Von Willebrand Disease (VWD): Diagnostic Differentiation of Pseudo, Mild, Moderate to Severe VWD Type 1 and 2 by a DDAVP Challenge Test on Top of the ISTH Classification

Review Article

Thromb Haemost Res. 2020; 4(1): 1040.

Von Willebrand Disease (VWD): Diagnostic Differentiation of Pseudo, Mild, Moderate to Severe VWD Type 1 and 2 by a DDAVP Challenge Test on Top of the ISTH Classification

Michiels JJ1*, Hermans C2, Smejkal P3, Penka M3, Batorova A4, Pricangova T4, Budde U5, Gadisseur A6 and Van Vliet H1

1Goodheart Institute in Nature Medicine & Health, Blood Coagulation and Vascular Medicine Center, The Netherlands

2Hemostasis Thrombosis Unit Haemophilia Clinic Division of Adult Haematology, St-Luc University Hospital, Belgium

3Department of Clinical Hematology, Masaryk University, Czech Republic

4Department of Hemostasis and Thrombosis, Medical School of Comenius University, Slovakia

5Central Laboratory, Asklepios Kliniken, Germany

6Department of Hematology, Antwerp University Hospita, Belgium

*Corresponding author: Jan Jacques Michiels, Goodheart Institute in Nature Medicine, Blood Coagulation and Vascular Medicine Center, Erasmus Tower Veenmos 13, 3069 AT, Rotterdam, The Netherlands

Received: March 21, 2020; Accepted: April 20, 2020; Published: April 27, 2020


A complete set of FVIIIl:C and von Willebrand factor ristocetine cofactor, collagen binding and antigen (VWF:RCo. VWF:CB, VWF:Ag) and Ristocetine Induced Platelet Agglutination (RIPA) and VWF multimeric analysis in a low resolution gel is mandatory to diagnose all variants of Von Willebrand Disease (VWD) according to ISTH (International Society on Thrombosis and Haemotasis) criteria. The response to DDAVP of VWF parameters is normal in pseudo-VWD, and mild VWD type 1 Bloodgoup O, but restrictive in carriers of recessive type 1 and 3 VWD. The response to DDAVP is restricted in pronounced VWD type 1 and 1/2E, transiently good in mild type 2A group II, good for VWF:CB but poor for VWF:RCo in VWD 2M, poor for VWF:RCo and VWF:CB in 2A group I, 2B, 2C and 2D, very poor in recessive VWD severe type 1m and absent in VWD type 3. VWF multimers in a low resolution gel are normal in VWD type 1 and 2M, but RIPA is normal in dominant VWD type 1 and decreased in dominant VWD type 2M.

Dominant VWD 1/2E due to mutations in the D3 domain of VWF result in defective multimerization, defective secretion and/or increased clearance of VWF. The triplet structure of each band and loss of large VWF multimers is charateristic for VWD type 2A and 2B due to increased proteolysis of each VWF band. Mild to moderate VWD 2A group II patients have normal FVIII:C and VWF:Ag, decreased VWF:RCo and VWF:CB, normal RIPA and transient correction of BT, FVIII:C, VWF parameters, and large multimers for a few hours post-DDAVP. Severe VWD 2A group I patients have low VWF:Ag and very low levels for VWF:RCo and VWF:CB, no RIPA and poor response of functional VWF:RCo and VWF:CB. VWD 2B is featured by loss of large VWF multimers due to increased proteolysis caused by increased interaction of platelets and mutated VWF.

Keywords: Von willebrand disease; Von willebrand factor; ADAMTS13; DDAVP; Von willebrand factor assays; Von willebrand factor multimers; Von willebrand factor mutations


The Von Willebrand Factor (VWF) mediates the adhesion and aggregation of platelets to the subendothelium at sites of vascular injury and therefore plays a crucial role in the earliest stages of primary hemostasis. The VWF is the carrier protein of coagulation Factor VIIII (FVIII) in the circulation. The hemostatic potency of VWF depends on the degree of multimerization with the largest multimers being most hemostatically effective in platelet adhesion and aggregegation, thereby securing primary hemostasis as measured by the bleeding time and PFA-100 closure times.

Congenital Von Willebrand Disease (VWD) is a hereditary lifelong bleeding disorder caused by a quatitative type 1 or a functional type 2 VWF deficiency or the absence of VWF and FVIII in type 3 VWD labeled pseudohemophilia by Erik von Willebrand [1,2]. The present evaluation describes the use of FVIII and the Von Willebrand Factor (VWF) assays VWF antigen (VWF:Ag), VWF ristocetine cofactor (VWF:RCo), VWF collagen binding (VWF:CB), VWF multimers, Ristocetine Platelet Aggregation (RIPA) and responses of FVIII and VWF parameters to DDAVP to correctly diagnose type 1 and type 2 VWD as manadory in routine daily practice when the ISTH (International Society on Thrombosis and Haemostasis) criteria are applied [3-5].

