GI Bleeding

David Green, MD, PhD

Northwestern University, Feinberg School of Medicine, Chicago, IL

This case was reviewed and updated in November 2012 by Dr. Alvin H. Schmaier and members of the Teaching Cases Subcommittee.

Copyright of the American Society of Hematology, 2006. ISSN: 1931-6860.

V. PATHOPHYSIOLOGY

The characterization of the types of von Willebrand disease is based on the agarose gel features of the protein shown below in a multimeric analysis.

"Plt" represents the multimeric features of platelet von Willebrand factor (vWF). "NP" is the vWF multimeric pattern of normal plasma. "1" represents the multimeric pattern of Type 1 vWD. Note that the pattern is normal, but with less intensity. "2A" is the multimeric pattern of Type 2A vWD with reduction in higher and intermediate vWF multimers. Please note that there is some variation of these patterns, hence two examples are given. "2B" represents the multimeric pattern of Type 2B vWD that shows loss of the higher molecular mass multimers. "3" is the absent vWF multimers seen with Type 3 vWD. The image was produced by Marlies Ledford and was published by White GC II and Sadler JE, von Willebrand Disease: Clinical Aspects and Therapy, In: Hoffman R et al., Hematology Basic Principles and Practice, Churchill Livingstone, Philadelphia, 2009, p.1963.

The characteristics of the three main types of von Willebrand disease are summarized in the chart below.

von Willebrand disease: Classification
Type 1
  • Autosomal dominant
  • Partial quantitative deficiency of von Willebrand factor
Type 2
  • Qualitative abnormalities in von Willebrand factor function.
  • Gene with point mutations, insertions, and missense mutations; usually autosomal dominant inheritance.
Type 2A
  • Characterized by decreased platelet-dependent von Willebrand factor function with selective deficiency of higher molecular weight multimers.
Type 2B
  • Increased affinity for platelet GPIb.
  • Characterized by absence of the higher molecular weight multimers of von Willebrand factor.
  • Associated with thrombocytopenia due to a gain of function mutation resulting in a von Willebrand factor molecule with enhanced platelet agglutination.
Type 2-M
  • Decreased platelet-dependent von Willebrand factor function with higher molecular weight multimers present.
  • Reduced binding of von Willebrand factor to GPIb-IX-V.
Type 2-N
  • Rare autosomal recessive disorder (von Willebrand factor Normandy) arising from a mutation in the factor VIII binding site on the von Willebrand factor molecule.
  • Without the protection provided by von Willebrand factor binding, factor VIII levels fall because of a markedly decreased half life.
  • von Willebrand multimers and antigen and activity levels may be normal.
  • Levels of factor VIII are low enough to make it possible to confuse this with classic hemophilia.
  • Specific diagnosis requires either demonstrating the lack of binding of von Willebrand factor to factor VIII or genetic analysis.
Type 3
  • Autosomal recessive.
  • Patients have a near absence of von Willebrand factor.
  • Due to mutations that result in either a complete absence of the protein or a markedly truncated molecule.
  • The most severe form (very impaired hemostasis).
  • Usually recognized in early childhood; is confused with hemophilia A.

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