Modern Management of Hemophilia A

The two main complications facing patients with hemophilia A are joint bleedings, leading to potentially disabling arthropathies, and the development of an inhibitor in response to treatment with factor VIII concentrates. The management of these two complications is the topic of this issue of Seminars in Thrombosis and Hemostasis. Prophylactic treatment of hemophilia patients, albeit expensive, has largely reduced bleeding episodes and thus hemorrhages into the large joints. This is particularly applicable to children. Should intra-articular bleeding lead to joint pathologies, orthopedic interventions can today largely correct these problems. The management of patients with inhibitors remains a major challenge, especially in those patients who have a high-titer inhibitor. Immune tolerance is the best option for these patients. For hemophiliacs with low-titer antibodies there are other options that are comprehensively reviewed in this issue.

The first article by Berntorp and Michiels briefly reviews the progress that has been made in managing hemophilic patients. The availability of factor concentrates has drastically changed the prognosis for these patients, who can today anticipate a reasonably normal life expectancy. Acute bleeding episodes can be managed or prevented successfully by appropriate prophylactic treatment modalities. Through prophylaxis, arthropathies, once major disabling complications of hemophilia, can be large prevented. The development of inhibitors still presents, unfortunately, a major problem. Although considerable progress has and is still being made in understanding this complication of hemophilia treatment, much more needs to be done to address this issue.

Next, Thompson reviews comprehensively the structure and function of the factor VIII gene and the factor VIII protein. The gene is located on the long arm of the X chromosome, and its structure has been largely elucidated. The factor VIII mRNA has been located not only in hepatocytes, but also in several other tissues. The mechanisms of secretion of the protein are also well-understood, and its association with von Willebrand factor (vWF) has long been recognized. VWF stabilizes factor VIII:C by preventing its proteolytic degradation. The structure of the factor VIII protein is also largely known, and abnormalities have been found in several hemophilic patients. The many binding sites within the molecule are expertly reviewed. This information is helpful in potentially developing new factor VIII concentrates, and gene therapy of hemophilia is in its early stages of development.

In the next contribution, Goodeve and Peake describe the molecular basis for hemophilia A and for the development of inhibitors. The understanding of the gene for factor VIII and the structure of the protein itself has opened the opportunity to identify abnormalities in gene structure and protein structure of hemophilia A patients. The authors comprehensively describe these defects. They furthermore review the present knowledge concerning the relationship of factor VIII mutation types and the acquisition of antibodies in response to factor concentrate treatment. There is a potential algorithm for predicting inhibitor development in newly diagnosed hemophilia A patients. In addition, the well-known difference between factor VIII assays appears to have a molecular basis. This knowledge will benefit the management of patients with hemophilia A.

Aspects of genetic counseling for hemophilia carriers are discussed by Ljung and Tedgård. In many instances carriers can be predicted based on their pedigree and on their factor VIII levels in plasma. In other cases, genotype assessment should be made, coupled with attempts to identify the pathogenic mutation in the factor VIII gene. Linked polymorphic markers may also be used to trace the inheritance, but there are limitations to this approach. It is important to offer potential carriers assistance in genetic information, testing and counseling to cope with the psychological and ethical problems associated with the state.

Roosendaal and Lafeber next review the pathogenetic mechanisms involved in hemophilic arthropathies. This is the most debilitating complication of hemophilia, caused by repeated bleedings into joints, most commonly of the lower limbs. The underlying mechanism(s) are still subject of debate, but agreement appears to exist on the facts that the underlying causes are multifactorial and include degenerative cartilage-mediated and inflammatory synovium-mediated components. These processes occur in parallel but do not necessarily depend on each other. At this time, when "a joint of no return" is reached remains unknown. This knowledge would clearly have an impact on the management of these patients with factor concentrates.

In the next article, Kilcoyne and Nuss review the radiological evaluation of hemophilic arthropathy. Staging of the hemophilic joints is important to identify the bleeding site and for appropriate therapy. Magnetic resonance imaging (MRI) is at this time the best method. It allows visualization of the bleed, evaluates subchondrial cysts and cartilage loss and follows the impact of treatment. Several MRI scales for evaluating hemophilic arthropathies are presented and are discussed critically.

Prophylaxis for severe hemophilia is reviewed by van den Berg and Fischer, taking into account experiences gathered in Europe and the United States. The objective of prophylactic factor concentrate administration is to convert a severe form of hemophilia to a moderate one, recognizing that the severity of the disease correlates with the number of bleeds encountered and especially with the development of hemophilic arthropathy. The latter is particularly devastating to the quality of life of these patients. Many hemophilia care centers have successfully reduced bleeds and arthropathies by using prophylaxis, albeit at a high cost. Two approaches have emerged: administration at preinfusion levels of > 1% factor VIII:C or factor IX:C or guidance by clinical bleeding patterns. For both approaches, early start of treatment is important. Prophylaxis may be less important when hemophiliacs reach adulthood. All children with severe hemophilia should receive prophylaxis in order to reduce bleedings and arthropathies.

