by a decreased frequency of transfusion and therefore less risk of AIDS or liver disease.

CIRCULATING

ANTICOAGULANTS

AGAINST

FACTOR

1X

In general, in parallel to the situation in classic hemophilia, circulating anticoagulants against Christmas factor (factor IX) arise in individuals with Christmas disease who have been transfused with plasma or factor IX-containing fractions.267-z6s In an early review, Margolius et alzo6 reported the prevalence of such anticoagulants to be 12% in patients with Christmas disease; more recent data would suggest that this is an overestimate. As is the case in classic hemophilia, the anticoagulants appear to be antibodies specific for their antigen, Christmas factor or factor IX, and the question arises whether they are synthesized in response to what, to the patient, is a foreign antigen.z70-27’2 The inhibitors have belonged to the IgG class, particularly IgG,, and are probably polyclonal in origit?275; exceptionally, a patient studied by Pike et a1.27” appeared to have a monoclonal antibody. Circulating anticoagulants against Christmas factor may also belong to the immunoglobulin A @A) class .277 The antibodies have been nonprecipitating, as in the case of anticoagulants against antihemophilic factor, but, unlike antibodies to factor VIII, inhibition of their antigen, factor IX, appears to be I>apid:74'78 A familial tendency to the formation of circulating anticoagulants is not clearly established in Christmas disease, but this :tppears to have been the case in a family described by George et al “”

Of four related patients with severe Christmas disease, three, all of whom had been transfused, had circulating anticoagulants against factor IX. Notably, in the fourth patient, who did not have an anticoagulant, George et al. were able to show that plasma lacked antigens related to factor IX, supporting the view that inhibitors are more likely to appear in patients with a deficiency of antigen. As in the case of classic hemophilia, the presence of circulating anticoagulants appears to enhance the bleeding tendency and is dficult to treat. Control of bleeding episodes by infusion of plasma OI concentrates of factor IX may be followed by the anticipated anamnestic rise in inhibitor titer.270827Y By filtering the patient’s plasma through columns of insolubilized protein A-Sepharose (protein A binds y-globulin), Nilsson and her collaboratorsz80 reduced by four fifths the plasma titer of antibodies against factor IX in a patient with Christmas disease who required treatment for a pseudotumor. The remaining antibodies were neutralized by transfusion of factor IX, allowing successful surgery. Alternatively, Theodorsson et al.“” proposed filtering plasma through columns of purified factor LX bound to Sepharose, allowing a more specific removal of the offending antibodies. In an intriguing study by Nilsson et aLz8’ the intravenous administration of immunoglobulin appeared to suppress the rise in antibody titer against factor IX after its temporary control by protein A-Sepharose adsorption. Attempts to reduce synthesis of antibodies against Christmas factor have had variable success. For example, administration of cyclophosphamide and a factor IX concentrate has been tried, but success is chancy.27s,283 Induction of immune tolerance by combined therapy with intravenous IgG, cyclophosphamide, and factor IX has been used in patients with Christmas disease and a circulating anticoagulant.z84 Rarely, circulating anticoagulants against factor IX that arise in patients with Christmas disease may disappear spontaneously; thereafter, the patient may be treated with concentrates of Christmas factor without difficulty.277 Spontaneously arising anticoagulants against Christmas factor (factor IX) are much rarer than are those against antihemophilic factor (factor VIII). Instances of such spontaneous anticoagulants have been described in patients with Takayasu’s arteritis”‘” and in other disorders. 28X- 288 CONCLUDING

REMARKS

During the first two decades of the 20th century, the median life expectanc.y at 1 year of age for patients with classic hemophilia was 57.9 years for those whose disease was mild, 37.3 years for those whose disease was of moderate severity, and 29.9 vears for* those with DAf, S1a.y 1993

339

severe disease.2o8 With the introduction, successively, of treatment by infusion of plasma and of fractions of plasma rich in antihemophilic factor (factor VIII), the prognosis of classic hemophilia has gradually improved so that in the decade 1971 to 1980, life expectancy at 1 year of age was increased to 69.5, 67.1, and 60.5 years for patients with mild, moderately severe, and severe disease, respectively. With the ad: vent of the AIDS epidemic, the prognosis for severely affected patients has changed drastically. Thus, the comparable figures for the decade 1981 to 1990 had decreased to 60.0, 64.1, and 39.8 years, respectively. A similar analysis for patients with other hereditary hemorrhagic disorders is not, to my knowledge, available. These prognostic data underline the need for the development of new ideas about treatment, particularly gene therapy, which may provide a fresh approach to this difficult problem. ACKNOWLEDGMENTS

Otherwise uncredited studies carried out at Case Western Reserve University were supported by grant HL1661 from the National Heart, Lung, and Blood Institute, the National Institutes of Health, U.S. Public Health Service, and by grants from the American Heart Association and its Northeast Ohio Affiliate. REFERENCES 1. Lane S: Hemorrhagic 1:185-188. 2. Feissly R: Beitrage

diathesis.

