Hemophilia A

COAGULATION DISORDERS l

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MD

Jeanne M. Lusher,

Hemophilia A (factor VIII deficiency) is the most common form of hemophilia. It is inherited as an X-linked recessive trait and thus affects males almost exclusively.13 Although no accurate statistics are available, it is estimated that 20,000 persons in the United States have hemophilia; of these 80% to 85% (16,000 to 17,000) have hemophilia A. As noted in the article by Drs. Larson and High, there is considerable heterogeneity in the genetic abnormalities that underlie factor VIII (FVIII) deficiency. The ability to analyze DNA polymorphisms in the FVIII gene, and to even determine the precise defect in the FVIII gene within some families, has resulted in much greater accuracy in carrier detection and has allowed accurate in utero diagnosis within the first trimester of pregnancy. 5 • 12 The FVIII gene has a high mutation rate; thus, approximately one third of newly diagnosed hemophiliac infants have no family history of hemophilia. Such sporadic cases are thought to reflect the introduction of new mutations into previously unaffected families. 5 It is impossible to cover all aspects of hemophilia A in a single article. The reader is thus referred to several recently published books concerning hemophilia and its complications. 9• 10• 18

LABORATORY DIAGNOSIS AND

SEVERITY

As noted, highly sophisticated methods of determining whether a fetus is affected are now available, should a family desire such testing. These involve not only linkage analyses 22 but also direct analysis of the From the Division of Hematology/Oncology, and Regional Comprehensive Hemophilia Center, Children's Hospital of Michigan; and Wayne State University School of Medicine, Detroit, Michigan

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 6 •NUMBER 5 •OCTOBER 1992

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FVIII gene 5, 12; however, for routine testing of an infant or child suspected of having hemophilia (because of a family history of hemophilia or because of excessive bruising and/or joint bleeding), a partial thromboplastin time (PTT) and FVIII and factor IX (FIX) assay should be done, If there is a definite family history of hemophilia A or hemophilia B, one need not assay other factors. The normal PTT is a range (which will vary somewhat depending on the reagents and instrument used by the particular laboratory); a prolonged PTT usually indicates that the FVIII level is 30% or less, FVIII (and/or FIX) assay can be done from an aliquot of plasma from the same citrated blood sample. In general, clinical severity correlates well with the patient's baseline FVIII level. Those with FVIII assay values less than 0.02 U/mL (less than 2%) are considered severe, those with values of 0.02 to 0.05 U/mL (2% to 5%) are moderate, and those with greater than 0.05 U/mL (greater than 5%) are mild. Persons with severe hemophilia A, especially those with less than 0. 01 U/mL (less than 1%) FVIII generally have spontaneous (as well as traumatically induced) bleeding episodes, whereas those with mild hemophilia A generally have no spontaneous bleeding episodes but do bleed excessively with trauma or surgical procedures. Although there is considerable heterogeneity in the underlying genetic defects that result in hemophilia A, 5 the mutation in the FVIII gene will be the same in affected members of a particular family, and the degree of severity will be similar in affected family members (i.e., if a male with hemophilia has less than 0.01 U/mL FVIII, other hemophiliac relatives would also have less than 0.01 U/mL FVIII). Diagnosis in the Newborn Infant

Neither FVIII nor FIX crosses the placenta. Thus, if hemophilia is suspected, the diagnosis can be made by collecting a cord blood sample (from a vessel on the infant side of the placenta using a needle and syringe) for FVIII or FIX assay. If a woman who is a known or possible carrier is pregnant, arrangements should be made in advance to collect such a cord blood sample for assay. BLEEDING MANIFESTA TIO NS

Bleeding in the Neonatal Period and the First Year of life

Although fortunately uncommon, intracranial hemorrhage (ICH) may occur during vaginal delivery. Such instances of ICH are usually associated with some degree of cephalopelvic disproportion, a long, difficult labor in a gravida I woman, or precipitous delivery. This serious complication usually can be avoided by proper prenatal obstetrical care; on occasion, cesarean section may be indicated.

