Hemophilia A and von Willebrand disease are caused by qualitative or quantitative defects involving the factor VIII–vWF complex. As background for subsequent discussion of these disorders, it is useful to review the structure and function of these two proteins (
Fig. 12.31
As described earlier, factor VIII is an essential cofactor for factor IX, which activates factor X in the intrinsic coagulation pathway. Circulating factor VIII binds noncovalently to vWF, which exists as large multimers of up to
Fig. 12.31 StructureandfunctionoffactorVIII–vonWillebrandfactor(vWF)complex.FactorVIIIandvWFcirculateasacomplex.vWFalsoispresentinthesubendothelialmatrixofnormalbloodvessels.FactorVIIItakespartinthecoagulationcascadebyactivatingfactorXbymeansoffactorIX(not shown).vWFcausesadhesionofplateletstosubendothelialcollagen,primarilythroughtheglycoproteinIb(GpIb)plateletreceptor.Factor VIII Clotting cascade Activated, aggregated platelets X XavWF GpIb GpIIb/IIIa Fibrinogen Circulating vWF with Factor VIII Subendothelial vWF Platelet Endothelial defect Platelet n 20 Megadaltons in weight. Endothelial cells are the major source of plasma vWF, whereas most factor VIII is synthesized in the liver. vWF is found in the plasma (in association with factor VIII), in platelet granules, in endothelial cells within cytoplasmic vesicles called Weibel-Palade bodies, and in the subendothelium, where it binds to collagen.
When endothelial cells are stripped away by trauma or injury, subendothelial vWF is exposed and binds platelets, mainly through glycoprotein Ib and to a lesser degree through glycoprotein IIb/IIIa (
Fig. 12.31 ). The most important function of vWF is to facilitate the adhesion of platelets to damaged blood vessel walls, a crucial early event in the formation of a hemostatic plug. Inadequate platelet adhesion is believed to underlie the bleeding tendency in von Willebrand disease. In addition to its role in platelet adhesion, vWF also stabilizes factor VIII; thus, vWF deficiency leads to a secondary deficiency of factor VIII.
The various forms of von Willebrand disease are diagnosed by measuring the quantity, size, and function of vWF. vWF function is assessed using the ristocetin platelet agglutination test. Ristocetin somehow “activates” the bivalent binding of vWF and platelet membrane glycoprotein Ib, creating interplatelet “bridges” that cause platelets to clump (agglutination), an event that can be measured easily. Thus, ristocetin-dependent platelet agglutination serves as a useful bioassay for vWF.
With this background we now turn to the discussion of diseases resulting from deficiencies of factor VIII–vWF complex.
von Willebrand disease is transmitted as an autosomal dominant disorder. It usually presents as spontaneous bleeding from mucous membranes, excessive bleeding from wounds, and menorrhagia. It is underrecognized, as the diagnosis requires sophisticated tests and the clinical manifestations often are quite mild. Actually, this disease is surprisingly prevalent, particularly in persons of European descent. It is estimated that approximately 1% of people in the United States have von Willebrand disease, making it the most common inherited bleeding disorder.
People with von Willebrand disease have compound defects in platelet function and coagulation, but in most cases only the platelet defect produces clinical findings. The exceptions are rare in patients with homozygous von Willebrand disease, in whom there is a concomitant deficiency of factor VIII severe enough to produce features resembling those of hemophilia (described later).
The effects of the causative mutations vary, allowing von Willebrand disease to be divided into several subtypes