Clinical Review

Von Willebrand Disease: Approach to Diagnosis and Management

2018 March/April;13(2):14-24

References

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53. Lillicrap D, Poon MC, Walker I, et al. Efficacy and safety of the factor VIII/von Willebrand factor concentrate, Haemate-P/Humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002;87:224–30.

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VWD Assays

VWF:Ag represents the quantity of VWF protein (antigen) in the plasma measured using an enzyme-linked immunosorbent assay (ELISA) or latex immunoassay. The normal range is approximately 50 to 200 IU/dL.

VWF:RCo is a functional assay that determines the capacity of VWF to agglutinate platelets via the platelet receptor GPIbα in the presence of ristocetin. The normal range is approximately 50 to 200 IU/dL. Novel methods of measuring VWF’s platelet-binding activity are increasingly being adopted by clinical laboratories and are associated with greater precision and improved lower limits of detection and coefficients of variation.^28,29 The first is the VWF:Act, a rapid automated assay that measures VWF activity using an antibody directed to the GPIbα binding site of VWF.²⁸ The second novel assay is VWF:GPIbM, which involves a gain-of-function GPIB construct that binds VWF without ristocetin.^30,31 For simplicity, VWF:RCo will be used to refer to VWF platelet-binding activity in the ensuing text. Factor VIII:C is a functional FVIII assay that determines the activity of FVIII in aPTT-based assays. The normal range is approximately 50 to 150 IU/dL.

VWF multimer analysis by SDS-agarose electrophoresis assesses VWF oligomers in plasma.³² Normal plasma contains multimers composed of over 40 VWF dimers, and these multimers are classified as high (HMW), intermediate (IMW), or low molecular weight (LMW). HMW multimers are decreased or missing in types 2A and 2B VWD, and IMW multimers may also be absent in type 2A VWD.

Low-dose RIPA tests the capacity of the patient’s platelets to agglutinate at low concentrations of ristocetin (~0.5 mg/mL). This is in contrast to the VWF:RCo, in which formalin-fixed control platelets are used. With type 2B, the platelet membrane is “overloaded” with high-affinity mutant VWF, resulting in abnormal platelet agglutination at low ristocetin concentrations. In some cases of type 2B VWD, all variables except RIPA may be normal.²⁹

VWF:FVIIIB is an ELISA-based assay that determines the ability of VWF to bind FVIII and is used to make the diagnosis of type 2N VWD.¹⁹

VWF:CB is an ELISA-based assay that measures the ability of VWF to bind to collagen, a function of VWF that is dependent on the collagen-binding domain (A3) and on the presence of HMW multimers. VWF:CB helps to distinguish between types 1 and 2 VWD by reflecting the loss of HMW multimer forms (type 2A VWD) or can reflect a specific collagen-binding deficiency (type 2M VWD).³³ The normal range is approximately 50 to 200 IU/dL. This assay is not available in most clinical laboratories.

VWFpp/VWF:Ag takes advantage of 2 facts: the VWF propeptide is secreted in a one-to-one ratio to VWF subunits and has a stable half-life in plasma. Thus, an increased ratio identifies patients with mutations that increase VWF clearance, such as type 1C VWD.³⁴ The mean ratio in normal individuals is 1.3, with a normal range of 0.54 to 1.98.

Genotyping should be considered when specialized testing with the VWF:FVIIIB, RIPA, or VWF:CB assays is unavailable and a diagnosis of type 2 VWD is suspected. A guideline on VWD genetic testing has been published by the UK Haemophilia Centre Doctors Organisation.³⁵

Interpretation of Clinical History and Laboratory Investigations

Normal plasma levels of VWF are approximately 100 IU/dL (100%, corresponds to ~10 μg/mL) with a population range of 50 to 200 IU/dL (50%–200%). There are a number of preanalytical variables (patient specific or laboratory specific) that affect the results of VWF laboratory testing. Patient-specific variables that are associated with increased VWF levels include increasing age, African ethnicity, exercise, inflammatory disease states, blood group A or B, increased levels of epinephrine, cocaine use, and neuroendocrine hormone levels. Decreased VWF levels are associated with medications such as valproic acid, hypothyroidism, autoantibodies, and blood group O. Individuals with blood group O have VWF levels that are 25% lower than levels in other blood groups.³⁶ Several analytical variables also can complicate the diagnosis of VWD: methods for established reference ranges, limitations to the sensitivity of assays, and sample handling issues.¹¹ These factors (summarized in Table 3) must be considered when interpreting VWF laboratory results, and at least 2 sets of tests using fresh samples are needed to confirm the diagnosis of VWD. Testing should be avoided in stressed, ill, or pregnant patients.

Mild type 1 VWD can be a difficult diagnosis to make because of the overlap of bleeding symptoms among normal individuals and those with mild type 1 VWD, as well as the variability of VWF levels. There is no consensus on the exact VWF levels required to confirm the diagnosis: the NHLBI Expert Panel recommends VWF:Ag and VWF:RCo levels less than 0.30 IU/mL to diagnose type 1 VWD,¹¹ whereas the ISTH-SSC Subcommittee on von Willebrand factor recommends using VWF:RCo and VWF:Ag levels greater than 2 standard deviations below the population mean.³⁷ In the absence of a bleeding history, slightly reduced VWF levels do not predict future significant bleeding events.³⁸ Therefore, regardless of the laboratory cut-off used, the cornerstone of a VWD diagnosis should be a history of excessive mucocutaneous bleeding.