Importance of the FcγRIIa-Arg/His-131 Polymorphism in Heparin-induced Thrombocytopenia Diagnosis

Christilla Bachelot-Loza; Raphaël Saffroy; Dominique Lasne; Gilles Chatellier; Martine Aiach; Francine Rendu

doi:10.1055/s-0037-1614938

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 79(03): 523-528
DOI: 10.1055/s-0037-1614938

Review Articles

Schattauer GmbH

Importance of the FcγRIIa-Arg/His-131 Polymorphism in Heparin-induced Thrombocytopenia Diagnosis

Authors

Christilla Bachelot-Loza

¹Inserm U 428, Faculté des Sciences pharmaceutiques, Paris, France
Raphaël Saffroy

¹Inserm U 428, Faculté des Sciences pharmaceutiques, Paris, France
Dominique Lasne

¹Inserm U 428, Faculté des Sciences pharmaceutiques, Paris, France
Gilles Chatellier

²Service d’Informatique médicale, Hôpital Broussais, Paris, France
Martine Aiach

¹Inserm U 428, Faculté des Sciences pharmaceutiques, Paris, France
Francine Rendu

¹Inserm U 428, Faculté des Sciences pharmaceutiques, Paris, France

Abstract

Summary

Heparin-induced thrombocytopenia (HIT) involves heparin-dependent antibodies which induce platelet activation. In the present study, we searched for a relationship between the polymorphism of the Fc receptor (FcγRIIa) and the development of HIT. In this purpose, all the donors were genotyped for their FcγRIIA and HIT patients were selected on the basis of at least one positive answer by ¹⁴C-serotonin release assay (SRA). The frequency distribution of the FcγRIIa polymorphism in the HIT patient group was similar to that observed in the healthy control group. Moreover, a statistical analysis taking into account our results and those of 3 previously published studies, suggested at most only a weak association between HIT and the FcγRIIa-131 polymorphism.

Laboratory tests used to diagnose HIT rely on the activation of normal donor platelets but fail to detect every HIT positive patient. We determined the role of FcγRIIa-131 polymorphism on the reactivity of control platelets to HIT plasmas. When control platelet FcγRIIa-131 was of Arg/Arg form, only 47% of the HIT plasmas were positive by SRA, compared to 81% and 74% for His/His or His/Arg forms, respectively. We also compared the level of anti PF4/heparin antibodies in the HIT plasmas with the response obtained by SRA. The mean anti PF4/heparin antibodies level in HIT plasma was significantly lower in negative SRA than in positive tests when using control platelets from FcγRIIa-Arg/Arg131 and heterozygous donors. Thus, the variability of control platelets to respond to HIT plasmas in the SRA test is related to both the FcγRIIa-131 polymorphism, and to the amount of anti PF4/heparin antibodies.

