von Willebrand disease (VWD) is a result of quantitative and qualitative abnormalities in von Willebrand factor (VWF), a plasma protein serving as a carrier for factor VIII and as an adhesive link between platelets and damaged blood vessel walls. Table 80–1 presents the nomenclature used in discussing the functions of VWF.
TABLE 80–1von WILLEBRAND FACTOR AND FACTOR VIII TERMINOLOGY ||Download (.pdf) TABLE 80–1 von WILLEBRAND FACTOR AND FACTOR VIII TERMINOLOGY
|Factor VIII |
|Antihemophilic factor, the protein that is reduced in plasma of patients with classic hemophilia A and VWD and is measured in standard coagulation assays |
|Factor VIII activity (factor VIII:C) |
|The coagulant property of the factor VIII protein (this term is sometimes used interchangeably with factor VIII) |
|Factor VIII antigen (VIII:Ag) |
|The antigenic determinant(s) on factor VIII measured by immunoassays, which may employ polyclonal or monoclonal antibodies |
|von Willebrand factor (VWF) |
|The large multimeric glycoprotein that is necessary for normal platelet adhesion, a normal bleeding time, and stabilizing factor VIII |
|von Willebrand factor antigen (VWF:Ag) |
|The antigenic determinant(s) on VWF measured by immunoassays, which may employ polyclonal or monoclonal antibodies; inaccurate designations of historical interest only include factor VIII-related antigen (VIIIR:Ag), factor VIII antigen, AHF antigen, and AHF-like antigen |
|Ristocetin cofactor activity (or: von Willebrand factor activity; VWF:act) |
|The property of VWF that supports ristocetin-induced agglutination of washed or fixed normal platelets |
ETIOLOGY AND PATHOGENESIS
VWF is synthesized in endothelial cells and megakaryocytes.
Posttranslational modification of the molecule involves glycosylation, sulfation, and multimer formation through extensive disulfide bond formation.
VWF is stored in platelets and in Weibel-Palade bodies in endothelial cells.
Secretion of VWF from Weibel-Palade bodies is both constitutive and regulated. High-molecular-weight multimers with the greatest activity are released in response to agents such as thrombin in vitro or desmopressin (DDAVP) in vivo.
A specific VWF processing protease can reduce the size of high-molecular-weight multimers in plasma.
VWF plays an important role in platelet aggregation at sites of vessel injury.
VWF stabilizes factor VIII through formation of a noncovalent complex between the two proteins.
A large number of mutations of the VWF gene have been discovered and more than 20 distinct subtypes of VWD have been described. Table 80–2 presents a simplified classification of VWD.
Types 1 and 3 are deficiencies of normal VWF, either partial (type 1) or complete (type 3).
Type 2 includes the qualitative abnormalities of VWF structure and/or function. The quantity of VWF (VWF antigen) in type 2 disease may be normal but is usually reduced.
Platelet-type VWD is an inherited platelet abnormality due to a mutation in glycoprotein Ib (CD42b, c). It is discussed in Chap. 76.
TABLE 80–2CLASSIFICATION OF VON WILLEBRAND DISEASE