Enzyme-linked immunosorbent assay (ELISA) can be used to measure VWF concentration in plasma or VWF antigen (VWF:Ag) levels, and the VWF ristocetin cofactor (VWF:RCo) assay can be used to obtain VWF:RCo levels.2 Once these levels have been measured, the ratio of VWF:RCo and VWF:Ag can be calculated and used to diagnose type 1 and 2 VWD.2

VWF can be functionally assessed by estimating its ability to bind to platelets, collagen, and factor VIII. Ristocetin-based tests, which measure the ability of VWF to bind to platelets, are limited and have prompted the development of more precise assays that use platelet binding to a recombinant glycoprotein (GP1bM). These VWF:GP1bM tests show high negative predictive value and sensitivity in diagnosing type 2 VWD.

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Collagen-binding assays measure concentrations of high molecular weight multimers, which enhance the binding capacity of VWF to collagen types I, III, IV, VI; these assays are sensitive to type 2 VWD, which is characterized by a loss of high molecular subunits of VWF.  The 2N binding assay provides the ratio of factor VIII activity levels to VWF:Ag, and a ratio of less than 1 can assist the diagnosis of 2N. Because they are characterized by low levels of factor VIII and have similar presentation, type 2N and type 3 VWD may be confused with mild hemophilia A. Platelet aggregation studies use ristocetin added to plasma and platelets and are used for diagnosing type 2B VWD.1


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VWF:Ag levels, VWF activity levels, factor VIII activity levels, and blood type must all be taken in consideration when diagnosing VWD. Because of laboratory variability in sample collection, handling, and storage and interindividual variability of results, the authors recommended conducting repeat testing when diagnosing and managing VWD.1

Variations in the VWF gene limit the clinical interpretation of genetic analysis. The presence of VWF missense mutations varies in patients with type 1 VWD and with less severe bleeding phenotypes, and many patients with low levels of VWF lack mutations. Patients may harbor mutations and remain asymptomatic.2 Genetic testing is most useful in confirming types 2A, 2B, 2M, or 2N, though it can also be used to identify missing portions of VWF in patients with type 3 disease.1,2

Other variables have also been shown to be associated with VWD. For example, blood group O has been reported as being associated with low levels of VWF antigen. Additionally, estrogen supplementation may affect VWF levels, though there is no definitive evidence; investigation of VWF levels is recommended in patients taking estrogen.1

Pharmacologic therapy with agents such as desmopressin (DDAVP), antifibrinolytics, and VWF replacement is the mainstay of treatment in VWD. DDAVP releases factor VIII and VWF from endothelial cells and is available in intranasal, subcutaneous, and intravenous forms. The NHLBI recommends restricting fluid intake after DDVAP administration and monitoring sodium levels in specific conditions (tonsillectomy or inpatient procedures) to avoid hyponatremia side effects. Furthermore, the NHLBI suggests avoiding the use of DDAVP in patients younger than 3 years because there is a greater risk of seizures.1

The antifibrinolytics aminocaproic acid and tranexamic acid are better tolerated than DDVAP, so they are used in mucocutaneous membranes and inpatient procedures in the case of DDVAP intolerance. Tranexamic acid can be used in primary treatment of heavy menstrual bleeding, with a recommend dose of 1.3 g given 3 times a day for 5 days. VWF replacement is indicated in type 3 disease or in milder forms of bleeding during perioperative management when a patient is intolerant to DDAVP.1

The lack of reliable testing is a major diagnostic limitation, and many challenges remain. According to Amy Dunn, MD, of Nationwide Children’s Hospital in Columbus, Ohio, “Children with mild bleeding episodes are not referred [for] testing.” Although the International Society of Thrombosis and Hemostasis (ISTH) is working towards the standardization of bleeding assessment tools used in children, the assessment of VWD in patients with heavy menstrual bleeding remains an unmet need, Dr Dunn added.

“Further studies are required to classify women with low VWF levels compared with men with low VWF [levels and] to appropriately evaluate and manage these patients,” she explained.

References

1.     O’Brien S, Saini S. von Willebrand disease in pediatrics: evaluation and management [published online April 25, 2019]. Hematol Oncol Clin North Am. doi:10.1016/j.hoc.2019.01.010

2.      Ng C, Motto DG, Di Paola J. Diagnostic approach to von Willebrand disease [published online March 26, 2015]. Blood. doi:10.1182/blood-2014-08-528398