4. 5. 6. 7. 8. 3. 10. it

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of blood. Lancet 1840;

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55. Cardo LI: Human factor IX for the treatment of hemophilia B (letter). J,%%,% 1991;266:794. 56. MBnachk D, O’Malley JP, Schorr JB, et al: Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III in patients with hereditary antithrombin III deficiency. Blood 1990; 75:33-39. 57. Mannucci PM, Ruggeri ZM, Pareti FI, et al: 1-Desamino-8-o-arginine vasopressin: A new pharmacologic approach to the management of haemophilia and von Willebrand’s disease. lancet 1977; 1:859-872. 58. Ingram GIC, Vaughan Jones R: The rise in clotting factor VIII induced in man by adrenaline: Effect of alpha and beta blockers. J Physioi 1966; 187:447454. 59. Gader AMA, Clarkson AR, Cash JD: The plasminogen activator and coagulation factor VIII responses to adrenaline, noradrenaline, isoprenaline and salhutamol in man. Thromb Res 1973; 29-16. 60. Lethagen S, Harris AS, SjGrin E, et al: Intranasal and intravenous administration of desmopressin: Effect on tVIII/vWf, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58:1033- 1036. 61. Rose EH, Aledort LM: Nasal spray desmopressin iDDAVPl for mild hemophilia A and von Willebrand disease. Ann Intern Med 1991; 114:563-568. 62. Moffat EH, Giddings JC, Bloom AL: The effect of desamino-o-arginine vasopressin (DDAVP) and naloxone infusions on factor VIII and possible endothe&l cell (EC) related activities. Br J Haematol 1984; 57:651-662. 63. Rodeghieru F, Castman G, Mannucci PM: Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease. Blood Rev 1991; 5:155- 161. 64. Greer IA, McLaren M, Belch JJF, et al: Endothelial stimulation by DDAVP in von Willebrand’s disease and haemophilia. Haemostasis 1986; 16:15-19. 65. Diaz M, Aledort L, Forster A: Angioedema in association with the use of DDAVP (abstract). Blood 1986; 68(Suppl):331a. 66. Lowe G, Pettigrew A, Middleton S, et al: DDAVP in haemophilia (letter). Lancet 1977; 2614-615. 67. Smith TJ, Gill JC, Hathaway WE: Hyponatremia and seizures in young children given DDAVP (abstract). Blood 1988; 72(Suppl 1):310a. 68. Weinstein RE, Bona RD, Altman AJ, et al: Severe hyponatmmia after repeated intravenous administration of desmopressin. Am J Hematol 1989; 32:258261. 69. McLeod BC: Myocardial infarction in a blood donor after administration of desmopressin (letter). Lancet 1990; 336:1137-1138. 70. Byrnes JL, Larada A, Moake JL: Thrombosis following desmopressin for uremic bleeding. Am J Hematol 1988; 28:63- 65. 71. O’Brien JR, Green PJ, Salmon G, et al: Desmopressin and myocardial infarction (letter). kncet 1989; 1:664. 772. Bond L, Bevan D: Myocardial infarction in a patient with hemophilia treated with DDAVP (letter). N Engl J Med 1988; 318:121. 73. van Dantzig JM, Duren DR, ten Cate JW: Desmopressin and rn-vocardial infarction (letter). Lancer 1989; 1:664. 74. Mannucci PM, Lusher JM: Desmopressin and thrombosis. Lancer 1989: 2:675-676. 7.5. Walsh PN, Rizza CR, Matthews JM, et al: Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: .A douhleblind controlled trial. Br J Naematol 1971; 20:463-475. 76 Kaspar CK, Dietrich SL: Hemophilia and related conditions, in (:onn Hi+’ ledi (.urrent Therapy. Philadelphia, WB Saunders, 1982, p 273 inr, May

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