An update on type 2B von Willebrand disease

Abstract

Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients’ abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.

Keywords::

• bleeding disorder
• deamino arginine vasopressin
• inherited thrombocytopenia
• type 2B von Willebrand disease
• von Willebrand factor

Financial & competing interests disclosure

M Streiff has received research funding from Sanofi-Aventis and Bristol-Myers Squibb, honoraria for CME lectures from Sanofi-Aventis and Ortho-McNeil, consulted for Sanofi-Aventis, Eisai, Daiichi-Sankyo, Boerhinger-Ingelheim and Janssen HealthCare and has given expert witness testimony in various medical malpractice cases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Type 2B von Willebrand disease (VWD) is an autosomal dominant disorder characterized by a gain of function mutation of the von Willebrand factor (VWF), causing increased binding to platelet GPIbα receptors and increased clearance of both VWF multimers and platelets from the bloodstream.

• The enhanced binding of VWF to platelets in type 2B VWD results in clearance of large high molecular weight (HMW) VWF multimers and platelets, which clinically manifests as a bleeding disorder.

• Diagnostic challenges are mainly due to phenotypic similarity with type 2A VWD and other disorders like Bernard-Soulier syndrome (BSS) and platelet-type VWD, the latter characterized by gain of function mutations in platelet GPIbα, not VWF causing the same phenotype.

• The management approach to type 2B VWD, as well as all types of VWD, is based on non-randomized studies, quasi-experimental studies, non-experimental descriptive studies and expert reports. No randomized-controlled management trials have been conducted investigating the appropriate agents to use and the duration of treatment in cases of bleeding or for prophylaxis prior to invasive procedures.

• Desmopressin (DDAVP) use in type 2B VWD is controversial. It is generally contraindicated in these patients due to associated worsening of thrombocytopenia and increased risk of bleeding, although there is increasing evidence that DDAVP may have beneficial hemostatic effects in this patient population.

• The use of factor concentrates as a means of factor VIII/VWF replacement is often the management approach of choice for bleeding or prophylaxis, although the guidelines governing its use and the approach to safeguard against elevated factor VIII activity during treatment are not well-delineated.

• Given the increased risk of bleeding among pregnant women with type 2B VWD, a multidisciplinary approach to care is recommended early on, encompassing physicians with expertise in management of the disease. These include hematologists, obstetricians, anesthesiologists and pediatricians.

• Challenges exist in making the available diagnostic tests more uniform and available, as well as introducing newer tests with less potential for error.

• An initiative should be in place to train and recruit basic and clinical researchers as well as clinicians with expertise in hemostasis and non-malignant hematology to address the current shortages of physicians/scientists in these fields.

Notes

Adapted from the NHLBI guidelines on VWD.

Data taken from [99].

Adapted from the NHLBI guidelines on VWD.

Data taken from [99].