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von Willebrand Comprehensive PanelTest code(s) 19790
Question 1. What is the function of von Willebrand factor?
von Willebrand factor (VWF) has two important hemostatic functions: (1) mediating platelet-subendothelium adhesion and platelet aggregation at sites of vascular injury, (2) binding and stabilization of circulating blood clotting factor VIII (FVIII).
Question 2a. How is von Willebrand disease classified?
von Willebrand disease (VWD) is a bleeding disorder in which there is a quantitative or qualitative abnormality of von Willebrand factor (VWF). It may be inherited or acquired. The acquired form is usually secondary to valvular stenosis, hypothroidism, monoclonal gammapathies of unknown origin, or following use of left-ventricular assist devices.
The disease is classified into 3 types. Type 1 is characterized by a partial quantitative deficiency of VWF, type 2 by a qualitative defect in VWF function, and type 3 by an almost complete deficiency of VWF.
Question 2b. How are the qualitative defects classified?
The qualitative defects are further divided into 4 categories; types 2A, 2B, 2M, and 2N. Type 2A is characterized by decreased platelet adhesion resulting from a deficiency of high molecular weight multimers. Type 2B includes variants with increased affinity for platelet glycoprotein I and proteolytic degradation of high molecular weight multimers. Type 2M is characterized by decreased VWF-dependent platelet adhesion without a deficiency of high molecular weight multimers. Last, with type 2N VWD, there is a decreased binding affinity for FVIII.
Question 3. What factors influence VWF levels?
There are multiple factors that affect the plasma concentration of VWF. A major contributor is blood group. On average, levels are lower in blood group O individuals in comparison to non-blood group O individuals. Why the difference? The blood group A and B alleles encode glycosyltransferases that add carbohydrate moieties to the precursor side chains, converting them to the A or B antigens. The O alleles do not encode this transferase and thus express the unmodified precursor. VWF undergoes glycosylation, and the ABO carbohydrate structures have been identified within the A1 domain of the protein. Although the exact mechanism is unknown, 1 hypothesis is that the reduced level of glycosylated VWF in blood group O individuals is associated with decreased survival of the protein.1
Question 4. If blood group O individuals on average have lower levels than non-blood group O individuals, why are there not blood group-specific reference ranges?
The major determinant of bleeding symptoms or risk is low VWF. As recommended by the National Heart, Lung and Blood Institute VWD expert panel, population based reference ranges, rather than blood group-specific ranges, may be more useful clinically.2
Question 5. What is the significance of the Ristocetin Cofactor Activity (VWF:RCo)? Is this the same assay as the Ristocetin Induced Platelet Aggregation (RIPA) assay?
The Ristocetin Cofactor Activity assay is the most commonly performed automated test to assess VWF function. It measures the ability of VWF in the patient plasma to induce platelet agglutination in the presence of ristocetin. In combination with the VWF Antigen assay, it is used to assist in the discrimination of the quantitative (types 1 and 3) from the qualitative (type 2 VWD) defects. With type 1 and type 3 VWD, the VWF antigen and VWF:RCo will be proportionally decreased. With type 2 VWD, the VWF antigen may be normal to reduced, whereas the VWF:RCo will be greatly reduced in comparison to the antigen level.
In contrast, the RIPA assay measures the aggregation of the patient's platelet rich plasma to various concentrations of ristocetin, thus providing an assessment of platelet-VWF interaction. It is useful to discriminate type 2B VWD from other functional defects. Type 2B is characterized by increased responsiveness, whereas types 2A and 2M yield reduced responsiveness (in type 1 VWD, the level is dependent on the plasma concentration of VWF). However, a major limitation of the RIPA assay is the requirement for fresh blood; this necessitates near patient testing. If local testing is not an option, an alternative is VWD Mutation Analysis (test code 19837[X]) which is useful for subtyping the qualitative defects.
Question 6. What is the Collagen Binding Activity (CBA) assay measuring?
The CBA assay is a functional assay that detects VWF adhesive activity to collagen. In vivo, collagen within the subendothelial matrix is exposed subsequent to endothelial cell damage. VWF binding to exposed collagen is critical for platelet adhesion, aggregation, and eventual clot formation. Used in combination with the VWF:RCo and VWF:Ag assays, the CBA assay assists in the identification and discrimination of most types of VWD (types 1, 2A, 2B, 2M, and 3). These 3 tests make up a much more powerful test panel than the 2 test combination of VWF:Ag and VWF:RCo.3
Question 7. What is the clinical significance of an elevated VWF?
VWF and factor VIII belong to a class of proteins whose levels increase in response to stress and inflammation (positive acute phase proteins). Since an acute phase response may mask the presence of VWD, it may be advisable to repeat testing at a time more representative of baseline, if clinical suspicion is high.
Question 8. How might sample collection, processing, and storage impact results?
VWF and factor VIII are unique proteins in that both are susceptible to cold-activation. Storage of the whole blood citrate tube at cold temperatures (2-4°C) before centrifugation may lead to subsequent activation and loss of VWF and, consequently, factor VIII activity. Depending on the tests ordered, the potential for misdiagnosis as hemophilia or VWD exists. The exact mechanism is unknown, though it is presumed that whole blood exposure to cold temperatures is activating VWF proteases and/or other enzymes which in turn degrade VWF.4 Therefore, it is absolutely critical that whole blood samples are stored at room temperature prior to centrifugation. The following illustration outlines the recommended procedure for preparation of platelet poor plasma.
Question 9. My female patient has decreased factor VIII, yet the von Willebrand factor studies were all normal. Does she have VWD?
In the absence of a factor VIII inhibitor, the differential diagnosis for low factor VIII in a female patient includes hemophilia A carrier, type 2N VWD, or a pre-analytic etiology (ie, improper sample collection). Type 2N VWD is characterized by defective VWF – factor VIII binding. As a result, factor VIII is not protected from proteolytic degradation in circulation and levels decrease. Patients with type 2N VWD may have normal VWF studies (antigen, ristocetin cofactor activity, and multimers), yet have reduced levels of factor VIII activity. The same pattern of results is observed in hemophilia A carriers.
The VWF:Factor VIII Binding Activity assay (test code 70068) is used to discriminate type 2N VWD from hemophilia A. Patients with the former will exhibit defective binding in the assay, whereas binding will be normal in hemophilia A patients.
- Franchini M, Capra F, Targher G, et al. Relationship between ABO blood group and von Willebrand factor levels: from biology to clinical implications.Thromb J. 2007;5:14.
- The diagnosis, evaluation and management of von Willebrand disease. NIH Publication #08-5832. Published December 2007. https://www.nhlbi.nih.gov/files/docs/guidelines/vwd.pdf. Accessed March 15, 2016.
- Favaloro EJ. Diagnosis and classification of von Willebrand disease: a review of the differential utility of various functional von Willebrand factor assays. Blood Coagul Fibrinolysis. 2011;22:553-564..
- Favaloro EJ, Soltani S, McDonald J. Potential laboratory misdiagnosis of hemophilia and von Willebrand disorder owing to cold activation of blood samples for testing.Am J Clin Pathol. 2004;122:686-692.