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treatment with or may not in a neonate with Because and von Willebrand factor are normal in persons hemophilia (including neonates with hemophilia), some will not bleed excessively following circumcision; however, others do. Thus, this procedure should either be avoided or preceded with FVIII replacement therapy. Unless subjected to trauma or surgery, most infants with hemophilia will not require treatment with FVIII during the first year of life. Scattered bruises are common, but bleeding into joints or muscles usually does not occur until the child is learning to walk and run. Then, frequent falls onto hard surfaces often result in acute hemarthroses or large soft-tissue hemorrhages and/or tongue and mouth lacerations requiring treatment. Immunizations in the Child with

As soon as a diagnosis of hemophilia is made, the infant or child should be immunized against hepatitis B, using the recombinant (r) hepatitis B vaccine. (Although currently marketed FVIII concentrates are unlikely to transmit hepatitis B or C, persons with hemophilia may at times require transfusion of packed red blood cells, and all blood products, despite donor screening, carry a slight risk of transmitting hepatitis.) There is currently no vaccine for hepatitis C. The hepatitis B vaccine, as well as other injectable vaccines recommended for all children, should be given carefully, with a small-gauge needle and with application of pressure to the site for 2 to 3 minutes. BLEEDING MANIFESTATIONS IN CHILDHOOD AND BEYOND

As noted previously, once a child with hemophilia is learning to walk and run and becomes much more mobile, injuries necessitating treatment often become common. and Mouth lacerations

These occur in the toddler age group, usually resulting from biting the tongue or lip during a fall, and they are often difficult to manage. A dose of FVIII will result in cessation of bleeding; however, the clot is easily dislodged, especially in the case of tongue lacerations. Thus, in infants and toddlers, management should consist of not only FVIII replacement therapy but also hospitalization, sedation, giving the child nothing mouth, intravenous fluids, and an antifibrinolytic agent (epsilon aminocaproic acid or tranexamic acid).

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Acute Hemarthroses and Their Complications

Acute hemarthroses should be treated immediately, in an attempt to stop bleeding and to prevent accumulation of large amounts of blood in the joint space, which can serve as an irritant to the synovial membrane. Synovial proliferation into the joint space can result in trauma to the highly vascular synovial membrane projections with routine activities, ultimately resulting in a vicious cycle of rebleeding, greater synovial proliferation and thickening, and erosion of underlying cartilage and even bone. Home treatment/self-infusion programs allow for immediate treatment of joint (or other) bleeding. Since the introduction of home treatment in the early 1970s, such programs have gained widespread popularity, allowing the person with hemophilia much greater freedom, much less time lost from work or school, and prompt treatment of bleeding episodes. Although older children and adults usually can tell when they begin bleeding into a joint (often describing a peculiar tingling sensation well before there is painful distention of the joint), detection of an early hemarthrosis in younger children is far more difficult. Often, a hemarthrosis is detected only after a parent notices that the child is limping or has obvious joint swelling. Because immediate treatment of acute hemarthrosis is extremely important if one is to prevent the progressive changes leading to chronic, debilitating joint disease, there is now considerable interest in beginning a regimen of prophylactic treatment (with FVIII concentrate given three times per week) at 1 or 2 years of age in children with severe hemophilia. Although the authors are not aware of this being done at present in any US hemophilia centers, reports of success with such prophylactic regimens in Sweden (IM Nilsson, personal communication) have generated considerable interest in this approach. If one is planning such a program, considerations must include venous access problems (some have used indwelling port devices), parental acceptance, product safety, and cost. Nonetheless, if chronic joint disease can be completely prevented, such an approach has definite appeal. As mentioned previously, highly vascular synovial proliferation (resulting from recurrent joint bleeding) can result in frequent episodes of rebleeding into a particular joint (often referred to as a target joint). In an attempt to break this vicious cycle of rebleeding, every-other-day prophylaxis with FVIII concentrates can be tried for 12 weeks or more. If this does not improve the situation, synovectomy should be considered. Although radionuclide synovectomy24 has been used in several countries including Canada, Sweden, Brazil, and Israel, and is being used in a few US centers, most orthopedic surgeons affiliated with US hemophilia centers perform surgical (often arthroscopic) synovectomies. Although a decrease or cessation of recurrent hemarthroses follows synovectomy by either method (open or arthroscopic synovectomy), joint mobility is often improved (or at least maintained) following arthroscopic synovectomy. 27

