On the Role of Platelet FcγRIIa Phenotype in Heparin-Induced Thrombocytopenia

John T Brandt; Craig E Isenhart; Jeanne M Osborne; Alaa Ahmed; Clark L Anderson

doi:10.1055/s-0038-1649983

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 74(06): 1564-1572
DOI: 10.1055/s-0038-1649983

Original Articles

platelets

Schattauer GmbH Stuttgart

On the Role of Platelet FcγRIIa Phenotype in Heparin-Induced Thrombocytopenia

Authors

John T Brandt

¹The Department of Pathology, The Ohio State University, Columbus, Ohio, USA
Craig E Isenhart

¹The Department of Pathology, The Ohio State University, Columbus, Ohio, USA
Jeanne M Osborne

²The Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA
Alaa Ahmed

²The Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA
Clark L Anderson

²The Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

Abstract

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Summary

Heparin induced thrombocytopenia (HIT) is characterized by the formation of antibodies that activate normal donor platelets in vitro in the presence of heparin. We asked whether the commonly observed donor-specific variation in the platelet aggregation response to HIT antibodies is influenced by the density of FcγRII on platelets or by the Arg/His 131 allelic polymorphism of platelet FcγRII. We found that platelets with the His/Hisl31 FcγRII phenotype were unresponsive to HIT antibody (0/9) whereas platelets with the Arg/Argl31 phenotype responded well (7/9). His/Hisl31 platelets were largely unresponsive also to a murine IgG₁ antiplatelet monoclonal antibody (UR1) known to activate platelets by FcγRII clustering. We then determined the frequency distribution of FcγRIIa Arg/His 131 phenotypes on a series of 200 patients evaluated for HIT and 100 non-thrombocytopenic hospitalized patients. The frequency of the His/Hisl31 phenotype was significantly increased (34.4%) in the 96 thrombocytopenic patients with HIT antibody compared to the 104 thrombocytopenic patients without HIT antibody and the 100 non-thrombocytopenic patients (∼19%). Thus, the FcγRII phenotype regulates the in vitro activation response of normal platelets to HIT antibody and is a risk factor for the thrombocytopenia of HIT

