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

ABSTRACT

Platelet-type von Willebrand disease (PT-VWD, or pseudo-VWD) and type 2B VWD share a common bleeding phenotype with different etiologies. Both PT-VWD and type 2B VWD represent an enhanced binding between the plasma von Willebrand factor (VWF) to its platelet ligand, glycoprotein Ib α (GP1BA). However, type 2B VWD results from a functionally abnormal VWF molecule, whereas PT-VWD is caused by hyperresponsive platelets due to defects in the platelet GP1BA gene. The laboratory discrimination between the two disorders can be a challenge because simple phenotypic testing will not differentially identify the disorders, and the more complex testing approaches are often poorly applied. Definitive diagnosis is critical for treatment decisions and can be most definitively achieved by identifying the gene defect at either the VWF or GP1BA loci. A systematic international molecular genetic study would be helpful to address the question of whether PT-VWD is being misdiagnosed as type 2B VWD. Such a study can be facilitated by an international online database/disease registry to enhance international awareness about this otherwise long-recognized diagnostic dilemma.

KEYWORDS

Platelet-type VWD - pseudo-VWD - GP1BA - RIPA - VWF - platelet - type 2B VWD

REFERENCES

• 1 Bithell T C, Parekh S J, Strong R R. Platelet-function studies in the Bernard-Soulier syndrome.  Ann N Y Acad Sci. 1972;  201 145-160
• 2 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 35657-35663
• 3 Andrews R K, Gardiner E E, Shen Y, Whisstock J C, Berndt M C. Glycoprotein Ib-IX-V.  Int J Biochem Cell Biol. 2003;  35 1170-1174
• 4 Huizinga E G, Tsuji S, Romijn R A et al.. Structures of glycoprotein Ib alpha and its complex with von Willebrand factor A1 domain.  Science. 2002;  297 1176-1179
• 5 Ozaki N, Asazuma K, Suzuki-Inoue K, Berndt M C. Platelet GPIb-IX-V-dependent signaling.  J Thromb Haemost. 2005;  3 1745-1751
• 6 Du X. Signaling and regulation of the platelet glycoprotein Ib-IX-V complex.  Curr Opin Hematol. 2007;  14 262-269
• 7 López J A, Leung B, Reynolds C C, Li C Q, Fox J EB. Efficient plasma membrane expression of a functional platelet glycoprotein Ib-IX complex requires the presence of its three subunits.  J Biol Chem. 1992;  267 12851-12859
• 8 Modderman P W, Admiraal L G, Sonnenberg A, von dem Borne A E. Glycoproteins V and Ib-IX form a noncovalent complex in the platelet membrane.  J Biol Chem. 1992;  267 364-369
• 9 Luo S Z, Mo X, Afshar-Kharghan V, Srinivasan S, López J A, Li R. Glycoprotein Ibα forms disulfide bonds with 2 glycoprotein Ibβ subunits in the resting platelet.  Blood. 2007;  109 603-609
• 10 Clemetson K J. A short history of platelet glycoprotein Ib complex.  Thromb Haemost. 2007;  98 63-68
• 11 Vanhoorelbeke K, Ulrichts H, Van de Walle G, Fontayne A, Deckmyn H. Inhibition of platelet glycoprotein Ib and its antithrombotic potential.  Curr Pharm Des. 2007;  13 2684-2689
• 12 Jain S, Zuka M, Liu J et al.. Platelet glycoprotein Ibα supports experimental lung metastasis.  Proc Natl Acad Sci USA. 2007;  104 9024-9028
• 13 Hoffmeister K M, Felbinger T W, Falet H et al.. The clearance mechanism of chilled blood platelets.  Cell. 2003;  112 87-97
• 14 Hoffmeister K M, Josefsson E C, Isaac N A, Clausen H, Hartwig J H, Stossel T P. Glycosylation restores survival of chilled blood platelets.  Science. 2003;  301 1531-1534
• 15 López 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 transmemberane protein with homology to leucin-rich alpha 2- glycoprotein.  Proc Natl Acad Sci USA. 1987;  84 5615-5619
• 16 López J A, Dong J F. Structure and function of the glycoprotein Ib-IX-V complex.  Curr Opin Hematol. 1997;  4 323-329
• 17 Andrews R K, López J A, Berndt M C. Molecular mechanisms of platelet adhesion and activation.  Int J Biochem Cell Biol. 1997;  29 91-105
• 18 Vicente V, Kostel P J, Ruggeri Z M. Isolation and functional characterisation of the von Willebrand factor-binding domain located between residues His(1)-Arg (293) of the alpha chain of glycoprotein Ib.  J Biol Chem. 1988;  263 18473-18479
• 19 Vicente V, Houghten R A, Ruggeri Z M. Identification of a site in the alpha chain of platelet glycoprotein Ib that participates in von Willebrand factor binding.  J Biol Chem. 1990;  265 274-280
• 20 Murata M, Ware J, Ruggeri Z M. Site directed mutagenesis of a soluble recombinant fragment of platelet glycoprotein Ib α demonstrating negatively charged residues involved in von Willebrand factor binding.  J Biol Chem. 1991;  266 15474-15480
• 21 Peterson F E, Handin R I. Transient expression of recombinant glycoprotein Ib α polypeptides in COS cells that inhibit von Willebrand factor binding to the platelet glycoprotein IB/IX complex.  Thromb Haemost. 1992;  68 203-207
• 22 Othman M, Notley C, Lavender F L et al.. Identification and functional characterisation of a novel 27bp deletion in the macroglycopeptide-coding region of the GPIb alpha gene resulting in platelet-type von Willebrand disease.  Blood. 2005;  105 4330-4336
• 23 Chen J, López J A. The mysteries of a platelet adhesion receptor. Inside Blood.  Blood. 2005;  105 4154-4155