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Intramuscular

This results from traumatic injury and also should be treated immediately. Common sites include thigh, calf, forearm, and iliopsoas muscles. Although intramuscular bleeding involving an extremity is easily recognized, bleeding into the iliopsoas is not. The latter can imitate hemarthrosis of the hip joint, gastroenteritis, or groin muscle pull. 8 Iliopsoas hemorrhage can be recognized by flexion of the thigh, resistance to passive extension of the thigh, and paresthesias below the inguinal ligament. The diagnosis can be confirmed by roentgenographic or ultrasound examination. Management of intramuscular bleeding includes rest of the affected muscle area and FVIII replacement until the muscle mass has become soft and has decreased in size. Whereas often one (or two) doses of FVIII concentrate will suffice for treatment of an early acute hemarthrosis, often several days of treatment are needed for intramuscular hemorrhages. This is particularly true for iliopsoas hemorrhages, which are often so extensive by the time they are detected that anemia coexists. Occasionally, extensive soft-tissue hemorrhage into the forearm results in "compartment syndrome," a condition in which increased pressure within a confined space results in circulatory compromise. Immediate treatment should include infusion of FVIII concentrate, elevation of the extremity, and cold treatment. Fasciotomy may be required to preserve function. If a compartment syndrome evolves despite usual FVIII dosage for a soft-tissue hemorrhage into the forearm, one should suspect an inhibitor antibody.

As mentioned earlier, ICH in the neonate may result from a long, difficult vaginal delivery or precipitous delivery. Although fortunately far less common than joint, muscle, or other soft-tissue bleeding, ICH resulting from trauma can occur at any age. Immediate treatment with FVIII should be given for any suspected ICH, i.e., before it is confirmed. As noted in Table 1, an initial large bolus dose of FVIII should be given (50 U/kg). If ICH is confirmed, FVIII should then be given by continuous infusion to maintain a level of at least 0.50 U/mL (at least 50%) for a period of 21 days. In view of the high rate of recurrence of ICH in persons with hemophilia, most recommend prophylactic treatment with FVIII being given every other day for a period of at least 6 months following ICH. Hematuria

Spontaneous, painless, gross hematuria is not in persons with hemophilia. If other causes of hematuria are ruled out (e.g.,

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Table 1. HEMOPHILIA A-RECOMMENDED DOSAGES OF FACTOR VIII* Type of Bleeding Acute hemarthrosist Early Late

Intramuscular hemorrhaget Life-threatening situations:j: lntracranial hemorrhage Major surgery Major trauma Tongue or neck bleeding with potential airway obstruction Painless spontaneous gross hematuria

Severe abdominal pain:j: Tongue and mouth lacerations:j:

Tooth extraction (permanent teeth)t

Initial Dose (Factor VIII, U/kg)

Repeated Doses (Factor VIII, U/kg)

10 20

Seldom necessary 20 every 12 hr

20-30

20 every 12 hr (often several days of treatment) 25-30 every 8-12 hr or (preferably) as a continuous infusion (3-4 U/ kg/hr)

50

Ice packs, non-weight bearing sling or lightweight splint; rarely joint aspiration Non-weight bearing support; complete bed rest for iliopsoas hemorrhage

