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

Table 1 Classification of von Willebrand disease according to International Society on Thrombosis and Haemostasis guidelines 1994-2007[13-15]

1 Inherited VWD caused by genetic mutations at the VWF locus includes a broad spectrum of recessive and dominant variants of VWD

2 WD Type 1 is quantitative deficiency of VWF mainly based on a normal VWF:RCo/VWF:Ag ratio. Type 2 VWD is a qualitative deficiency of VWF as documented by a decreased VWF:RCo/VWF:Ag ratio. Type 3 refers to virtually complete deficiency of VWF

3 VWD Type 2 refers to qualitative variants with absence of high molecular weight VWF multimers and distinguishes 2A (IIA, IIB, IIE, and IID) 2B, 2M and 2 N

4 VWD Type 2M or 2U is a distinct entity with decreased platelet dependent function (VWF:RCo) and presence of large VWF multimers

5 VWD Type 2A (IIA, IIC, IIE and IID) refers to qualitative variants with absence of HMW multimers, normal or decreased RIPA and decreased VWF: VWF:RCo/VWF:Ag ratio

6 VWD Type 2B is a qualitative variant with absence of HMW multimers, decreased VWF:RCo/VWF:Ag ratio and increased RIPA

7 VWD Type 2N is a mild hemophilia due to FVIII binding defect of VWF, presence of large VWF multimers, normal VWF:RCo/VWF:Ag ratio and decreased FVIII/VWF:Ag ratio

VWD: Von Willebrand disease; VWF: Von Willebrand factor; RIPA: Ristocetin-induced platelet aggregation.

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.

Table 3 Desmopressin challenge test (0.3 μg/kg in 100 mL physiological saline intravenously over 30 min) proposed by the International Society on Thrombosis and Haemostasis

Blood sampleDDAVP	At 15 min	After DDAVP				After DDAVP12 h
		1 h	2 h	4 h	6 h
Ivy BT	+	-	+	-	-	+
PFA-100	+	+	+	+	+	+
RIPA	+	+	+	+	+	+
FVIII:C	+	+	+	+	+	+
VWF:Ag	+	+	+	+	+	+
VWF:RCo	+	+	+	+	+	+
VWF:CB	+	+	+	+	+	+
VWF:MM	+	+	+	+	+	+
VWF propeptide	+	+	+	+	+	+

This challenge test has been used at the Goodheart Institute, Rotterdam since 1992 to calculate the recovery and half life times of FVIII:C and VWF parameters for the diagnosis and charaterization of VWD type 1, 2 and 3[18]. VWD: Von Willebrand disease; VWF: Von Willebrand factor; RIPA: Ristocetin induced platelet aggregation; DDAVP: Desmopressin; MM: Multimers.