Changing insights in the diagnosis and classification of autosomal recessive and dominant von Willebrand diseases 1980-2015

Table 2 European Clinical, Laboratory and Molecular criteria of von Willebrand disease

Mild type 1: VWF:Ag < 35%, normal VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratio > 0.7

Type 1 with VWF:Ag above 35% with manifest bleeding can be included

Autosomal recessive VWD

Type 3 recessive with VWF:Ag and FVIII:C undetectable

Type 1 severe recessive VWD with VWF:Ag and VWF:RCo detectable < 5%, high FVIII:C/VWF:Ag ratio in particular after DDAVP

Type 2C recessive with increased FVIII:C/VWF:Ag ratio (secretion defect) and loss of large VWF mutimers due a mulimerization defect caused by homozygous or double heterozygous mutations in the D1-D2 of the VWF gene (Figure 8)

Type 2N recessive with FVIII:C/VWF:Ag ratio < 0.5 due to FVIII-VWF binding defect caused by mutations in the D’ FVIII-binding domain (Figure 8)

Type 2 autosomal dominant VWD 2A, 2B, 2E and 2M (Figure 8)

2A/2M: Decreased RIPA (Ristocetin Induced Platelet Aggregometry, 2B increased RIPA, decreased VWF:RCo/VWF:Ag ratio < 0.7

2A: Loss of large MM caused by increased VWF proteolysis due to mutations in the A2 domain of the VWF gene

2B: Increased RIPA (0.8 mg/mL) and thrombocytopenia with VWD type 2 due to gain of function mutation in the GpIb receptor in the A1 domain

2E: Type 1/2, loss of large multimers due to multimerization defect and increased clearance due to mutations in the D3 multimerization domain

2M: Decreased VWF:RCo/VWF:Ag ratio (< 0.6), normal VWF:CB/VWF:Ag ratio (> 0.7), decreased RIPA due to loss of function mutation in the A1 domain

2M-CBD: Collagen binding defect, VWF:RCo/VWF:Ag ratio > 0.7 and VWF:CB/VWF:Ag ratio < 0.7 due to mutation in the A3 domain

VWD: Von Willebrand disease; VWF: Von Willebrand factor; RIPA: Ristocetine induced platelet aggregation; MM: Multimers.