Increased fluids by mouth; corticosteroids and factor VIII used by some

None

20-40

Other Treatment

20-45 every 12 hr

20

20 every 12 hr

20

20 every 12 hr (often not necessary in cases of uncomplicated extractions)

An antifibrinolytic agent (tranexamic acid or E-aminocaproic acid), sedation, nothing by mouth in small child; local application of oral adhesive gauze may be beneficial for gum bleeding Antifibrinolytic agent beginning 1 day preoperatively; continue 7-10 days

*Refers to viral-attenuated plasma-derived factor VIII or recombinant FVlll. tin individuals who have mild hemophilia A, DDAVP (desmopressin) is the treatment of choice rather than factor VIII concentrates. :j:These situations should be treated in a comprehensive hemophilia center. If first seen in another hospital, the hemophilia center should be contacted and the patient transferred after emergency treatment is given at the local hospital. Adapted from Lusher JM, Warrier I: Hemophilia. Pediatrics in Review 12:275, 1991; with permission.

HEMOPHILIA A

renal but drink liberal amounts of In our over the years, the duration of such painless gross hematuria is usually a few days whether one uses FVIII corticosteroids, bed rest, or none of these. On the other hand, if hematuria has resulted from flank trauma, further evaluation and FVIII concentrates are recommended. Procedures If a surgical procedure is judged to be indicated, dose cooperation among medical, surgical, nursing, and coagulation laboratory personnel is essential. One should check for inhibitor antibody to FVIII preoperatively, even though the patient has never had an inhibitor. Surgery should be done in a hospital with a hemophilia center (or at least in a hospital with medical personnel who are experienced in the care of persons with hemophilia). An initial bolus dose of FVIII should be given 30 to 45 minutes preoperatively, followed by a continuous infusion of FVIII (see Table 1), to avoid peak and trough levels of FVIII and to avoid the possibility of delayed doses of FVIII. Although depending somewhat on the type and extent of surgery performed, in general, the patient's FVIII level should be monitored at least once daily while continuous infusions are being given during the postoperative period. When the patient is ready for discharge, if further FVIII replacement therapy is needed, this can be given at home by intravenous bolus.

Dental Procedures

Good oral hygiene is particularly important for persons with hemophilia, to prevent the need for teeth extractions and local anesthetic injections. Should an invasive procedure become necessary, however, dose cooperation between medical and dental personnel is extremely important. In the case of dental extractions or other oral surgical procedures, an antifibrinolytic agent (epsilon aminocaproic acid or tranexamic acid) should be given for 7 to 10 days, beginning the night before the procedure. Although oral surgical technique and local wound care are quite important in preventing excessive bleeding, a dose of FVIII should be given just prior to the procedure. Mandibular anesthetic blocks should be avoided. Nitrous oxide (or general anesthetic for extensive procedures) is preferable. Depending on the extent of the procedure and the extent of tissue damage, follow-up doses of FVIII may be indicated. COMPREHENSIVE CARE

Hemophilia is (at least currently, until gene insertion therapy becomes a reality) a bleeding disorder. As is true of other

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genetic and/or chronic disorders, hemophilia and its treatment can affect many systems and many aspects of affected individuals' lives. In the mid 1970s the US Congress appropriated $4.5 million to establish regional comprehensive hemophilia centers. Providing a vast array of services (educational, psychosocial, vocational counseling, musculoskeletal, dental, medical, genetic counseling, surveillance for inhibitors, liver disease, and so on), such comprehensive care teams have greatly improved the lives of persons with hemophilia (and often their family members as well). During the past decade, the hemophilia team has had to become knowledgeable in the area of HIV infection as well. In many instances, linkages have been established with infectious disease experts. The network of hemophilia centers, in collaboration with the National Hemophilia Foundation and its chapters, the Centers for Disease Control (CDC), the Department of Maternal and Child Health and the National Institutes of Health's (NIH) National Institute for Allergy and Infectious Disease (NIAID), have conducted a number of collaborative studies aimed at providing better comprehensive care for persons with hemophilia.

