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von Willebrand Disease
von Willebrand disease (VWD) is the most common hereditary bleeding disorder affecting as much as 1% of the general population. The VWF (von Willebrand factor) protein has three essential hemostatic functions: (1) binding to FVIII thereby prolonging its half-life, (2) binding to collagen in the underlying subendothelial matrix, and (3) binding to platelets; thus, VWF recruits platelets to the injury site by functioning as a bridge between platelets and the subendothelial matrix. Therefore, deficiency in VWF highlights the indispensable role of VWF in primary and secondary hemostasis and explains the unique features of bleeding manifestations of VWD. Patients who are symptomatic for this disease have mucosal bleeding symptoms and bleeding immediately after invasive procedures or surgery. Severe VWD may also present as gastrointestinal bleed and bleeding in muscles and joints. The most common presentation in males is epistaxis, whereas in females is menorrhagia. The bleeding history is the most important criteria to seek and establish a diagnosis of VWD. PTT is often normal and thus specific testing for VWD antigen and function is required. VWD workups should only be performed for patients with bleeding history. A family history of bleeding is useful to establish the autosomal dominant inheritance. Minor mucosal bleeding does not require treatment, whereas minor invasive procedures (e.g., dental procedures) can be treated with antifibrinolytics or desmopressin (DDAVP) (if proven beneficial). For major surgeries or trauma, a VWF-containing product (Humate-P or Wilate) is recommended.
In 1926 Erik Adolf von Willebrand characterized a bleeding disorder in a family in the Aland archipelago off the coast of Finland. 23 of 66 members of the family, mainly females, had bleeding problems. He first called the disease “hereditary pseudohemophilia” but renamed it “constitutional thrombopathy” to emphasize involvement of platelet. VWD is caused by a qualitative or quantitative deficiency of the VWF protein and is the most common inherited bleeding disorder. Common bleeding manifestations include mucosal bleeding, menorrhagia, and bleeding immediately after invasive procedures or surgery.
The Protein
VWF is a huge glycoprotein composed of many individual monomers that are linked together to form multimers. Each monomer contains the sites of VWF hemostatic functions: binding to collagen, binding to platelets, and binding to coagulation FVIII ( Fig. 109.1 ). However, the larger the multimers the more efficient they are at carrying their hemostatic functions.
VWF is synthesized as a large pro-VWF and undergoes several posttranslational modifications necessary for proper function and secretion. Monomers are dimerized in the endoplasmic reticulum and then glycosylated in the Golgi apparatus. Following glycosylation, the C terminal dimers are then N-terminal multimerized up to 20 million daltons in size. The VWF propeptide is cleaved and packed together with mature VWF in specialized compartments called Weibel–Palade Bodies (WPB) in endothelial cells. The VWF propeptide (VWFAgII) is important for proper VWF multimerization and storage. WPB store other proteins that modulate coagulation, angiogenesis, and inflammation, such as coagulation FVIII, tissue plasminogen activator, P-selectin, P-selectin cofactor (CD63), osteoprotegerin, angiopoetin-2, endothelin-1, and interleukin 8. Interestingly, the formation of WPBs is defective in VWD. On activation, endothelial cells secrete VWF along with the other content of WPB. Secreted VWF circulates in a globular form until it gets exposed to subendothelial collagen, where it binds and, under high shear stress, uncoils into a linear chain. The largest multimeric forms of the protein play an important role in recruiting platelets to the injury sites. The third hemostatic function of VWF is to carry coagulation FVIII. It protects FVIII from degradation and brings it in close proximity to phospholipids on the surface of activated platelets and injured endothelium, where coagulation is initiated.
Platelet-Derived von Willebrand Factor
VWF is also produced in megakaryocytes and stored as large VWF multimers in alpha granules within the platelets. Platelet-derived VWF is important for platelet adhesion, aggregation, and thrombus formation. Although, platelet-derived VWF is encoded by the same gene in chromosome 12, its glycosylation, which differs from endothelial-derived VWF, renders it resistance to ADAMTS13 cleavage. It is estimated that ∼20% of circulating VWF is derived from platelets and they represent the largest multimers in the multimer assay. Recent studies using transgenic mouse models and transplantations demonstrate that endothelial-derived VWF is necessary for hemostasis (prevention of blood loss), whereas platelet-derived VWF is more important for clot formation and stability. Thus, platelet-derived VWF may represent a new target for stroke and arterial thrombosis.
Pathophysiology
Overview of Molecular Variants and Prevalence
See Fig. 134.1 for protein domains and encoding exons; see Fig. 109.2 for VWD subtype characteristics.
Type 1 von Willebrand Disease
Type 1 VWD is the most common type of VWD (75%–80% of all VWD), with a prevalence of 1% of the population, but symptomatic disease (bleeding) affects only a fraction of this population. Type 1 VWD is a quantitative defect, causes mainly by missense mutations that lead to decreased amount of VWF protein and thus decreased function. The ratio of VWF antigen to activity approximates 1. Western blot analysis of VWF in plasma of patients with type I VWD shows normal pattern of all multimers but in decreased amount. Only in severe cases of type 1 VWD, factor VIII levels are proportionally low, as each VWF monomer can bind a molecule of FVIII, and it is estimated that only ∼20% of VWF binding sites are saturated. Thus, the ratio of FVIII/VWF antigen tends to be greater than 1.5 in most cases of type I VWD. A defect in the VWF gene can be found in about 63%–70% of patients, particularly if the VWF level is <35%. Thus, mutational analysis is not recommended for diagnosis of type I VWD as it will miss nearly 40% of the cases. The majority of type 1 VWD mutations result in decreased synthesis and/or secretion, with the exception of mutations that result in increased clearance, classified as type 1C. VWF Vicenza is an example of type IC VWD. Type 1C can be differentiated from other type I VWDs by increased levels of VWF propeptide in comparison to VWF antigen. In addition, DDAVP challenge may be useful for diagnosis as it shows increased peak level of VWF (5–10 × baseline levels) 15–30 minutes after DDAVP challenge that rapidly decrease (>50% decrease after 4 hours).
Type 2 von Willebrand Disease
Type 2 VWD (15%–20% of VWD) by definition is a qualitative defect in which one of its functions is affected, whereas the antigen is borderline to normal. There are four subclassifications of type 2 VWD based on the defect and the multimer pattern.
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