Coagulation
Hereditary bleeding disorders
von Willebrand's disease

Author: Jeremy Parsons, M.D. (see Authors page)

Revised: 28 April 2016, last major update April 2013

Copyright: (c) 2003-2016, PathologyOutlines.com, Inc.

PubMed Search: von Willebrand's disease


Cite this page: von Willebrand's disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/coagulationvonwillebranddisease.html. Accessed December 6th, 2016.
Definition / General
  • Most common hereditary bleeding disorder, affecting 1 - 2% of population, no gender preference (eMedicine)
  • Often mild and undiagnosed; may be masked by acute phase reactions
  • Unmarked vWD is still a common underlying cause of hysterectomy; test women with menorrhagia during first few days of period
  • Due to quantitative or qualitative deficiencies of von Willebrand factor (vWF), found on chromosome #12
  • Symptoms are similar to a platelet function defect (epistaxis, easy bruising, bleeding, menorrhagia)

  • vWF is synthesized by:
    • Endothelial cells, stored in Weibel-Palade bodies, secreted into plasma and subendothelium
    • Megakaryocytes, present in platelets in alpha granules

  • vWF is large polypeptide that polymerizes to form multimers of up to 100 subunits
  • Plays a role in platelet plug and fibrin clot, both essential to hemostasis at site of endothelial injury, particularly in high flow vessels
  • vWF mediates platelet adhesion to endothelium (and formation of platelet plug) by serving as a bridge between them - binds to GPIb glycoprotein on platelet surface and to exposed subendothelium at site of endothelial injury (Best Pract Res Clin Haematol 2001;14:257, Thromb Haemost 1998;79:456)
  • vWF supports coagulation (fibrin clot) by serving as protective carrier protein for factor VIII; without vWF, factor VIII has shorter half life and its plasma levels are lower

  • Note: type O patients have lower levels of vWF (75 IU/dl), type AB patients have highest levels (123 IU/dl) (Blood 1987;69:1691); levels increase with age and with acute phase reactions
Etiology
  • Type 1: mutations throughout the gene, not well characterized (OMIM #193400)
  • Type 2A: mutation in proteolysis site (most common type 2A mutation)
  • Type 2A: loss of propeptide, required for multimer formation from dimers
  • Type 2A: mutation in C-terminus, required for dimer formation from monomers
  • Type 2B: mutation in GPIb binding site, causing increased binding of vWF to GPIb
  • Type 2M: mutation in GPIb binding site, causing decreased binding of vWF to GPIb
  • Type 2N: mutation in N-terminis (factor VIII binding site), leading to decreased binding of vWF to factor VIII
  • Type 3: mutations throughout the gene, not well characterized
Diagrams / Tables

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Binding of von Willebrand factor

Clinical Features
  • Clinical note: As a general rule in coagulation, type I deficiencies refer to a decrease in the absolute amount of a normal factor and type II deficiencies indicate a defective protein that may be present in normal amounts

  • Type 1 (70 - 80%):
    • Most common, autosomal dominant, partial quantitative deficiency of vWF but normal function
    • Causes mild / moderate bleeding disorder
    • Low factor VIII, vWF antigen and ristocetin cofactor
    • Low / normal ristocetin induced platelet aggregation, normal or all sizes decreased in multimer analysis, mean ristocetin cofactor / vWF antigen ratio is 1.0
    • Normal platelet count


  • Type 2 (15 - 20%):
    • Qualitative deficiency of vWF, variable quantitative deficiency, usually mild / moderate bleeding disorder, but may be severe


  • Type 2A:
    • Most common type 2 subtype
    • Autosomal dominant
    • Low/normal factor VIII activity and vWF
    • Relative reduction of intermediate and high molecular weight multimers due to in vivo proteolytic degradation or defective multimer assembly and secretion
    • Markedly reduced ristocetin cofactor, low ristocetin induced platelet aggregation
    • Platelet vWF has similar abnormalities as plasma vWF
    • Mean ristocetin cofactor / vWF antigen ratio is 0.3
    • Normal platelet count


  • Type 2B:
    • Autosomal dominant, hemostatic defect due to intermittent thrombocytopenia and qualititatively abnormal vWF, with increased binding of vWF to GPIb (platelet vWF receptor), causing faster clearing of vWF coated platelets from the bloodstream
    • The platelet count drops further during pregnancy, surgery, DDAVP therapy
    • Have low / normal factor VIII activity and vWF
    • Reduction of high molecular weight multimers but increase in low molecular weight fragments
    • Reduced ristocetin cofactor but increased ristocetin induced platelet aggregation
    • Mean ristocetin cofactor / vWF antigen ratio is 0.6

    • Note: Rapid clearance of platelets can be a problem following DDAVP therapy in Type 2B VWD; if a previous patient trial of DDAVP has not been performed, then it is unwise to use DDAVP in an urgent bleeding situation as the resulting thrombocytopenia often complicates the problem


  • Type 2C:
    • Autosomal recessive
    • Reduction of high molecular weight multimers, increase in small multimers and qualititatively abnormal individual multimers
    • Reduced ristocetin cofactor activity out of proportion to reductions in vWF


  • Type 2M:
    • Rare
    • Autosomal dominant, decreased platelet directed function NOT due to a decrease of high molecular weight multimers, but otherwise similar to type 2A (may be due to mutation that impairs vWF and GPIb binding)
    • Low/normal factor VIII and vWF, normal multimer analysis, but very low ristocetin cofactor and low / normal ristocetin induced platelet aggregation
    • Mean ristocetin cofactor / vWF antigen ratio is < 1.0


  • Type 2N:
    • Rare, autosomal recessive
    • Markedly reduced affinity of vWF for factor VIII, causes reduction of factor VIII levels to 5% of reference range
    • Other vWF lab tests are normal
    • Often misdiagnosed as hemophilia A (which is X linked recessive), but males and females in type 2N are equally affected
    • Assay that measures binding of factor VIII to vWF is available in specialized laboratories

    • Note: Type 2N VWD is sometimes referred to as the Normandy variant


  • Type 3:
    • Very rare
    • Autosomal recessive, often associated with consanguinity
    • Most severe clinical bleeding
    • Homozygous patients have marked deficiencies of plasma vWF and factor VIII activity, no vWF in platelets and endothelial cells, no secondary transfusion response, no response to DDAVP
    • Also undetectable ristocetin cofactor, low ristocetin induced platelet aggregation, all multimer sizes are absent


  • Platelet type or pseudo von Willebrand's disease:
    • Rare disorder of mutation in GPIb (not vWF gene), causing increased binding of vWF to GPIb, with similar clinical findings as type 2B
Diagnosis
  • Testing: factor VIII activity, vWF antigen, vWF activity (often done by "ristocetin cofactor" assay); possible additional tests include vWF multimer size determination and blood type (vWF is significantly decreased in type O patients)

  • Repeat testing is often required because vWF and factor VIII become elevated during minor illnesses, injury, stress, pregnancy, estrogen use, other acute phase reactions or in newborns
Treatment
  • DDAVP (desmopressin) temporarily increases vWF and factor VIII levels 2 - 3x; for patients who don't respond, give vWF-containing factor VIII concentrates