Bleeding manifestations

A standardized questionaire for bleeding history of suspected VWD include epistaxis, cutaneous bruises and hematomas, minor wounds, tooth extraction, bleeding after minor and major trauma and surgery and menarche and menorrhagias for women [6]. Each possible bleeding event is scored as 1 point when present and no action, as 2 points when present with medical attention and as 3 points when pronounced with intervention. A score of less than 2 points excludes a bleeding tendency. One clear cut bleeding even and a score of more than 2 points is a clear indication for laboratory screening in search for a bleeding defect. The sensitivity, specificity and negative predictive vaues of a bleeding score of more than 3 in male and 5 in female are 65%, 99% and 99.6% respectively. If less restricive cutoff had been choosen (a score higher than 2 in males and females), the sensitivity and specificity for diagnosis of carriers of VWD would have been 78.5% and 86.9% respectively. In our experience one clear cut prolonged bleeding episode oe event with attention (score 2) or with intervention (score 3) is suspcious for a bleeding diathesis. A positive bleeding score of VWD specific bleeding manifestations during childhood in particular bleeding after umbilical cord loss, after the first menarch and after minor or major trauma or surgery are indicative for a congenital VWD bleeding disorder.

In this report bleeding severity in patients with VWD were graded as very mild, mild moderate and severe according to Dr Eikenboom et al (Leiden University Medical Center) [7].

Very mild: only one or or two unclear minor bleeding symptoms of minor clinical significance.

Mild: one or two obvious symptoms such as recurrent epistaxis, profuse menstruations, or frequent hematomas, which usually do not require treatment. This is usually mild VWD type 1 (Figures 1 and 2).

Moderate: more than two bleeding symptoms for which FVIII/ VWF concentrate transfusion was needed because of abnormal bleeding after surgery, trauma or both, orhas bled for more than 24 hours after tooth extraction. A moderate bleeding type is usually recognized in childhood in dominant or recessive VWD type 2 and pronounced type 1.

Severe: the VWD patient has severe or moderate pseudohemophilia, hemarthrosis, muscle bleeding, and a need for prophylactic FVIII/VWF concentrate.

Laboratory diagnosis and ISTH classification of VWD

The laboratory methods of platelet function, FVIII:C VWF parameters and DDAVP challenge test are described in great detail [2]. The laboratory diagnosis of VWD is based on decreased values of FVIII, VWF parameters and the results of RIPA, VWF:RCo/Ag ratio, VWF:CB/Ag ratio, FVIII/VWF:Ag ratio and subsequently classified according to the following criteria [1-5,7].

VWD type 1 is a quantitative VWF deficiency below the level of normal with equally decreased values of VWF:Ag, VWF:RCo, VWF:CB, a normal VWF:RCo/Ag or VWF:CB/Ag ratio and normal VWF multimers. A decreased FVIII/VWF:Ag ratio below 0.50 is indicative for a FVIII binding defect on VWF (VWDtype 2N). An increased ratio of FVIII/VWF:Ag above around 2.00 in VWD type 1 after DDAVP is indicative for a secretion defect as one of the mechanisms of decreased VWF parameters.

VWD type 2 is a qualitative VWF deficiency with normal or decreased values for FVIII and VWF:Ag, and much lower values for the functional VWF parameters VWF:RCo and VWF:CB with decreased ratios (<0.60) of VWF:RCo/Ag and VWF:CB/Ag and loss of large VWF multimers. VWD type 2 can be subclaasified as 2A with normal or decreased RIPA, 2B with increased RIPA, and 2M with selective loss of VWF:RCo but normal VWF:CB and multimers [1-5].

The spectrum of VWD type 1 and type 2: one center experience 1990-2000

Michiels & Van Vliet analysed between 1992 and 1997 275 index cases of patients coded as VWD irrespective of blood O or non-O in the Academic Medical Center Rotterdam with a referral region of about 2 million inhabitants [2]. The first group of 128 (46.5%) index patients had VWF antigen and functional levels around 40% to 60%, a very mild bleeding tendency, no family history, normal Ivy bleeding times, usually showed normal responses of VWF and FVIII:C to DDVAP when tested on indication, do not have von Willebrand disease and were diagnosed as pseudo von Willebrand [4,10]. The other 167 index patients of 94 families were diagnosed as ISTH defined VWD and classified as mild VWD type in 65 families, severe dominant VWD type 1 in 10 families (of which 2M in 3), type 2A, 2B and 2N in 10, 4 and 2 families and recessive type 3 in 3 families respectively [3]. Out of the 65 families with mild VWD 1 we prospectively investigated the DDAVP responses of the probands or index cases of 24 families (Table 1) with VWF levels between 20 and 60% [2]. The diagnosis of mild VWD type 1 was based on a personal bleeding history and decreased values for FVIIII, VWF:Ag VWF:RCo and VWF:CB with normal rations for VWF:RCo/Ag and VWF:CB/ Ag. Bleeding manifestation in the proband of 24 index family cases (Table 1) were usually mild and occasionally moderate. The Ivy bleeding times were usually normal or only slightly prolonged in only a few cases. The values for VWF:Ag VWF:RCo and VWF:CB were between 0.20 and 0.60, with normal ratios for VWF:RCo/Ag (0.62- 1.08) in all and normal ratios for VWF:CB/Ag in 21 of 24 cases of mild VWD type 1 (Table 1). DDAVP has been administered intravenously to each of the 24 idex cases with mild VWD type 1 (Table 2).