Von Willebrand disease

Von Willebrand disease (VWD) is usually due to an inherited mutation in the von Willebrand factor (VWF) gene.[1][20]

Mutations in type 1, 2A, 2B, and 2M VWD are mainly inherited in an autosomal dominant pattern.[20] Mutations in type 2N and type 3 VWD are inherited in an autosomal recessive pattern.[20]

The aetiology of type 1 VWD is more complex and less clear than for other types of VWD, and its inheritance is complicated by incomplete penetrance and variable expressivity.[15][21] Genetic and non-genetic factors may be implicated. Genetic linkage studies report that type 1 VWD is linked to the VWF gene in approximately 70% of cases.[22] Linkage is strongest in cases with lower levels of VWF (i.e., more severe phenotype). VWF gene mutations in type 1 VWD are mostly missense mutations.[23][24] Patients with type 1 VWD who do not have VWF gene mutations may have other genetic mutations that alter VWF secretion, clearance, or glycosylation (e.g., ABO, STXBP5, CLEC4M, STAB2, FUT1), resulting in decreased VWF levels.[25] Other factors that may affect VWF levels in type 1 VWD include age, blood group, ethnicity, thyroid status, inflammation, stress, and hormone levels.[7][19][26][27][28]

In type 2 VWD, VWF gene mutations impact the function and structure of the VWF protein, which impairs platelet adhesion/aggregation (type 2A, 2B, and 2M VWD) or clotting factor VIII (FVIII) binding (type 2N VWD).[1] VWF gene mutations in type 2 VWD are commonly missense substitutions involving exon 28.[29]

In type 3 VWD, VWF gene mutations are commonly nonsense mutations or frameshifts due to small insertions or deletions, which result in null VWF alleles.[1][30] Large deletions, splice site mutations, and missense mutations are less common.[1][30]

VWF is a glycoprotein synthesised in endothelial cells and megakaryocytes, and secreted into the blood as high-molecular-weight VWF multimers (HMWMs).[31] HMWMs mediate platelet adhesion to exposed subendothelium at sites of vascular injury. VWF also stabilises and carries FVIII (clotting factor) in the blood, a function not dependent on multimer size.

Patients with VWD have a deficiency of VWF or abnormal functioning (defective) VWF, which results in bleeding symptoms (predominantly mucosal bleeding, e.g., epistaxis).[7][8] Patients may also experience excessive post-operative bleeding or excessive bleeding with trauma/minor wounds.[7][8][9] Symptoms may be exacerbated by drugs that inhibit platelet function (e.g., aspirin).[32]

Type 1 VWD is characterised by partial quantitative deficiency of normal functioning VWF, which may be caused by genetic or non-genetic factors.[1][20] In some cases, type 1 VWD is characterised by accelerated clearance (shortened half-life) of VWF (referred to as type 1C VWD).[5][6] Bleeding symptoms in type 1 VWD are variable (e.g., due to variable penetrance and expressivity, and variable VWF levels) but usually mild and less severe than types 2 and 3.[7][15][33][34] Some patients may be asymptomatic (e.g., those with incomplete penetrance, or with null mutations in the VWF gene).[34]

Type 2A VWD is characterised by decreased VWF-dependent platelet adhesion and deficiency of HMWMs.[1] This is usually caused by genetic mutations that interfere with the assembly and secretion of HMWMs.[35] However, it may also arise from mutations in the A2 domain, which increases susceptibility of VWF to cleavage by ADAMTS13 with consequent reduction in VWF multimer size.[35]

Type 2B VWD is characterised by increased binding of VWF to platelets via glycoprotein Ib due to a gain-of-function mutation in the VWF gene.[1] As a result, VWF is more readily cleaved by ADAMTS13 and the platelet-VWF complex is cleared by the reticuloendothelial system. Patients often have mild to moderate thrombocytopenia.[13] A similar syndrome can arise from a mutation in platelet glycoprotein Ib, which also results in spontaneous binding to VWF (known as platelet type or pseudo-VWD). Genetic testing and ristocetin-induced platelet agglutination (RIPA) mixing studies can be used to differentiate type 2B VWD and platelet type (pseudo)-VWD.[36]

Type 2M VWD is characterised by decreased VWF-dependent platelet adhesion without a deficiency of HMWHs.[1] This is due to genetic mutations that disrupt VWF binding to platelets or to subendothelium.

Type 2N VWD is characterised by a marked decrease in the affinity of VWF for FVIII due to mutations in the FVIII-binding region of VWF.[37] Consequently, FVIII has a very short half-life, and plasma FVIII levels are reduced to 5% to 25% (0.05 to 0.25 international units [IU]/mL).[38] Heterozygotes for type 2N are usually asymptomatic because type 2N mutations are inherited in an autosomal recessive pattern.[20]

Type 3 VWD is characterised by a complete or near absence of VWF, which results in very low FVIII levels (0.01 to 0.05 IU/mL).[15][39] Patients with type 3 VWD have FVIII levels low enough to result in joint bleeding and other symptoms more typical of haemophilia A.[9][8][12] Heterozygotes for type 3 are usually asymptomatic because type 3 mutations are inherited in an autosomal recessive pattern.[20]

International Society on Thrombosis and Haemostasis (ISTH) Subcommittee on von Willebrand Factor[1]

The ISTH categorises VWD into three main types (1, 2, and 3) based on whether the cause is a deficiency or defect of VWF. Type 2 VWD is further divided into subtypes based on the underlying pathophysiology.

Type 1: partial quantitative deficiency of VWF*
Type 2: qualitative VWF defects
- Type 2A: decreased VWF-dependent platelet adhesion due to a selective deficiency of high-molecular-weight VWF multimers
- Type 2B: increased affinity of VWF for platelet glycoprotein Ib
- Type 2M: decreased VWF-dependent platelet adhesion without a selective deficiency of high-molecular-weight VWF multimers
- Type 2N: markedly decreased binding affinity for factor VIII
Type 3: virtually complete deficiency of VWF

*A subtype of type 1 VWD has been identified that is characterised by accelerated clearance (shortened half-life) of VWF, referred to as type 1C VWD.[5][6] This subtype has clinical importance because desmopressin is not an effective therapy for type 1C VWD.

Pathophysiology

Classification

International Society on Thrombosis and Haemostasis (ISTH) Subcommittee on von Willebrand Factor[1]