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INTRODUCTION

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LEARNING OBJECTIVES

After studying this chapter you should:

  • Understand the genetics, clinical features, diagnosis, and treatment of hemophilias A and B.

  • Understand the genetics, clinical features, diagnosis, and treatment of von Willebrand disease.

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No hematologic disorder has more historical import and portent than hemophilia. Figure 15-1 shows the descendants of Queen Victoria and Prince Albert. One of their three sons, Leopold, Duke of Albany, suffered from a life-long bleeding -disorder, as did nine grandsons and great grandsons, including members of the Russian, Prussian, and Spanish royal families. Particularly foreboding was the affliction of young Prince Alexie, the only son of Czar Nicholas and Czarina Alexandra. His illness was but one of many travails that beset the Russian royal family and led to their dethronement and execution during the Bolshevik revolution.

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Hemophilia

Hemophilia A (Factor VIII Deficiency)

Hemophilia B (Factor IX Deficiency)

Phenotypically Identical:

 Hemarthroses

 Hematoma

 GI and GU Bleeding

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FIGURE 15-1

Family tree of Queen Victoria of England, Prince Albert, and their descendants. The frontispiece preceding Chapter 13 shows photographs of Prince Leopold, Duke of Albany, son of Queen Victoria, and Czarevich Alexei, son of Czar Nicholas and Czarina Alexandra of Russia.

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HEMOPHILIA A (FACTOR VIII DEFICIENCY)

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Hemophilia A is the inherited bleeding disorder most often associated with severe morbidity, frequently requiring hospitalization. It is due to deficiency of factor VIII. When activated, factor VIII forms a complex with activated factor IX, enabling the efficient proteolytic activation of factor X (see bottom of sidebar and Chapter 13 for more information about factor VIII). Hemophilia A occurs in about 1 in 5000 male births. The gene encoding factor VIII is located near the tip of the long arm of the X chromosome. Thus, hemophilia A is inherited in an X-linked manner, with female heterozygous carriers passing the disease on to half of their sons. The royal families depicted in Figure 15-1 comprise a typical kindred demonstrating X-linked transmission. About 30% of patients have no family history of abnormal bleeding. Most of these cases are due to spontaneous mutations. Although hemophilia A can occur in homozygous females, often owing to consanguinity, most females who bleed abnormally are heterozygous carriers of the hemophilia gene. Although the mechanism for their low factor VIII levels is not known, skewed X-inactivation (lyonization) has been hypothesized.

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CLINICAL PRESENTATION

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Patients with hemophilia A tend to have deep bleeding into joints (hemarthroses) or muscle beds, rather than bleeding from mucosal surfaces. Patients with repeated joint hemorrhage develop chronic disability due to swelling, deformity, severe pain, limitation of motion, and contractures that can be corrected only by joint replacement. Less often patients have bouts of gastrointestinal or genitourinary bleeding and, rarely, intracerebral hemorrhage—a catastrophic event. Patients are assigned to one of three levels of ...

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