The next article by Aledort examines orthopedic outcomes and cost issues for hemophilia prophylaxis. Even when cryoprecipitate was the source of factor VIII replacement, it was recognized that bleedings could be reduced and joint pain ameliorated. These early observations, coupled with better factor concentrates and better assay procedures, resulted in the concept of preventing disabling arthropathies by early therapeutic intervention, thus leading to the use of factor concentrates for prophylaxis. Most of the studies leading to this practice are reviewed, and scoring systems used to stage success of treatment are illustrated. These advances, leading to decreased morbidity and a drastically improved quality of life, are expensive, whereby the factor concentrates are most costly. Studies are being conducted to fine-tune the timing of prophylaxis and to find the most effective dose that will provide adequate protection.

Fijnvandraat and coworkers next describe the immunologic events underlying the development of inhibitors in hemophilia A patients. These antibodies develop in some, but not all, patients in response to treatment with factor VIII concentrates. Inhibitors present a major complication of hemophilia treatment, and much effort has been spent on understanding the inhibitor development. Studies have revealed that antibodies bind to specific regions in the A and C domains of the factor VIII molecule, where they interfere with the binding of factor VIII to factor IX, factor Xa, or phospholipids. Although the entire mechanisms underlying inhibitor development are not yet fully understood, the authors describe expertly what is known at this time and link this knowledge to future perspectives on how inhibitor formation may be interfered with.

The next contribution by Mariani and coworkers gives an update on the status of immune tolerance in hemophilia A patients with inhibitors. Several large studies have been conducted to investigate this issue, but differences in protocols make accurate comparisons difficult, including the definition of "success." Two variables appear, however, to be fairly consistent throughout the studies: the inhibitor titer and the length of treatment. Immune tolerance is induced by administering high doses of factor VIII concentrate with or without concomitant immunosuppressive measures. Patients with low-titer inhibitors will usually respond to this treatment, whereas those with high-titer inhibitors still present a problem. The higher the titer is, the longer the period of refractoriness to factor VIII will be. Although the data from several registries are helpful in addressing this issue, prospective and randomized trials may be needed to come to firm recommendations.

Astermark next reviews the treatment options available at this time for bleeding hemophilic patients who also have an inhibitor. This problem presents a major challenge for the health care provider. In principle, when a patient has a low-responding inhibitor titer, it is usually possible to overcome this by administration of the factor that is lacking, either factor VIII or factor IX. If the patient has a high titer, this approach frequently fails. There are three alternative options to achieve hemostasis: use of activated or non-activated prothrombin complex concentrates, administration of porcine factor VIII concentrates or employing recombinant factor VIIa. The author extensively discusses these options, including benefits and side effects. At present recombinant factor VIIa appears to be the most useful concentrate, but it is costly.

The management of musculoskeletal complications of hemophilia is discussed by Rodriguez-Merchan. Based on his experience as an orthopedic surgeon, the author expertly discusses all treatment options for all forms of hemarthroses, synovitis, osteonecrosis, articular deformities, flexion contractures, and the possibility of performing multiple procedures at the same time of surgery. In addition, the handling of fractures is reviewed. The management of bleedings into muscles of hemophiliacs, including pseudotumors, is examined as well. With the advent of successfully correcting the hemostasis system of hemophiliacs, it appears that almost any orthopedic procedure can be safely performed, but the cooperation between orthopedic surgeons and hematologists is absolutely essential.

As alluded to in the preceding article, chronic hypertrophic hemophilic synovitis is an inevitable result of intra-articular hemorrhages. Its treatment by radionuclide synovectomy is described by Rodriguez-Merchan. The procedure, using radioactive material, is easy to perform and is effective and economically acceptable. The problem is that synovitis leads to more bleeding that, in turn, results in more synovitis. This potentially crippling cycle must be appropriately treated. The author extensively reviews indications, procedures, outcomes, and safety based on long years of experience.

In the following article Lethagen reviews the use of desmopressin (DDAVP) in hemophilia A patients to treat bleeding episodes. DDAVP, in contrast to factor concentrates, does not transmit blood-borne substances and is well tolerated without serious side effects. It can be administered intravenously or intranasally as a spray. DDAVP releases factor VIII and vWF into the circulation and thus increases plasma levels temporarily. Because the increase is not that large, only patients with mild hemophilia A will profit. DDAVP can thus be administered before minor surgical procedures, immediately following minor trauma or whenever the need may arise. It is important to give a test dose first to ascertain that the desired plasma levels can be achieved. Side effects of DDAVP are usually minor.

In the last contribution, High extensively reviews the status of gene transfer for the treatment of both hemophilia A and hemophilia B. This approach is relatively new, and it attempts to induce high enough levels of factors VIII or IX to achieve long-lasting hemostasis. At this time, many animal models have been studied with mixed results. The availability of an appropriate gene delivery vehicle is in the moment the greatest obstacle to the successful clinical application of this technique to humans. Nevertheless, at this time five trials are being conducted, three in hemophilia A patients and two in hemophilia B subjects. These studies are reviewed in detail. Most of the research is at present conducted on animal models in order to determine which approach can be safely extended to humans. This form of treatment is extremely complex, but would, if successful, drastically change the outlook for hemophiliacs.

I am grateful to all authors for their excellent contributions and most appreciative of the efforts by Professor Erik Berntorp, who assembled this very interesting and informative issue of Seminars in Thrombosis and Hemostasis.