Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children

Juan Pablo Frontroth; Mirta Hepner; Gabriela Sciuccati; Aurora Feliú Torres; Graciela Pieroni; Mariana Bonduel

doi:10.1160/TH10-04-0213

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 104(06): 1158-1165
DOI: 10.1160/TH10-04-0213

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Prospective study of low-dose ristocetin-induced platelet aggregation to identify type 2B von Willebrand disease (VWD) and platelet-type VWD in children

Juan Pablo Frontroth

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

,

Mirta Hepner

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

,

Gabriela Sciuccati

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

,

Aurora Feliú Torres

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

,

Graciela Pieroni

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

,

Mariana Bonduel

¹Laboratorio de Hemostasia y Trombosis, Servicio de Hematología-Oncología, Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos Aires, Argentina

› Institutsangaben

Abstract

Summary

Type 2B von Willebrand disease (VWD2B) and platelet-type von Wille-brand disease (PT-VWD) are rare bleeding disorders characterised by an increased ristocetin-induced platelet aggregation (RIPA) at low dose of ristocetin. It was the objective of this study to detect children with VWD2B and PT-VWD using RIPA at low dose of ristocetin (0.5 mg/ml) in the screening evaluation of bleeding disorders, and to analyse the phenotypic data along with the molecular findings. Over a 14-year period, 641 children with personal and family bleeding symptoms or bleeding from birth with previously uncharacterised haemostatic disorders were prospectively studied. Six unrelated patients (0.93%) showed RIPA at low dose of ristocetin. RIPA-based mixing studies identified that the plasma of the six probands and at least one parent from five unrelated families induced aggregation of normal platelets with the addition of low-dose ristocetin. None of the probands’ platelets showed aggre-gation with cryoprecipitate. Low ristocetin cofactor activity/VWF antigen ratio with absent collagen binding activity or thrombocytopenia were detected respectively in only two patients. Molecular analysis of exon 28 of the VWF gene identified mutations in only three patients. No mutation in the GP1BA gene was found. In this large prospective paediatric study, the screening approach including RIPA at low dose of ristocetin permitted the detection of patients with VWD2B that would otherwise have been missed. No patient with phenotype or genotype of PT-VWD was identified. Heterogeneity of bleeding symptoms and phenotypic parameters were found among members of the same family.

Keywords

Bleeding - children - platelet aggregation - ristocetin - von Willebrand disease type 2B

