Earlier this year, clinical practice guidelines for the diagnosis and management of von Willebrand disease (VWD) were published in Blood Advances.

The guidelines (https://bit.ly/2OIfKLE) are a collaborative effort from the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia.

Guideline author Paula James, MD, of Queens University, Kingston, Ont., reviews some of the recommendations in these guidelines with host David H. Henry, MD, in this episode.

Case discussion

A patient presents with the complaint of heavy menstrual bleeding, which could indicate a bleeding disorder such as VWD. How does one diagnose or rule out VWD?

Tests to order include CBC, prothrombin time (PT), and partial thromboplastin time (PTT).
Results of CBC, PT, and PTT could be normal, which would necessitate special testing to specifically look at factor VIII and von Willebrand factor (VWF).
A patient’s family history may be helpful, as most types of VWD are autosomal dominant, though two subtypes are recessive.

Diagnostic evaluation of VWD

VWF is the chaperone protein for factor VIII in the intrinsic pathway, which is measured by the PTT.
In more severe forms of VWD, the PTT is prolonged because of factor VIII.
VWF is measured separately because it is not reflected in the PT or PTT.
The recommendation is to measure VWF antigen and employ a functional assay to see how well VWF binds platelets.
- The recommendation in the new guidelines is to use the GPIbM assay rather than the ristocetin cofactor assay.
  - Many labs in the United States are still using the ristocetin cofactor assay. However, in Canada, Europe, and other parts of the world, many labs have moved to a newer assay that is automated. It has a much lower coefficient of variation and fewer issues with measurement of VWF in Black populations, which is a major issue with the cofactor assay.

Types of VWD

Type 1 VWD is characterized by a decreased amount of VWF.
- Type 1 patients have low VWF antigen and low platelet-dependent VWF function to a similar degree, with low or normal factor VIII.
Type 2 VWD is characterized by aberrant VWF.
- The functional assay is a lot lower than VWF antigen.
- The platelet-dependent function to VWF antigen ratio cutoff is 0.7.
- Further testing is warranted to determine subtypes (2A, 2B, 2N, or 2M), including VWF multimers. Genetic testing can be helpful to further delineate subtypes.
Type 3 VWD is characterized by the absence of VWF.
- The patient will have a VWF antigen level of 0, platelet-dependent VWF function of 0, and a reduced factor VIII level (usually less than 10%).

Pregnant patients with VWD

There is a protective adaptation in pregnancy, in which factors normalize in the third trimester, which works to prevent hemorrhage at delivery.
This protective effect is because of the hormonal changes of pregnancy, and it is seen in patients with milder forms of VWD.
WVF levels peak within 8-24 hours after delivery and then slowly return to baseline.
There is a risk of delayed postpartum hemorrhage once VWF levels return to baseline, which tends to happen 7-14 days postpartum.

Procedural planning: Desmopressin challenge test

Desmopressin causes the release of VWF from the Weibel-Palade bodies of the endothelium, and it can be used as prophylaxis or treatment of bleeding in type 1 VWD.
The desmopressin challenge test is used to check how the patient responds to desmopressin when well, to predict the patient’s response after an anticipated procedure.
The test involves measuring VWF levels before desmopressin is given and at 1 hour, 2 hours, and 4 hours after desmopressin administration.
The idea is to measure the magnitude of increase in VWF levels and observe how sustained that increase is to predict the patient’s response to desmopressin after future procedures.
There is a subset of patients with type 1 VWD who have increased clearance of VWF that causes their decreased VWF levels. They may not have a sustained plateau in the VWF level after desmopressin, which emphasizes why testing as far as 4 hours after desmopressin administration is important.
The dose of desmopressin given in this test is typically 0.3-0.4 mcg/kg.

Recommendations for preprocedure prophylaxis for type 1 VWD

Minor procedures (e.g., wisdom tooth extraction)
- The patient should receive an antifibrinolytic agent, such as tranexamic acid or aminocaproic acid, 2 hours before the procedure, followed by desmopressin 30-60 minutes prior to the procedure.
- After the procedure, the patient should continue to receive the antifibrinolytic agent for 3-4 days.
Major procedures/surgeries (e.g., gallbladder removal)
- The guidelines do not recommend desmopressin for major procedures because patients need to be fluid-restricted for approximately 24 hours after administration because of the risk of hyponatremia.
  - Desmopressin is a synthetic analog of vasopressin, which results in the accumulation of free water similarly to vasopressin.
- The guidelines do recommend giving VWF-containing concentrate to increase VWF and factor VIII to greater than 50% from baseline for at least 3 days.
- VWF concentrates can be given every 12 hours or as continuous intravenous infusions.
- Tranexamic acid should be given as an adjuvant both prior to the procedure and in the days following.
- Cryoprecipitate is not recommended because it can’t be virally inactivated.

Preprocedure prophylaxis in type 2 or 3 VWD

Desmopressin does not work for most patients with type 2 or 3 VWD. So even for minor procedures, these patients will need to receive VWF concentrate coupled with antifibrinolytics.

Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia.

Disclosures

Dr. Henry has no relevant disclosures. Dr. James disclosed relationships with Baxter/Baxalta/Shire, CSL Behring, Bayer, and Octapharma.

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