Semin Thromb Hemost 2011; 37(5): 464-469
DOI: 10.1055/s-0031-1281030
© Thieme Medical Publishers

Platelet-Type Von Willebrand Disease: A Rare, Often Misdiagnosed and Underdiagnosed Bleeding Disorder

Maha Othman1
  • 1Assistant Professor, Department of Anatomy and Cell Biology, Queen's University; and Professor, Laurentian University-St. Lawrence College Collaborative Program, St. Lawrence College, Kingston, Ontario, Canada
Further Information

Publication History

Publication Date:
18 November 2011 (online)

ABSTRACT

Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant rare bleeding disorder characterized by hyperresponsive platelets. This inherent platelet function defect is due to a gain-of-function mutation within the GP1BA gene coding for the platelet surface glycoprotein Ib alpha protein, the receptor for the adhesive protein von Willebrand factor (VWF). The defect results in excessive and unnecessary platelet–VWF interaction with subsequent removal of the hemostatically efficient high molecular weight VWF as well as platelets from the circulation, leading to thrombocytopenia and bleeding diathesis. Patients with PT-VWD present with mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy and following aspirin ingestion or drugs that have antiplatelet activity. Laboratory testing shows low VWF:ristocetin cofactor and low or normal VWF:antigen and characteristically an enhanced ristocetin-induced platelet agglutination (RIPA). These laboratory features are also indicators of the closely similar and more common bleeding disorder type 2B VWD. Simplified RIPA mixing assays, cryoprecipitate challenge, and flow cytometry can differentiate between the two disorders. However, the gold standard is to identify mutations within the VWF gene (indicating type 2B VWD) or the platelet GP1BA gene (confirming PT-VWD). Treatment is based on making a correct diagnosis of PT-VWD where platelet concentrates instead of VWF/factor VIII preparations should be administered. A recent fairly large retrospective/prospective registry-based international study showed that PT-VWD is very rare, likely to be misdiagnosed as type 2B VWD or idiopathic thrombocytopenic purpura, and represents 15% of type 2B VWD diagnoses.