Volltext

Referenzen

References
1 Ruggeri ZM, Pareti FI, Mannucci PM. et al. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand disease.. N Eng J Med 1980; 302: 1047-1051.
2 Miller JL, Castella A. Platelet-type von Willebrand’s disease: characterization of a new bleeding disorder.. Blood 1982; 60: 790-794.
3 Weiss HJ, Meyer D, Rabinowitz R. et al. Pseudo-von Willebrand disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Wille-brand factor and enhanced adsorption of its high-molecular weight multimers.. N Eng J Med 1982; 306: 326-333.
4 Othman M. Platelet-type von Willebrand disease and type 2B von Willebrand disease: A story of nonidentical twins when two different abnormalities evolve into similar phenotypes.. Semin Thromb Hemost 2007; 33: 780-786.
5 Favaloro EJ. 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 side of a multidenominational or multifaceted primary-hemostasis coin? Semin Thromb Hemost 2008; 34: 113-127.
6 Othman M, Favaloro EJ. Genetics of type 2B von Willebrand disese: “True 2B“, “tricky 2B“, or “not 2B”.. What are the modifiers of the phenotype? Semin Thromb Hemost 2008; 34: 520-531.
7 Hampshire D. International Society on THrombosis and Haemostasis von Wille-brand factor database.. Available at: http://www.vwf.group.shef.ac.uk/index.html. Last accessed 14^th December, 2009.
8 Miller JL, Cunningham D, Lyle VA. et al. 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.
9 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of Subcommittee on von Willebrand factor.. J Thromb Haemost 2006; 4: 2103-2114.
10 Casonato A, Sartorello F, Pontara E. et al. A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive pheno-type and a difficult diagnosis.. Thromb Haemost 2007; 98: 1182-1187.
11 Federici AB, Mannucci PM, 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: 526-534.
12 Montgomery RR. At least Type VWD2B is a discrete variant of VWD, isn’t it?. Blood 2009; 113: 501.
13 Federici AB. Diagnosis of inherited von Willebrand disease: a clinical perspective.. Semin Thromb Haemost 2006; 32: 555-565.
14 Favaloro EJ, Bonar R, Meiring M. et al. 2B or not 2B? Disparate discrimination of functional VWF discordance using different panels or methodologies may lead to success or failure in the early identification of type 2B VWD.. Thromb Haemost 2007; 98: 346-358.
15 Weiss HJ. Sussman II 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.
16 Holmberg L, Berntorp E, Donnér M. et al. 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.
17 Takimoto Y, Imanaka F. Type 2B Hiroshima: a variant of von Willebrand disease characterized by chronic thrombocytopenia and the presence of all von Wille-brand factor multimers in plasma.. Int J Hematol 1999; 70: 127-131.
18 Nichols WL, Hultina MB, James AH. et al. von Willebrand disease (VWD): evidence based diagnosis and management guidelines, the National Heart, Lung and Blood Institute (NHLBI) Expert Panel report (USA).. Haemophilia 2008; 14: 171-232.
19 Bowman M, Riddel J, Rand ML. et al. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire.. J Thromb Haemost 2009; 7: 1418-1421.
20 Bonduel M, Frontroth JP, Hepner M. et al. Platelet aggregation and adenosine triphosphate release in children and adults.. J Thromb Haemost 2007; 5: 1782-1783.
21 Wu KK, Hoak JC. Spontaneous platelet aggregation in arterial insufficiency: mechanism and implications.. Thromb Haemost 1976; 35: 702-711.
22 Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies.. Nucleic Acids Res 1991; 19: 5444.
23 Wenger RH, Kieffer N, Wicki AN. et al. Structure of the human blood platelet membrane glycoprotein Ib alpha gene.. Biochem Biophys Res Commun 1988; 156: 389-395.
24 Mancuso DJ, Tuley EA, Westfield LA. et al. Structure of the gene for human von Willebrand factor.. J Biol Chem 1989; 264: 19514-19527.
25 Kenny D, Newman PJ, Morateck PA. et al. A dinucleotide deletion results in defective membrane anchoring and circulating soluble glycoprotein Ib alpha in a novel form of Bernard-Soulier syndrome.. Blood 1997; 90: 2626-2633.
26 Kroner PA, Kluessendorf ML, Scott JP. et al. Expressed full-length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets.. Blood 1992; 79: 2048-2055.
27 Enayat MS, Guilliatt AM, Lester W. et al. Distinguishing between type 2B and pseudo-von Willebrand disease and its clinical importance.. Br J Haematol 2006; 133: 664-666.
28 Favaloro EJ. 2B or not 2B? Differential identification of type 2B, versus pseudo-von Willebrand disease.. Br J Haematol 2006; 135: 141-142.
29 Enayat MS. 2B or not 2B? Differential identification of type 2B, versus pseudo-von Willebrand disease – response to Favaloro.. Br J Haematol 2006; 135: 143.
30 Whalley IN, Perry DJ. 2B or not 2B? Differential identification of type 2B, versus pseudo-von Willebrand disease.. Br J Haematol 2007; 136: 345.
31 Favaloro EJ. 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.
32 Othman M, Lillicrap D. Distinguishing between non-identical twins: platelet type and type 2B von Willebrand disease.. Br J Haematol 2007; 138: 665-666.
33 Favaloro EJ, Patterson D, Denholm A. et al. Differential identification of PT-VWD from type 2B VWD and GPIBA nomenclature issues – response to Othman.. Br J Haematol 2008; 142: 314-315.
34 Loffredo G, Baronciani L, Noris P. et al. von Willebrand disease type 2B must be always considered in the differential diagnosis of genetic thrombocytopenias with giant platelets.. Platelets 2006; 17: 149-152.
35 Slayton WB, Patel M, Sola-Visner M. et al. Type 2B von Willebrand disease associated with the release of platelet agglutinates from megakaryocytes in the bone marrow.. J Pediatr Hematol Oncol 2008; 30: 708-711.
36 Baronciani L, Federici AB, Castaman G. et al. Prevalence of type 2b “Malmö/New York” von Willebrand disease in Italy: the role of von Willebrand factor gene conversion.. J Thromb Haemost 2008; 6: 887-890.
37 Favaloro EJ. An update on the von Willebrand factor collagen binding assay: 21 years of age and beyond adolescence but not yet a mature adult.. Semin Thromb Haemost 2007; 33: 727-744.
38 Saba HI, Saba SR, Dent J. et al. Type IIB Tampa. A variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates and spontaneous platelet aggregation.. Blood 1985; 66: 282-286.
39 Lopez-Fernandez MF, Lopez-Berges C, Martin-Bernal JA. et al. Type IIB von Willebrand’s disease associated with a complex thrombocytopenic thrombocytopathy.. Am J Hematol 1988; 27: 291-298.
40 Moll S, Rico Lazarowski A, White GCII. Giant platelet disorder in a patient with type 2B von Willebrand’s disease.. Am J Hematol 1998; 57: 62-67.
41 Nurden P, Chretien F, Poujol C. et al. Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease.. Br J Haematol 2000; 110: 704-714.
42 Peak IR, Goodeve AC. Genetic testing for von Willebrand disease: the case for.. J Thromb Haemost 2010; 8: 13-16.
43 Favaloro EJ. Genetic testing for von Willebrand disease: the case against.. J Thromb Haemost 2010; 8: 6-12.
44 Favaloro EJ. Time to seek further clarity in the molecular analysis of von Wille-brand disease?. Thromb Haemost 2009; 102: 175-177.
45 Keeney S, Bowen D, Cumming A. et al. The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctor’s Organisation Haemophilia Genetics Laboratory Network.. Haemophilia 2008; 14: 1099-1111.