Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an autosomal dominant or recessive inheritance due to quantitative or qualitative deficiency of Von Willebrand factor (VWF). Some reports suggest that VWD has a prevalence of about 1% in the general population, but the prevalence of clinically relevant cases is lower, ∼ 100/million population.
VWF is a large multimeric glycoprotein that is synthesized in megakaryocytes and endothelial cells. It is stored within specific storage granules, the α – granules of platelets and Weibel – Palade bodies within endothelial cells. VWF is an acute phase reactant and the levels of VWF increase with physiological or pathological stress such as exercise, emotional stress, pregnancy, infections and inflammatory conditions.
The primary translation product contains a signal peptide of 22 amino acids, a propeptide of 741 residues and the basic VWF monomer of 2050 amino acids. Each mature monomer contains nine domains: three A domains (A1, A2, and A3), one B domain, two C domains (C1, C2), and three D domains (D’, D3, and D4) with a specific function; elements of note are:
■ The D’/D3 domain binds to FVIII, heparin
■ The A1 domain binds to platelet GPIb receptor, heparin, and collagen
■ The A3 domain binds to collagen.
Two monomers of VWF are initially dimerized through disulfide bond formation at their C – termini. The C – terminal dimers are then N – terminal multimerized into multimers of 0.6 kD to 20 million daltons.
Unusually large VWF multimers that are synthesized and secreted by endothelial cells are processed into normal sized multimers in the plasma through the action of a novel VWF – cleaving metalloprotease, ADAMTS13, which cleaves VWF within its A2 domain.
This cleavage event is believed to occur under conditions of high shear stress in parts of the circulation, which partially unfolds the VWF molecule exposing the cleavage site. This physiologic regulation protects against abnormal platelet – VWF aggregation in the microvasculature
High – molecular – weight (HMW) VWF multimers mediate platelet adhesion at sites of vascular injury by binding to subendothelial matrix and to platelets. VWF also serves as a carrier protein for plasma coagulation factor, FVIII. Therefore, defects in VWF can cause bleeding with features typical of platelet dysfunction, or of mild to moderately severe hemophilia A, or of both.
Genetics of VWD
The VWF gene spans 178 kilobases in the human genome, and is localized to the tip of the short arm of chromosome 12, at 12p13.3. In general, quantitative abnormalities of the VWF gene are due to promoter, frameshift nonsense mutations, and large deletions, whereas missense mutations typically result in qualitative defects.
In several families, no mutations have been identified within the VWF gene implying the role of modifier genes in clinical expression of VWD. ABO blood type is shown to be an important modifier of VWF plasma levels; patients with “O” type have lower plasma levels of VWF while “AB” blood type is associated with the highest plasma levels of VWF.
In general, VWD is a mild bleeding disorder. Unlike hemophilia, spontaneous bleeding symptoms and bleeding within the internal organs such as CNS or joints is extremely rare in patients with VWD The primary clinical presentation in patients with VWD is mucocutaneous bleeding such as:
■ Superficial bruising
■ Subcutaneous hematoma
■ Gastrointestinal mucosal bleeding
■ Post – partum hemorrhage
■ Bleeding after common surgical procedures such as wisdom tooth extraction or tonsillectomy and adenoidectomy.
Clinical subtypes of VWD
VWD subtypes: VWD is classified into three major subtypes: type 1, type 2 and type 3. It is best understood as either quantitative deficiency (type 1 or type 3) or a qualitative deficiency (type 2A, 2B, 2N, 2M).
Type 1 VWD: This subtype may be caused by mutations that results in decreased synthesis or promote increased clearance of VWF from circulation. Proportionate reductions in VWF:Ag, VWF:RCo, and FVIII activity and a normal distribution of VWF multimers is consistent with type I VWD. These patients respond to pharmacological agents such as DDAVP which act to raise endogenous levels of VWF through release from endothelial storage granules.
Type 2A VWD: Is typically caused by mutations that interfered with the assembly or secretion of HMW multimers of VWF or that increase the susceptibility of VWF to proteolysis. This results in a disproportionate reduction in VWF:RCo compared to VWF:Ag and defi cit of HMW multimers. Although these patients may respond to DDAVP, VWF concentrates are often required for the treatment of moderate to severe bleeding.
Type 2B VWD: This subtype is caused by “gain of function” mutation in the A1 region of VWF leading to spontaneous binding of VWF to platelets which leads to proteolytic degradation and depletion of the HMW multimers and platelets. These patients typically present with thrombocytopenia, reduced VWF levels and absence of HMW multimers
Type 2M: This describes VWF variants that exhibit decreased VWF – dependent platelet adhesion despite the presence of HMW multimers. This results in laboratory results where the VWF:RCo assay is disproportionately decreased compared to VWF:Ag. The distinction from type 2A VWD depends on VWF multimer analysis. Pharmacological treatment with DDAVP is generally effective for the treatment of bleeding manifestations.
Type 2N: This type is caused by genetic mutations in the FVIII binding domain of VWF. This results in rapid clearance of FVIII from plasma and results in low residual FVIII plasma levels. This subtype of VWD has been referred to as “autosomal hemophilia” or the “Normandy” variant.
Type 3 VWD: This subtype is characterized by undetectable levels of VWF:Ag and VWF:RCo and complete absence of VWF on multimer analysis. FVIII levels are usually very low (1 – 9%). Such VWD patients have the most severe bleeding manifestations and may exhibit a clinical phenotype similar to moderate hemophilia A.
Treatment of VWD
The principles of treatment of bleeding in patients with VWD include: (1) increasing functional VWF levels and (2) enhancing clot stability. Specific treatment options to raise VWF levels include DDAVP and VWF concentrates. Adjuvant therapies such as antifi brinolytics and local hemostatic agents are used to enhance clot stability. Hormone suppression therapy can be used to control menorrhagia; estrogens are also shown to increase VWF levels.