Full Text

References

References
1 Bell WR, Tomasulo PA, Alving BM, Duffy TP. Thrombocytopenia occuring during the administration: A prospective study in 52.. Ann Intern Med 1976; 85: 155-60.
2 Cines DB, Kaywin P, Bina M, Tomaski A, Schreiber AD. Heparin-associated thrombocytopenia.. N Engl J Med 1980; 303: 788-95.
3 King DJ, Kelton JG. Heparin-associated thrombocytopenia.. Ann Intern Med 1984; 100: 535-40.
4 Warkentin TE, Kelton JC. Heparin-induced thrombocytopenia.. Annu Rev Med 1989; 40: 31-44.
5 Chong BH. Heparin-induced thrombocytopenia.. Br J Haematol 1995; 89: 431-9.
6 Trowbridge AA, Caraveo J, Green JB, Amaral B, Stone MJ. Heparin-related immune thrombocytopenia. Studies of antibody-heparin specificity.. Am J Med 1978; 65: 277-83.
7 Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation.. Lancet 1982; ii: 1246-8.
8 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: Laboratory studies.. Blood 1988; 72: 925-30.
9 Adelman B, Sobel M, Fujimura Y, Ruggeri ZM, Zimmerman TS. Heparin-associated thrombocytopenia: Observations on the mechanism of platelet aggregation.. J Lab Clin Med 1989; 113: 204-10.
10 Anderson GP. Insights into heparin-induced thrombocytopenia.. Br J Haematol 1992; 80: 504-8.
11 van de Winkel JGJ, Capel PJA. Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications.. Immunol Today 1993; 14: 215-21.
12 Cassel DL, Keller MA, Surrey S, Schwartz E, Schreiber AD, Rappaport EF, McKenzie SE. Differential expression of FcγRIIA, FcγRIIB and FcγRIIC in hematopoietic cells. Analysis of transcripts.. Molec Immun 1993; 30: 451-60.
13 Wu Z, Markovic B, Chesterman CN, Chong BH. Characterization of Fcγ receptors on human megakaryocytes.. Thromb Haemost 1996; 75: 661-7.
14 Tax WJM, Hermes FFM, Willems RW, Capel PJA, Koene RAP. Fc receptors for mouse IgG1 on human monocytes: polymorphism and role in antibody-induced T cell proliferation.. J Immunol 1984; 133: 1185-9.
15 Anderson CL, Ryan DH, Looney RJ, Leary PC. Structural polymorphism of the human monocyte 40 kilodalton Fc receptor for IgG.. J Immunol 1987; 138: 2254-6.
16 Ceuppens JL, Van Vaeck F. Direct demonstration of binding of anti-leu 4 antibody to the 40 kDa Fc receptor on monocytes as a prerequisite for anti-leu 4-induced T cell mitogenesis.. J Immunol 1987; 139: 4067-71.
17 Bachelot C, Saffroy R, Gandrille S, Aiach M, Rendu F. Role of FcγRIIa gene polymorphism in human platelet activation by monoclonal antibodies.. Thromb Haemost 1995; 74: 1557-63.
18 Clark MR, Clarkson SB, Ory PA, Stollman N, Goldstein IM. Molecular basis for a polymorphism involving Fc receptor II on human monocytes.. J Immunol 1989; 143: 1731-4.
19 Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel PJA. Molecular basis for a polymorphism of human Fcγ receptor II (CD32).. J Exp Med 1990; 172: 19-25.
20 Tate BJ, Witort E, McKenzie IFC, Hogarth PM. Expression of the high responder/non-responder human FcγRII. Analysis by PCR and transfection into FcR COS cells.. Immunol Cell Biol 1992; 70: 79-87.
21 Warmerdam PAM, van de Winkel JGJ, Vlug A, Westerdaal NAC, Capel PJA. A single amino acid in the second Ig-like domain of the human Fcγ receptor II is critical for human IgG2 binding.. J Immunol 1991; 147: 1338-43.
22 Parren PWHI, Warmerdam PAM, Boeije LCM, Arts J, Westerdaal NAC, Vlug A, Capel PJA, Aarden LA, van de Winkel JGJ. On the interaction of the IgG subclasses with the low affinity FcγRIIa (CD32) on human monocytes, neutrophils, and platelets.. J Clin Invest 1992; 90: 1537-46.
23 Sanders LAM, van de Winkel JGJ, Rijkers GT, Voorhorst-Ogink MM, de Haas M, Capel PJA, Zegers BJM. Fcγ receptor IIa (CD32) heterogeneity in patients with recurrent bacterial respiratory tract infections.. J Infect Dis 1994; 170: 854-61.
24 Breduis RGM, Derkx BHF, Fijen CAP, de Wit TPM, de Haas M, Weening RS, van de Winkel JGJ, Out TA. Fcγ receptor IIa (CD32) polymorphism in fulminant meningococcal septic shock in children.. J Infect Dis 1994; 170: 848-53.
25 Blasini AM, Stekman IL, Leon-Ponte M, Caldera D, Rodriguez MA. Increased proportion of responders to a murine anti-CD3 monoclonal antibody of the IgG1 class in patients with systemic lupus erythematosus (SLE).. Clin Exp Immunol 1993; 94: 423-8.
26 Duits AJ, Bootsma H, Derksen RHWM, Spronk PE, Kater L, Kallenberg CGM, Capel PJA, Westerdaal NAC, Spierenburg GTH, Gmelig-Meyling FHJ, van de Winkel JGJ. Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients.. Arthr Rheumat 1995; 39: 1832-6.
27 Arepally G, McKenzie SE, Jiang XM Poncz M, Cines D. FcγRIIA H/R131 polymorphism, subclass-specific IgG anti-heparin:platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis.. Blood 1997; 89: 370-5.
28 Fratantoni JC, Pollet R, Gralnick HR. Heparin-induced thrombocytopenia: confirmation of diagnosis with in vitro methods.. Blood 1975; 45: 395-401.
29 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia.. Blood 1986; 67: 27-30.
30 Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AG, Carter CJ. Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia.. J Lab Clin Med 1984; 103: 606-12.
31 Warkentin TE, Hayward CPM, Smith CA, Kelly PM, Kelton JC. Determinants of donor platelet variability when testing for heparin-induced thrombocytopenia.. J Lab Clin Med 1992; 120: 371-9.
32 Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia.. Thromb Haemost 1993; 69: 344-50.
33 Amiral J, Bridey F, Dreyfus M, Vissac AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.. Thromb Haemost 1992; 68: 95-6.
34 Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen.. Thromb Haemost 1994; 71: 247-51.
35 Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.. J Clin Invest 1994; 93: 81-8.
36 Kelton JC, Smith CA, Warkentin TE, Hayward CPM, Denomme GA, Horsewood P. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4.. Blood 1994; 83: 3232-9.
37 Burgess JK, Lindeman R, Chesterman CN, Chong BH. Single amino acid mutation of Fcγ receptor is associated with the development of heparin-induced thrombocytopenia.. Br J Haematol 1995; 91: 761-6.
38 Brandt JT, Isenhart CE, Osborne JM, Ahmed A, Anderson CL. On the role of platelet FcγRIIa phenotype in heparin-induced thrombocytopenia.. Thromb Haemost 1995; 74: 1574-2.
39 Abo T, Tilden AB, Balch CM, Kumagai K, Troup GM, Cooper MD. Ethnic differences in the lymphocyte proliferative response induced by a murine IgG1 antibody, Leu-4, to the T3 molecule.. J Exp Med 1984; 160: 303-9.
40 Osborne JM, Chacko GW, Brandt JT, Anderson CL. Ethnic variation in frequency of an allelic polymorphism of human FcγRIIA determined with allele specific oligonucleotide probes.. J Immunol Meth 1994; 173: 207-17.
41 Amiral J, Marfaing-Koka A, Wolf M, Alessi MC, Tardy B, Boyer-Neumann C, Vissac AM, Fressinaud E, Poncz M, Meyer D. Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia.. Blood 1996; 88: 410-6.