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Diagnosis of von Willebrand disease (VWD) Type 2N
Evaluation and genetic counseling of patients with mild-to-moderate hemophilia A with an atypical inheritance pattern
Evaluation of hemophilia A patients with a shortened survival of infused factor VIII (FVIII) (not caused by a specific FVIII inhibitor)
Evaluation of female patients with low FVIII activity and no prior family history of hemophilia A
Evaluation of patients with Type 1 or Types 2A, 2B, or 2M VWD with FVIII activity discordantly-lower than the von Willebrand factor antigen level
Hemophilia A (HA) and von Willebrand disease (VWD) are bleeding disorders caused by quantitative or qualitative defects in factor VIII (FVIII) or von Willebrand factor (VWF), respectively, and constitute 2 of the most common bleeding disorders. Hemophilia A is inherited as an X-linked recessive disorder while most subtypes of VWD are inherited as autosomal dominant disorders.
VWF plays 2 essential roles in hemostasis. VWF mediates platelet adhesion to damaged blood vessel walls and VWF is a carrier protein for FVIII.
Noncovalent binding of FVIII to VWF is necessary for normal survival of FVIII in the blood circulation. In patients with severe VWD, the circulating half-life of endogenous or infused FVIII is shortened.
Mutations within the VWF gene regions encoding for the FVIII binding domain of VWF may produce a phenotype of isolated FVIII "deficiency" associated with a clinically mild-to-moderate bleeding disorder which may be misdiagnosed as HA. This mild VWD phenotype was first described in patients from the Normandy region of France, VWD Normandy (VWD Type 2N). VWD Type 2N inheritance pattern is autosomal recessive.
In an international survey, VWD Normandy was detected in 58 (4.8%) of 1,198 patients previously diagnosed as having mild hemophilia A. Three VWF gene mutations (VWF Thr791Met, Arg816Trp, and Arg854Gln) accounted for 96% of patients with mutations in the FVIII binding domain of VWF.(3) Patients who are homozygous for 1 of the 3 common mutations have reduced levels of FVIII activity, whereas patients who are heterozygous typically have normal FVIII activity. However, patients who are heterozygous for 1 of the 3 common VWD Type 2N mutations may have decreased FVIII activity in the presence of a second (compound heterozygous) mutation in the VWF gene that typically results in a Type 1 or Type 3 VWD (quantitative defect). VWD Type 2N also has been associated with a more severe bleeding phenotype among patients who are homozygous for other mutations (VWF Glu24Lys) within the FVIII binding domain of VWF.(1,2)
Additional studies suggest that 1.5% (3/199) to 13.8% (5/36) of patients with vWD Type 1 have a FVIII binding defect.(2,4)
The diagnosis of VWD Type 2N is important for appropriate genetic counseling, because the inheritance of VWD Type 2N is autosomal recessive (as opposed to the X-linked recessive inheritance of HA).
Optimal treatment or prophylaxis of bleeding requires products containing functional VWF.
Interpretive report will include specimen information, assay information, background information, and conclusions based on the test results.
Clinical information and results of patient testing (factor VIII coagulant activity, von Willebrand factor antigen, and ristocetin cofactor activity) are useful for test interpretation.
On-site Hemophilia Center, Special Coagulation, and/or Medical Genetics consultations are available for registered Mayo Clinic patients and may be especially helpful in complex cases. Phone consultations are available for Mayo Medical Laboratories clients.
This test will not detect other rare mutations within the known factor VIII binding domain of the von Willebrand factor (VWF) gene or other mutations in the VWF gene.
1. Tuley EA, Gaucher C, Jorieux S, et al: Expression of von Willebrand factor "Normandy": an autosomal mutation that mimics hemophilia A. Proc Natl Acad Sci USA 1991;88:6377-6381
2. Schneppenheim R, Budde U, Krey S, et al: Results of a screening for von Willebrand disease type 2N in patients with suspected hemophilia A or von Willebrand disease type 1. Thromb Haemost 1996;76:598-602
3. Mazurier C, Meyer D: Factor VIII binding assay of von Willebrand factor and the diagnosis of type 2N von Willebrand disease-results of an international survey. On behalf of the Subcommittee on von Willebrand Factor of the Scientific and Standardization committee of the ISTH. Thromb Haemost 1996;76:270-274
4. Nesbitt IM, Goodeve AC, Guilliatt AM, et al: Characterization of type 2N von Willebrand disease using phenotypic and molecular techniques. Thromb Haemost 1996;75:959-964