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References

References
1 Ansell J, Deykin D. Heparin-induccd thrombocytopenia and recurrent thromboembolism. Am J Hematol 1980; 8: 325-332
2 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. In: Progress in Hemostasis and Thrombosis Vol 10. Coller BS. (ed) Philadelphia: W. B. Saunders; 1991. pp 1-34
3 Chong BH. Heparin-induced thrombocytopenia. Aust NZ J Med 1992; 22: 145-152
4 Kelton JG, Sheridan D, Santos A, Smith J, Steeves K, Smith C, Brown C, Murphy WG. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-930
5 Chong BH, Castaldi PA, Berndt MC. Heparin-induced thrombocytopenia: effects of rabbit IgG, and its Fab and Fc fragments on antibody-heparin-platelet interaction. Thromb Res 1989; 55: 291-295
6 Chong BH, Ismail F, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-240
7 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
8 Babcock RB, Dumper CW, Scharfman WB. Heparin-induced immune thrombocytopenia. N Engl J Med 1976; 295: 237-241
9 Fratantoni JC, Pollet R, Gralnick HR. Heparin-induced thrombocytopenia: confirmation of diagnosis with in vitro methods. Blood 1975; 45: 395-401
10 Salem HH, van der Weyden MB. Heparin induced thrombocytopenia. Variable platelet-rich plasma reactivity to heparin dependent aggregating factor Pathology 1983; 15: 297-299
11 Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AG, Carter CJ. Clinical usefulness of testing for a heparin-dependent platelet aggregating factor on patients with suspected heparin-associated thrombocytopenia. J Lab Clin Med 1984; 103: 606-612
12 Warkentin TE, Hayward CP M, Smith CA, Kelly PM, Kelton JG. Determinants of donor variability when testing for heparin-induced thrombocytopenia. J Lab Clin Med 1992; 120: 371-379
13 Gruel Y, Rupin A, Darnige L, Moalic-Reverdiau P, Poumier-Gaschard P, Binet C, Bardos P, Leroy J. Specific quantification of heparin-dependent antibodies for the diagnosis of heparin-associated thrombocytopenia using an enzyme-linked immunosorbent assay. Thromb Res 1991; 62: 377-387
14 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: 344-350
15 Isenhart CE, Brandt JT. Platelet aggregation studies for the diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol 1993; 99: 324-330
16 Greinacher A, Mueller-Eckhardt G. Heparin-associated thrombocytopenia: no association of immune response with HLA. Vox Sang 1993; 65: 151-153
17 van de Winkle JG J, Anderson CL. Biology of human immunoglobulin G Fc receptors. J Leukocyte Biol 1991; 49: 511-524
18 Warmerdam PA M, van de Winkel JG J, Gosselin EJ, Capel PJ A. Molecular basis for a polymorphism of human Fcγ receptor II (CD32). J Exp Med 1990; 172: 19-25
19 Clark MR, Stuart SG, Kimberly RP, Ory PA, Goldstein IM. A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes. Eur J Immunol 1991; 21: 1911-1916
20 Warmerdam PA M, van de Winkel JG J, Vlug A, Westerdaal NA C, Capel PJ A. A single amino acid in the second Ig-like domain of the human Fcγ receptor II is critical for human IgG₂binding. J Immunol 1991; 147: 1338-1343
21 Tax WJ M, Willems HW, Reekcrs PP M, Capel PJ A, Koene RA P. Polymorphism in mitogenic effect of IgG, monoclonal antibodies against T3 antigen on human T cells. Nature 1983; 304: 445-447
22 Tax WJ M, Hermus FF M, Willems II W, Cappel PJ A, Koene RA P. Fc receptors for mouse IgG, on human monocytes: polymorphism and role in antibody-induced T cell proliferation. J Immunol 1984; 133: 1185-1189
23 van de Winkel JG J, Fax WJ M, van Bruggen MC J, van Roozendaal CE P, Willems HW, Vlug A, Capel PJ A, Koene RA P. Characterization of two Fc receptors for mouse immunoglobulins on human monocytes and cell lines. Scand J Immunol 1987; 26: 663-672
24 Anderson CL, Ryan DH, Looney RI, Leary PC. Structural polymorphism of the human monocyte 40 kd Fc receptor for IgG. J Immunol 1987; 138: 2254-2256
25 Looney RJ, Anderson CL, Ryan DH, Rosenfeld SI. Structural polymorphism in the human platelet Fcγ receptor. J Immunol 1988; 141: 2680-2683
26 Tomiyama Y, Kunicki TJ, Zipf TF, Ford SB, Aster RH. Response of human platelets to activating monoclonal antibodies: importance of FcγRII (CD32) phenotype and level of expression. Blood 1992; 80: 2261-2268
27 Parren PW H I, Warmerdam PA M, Boeije LC M, Capel PJ A, van de Winkle JG J, Aarden LA. Characterization of IgG FcR-mediated proliferation of human T cells induced by mouse and human anti-CD3 monoclonal antibodies. Identification of a functional polymorphism to human IgG₂, anti- CTO J Immunol 1992; 148: 695-701