AVAILABLE PRODUCTS FOR TREATMENT

Plasma-Derived Products

Available products for treatment of persons with hemophilia A include cryoprecipitate and a variety of plasma-derived FVIII concentrates of intermediate purity, high purity, and ultra-high purity. 1• 23 Although cryoprecipitates are still used by a few US hemophilia centers, most use commercially prepared clotting factor concentrates because they are more easily stored, reconstituted, and administered and are pasteurized or solvent-detergent treated and thus less likely to transmit hepatitis C and other blood-borne viruses. All blood and plasma collection facilities are required to test donors for antibodies to the human immunodeficiency virus (HIV), hepatitis B surface antigen (HB 5 Ag), HB core antibody, antibody to hepatitis C virus (HCV), and alanine aminotransferase (ALT). Thus, the initial starting plasma contains far less virus than if these screening procedures were not in place. The viral load is further reduced by the fractionation and purification steps used in preparing FVIII concentrates. Additionally, each of the commercially available FVIII concentrates is subjected to viral attenuation by either pasteurization or solvent-detergent treatment (Table 2). Although one can never be absolutely certain about the viral safety of blood and blood products, the plasma-derived FVIII concentrates currently marketed in the United States appear to be safe in terms of HIV as well as hepatitis viruses; however, recent reports of parvovirus transmission by pasteurized as well as solvent-detergent treated clotting factor concentrates2 indicate that we should not feel completely secure when using human plasma-derived products.

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2. FACTOR VIII PRODUCTS LICENSED IN THE UNITED STATES

Product Name

Manufacturer

Method of Viral Inactivation

Intermediate purity and high purity FV/11 products derived from human plasma Profilate OSD Alpha Solvent-detergent (tri[n-butyl] phosphate [TNBP] and polysorbate 80), 27°C, 6 hr Koate-HP Cutter Solvent-detergent (TNBP + polysorbate 80), 2:24°C, 6 hr NY Blood Center NY Blood Center Solvent-detergent (TNBP and FVlll-SD Cholate), 2:24°C, 6 hr Behringwerke Humate-P Heated in solution (pasteurized), (distributed by 60°C, 10 hr Armour) NY Blood Center Solvent-detergent (TNBP + Me late polysorbate 80), 2'24°C, 6 hr lmmunoaffinity purified FVlll products (uttrapure products) derived from human plasma Monoclate P Armour Pasteurized (60°C, 1O hr) Hemofil M Baxter-Hyland Solvent-detergent (TNBPffriton X-100), 25°C, 2:10 hr (Manufactured by Solvent-detergent (TNBPffriton Coagulation FVlll, Baxter-Hyland for X-100), 25°C, 2'10 hr Method M American Red Cross)

Recombinant Factor Viii Recombinant (r) FVIII, 11 produced by two US manufacturers, has been in prelicensure clinical trials since 1987. Cutter's (Miles/Cutter's, Berkely, CA) r FVIII (Kogenate) and Baxter/Hyland's (Glendale, CA) r FVIII (Recombinate) both appear to be safe, effective, and well tolerated. 19 • 26 • 28 The US Food and Drug Administration's (FDA' s) Blood Product Advisory Committee recommended approval of both of these products in mid-December of 1991; thus, it is likely that both will be licensed during 1992. Potential advantages of r FVIII include viral safety, the promise of an unlimited supply of and (at least ultimately) lower cost.

