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Classification of von Willebrand disease

Inherited VWD can be divided into three categories that reflect the pathophysiology. Type 1 and type 3 VWD reflect, respectively, the partial or virtually complete deficiency of VWF, while type 2 reflects qualitative deficiency of VWF. Type 2 can then be subdivided into four variants (type 2A, 2B, 2M and 2N) according to specific details of the phenotypic features.

VWD is caused by mutation of the VWF locus

This leads to that lower levels of the protein is synthesized, a defect function or total loss of the protein.

  • Type 1 VWD refers to partial quantitative deficiency of VWF.
  • Type 2 VWD refers to qualitative deficiency of VWF.
  • Type 3 VWD refers to virtually complete deficiency of VWF.
  • Subtype 2A refers to qualitative variants with decreased platelet-dependent function and ristocetin cofactor activity and absence of high molecular weight multimers. 
  • Subtype 2B refers to qualitative variants with increased affinity for GPIb leading to rapid clearance of the VWF.
  • Subtype 2M refers to qualitative variants with decreased platelet dependent function. Laboratory results are generally similar to those in type 2A, with the exception that there are high molecular multimers present.
  • Subtype 2N refers to qualitative variants characterised by normal levels of VWF antigen but with markedly decreased affinity for Factor VIII. Therefore, these patients display very low levels of FVIII in plasma.

VWD type 1

Type 1 is the most frequent form of VWD. It is inherited in an autosomal dominant pattern and is characterised by mild to moderate bleeding symptoms, normal or variably prolonged bleeding time and low levels of VWF:Ag and FVIII, but displays a normal multimeric structure. Definite diagnosis requires documentation of all three factors; inheritance, a history of bleeding and low levels of normal VWF. For a variety of reasons, these criteria may be impossible to satisfy in many of the patients who, nevertheless, may be at risk of bleeding and therefore may receive treatments to raise their low VWF levels.


Type 2 VWD

Type 2A is the most frequent subtype among type 2 VWD. Patients with type 2A VWD are identified by normal to low VWF:Ag levels with an abnormal multimeric pattern. It is mainly inhierited with an autosmal dominant pattern.

Type 2B can be identified beacuse of heightened response to ristocetin and absence of large multimers. The inheritance pattern is mainly autosomal dominant. Typical features for type 2B VWD are; mild thrombocytopenia with increased mean platelet volume, prolonged bleeding time, low to normal FVIII, low to normal VWF:Ag and heightened RIPA (Ristocetin induced platelet agglutination).

Type 2M VWD includes variants on which binding to platelets is impaired but the VWF multimeric distribution is normal.

Type 2N VWD is characterized by nornal levels of VWF:Ag and normal multimeric structure, but low plasma FVIII levels. It therefore resembles haemophilia, but its inheritance pattern is not X-linked but autosomal recessive.

Type 3 VWD

Type 3 (severe) VWD is caused by impaired biosynthesis of VWF and is characterised by unmeasurable levels of VWF in plasma and platelets. Since VWF also is the carrier of FVIII, plasma levels of FVIII are very low, only 1-5% of normal. As a consequence, patients affected with type 3 VWD have a severe bleeding tendency, characterised not only by mucocutaneous haemorrhages but also by haemarthroses and haematomas as observed in severe haemophilia. The inheritance pattern of type 3 VWD is autosomal recessive and its prevalence is approximately 1-10 per million population. 





Page updated: 2016-06-17