28 Salmon JE, Edberg JC, Brogle NL, Kimberly RP. Allelic polymorphisms of human Fcγ Receptor IIA and Fcγ Receptor IIIB; independent mechanisms for differences in human phagocyte function. J Clin Invest 1992; 89: 1274-1281
29 Parren PW H I, Warmerdam PA M, Boeije LC M, Arts J, Westerdaal NA C, Vlug A, Capel PJ A, Aarden LA, van de Winkel JG J. On the interactions of IgG subclasses with the low affinity FcγRIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG₂ J Clin Invest 1992; 90: 1537-1546
30 Anderson GP, van de Winkle JG J, Anderson CL. Anti-GPIIb/IIIa (CD41) monoclonal antibody-induced platelet activation requires Fc receptordependentcell-cell interaction. Br J Haematol 1991; 79: 75-83
31 Marti GE, Magruder L, Schuette WE, Gralnick HR. Flow cytometric analysis of platelet surface antigens. Cytometry 1988; 9: 448-455
32 Gosselin EJ, Brown MF, Anderson CL, Zipf TF, Guyre PM. The monoclonal antibody 41H16 detects the Leu4 responder form of human FcγRII. J Immunol 1990; 144: 1817-1822
33 Markwell MA K, Fox CF. Surface specific iodination of membrane proteins of viruses and eukaryotic cells using 1,3,4,6 tetrachloro 3,6 diphenylgly- colauril. Biochemistry 1978; 17: 4807-4817
34 Scatchard G. The attraction of proteins for small molecules and ions. Ann NY AcadSci 1949; 51: 660-672
35 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 Methods 1994; 173: 207-217
36 Bell GI, Karam JH, Rutter WJ. Polymorphic DNA region adjacent to the 5’ end of the human insulin gene. Proc Natl Acad Sci USA 1981; 78: 5759-5763
37 Anderson GP, Anderson CL. Signal transduction by the platelet Fc receptor. Blood 1990; 76: 1165-1172
38 Horsewood P, Hayward CP M, Warkentin TE, Kelton JG. Investigation of the mechanisms of monoclonal antibody-induced platelet activation. Blood 1991; 78: 1019-1026
39 Bredius RG M, de Vries CE E, Troelstra A, van Alphen L, Weening RS, van de Winkel JG J, Out TA. Phagocytosis of Staphylococcus aureus and Haemophilus influenzae type B opsonized with polyclonal human IgG₁ and IgG₂antibodies. Functional hFcγRIIa polymorphism to IgG₂ J Immunol 1993; 151: 1463-1472
40 Hulett MD, Witort E, Brinkworth RI, McKenzie IF C, Hogarth PM. Identification of the IgG binding site of the human low affinity receptor for IgG FcγRII. J Biol Chem 1994; 269: 15287-15293
41 McCrae KR, Shattil SJ, Cines DB. Platelet activation induces increased Fcy receptor expression. J Immunol 1990; 144: 3920-3927
42 Chong BH, Pilgrim RL, Cooley MA, Chesterman CN. Increased expression of platelet IgG Fc receptors in immune heparin-induced thrombocytopenia. Blood 1993; 81: 988-993
43 Warkentin TE, Hayward CP M, Boshkov LK, Santos AV, Sheppard J-AI, Bode AP, Kelton JG. Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity; an explanation for the thrombotic complications of heparin-induced ’ thrombocytopenia. Blood 1994; 84: 3691-3699
44 Boshkov LK, Warkentin TE, Hayward CP M, Andrew M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993; 84: 322-328
45 Fijen CA P, Bredius RG M, Kuijper EJ. Polymorphism of IgG Fc receptors in meningococcal disease: risk marker in complement deficient patients. Ann Intern Med 1993; 119: 636
46 Bredius RG M, Derkx BH F, Fijen CA P, de Wit TP M, de Haas M, Weening RS, van de Winkel JG J, Out TA. Fcy receptor Ha (CD32) polymorphism in fulminant meningococcal septic shock in children. J Infect Dis 1994; 170: 848-853
47 Sanders EA, van de Winkel JG J, Feldman RG, Voorhorst-Ogink MM, Rijkers GT, Capel PJ A, Zegers BJ. Fc gamma IIA receptor phenotype and opsonophagocytosis in two patients with recurrent bacterial infections. Immunodeficiency 1993; 4: 163-165
48 Gmella-Meyling FH J, Bootsma H, Derksen RH W M, Spronk PE, Kater L, Kallenberg CG M, Capel PJ A, van de Winkle JG J, Duits AJ. IgG Fc receptor Ha (CD32) polymorphism in SLE: skewed allotype distribution among patients with renal disease. Arthr Rheumat 1994; 37 (Suppl) S167 (abstract)
49 Blasini AM, Stekman IL, Leon-Ponte M, Caldera D, Rodriguez MA. Increased proportion of responders to a murine anti-CD3 monoclonal antibody of the IgG₁class in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 1993; 94: 423-428
50 Salmon JE, Millard SS, Arnett FC, Ramsey-Goldman R, McKenzie S, Reilly A, Kimberly RP. FcγRIIa is a non-MHC heritable risk factor for SLE in African-Americans. Arthr Rheumat 1994; 37 (Suppl) S167 (abstract)