Desmopressin (l -deamino-8-o-arginine vasopressin) is regarded as the treatment of choice for persons with mild hemophilia A, whenever an approximate threefold increase in FVIII will suffice for treatment of (or prevention of) bleeding. This synthetic agent is thought to act by causing an almost immediate release of FVIII/vWF from storage sites. 3• 20 21 • The drug may have other mechanisms of action as well, because it has been shown to enhance platelet adhesion and spreading at injury sites3 and to enhance hemostasis in persons with several types of congenital and acquired platelet function defects, as well as to decrease blood loss in hemostatically normal individuals undergoing surgical procedures. 20

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Among persons with hemophilia A, ideal candidates for desmopressin would be those whose baseline FVIII values exceed 0.08 U/mL (greater than 8 %) . Also, "carrier" females who have very low levels of FVIII and require surgery or dental extractions would be ideal candidates for desmopressin. Dosage is 0.3 µg/kg, given intravenously; the drug should be diluted in 50 mL normal saline solution and given over 10 to 15 minutes. This drug is remarkably free of undesirable side effects; however, desmopressin is a potent antidiuretic agent. This rarely causes problems but can result in hyponatremia, water intoxication, and convulsions in persons who are receiving large amounts of intravenous fluids postoperatively. Such complications can be avoided by recognition of this potential risk and by monitoring serum sodium levels. In infants and small children, the risk of hyponatremia and water intoxication must be kept in mind. Some degree of oral fluid restriction for 12 to 18 hours after desmopressin should be recommended. If one is planning to use multiple doses of desmopressin for surgical coverage or for treatment of extensive injury, one should keep in mind the possibility of tachyphylaxis (diminishing response with repeated doses) owing to transient depletion of the storage sites. 20 Interestingly, not all persons exhibit tachyphylaxis with desmopressin. In our experience, roughly two thirds of persons do. Persons who have tachyphylaxis will have tachyphylaxis again if given another course of frequent doses of desmopressin. Tachyphylaxis, as well as the extent of response to a single dose of desmopressin (i.e., 2- to 12-fold increase in FVIII) appears to be constant in individuals as well as among affected family members. Despite the fact that desmopressin effects a release in plasminogen activator, clinically significant fibrinolysis is rarely a problem. Thus, few still recommend the concomitant use of an antifibrinolytic agent, unless bleeding is in the oral cavity. A highly concentrated intranasal spray formulation of desmopressin has been developed by the manufacturers (Perring Pharmaceuticals, Malmo, Sweden). This formulation appears to provide excellent bioavailability/ 5 ' 21 is ideal for home use, and has been shown to increase FVIII levels to nearly the same extent as achieved with intravenous DDAVP. Although not licensed in the United States, the intranasal spray formulation is currently undergoing prelicensure clinical study in the United States by the authors in Detroit and by L. Aledort and associates in New York.

COMPLICATIONS OF TREATMENT

Complications of treatment with clotting factor concentrates include inhibitor formation 14 and transmission of blood-borne viruses. These are both described in other articles in this volume and will thus be only briefly commented upon here. Although it is widely stated that 15% of persons with hemophilia

