Clinical Aspects of and Therapy for Hemophilia A. Incidence. Clinical Severity

Chapter 106

Clinical Aspects of and Therapy for Hemophilia A

Doreen B. Brettler, Elissa M. Kraus, and Peter H. Levine

Introduction

Hemophilia A, the most common of the true hemophilias, accounts for approximately 85% of cases. It is an X-linked recessive bleeding disorder attributable to decreased plasma levels of properly functioning factor VIII (also known as antihemophilic factor).

Probably originally named haemorrhaphilia, the disease was referred to as hemophilia by Schцnlein in the early 1800s. 1 In 1893, Wright 2 noted that blood from patients with hemophilia demonstrated a prolonged clotting time. In 1911, Addis 3 showed that the latter could be corrected in vitro by adding normal plasma. In 1947, both Brinkhous4 and Quick 5 independently suggested a role for factor VIII in the generation of plasma thromboplastic activity. That same year, Pavlovsky 6 correctly inferred the presence of multiple types of hemophilia by showing that he could correct the clotting defect in certain hemophilic plasma samples by adding plasma from certain other hemophilic donors.

Lane 7 successfully transfused a patient with hemophilia in 1840, and plasma was first used as therapy in 1923 by Feisly. 8 Due to the minute quantities of factor VIII in plasma, its short half-life, and problems of circulatory volume overload, the vast majority of persons with hemophilia succumbed to hemorrhage early in life during the era of whole blood plasma therapy. In one study from Scandinavia, 9 for example, the mean age of death between the years 1950 and 1959 was 10.2 years for all persons with hemophilia.

In 1964 Pool et al. 10 analyzed the content of the annoying precipitate that formed transiently during the thawing of fresh frozen plasma and found it to contain a disproportionately high amount of factor VIII. Thus, the era of cryoprecipitate therapy began, and this treatment made the first meaningful improvement in life expectancy. For example, in the same Scandinavian study, 9 the average age at death between 1960 and 1969 doubled to 20.1 years.

The late 1960s saw the introduction of partially purified preparations of factor VIII, prepared by glycine precipitation of fresh plasma and later by polyethylene glycol precipitation. 11 More recently, therapeutic products highly purified from human plasma by the use of immunoaffinity chromatography have been available. MLID88264487  12 The first infusion of recombinant factor VIII was reported by White and colleagues in 1988. 13 Subsequently, >100 patients have been studied, all of whom have received recombinant factor VIII without difficulty. MLID91061845  14

Incidence

Both Hemophilia A and B were studied by the National Heart, Lung, and Blood Institute in 1972. 15 Their estimate of incidence was 25 cases per 100,000 males. Other studies have suggested lower figures, and most experts believe the correct figure to be approximately 20 cases per 100,000 males (1 per 10,000 of the whole population), with factor VIII deficiency accounting for 85% of these. Factor IX deficiency explains 14%, and the remaining cases involve the rare congenital clotting factor factor XI, X, VII, or V deficiencies. There is no reason to believe that the incidence of hemophilia varies in different races or by geographic areas of the world.

Among patients with hemophilia A being treated in the United States, 60% are classified as severe (i.e., have a factor VIII level of <1% of normal). Most of the remainder have moderate disease (factor VIII level >1% of normal). The number of people with mild disease is not known, as many such patients undoubtedly are mild bleeders and escape detection.

Clinical Severity

The frequency and severity of bleeding in hemophilia may be predicted from the factor VIII procoagulant level, assayed in comparison to a reference standard that is assumed to have factor VIII levels of 100%, corresponding to a factor VIII activity of 1.0 U/ml. The factor VIII level in normal persons ranges from 50% to 200% (0.50–2.0 U/ml). Those with factor VIII levels F1% of normal (F0.01 U/ml) have hemorrhages requiring therapy two to four times monthly on the average, although the range is large and the episodes are irregularly spaced. Such patients are classified as severe hemophiliacs. Those with factor VIII levels >5% of normal (>0.05 U/ml) are considered mild hemophiliacs and usually hemorrhage only due to trauma or surgery. Some such cases are not diagnosed until adult life. Occasional spontaneous hemarthrosis may occur in such patients, especially in joints damaged by previously undertreated post-traumatic hemorrhage. Patients whose factor VIII levels are between these two ranges are considered moderately severe, and their clinical picture falls between the two extremes. If such patients have had multiple untreated, or suboptimally treated hemarthroses with subsequent joint damage, the anatomic instability of these joints will cause frequent and severe bleeding, and the disease will therefore appear clinically more severe than the factor VIII assay would suggest.