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Diagnosis of von Willebrand disease (VWD) and differentiation of VWD subtypes or differentiation of VWD from hemophilia A (Note: this activity assay is most effective when it is combined with measurement of von Willebrand factor (VWF) antigen and factor VIII coagulant activity, preferably as a panel of tests with reflexive testing and interpretive reporting [eg, VWPR / von Willebrand Profile])
Monitoring therapeutic efficacy of treatment with DDAVP (desmopressin) or VWF concentrates in patients with VWD
von Willebrand factor (VWF) is a multimeric adhesive glycoprotein that is important for platelet-platelet and platelet-vessel hemostatic interactions. In addition, plasma VWF serves as a carrier protein for coagulation factor VIII, stabilizing its procoagulant activity. VWF circulates in the blood in 2 distinct compartments, plasma VWF and platelet VWF. Plasma VWF mainly reflects VWF synthesis and release from vascular endothelial cells. Platelet VWF (about 10% of the blood VWF) reflects VWF synthesis by bone marrow megakaryocytes with storage primarily in the alpha granules of circulating platelets. VWF antigen measurement assesses the mass of plasma VWF protein, but does not measure platelet VWF protein. The major function of VWF (mediating platelet-platelet or platelet-vessel interaction) is most commonly assessed by measurement of plasma VWF activity.
Patients with congenital severe type 3 von Willebrand disease (VWD) have markedly decreased or immeasurably low VWF antigen in the plasma (and in the platelets), and plasma VWF activity is very low or not detectable. Patients with types 2A and 2B variants of VWD (with abnormal plasma VWF function and multimeric structure) may have normal or decreased plasma VWF antigen, but typically have decreased plasma VWF activity, and decreased higher molecular weight VWF multimers in the plasma. Patients with type 2M or type 2N VWD have normal levels of antigen, but either decreased VWF activity not caused by absence of higher molecular weight VWF multimers (type 2M VWD), or decreased factor VIII coagulant activity (type 2N VWD). Patients with type 1 VWD (with decreased but normally functioning plasma VWF) have concordantly decreased plasma VWF antigen and activity. Patients with acquired von Willebrand syndrome (AVWS) may have either normal or decreased plasma VWF antigen, and decreased VWF activity.
Normal, full-term newborn infants may have mildly increased levels which reach adult levels by 90 days postnatal. Healthy, premature infants (30-36 weeks gestation) may have increased levels that reach adult levels by 180 days.
Note: Individuals of blood group "O" may have lower plasma von Willebrand factor (VWF) activity than those of other ABO blood groups, such that apparently normal individuals of blood group "O" may have plasma VWF activity as low as 40% to 50%, whereas the lower limit of the reference range for individuals of other blood groups may be 60% to 70%.
von Willebrand factor (VWF) activity is reduced in parallel with VWF antigen in von Willebrand disease (VWD), except in types 2A, 2B, and 2M, and some cases of acquired von Willebrand syndrome (AVWS) in which the VWF activity is disproportionately decreased relative to the level of VWF antigen.
The VWF activity may be decreased in congenital VWD or AVWS that may be associated with are variety of disorders including monoclonal gammopathies, lymphoproliferative disorders, autoimmune disorders, hypothyroidism, severe aortic stenosis, left ventricular assist device, and arteriovenous malformation.
The VWF activity may be increased in association with pregnancy or estrogen use (including oral contraceptives), acute ("acute-phase reactant") or chronic inflammation, exercise or stress, liver disease, vasculitis, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Such increases in VWF activity may obscure the laboratory diagnosis of mild VWD.
Measurement of von Willebrand factor (VWF) activity alone has limited diagnostic value. The diagnosis of von Willebrand disease (VWD) requires a combination of clinical and laboratory information. VWF activity assay results generally must be used together with assays of VWF antigen and factor VIII coagulant activity for optimum clinical utility and diagnostic efficiency.
Results may be affected by:
-Unfractionated heparin: >4.0 U/mL may cause an overestimation of the test result
-Hemoglobin: >70 mg/dL may cause the result to be underestimated
-Bilirubin: >4.2 mg/dL may cause the result to be underestimated
-Triglycerides: >1,020 mg/dL may cause the result to be underestimated
-Rheumatoid factor: >200 IU/mL may cause an overestimation of the test result
Specimens from patients who have received preparation of mouse monoclonal antibody for diagnosis or therapy may contain human antimouse antibody (HAMA). The presence of HAMA may cause an overestimation of results in immunoassays that utilize mouse monoclonal antibodies. This assay contains a blocking agent against HAMA to minimize this interference.
This assay (HemosIL von Willebrand factor [VWF] activity) performed on the ACL TOP instrument demonstrates the following validation characteristics: intra- and interassay precision (CV) are < or =10%; the lower limit of detection is 3%; with excellent linearity (r =0.999) up to 1,000%. For apparently healthy subjects (n=368) and for patients with type 1 von Willebrand disease (VWD) (n=57), the HemosIL VWF activity assay correlates well with the platelet agglutination assay for VWF ristocetin cofactor (RCo) activity. For patients with type 2A, 2B, or 2M VWD (independently determined by VWF:RCo, VWF antigen, and plasma VWF multimer analysis), the sensitivity and specificity of the HemosIL VWF activity is 100%. Moreover, compared to VWF:RCo, the HemosIL VWF activity is more sensitive to loss of the highest molecular weight VWF multimers among patients with AVWS. This is also reflected in type 3 VWD patients receiving Humate P therapy where the VWF activity is 10% to 20% lower than the VWF:RCo. Plasma VWF multimer analysis of these patients revealed loss of the highest molecular weight VWF multimers. Finally, a VWF activity:VWF antigen ratio >0.8 reliably excludes congenital type 2A and 2B VWD, and AVWS (including loss of the highest VWF multimers due to left ventricular assist device).
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