• 24 López J A, Andrews R K, Afshar-Kharghan V, Berndt M C. Bernard-Soulier syndrome.  Blood. 1998;  91 4397-4418
• 25 BSS database.  Available at: http://www.bernardsoulier.org/index.html Accessed October 24, 2007; 
• 26 Ruggeri Z M, Pareti F I, Mannucci P M, Ciavarella N, Zimmerman T S. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand disease.  N Engl J Med. 1980;  302 1047-1051
• 27 Castaman G, Federici A B, Rodeghiero F, Mannucci P M. von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment.  Haematologica. 2003;  88 94-108
• 28 Miller J L. Platelet-type von Willebrand disease.  Thromb Haemost. 1996;  75 865-869
• 29 Miller J L, Kupinski J M, Castella A, Ruggeri Z M. von Willebrand factor binds to platelets and induces aggregation in platelet-type but not type IIB von Willebrand disease.  J Clin Invest. 1983;  72 1532-1542
• 30 Miller J L. Sorting out heightened interactions between platelets and von Willebrand factor: “IIB or not IIB?” is becoming an increasingly answerable question in the molecular era.  Am J Clin Pathol. 1991;  00 681-683
• 31 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;  133 664-666
• 32 Favaloro E J. 2B or not 2B? Differential identification of type 2B, versus pseudo-von Willebrand disease.  Br J Haematol. 2006;  135 141-142
• 33 Whalley I N, Perry D J. 2B or not 2B? Differential identification of type 2B versus pseudo-, von Willebrand disease.  Br J Haematol. 2007;  136 345
• 34 Favaloro E. 2B or not 2B? Differential identification of type 2B versus pseudo-, von Willebrand disease-response to Whalley and Perry.  Br J Haematol. 2007;  136 345-346
• 35 Guermazi S, Conard J, Samama M M, Dellagi K. Type 2B and pseudo type 2B Von Willebrand disease; a report of three cases.  Pathol Biol. 2006;  54 159-165
• 36 Othman M, Lillicrap D. Distinguishing between non-identical twins: platelet type and type 2B von Willebrand disease.  Br J Haematol. 2007;  138 665-666
• 37 Nurden P, Lanza F, Bonnafous-Faurie C, Nurden A. A second report of platelet-type von Willebrand disease with a Gly233Ser mutation in the GP1BA gene.  Thromb Haemost. 2007;  97 319-321
• 38 ISTH VWD mutation database.  http://Available at: www.vwf.group.shef.ac.uk Accessed October 24, 2007; 
• 39 Ginsburg D, Sadler J E. von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1993;  69 177-184
• 40 Federici A B. Impaired megakaryocytopoiesis in type 2B von Willebrand disease. Inside Blood.  Blood. 2006;  108 2498-2499
• 41 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 USA. 1991;  88 4761-4765
• 42 Russell S D, Roth G J. von Willebrand disease: a mutation in the platelet glycoprotein Ibα gene associated with a hyperactive surface receptor.  Blood. 1993;  81 1787-1791
• 43 Takahashi H, Murata M, Moriki T et al.. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib α in Japanese patients with platelet-type von Willebrand disease.  Blood. 1995;  6 3727-3733
• 44 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;  8 311-315
• 45 Matsubara Y, Murata M, Sugita K, Ikeda Y. Identification of a novel point mutation in platelet glycoprotein Ib alpha, Gly to Ser at residue 233, in a Japanese family with platelet-type von Willebrand disease.  J Thromb Haemost. 2003;  1 2198-2205
• 46 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 α fragment.  J Clin Invest. 1993;  91 2133-2137
• 47 Moriki T, Murata M, Kitaguchi T et al.. Expression and functional characterisation of an abnormal platelet membrane glycoprotein Ib α (Met ²³⁹→Val) reported in patients with platelet-type von Willebrand disease.  Blood. 1997;  90 698-705
• 48 Weiss H J, Sussman I I. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers.  Blood. 1986;  68 149-156
• 49 Holmberg L, Berntorp E, Donner M, Nilsson I M. von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma.  Blood. 1986;  68 668-672
• 50 Weiss H J. Type 2B von Willebrand disease and related disorders of patients with increased ristocetin induced platelet aggregation: what they tell us about the role of von Willebrand factor in hemostasis.  J Thromb Haemost. 2004;  2 2055-2056
• 51 Sadler J E, Budde U, Eikenboom J C et al.. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.  J Thromb Haemost. 2006;  4 2103-2114
• 52 Weiss H J, Meyer D, Rabinowitz R, Pietu J P, Vicic W J, Rogers J. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced absorption of its high-molecular-weight multimers.  N Engl J Med. 1982;  306 326-332
• 53 Favaloro E J. Laboratory assessment as a critical component of the appropriate diagnosis and sub-classification of von Willebrand disease.  Blood Rev. 1999;  13 185-204
• 54 Hampshire D J, James P D, Peake I, Goodeve A C. The von Wilebrand factor (VWF) ISTH SSC online Database.  J Thromb Haemost. 2007;  5(Suppl 2) 206
• 55 ISTH standardization subcommittee SSC on von Willebrand factor. Minutes of July 2007. Geneva, Switzerland; Available at: http://www.med.unc.edu/isth/ssc/07sscminutes/07vwf.htm. Accessed October 24, 2007
• 56 Othman M, Leggo J, Notley C, James P, Lillicrap D. Platelet type von Willebrand disease: an underdiagnosed cause of excessive mucocutaneous bleeding.  J Thromb Haemost. 2007;  5(Suppl 2) 167