Case 360°™: Module #1: Issues and Challenges Associated with the Diagnosis and Classification of von Willebrand Disease

Introduction

Hello, I’m Robert Sidonio

Welcome to the first of a 2-part Case 360˚™ series designed to educate healthcare professionals on the nuances and real-life scenarios of people with von Willebrand disease (VWD). Despite being the most common inherited bleeding disorder,1 VWD can be challenging to diagnose and manage.

VWD is caused by deficiency in the level or function of a circulating glycoprotein termed von Willebrand factor (VWF). It promotes hemostasis by binding to the platelet receptor glycoprotein Ib (GPIb) and exposed blood vessel collagen and thereby increasing platelet adhesion and aggregation at sites of blood vessel injury. VWF circulates as a series of identical polymers called multimers; high-molecular-weight (HMW) multimers of VWF bind GPIb and collagen more strongly and are more effective for hemostasis than lower molecular weight forms. In addition, VWF binds to and chaperones coagulation factor VIII (FVIII), protecting it from premature proteolysis. Therefore, severe deficiency of VWF causes a concomitant deficiency of FVIII.2 So, in VWD, excessive bleeding is due to inadequate platelet binding and, in severe cases, reduced FVIII activity. 

Table 1. Classification of von Willebrand disease2-4

Table 1. Classification of von Willebrand disease

Heijdra JM, Cnossen MH, Leebeek FWG. Current and emerging options for the management of inherited von Willebrand disease. Drugs. 2017;77:1531-1547. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand factor. J Thromb Haemost. 2006;4:2103-2114. National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services

VWD is subdivided into types 1, 2, and 3 (Table 1). Type 1 accounts for 70% to 80% of inherited VWD cases and is a quantitative deficiency with partial loss of VWF.1 Individuals with type 1 VWD may be asymptomatic or have mild symptoms (eg, bleeding from gums or heavy menstrual cycles) until a severe injury or surgical procedure precipitates a significant bleeding episode. Rarely, they may have more severe symptoms including joint bleeds.

Type 2, which accounts for approximately 20% of inherited VWD cases, has a large reduction in VWF function but with normal or marginally decreased circulating VWF protein level.1 Type 2 subtypes are characterized by loss of HMW multimers (2A and 2B), defective platelet GPIb or collagen binding (2M), or reduced FVIII:C (2N, which is phenotypically similar to hemophilia A).5 In type 2B VWD there may be associated thrombocytopenia.

The most severe form, type 3 is rare and accounts for <5% of inherited VWD cases.1 It due to the absence of circulating VWF and is accompanied by low FVIII. Individuals with type 3 VWD have severe bleeding episodes that can be life-threatening if not recognized and treated.

Symptoms of VWD vary among patients. In children, the most frequent presenting symptoms are bruising and epistaxis.1 In adults, common symptoms are heavy menstrual bleeding, hematomas, and excessive bleeding from minor wounds.

If VWD is suspected, diagnosis is based on personal history of mucocutaneous bleeding, family history of bleeding, or both, along with laboratory tests showing abnormalities in VWF, FVIII, or both (Table 2).1 When a bleeding disorder is suspected, the first level of testing for VWD comprises measurements of the VWF antigen (VWF:Ag) level, platelet-binding activity of VWF (measured by means of a VWF–ristocetin cofactor activity [VWF:RCo] assay), and FVIII activity (FVIII:C).

Table 2. Summary of VWF designations, properties, and assays4

Table 2. Summary of VWF designations, properties, and assays

National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services

The VWF:RCo assay is the traditional assay of VWF interaction with platelets. It uses the drug ristocetin to activate VWF binding to platelets and consequent agglutination.  Unfortunately, this assay is compromised by a poor lower limit of detection, the need to use platelets as a test reagent, the need to use ristocetin, a drug that binds poorly to the VWF, and is not applicable for all genetic variants of VWF.

To avoid these issues, the VWF:GPIbM assay was developed and is gaining acceptance.6 It uses latex particles coated with a recombinant form of platelet glycoprotein GPIb that has gain-of-function variations that allow it to interact directly with VWF in the absence of ristocetin. The GPIbM assay has multiple advantages, including that it has an improved lower limit of detection, improved precision, and avoids some of the issues related to ristocetin. At the time of writing, commercial availability of VWF:GPIbM assays is limited, but in some countries these have replaced the VWF:RCo entirely. In Europe and Canada, an automated VWF:GPIbM is available, whereas in the United States, an ELISA version is available through the BloodCenter of Wisconsin.

The variability in clinical bleeding phenotype is influenced by the type of VWD.5 Also, bleeding risk and treatment approaches vary with type.

Based on current classifications, VWF:RCo levels below 30 IU/dL are diagnostic of definitive VWD (Table 3).1,5 Persons with a bleeding tendency who have borderline levels between 30 and 50 IU/dL (the lower limit of the normal range) are considered to have “low VWF” or “possible type 1 VWD.” Such patients are not classified as having definitive VWD, although they may require treatment before undergoing surgery or in the event of a bleeding episode, and practically, these patients may need treatment with antifibrinolytics or high-dose desmopressin (DDAVP).

Second-level testing for differential diagnosis and characterization may include collagen binding, assay of VWF multimers, and ristocetin-induced platelet aggregation (RIPA), which is required to distinguish 2A and 2B VWD.1 In some cases, genetic studies of VWF, GP1b, and/or FVIII may be conducted.

Table 3. A practical guide to identification of VWD in persons with a suspected bleeding disorder1,4,5

Table 3. A practical guide to identification of VWD in persons with a suspected bleeding disorder

a Units: IU/dL, %, or IU/mL may be used alternately as units for VWF and FVIII:C in various publications. Refer to locally established normal range values.
↓ refers to a decrease in the test result compared to the laboratory reference range.
* <30 IU/dL is designated as the level for definitive diagnosis of VWD; some individuals with type 1 or type 2 VWD have levels of VWF:RCo and/or VWF:Ag of 30-50 IU/dL.
† The VWF:Ag in the majority of patients with types 2A, 2B, and 2M is <50 IU/dL.

Leebeek FWG, Eikenboom JCJ. Von Willebrand’s disease. N Engl J Med. 2016;375:2067-2080. United States Department of Health and Human Services. The diagnosis, evaluation, and management of von Willebrand disease. Curnow J, Pasalic L, Favaloro EJ. Treatment of von Willebrand disease. Semin Thromb Hemost. 2016;42:133-146. National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services

This challenging Case 360˚™ follows a teenage girl with heavy menstrual bleeding and suspected VWD. However, diagnosis is complicated by the presence of several factors that can confound interpretation of VWD laboratory findings