Case 360°™ Module #2: New Developments in the Treatment and Therapeutic Monitoring of VWD

Introduction

Hello, I’m Robert Sidonio

Welcome to the second 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). Although VWD is the most common inherited bleeding disorder, its diagnosis, classification, and management can be challenging.1,2 In this particular Case 360˚™, we focus on management issues encountered by a young man with inherited VWD.

Bleeding due to VWD is caused by a deficiency or defect of von Willebrand factor (VWF), which has important roles in hemostasis.3 VWD is divided into 3 types:

  • Type 1, defined as a quantitative deficiency of VWF
  • Type 2, which includes several subtypes (2A, 2B, 2M, and 2N), with qualitative defects of VWF activity, and
  • Type 3, the most severe type, with a complete absence of VWF

VWF also chaperones and protects circulating FVIII from proteolysis. So, when VWF is very low or missing, factor VIII (FVIII) is also reduced.2

Most often, bleeding is mucocutaneous (eg, epistaxis, oral cavity or GI bleeding, heavy menstrual bleeding). If there is an associated FVIII deficiency, bleeding generally presents similar to hemophilia A (such as muscular hematomas, hemarthroses, and bleeding after trauma or surgery).1,3

Diagnosis is based on personal or family history of bleeding and laboratory tests that measure VWF platelet-binding activity (typically by means of the VWF ristocetin cofactor activity assay [VWF:RCo assay]), VWF protein level (VWF:Ag assay), and FVIII activity (Table 1).4 Additional confirmatory tests may be required, such as the GPIbM assay or collagen binding.
[Refer to Module 1 of this series titled “Issues and challenges associated with the diagnosis and classification of von Willebrand disease” for details of VWD testing and diagnosis.]

Table 1. Main laboratory tests used for VWD diagnosis and therapeutic monitoring4

Table 1. Main laboratory tests used for VWD diagnosis and therapeutic monitoring

Treatment rests on bringing VWF up to hemostatic levels and, to a lesser extent, the FVIII levels in case of acute bleeding or before an intervention. As described in Table 2, this can be achieved by increasing endogenous factor levels with desmopressin or by infusing coagulation factors in the form of VWF-containing concentrate (including pure recombinant VWF), and/or FVIII replacement if needed.1 Optimal treatment also entails monitoring VWF and FVIII levels. This is typically accomplished using the same tests used to diagnose VWD─the ristocetin cofactor and FVIII assays (Table 1).5 Additional clinical or laboratory monitoring may be required.

Table 2. Current treatment options for inherited VWD6

Table 2. Current treatment options for inherited VWD

IN, intranasal; IV, intravenous; PO, oral; SQ, subcutaneous.
*Recent recommendations (NHF MASAC Doc #232; NHF MASAC Doc #244) suggest that desmopressin should not be administered more often than once every 24 hours; not used for more than 3 consecutive days; not be used in children under 2 years of age; and used with caution in pregnant women, the elderly, and those with a history of heart disease, hypertension, or stroke.7
**Used in the same manner for heavy menstrual bleeding.

Republished with permission of AMERICAN SOCIETY OF HEMATOLOGY, from Advances in the diagnosis and treatment of Von Willebrand disease.", Sharma, Ruchika, and Veronica H. Flood. Blood 130.22 (2017): 2386-2391.; permission conveyed through Copyright Clearance Center, Inc.

Sidonio

Robert Sidonio Jr., MD

Table 3. Therapies Used for Von Willebrand Disease Subtypes1,3,4,9

Table 3. Therapies Used for Von Willebrand Disease Subtypes

National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services. Treatment of von Willebrand Disease", Jennifer Curnow, Leonardo Pasalic, Emmanuel J. Favaloro, Seminars in Thrombosis & Hemostasis Vol. 42 No. 2/2016, 133-146. Copyright © 2016, Rights Managed by © Georg Thieme Verlag KG.

Desmopressin is the most widely used drug for VWD and the favored therapy for type 1.
Those eligible for VWF(/FVIII) concentrates2 are:

  • type 3 VWD patients (who do not produce any endogenous VWF)
  • type 2B VWD patients (in whom desmopressin can cause thrombocytopenia)
  • type 1 and type 2 VWD patients who are insufficiently responsive to desmopressin, or who have contraindications to desmopressin use.

Excess levels of VWF and FVIII are associated with increased risk of thrombosis; endogenous or trough levels must be taken in to account when selecting a concentrate product, and care must be taken to avoid FVIII accumulation with repeat infusions of FVIII-containing concentrates.2,3 

Long-term prophylaxis with VWF concentrate may be useful for select patients with VWD and recurrent bleeding episodes.10 Prophylaxis is not as commonly used for VWD as for hemophilia, although beneficial results have been observed in several patient series.1 Nearly all patients required 50 VWF:RCo IU/kg 2 or 3 times a week in order to prevent bleeding.2 Again, we have to be concerned about FVIII accumulation with repeated infusions, so diligent monitoring must be maintained.

Now we’re ready to move on to the main course, the patient case study.
I am joined by Dr Kenneth Friedman and Dr Michelle Witkop.

Work through this case with us to see how we consider the intricacies of managing various issues facing a patient with inherited VWD.

Click on the Chart History/Case Details tab, where you will have the opportunity to review the case details, including clinical findings and lab results.