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A

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with severe thirds of inhibitors do so before the age 20 years, and is some evidence for genetic predisposition for inhibitor development. 14' 17 Inhibitors to FVIII appear to have developed in roughly the same prevalence following the use of plasma, cryoprecipitate, and intermediate-purity FVIII concentrates, In recent years, there has been some concern that there might be a higher incidence of inhibitor development in children being treated with at least some ultrapure FVIII products 16; however, it should be noted that the number of study subjects was small and the overall impression of most physicians treating hemophiliacs is that the incidence of inhibitors is not increasing despite wide use of ultra pure (monoclonal antibody purified) FVIII concentrates. Although 15 of 72 previously untreated patients in an ongoing prospective longitudinal study with r FVIII (Kogenate) have developed inhibitors, several points are noteworthy. These infants and small children are being followed by inhibitor assays every 3 months. No previous study has included such frequent surveillance for inhibitors. Nine of the 15 inhibitors have been present in low concentration only, and three of these have disappeared, despite continued "on demand" treatment with Kogenate. All but one of the 15 who developed inhibitors are still being treated with r FVIII. 19 Although not entirely dear at the present time, it seems possible that low-level inhibitors might have occurred (often transiently) in infants being treated with other FVIIIcontaining preparations in the past, had we closely looked for them. Further studies are underway in an attempt to better understand these interesting observations. Transmission of blood-borne viruses by dotting factor concentrates is discussed in the article by Telfer. Fortunately, the combination of donor screening procedures and viral attenuation procedures now being used has resulted in a much greater degree of viral safety of plasmaderived FVIII concentrates than in the past. Nonetheless, as previously noted, recent reports of transmission of parvovirus by pasteurized as well as solvent-detergent treated dotting factor concentrates indicate that we cannot become too complacent in this regard. Regarding the choice of a product for HIV-infected hemophiliacs, there has been considerable interest in the issue of product purity and effects on cellular immunity. Several recently published studies have shown better maintenance of cellular immunity in HIV-infected hemophiliacs who are receiving ultrapure FVIII concentrates4• 6 • 7 • 25; however, other studies are ongoing and this question seems to remain unanswered. High purity and ultrapure FVIII products are much more costly than intermediate-purity FVIII concentrates. 23 Thus, this issue has considerable economic impact. nPr
SUMMARY

Over the past few years considerable progress has been made in elucidating the molecular genetics of hemophilia A, in carrier detection

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and prenatal diagnosis, and in the production of safer clotting factor concentrates. Recombinant FVIII, shown to be safe and effective in ongoing prelicensure clinical trials that began in the spring of 1987, should soon be licensed and commercially available. There is now considerable interest in beginning prophylactic therapy regimens at 1 or 2 years of age, in an attempt to prevent chronic joint disease and other complications of serious bleeding episodes. The possibility of gene insertion therapy for persons with hemophilia now seems to be a realistic one-perhaps achievable in the 1990s. Although many problems remain-major problems resulting from HIV, HCV, and HBV infections; how to deal with existing musculoskeletal problems; how to pay for the higher-priced new technologies; high titer inhibitors; just to name a few-the many recent scientific advances and their clinical applications make this an exciting time. This is truly, as indicated in the title of the proceedings of the XIX Congress of the World Federation of Hemophilia, a new decade of hopes and challenges. 18 References 1. Addiego JE, Gomperts E, Liu S-L, et al: Treatment of hemophilia with a highly purified factor VIII concentrate prepared by anti-F VIIIc immunoaffinity chromatography. Thromb Haemost, in press 2. Azzi A, Ciappi S, Zakvrzewska K, et al: Human parvovirus B19 infection in hemophiliacs first infused with high purity, virally attenuated factor VIII concentrates. Am J Hematol, in press 3. Barnhart MI, Chen S-T, Lusher JM: DDAVP-does the drug have a direct effect on the vessel wall? Thromb Res 31:239, 1983 4. deBiasi R, Rocino A, Miraglia E, et al: The impact of a very high purity FVIII concentrate on the immune system of human immunodeficiency virus infected hemophiliacs-a randomized, prospective two year comparison with an intermediate purity concentrate. Blood 78:1919, 1991 5. Gitschier J, Kogan S, Diamond C, et al: Special lecture on genetic implications. In Lusher JM, Kessler CM (eds): Hemophilia and von Willebrand's Disease in the 1990s-A New Decade of Hopes and Challenges. Amsterdam, Excerpta Medica, . 1991, p 333 6. Goldsmith JM, Deutsche J, Tang M, et al: CD4 cells in HIV-1 infected hemophiliacs: Effect of factor FVIII concentrates. Thromb Haemost 66:1991 7. Gomperts ED, deBiasi R, DeVreker R: The impact of clotting factor concentrates on the immune system in individuals with hemophilia. Transfus Med Rev, in press 8. Handelsman JE, Glasser RA: Pathogenesis and treatment of hemophilic arthropathy and deep muscle hemorrhages. In Kasper CK (ed): Recent Advances in Hemophilia Care. New York, Alan R. Liss, 1990, p 199 9. Hilgartner MW, Pochedly C (eds): Hemophilia in the Child and Adult, ed 2. New York, Raven Press, 1989 10. Kasper CK (ed): Recent Advances in Hemophilia Care. New York, Alan R. Liss, 1990 11. Kaufman RJ: Recombinant DNA technology for the production of factor VIII for treatment of hemophilia A. In Lusher JM, Kessler CM (eds): Hemophilia and von Willebrand's Disease in the 1990s-A New Decade of Hopes and Challenges. Amsterdam, Excerpta Medica, 1991, p 235 12. Kogan SC, Doherty M, Gitschier J: An improved method of prenatal diagnosis of genetic diseases by analysis of amplified DNA sequences. Application to hemophilia A. N Engl J Med 317:985, 1987 13. Lusher JM, McMillan C: Severe factor VIII and factor IX deficiency in females. Am J Med 65:637, 1978