REFERENCES

  • 1 Weiss H J, Meyer D, Rabinowitz R et al. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers.  N Engl J Med. 1982;  306 (6) 326-333
  • 2 Othman M. Platelet-type von Willebrand disease and type 2B von Willebrand disease: a story of nonidentical twins when two different genetic abnormalities evolve into similar phenotypes.  Semin Thromb Hemost. 2007;  33 (8) 780-786
  • 3 Miller J L, Castella A. Platelet-type von Willebrand's disease: characterization of a new bleeding disorder.  Blood. 1982;  60 (3) 790-794
  • 4 Registry PT-VWD. Available at: http://http//www.pt-vwd.org Accessed February 9, 2011
  • 5 Lopez J A, Chung D W, Fujikawa K, Hagen F S, Papayannopoulou T, Roth G J. Cloning of the alpha chain of human platelet glycoprotein Ib: a transmembrane protein with homology to leucine-rich alpha 2-glycoprotein.  Proc Natl Acad Sci U S A. 1987;  84 (16) 5615-5619
  • 6 Ware J, Russell S, Ruggeri Z M. Cloning of the murine platelet glycoprotein Ibalpha gene highlighting species-specific platelet adhesion.  Blood Cells Mol Dis. 1997;  23 (2) 292-301
  • 7 Miller J L, Cunningham D, Lyle V A, Finch C N. Mutation in the gene encoding the alpha chain of platelet glycoprotein Ib in platelet-type von Willebrand disease.  Proc Natl Acad Sci U S A. 1991;  88 (11) 4761-4765
  • 8 Russell S D, Roth G J. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor.  Blood. 1993;  81 (7) 1787-1791
  • 9 Takahashi H, Murata M, Moriki T et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease.  Blood. 1995;  85 (3) 727-733
  • 10 Kunishima S, Heaton D C, Naoe T et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease.  Blood Coagul Fibrinolysis. 1997;  8 (5) 311-315
  • 11 Huizinga E G, Tsuji S, Romijn R A et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain.  Science. 2002;  297 (5584) 1176-1179
  • 12 Murata M, Russell S R, Ruggeri Z M, Ware J. Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment.  J Clin Invest. 1993;  91 (5) 2133-2137
  • 13 Moriki T, Murata M, Kitaguchi T et al. Expression and functional characterization of an abnormal platelet membrane glycoprotein Ib alpha (Met239—> Val) reported in patients with platelet-type von Willebrand disease.  Blood. 1997;  90 (2) 698-705
  • 14 Matsubara Y, Murata M, Sugita K, Ikeda Y. Identification of a novel point mutation in platelet glycoprotein Ibalpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease.  J Thromb Haemost. 2003;  1 (10) 2198-2205
  • 15 Nurden P, Lanza F, Bonnafous-Faurie C, Nurden A. A second report of platelet-type von Willebrand disease with a Gly233Ser mutation in the GPIBA gene.  Thromb Haemost. 2007;  97 (2) 319-321
  • 16 Othman M, Notley C, Lavender F L et al. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease.  Blood. 2005;  105 (11) 4330-4336
  • 17 Uff S, Clemetson J M, Harrison T, Clemetson K J, Emsley J. Crystal structure of the platelet glycoprotein Ib(alpha) N-terminal domain reveals an unmasking mechanism for receptor activation.  J Biol Chem. 2002;  277 (38) 35657-35663
  • 18 Dumas J J, Kumar R, McDonagh T et al. Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations.  J Biol Chem. 2004;  279 (22) 23327-23334
  • 19 Othman M. Differential identification of PT-VWD from type 2B VWD and GP1BA nomenclature issues.  Br J Haematol. 2008;  142 (2) 312-314 author reply 314-315
  • 20 Miller J L. Platelet-type von Willebrand disease.  Thromb Haemost. 1996;  75 (6) 865-869
  • 21 Federici A B, Mannucci P M, Castaman G et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients.  Blood. 2009;  113 (3) 526-534
  • 22 Nurden A T. Qualitative disorders of platelets and megakaryocytes.  J Thromb Haemost. 2005;  3 (8) 1773-1782
  • 23 Favaloro E J. 2B or not 2B? Differential identification of type 2B, versus pseudo-von Willebrand disease.  Br J Haematol. 2006;  135 (1) 141-142 author reply 143
  • 24 Favaloro E J. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin?.  Semin Thromb Hemost. 2008;  34 (1) 113-127
  • 25 Favaloro E J, Patterson D, Denholm A et al. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis.  Br J Haematol. 2007;  139 (4) 623-626
  • 26 Whalley I N, Perry D J. 2B or not 2B? Differential identification of type 2B, versus pseudo von Willebrand disease.  Br J Haematol. 2007;  136 (2) 345 author reply 345-346
  • 27 Othman M, Lillicrap D. Distinguishing between non-identical twins: platelet type and type 2B von Willebrand disease.  Br J Haematol. 2007;  138 (5) 665-666
  • 28 Othman M, Hamilton A. Platelet-type von Willebrand disease: results of a worldwide survey from the Canadian PT-VWD project.  Acta Haematol. 2010;  123 (2) 126-128
  • 29 Enayat M S, Guilliatt A M, Lester W, Wilde J T, Williams M D, Hill F G. Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importance.  Br J Haematol. 2006;  133 (6) 664-666
  • 30 Giannini S, Cecchetti L, Mezzasoma A M, Gresele P. Diagnosis of platelet-type von Willebrand disease by flow cytometry.  Haematologica. 2010;  95 (6) 1021-1024
  • 31 Franchini M, Montagnana M, Lippi G. Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease.  Int J Lab Hematol. 2008;  30 (2) 91-94
  • 32 Guerrero J A, Kyei M, Russell S et al. Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation.  Blood. 2009;  114 (27) 5541-5546
  • 33 Suva L J, Hartman E, Dilley J D et al. Platelet dysfunction and a high bone mass phenotype in a murine model of platelet-type von Willebrand disease.  Am J Pathol. 2008;  172 (2) 430-439
  • 34 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease.  Blood. 1987;  69 (2) 454-459
  • 35 Favaloro E. von Willebrand disease: local diagnosis and management of a global issue.  Semin Thromb Hemost. 2011;  37 (5) 440-455
  • 36 Hamilton A, Ozelo M, Leggo J et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study.  Thromb Haemost. 2011;  105 (3) 501-508

Maha Othman, M.D. , Ph.D. 

Department of Anatomy and Cell Biology, Queen's University, Boterell Hall

Room 915, Kingston, Ontario K7L 3N6, Canada

Email: [email protected]