Hemophilia

Overview of Hemophilia

The hemophilias are bleeding disorders caused by the absence or decrease of factor VIII in hemophilia A or factor IX in hemophilia B.

Coagulation

Factors VIII and IX (FVIII and FIX) are part of the coagulation cascade of secondary hemostasis. Classically, the coagulation cascade has two initial pathways leading to fibrin formation ( Fig. 18.1 ). These are the contact activation or intrinsic pathway, and the tissue factor or extrinsic pathway. The pathways are a series of reactions in which a zymogen of a serine protease is activated, which then catalyzes the next reaction in the cascade, ultimately resulting in cross-linked fibrin.

Roles of Factors VIII and IX in Coagulation

In vivo the coagulation cascade takes place on the surface of endothelial cells and platelets ( Fig. 18.2 ). The primary driver of secondary hemostasis is the factor VII or tissue factor pathway, which activates factor X to provide an initial thrombin burst. This is followed by amplification of factor Xa production by the complex of activated FVIII and FIX ( Fig. 18.3 ). Factor Xa produced by the factor VIIIa and IXa “tenase” complex, which also consists of calcium and phospholipids, then generates large amounts of thrombin and drives fibrin deposition and hemostasis.

Incidence

Hemophilia A occurs in approximately 1:5000 males, whereas hemophilia B occurs less frequently, in about 1:20,000 males. Inheritance patterns are not affected by race or geography. There are more than 17,000 affected people in the United States, and it is estimated that more than 400,000 people are affected worldwide. Many affected individuals are from resource-poor nations that do not report hemophilia cases.

Inheritance

Both FVIII and FIX are located on the X chromosome and so are passed on in an x-linked pattern ( Fig. 18.4 ). Up to 30% of cases do not have a positive family history. The inherited nature of hemophilia was recognized in the Talmud of the second century, which read, “If she circumcised her first son and he died, and her second son and he too died, she should not circumcise her third son.” More recently, one of the most famous hemophilia pedigrees is that of the “royal disease” of the house of Queen Victoria, whereby most of the royal houses of Europe carried hemophilia B ( Fig. 18.5 ).

Factor Level Determines Bleeding Phenotype

The baseline factor level of factor VIII or IX determines the severity of the bleeding symptoms ( Table 18.1 ). Lower baseline factor level correlates with bleeding rate ( Fig. 18.6 ). Although bleeding can occur at any location, hemorrhage into muscles or joints with little or no obvious trauma is the hallmark of hemophilia.

Molecular Basis of Hemophilia A and B