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14. Lusher Etiology, natural and management of factor VIII inhibitors. Ann NY Sci 509:89, 1987 in haemostatic 15. Lusher JM: Pharmacology and pharmacokinetics of disorders. Drug Investigation 2 (Suppl 5):25, 1990 16. Lusher JM, Salzman P, and the Monoclate Study Group: Viral safety and inhibitor development associated with factor VIII C ultra-purified from plasma in hemophiliacs previously unexposed to FVIII:C concentrates. Semin Hematol 27(Suppl 2):1, 1990 17. Lusher JM: Current perspectives on the significance and interpretation of factor VIII and factor IX inhibitors. Blood Coagulation and Fibrinolysis 2:3, 1991 18. Lusher JM, Kessler CM (eds): Hemophilia and von Willebrand's Disease in the 1990s-A New Decade of Hopes and Challenges. Amsterdam, Excerpta Medica, 1991 19. Lusher JM, Arkin S, Abildgaard C, et al: Recombinant F VIII (Kogenate) in previously untreated subjects with hemophilia A-a three year study. N Engl J Med, in press 20. Mannucci PM: Desmopressin (DDAVP) for treatment of disorders of hemostasis. Prag Hemost Thromb 8:19, 1986 21. Nilsson IM, Lethagen S: Current status of DDAVP formulations and their use. In Lusher JM, Kessler CM (eds): Hemophilia and von Willebrand's Disease in the 1990s-A New Decade of Hopes and Challenges. Amsterdam, Excerpta Medica, 1991 22. Peake IR, Lillicrap DP, Liddell MB, et al: Linked and intragenic probes for hemophilia A. Lancet 2:1003, 1985 23. Pierce GF, Lusher JM, Brownstein AP, et al: The use of purified clotting factor concentrates in hemophilia. Influence of viral safety, cost and supply on therapy. JAMA 261:3434, 1989 24. Rivard GE: Synoviorthese with radioactive colloids in hemophiliacs. In Kasper CK (ed): Recent Advances in Hemophilia Care. New York, Alan R. Liss, 1990, p 215 25. deBiasi R, Round A, Miraglia E, et al: The impact of a very high purity factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs: A randomized, prospective two-year comparison with interactive purity concentrate. Blood 78:1919-1922, 1991 26. Schwartz R, Abildgaard C, Aledort L, et al: Safety and efficacy of human recombinant DNA-derived factor VIII in treatment of hemophilia A. N Engl J Med 323:1800, 1990 27. Weide! J: Arthroscopy of the knee in hemophilia. In Kasper CK (ed): Recent Advances in Hemophilia Care. New York, Alan R Liss, 1990, p 231 28. White GC II, McMillan CW, Kingdon HS, et al: Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med 320:166, 1989

Address reprint requests to Jeanne M. Lusher, MD Division of Hematology/Oncology Children's Hospital of Michigan 3901 Beaubien Boulevard Detroit, MI 48201