The FcγRIIa polymorphism R/H131, autoantibodies against the platelet receptors GPIbα and FcγRIIa and a risk for thromboembolism in lupus anticoagulant patients

Katharina Schallmoser; Christiane Rosin; Regina Knittelfelder; Thomas Sailer; Silvia Ulrich; Claudia Zoghlami; Stephan Lehr; Ingrid Pabinger; Simon Panzer

doi:10.1160/TH04-07-0428

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(03): 544-548
DOI: 10.1160/TH04-07-0428

Platelets and Blood Cells

Schattauer GmbH

The FcγRIIa polymorphism R/H131, autoantibodies against the platelet receptors GPIbα and FcγRIIa and a risk for thromboembolism in lupus anticoagulant patients

Autoren

Katharina Schallmoser

¹Clinic for Blood Group Serology, Medical University of Vienna

²Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Graz
Christiane Rosin

¹Clinic for Blood Group Serology, Medical University of Vienna
Regina Knittelfelder

¹Clinic for Blood Group Serology, Medical University of Vienna
Thomas Sailer

³Department of Internal Medicine, Division of Haematology and Haemostaseology
Silvia Ulrich

²Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Graz
Claudia Zoghlami

³Department of Internal Medicine, Division of Haematology and Haemostaseology
Stephan Lehr

⁴Department of Medical Computer Sciences – Clinical Biometrics, Medical University Vienna, Austria
Ingrid Pabinger

³Department of Internal Medicine, Division of Haematology and Haemostaseology
Simon Panzer

¹Clinic for Blood Group Serology, Medical University of Vienna

Abstract

Summary

There is a clear propensity of individuals with lupus anticoagulant (LA) for thromboembolic disease (TE). Yet, it is not clear how individuals at risk for TE can be differentiated from those who are not. The FcγRIIa receptor is the only Fc receptor expressed by platelets. As platelets can be activated via this receptor, we have compared gene frequencies of the FcγRIIa polymorphism R/H131 in 46 and 27 patients with (LA/TE+) and without TE (LA/TE-), respectively, in an exploratory study. Furthermore, we investigated the presence of autoantibodies against FcγRIIa and/or GPIbα, which is in close proximity to the FcγRIIa and interacts with it functionally, and a possible linkage of antibody formation to HLA class II alleles. The FcγRIIa-R/R131 genotype was significantly less frequent in patients with LA compared to controls (p< 0.025). These findings were due to an increased frequency of heterozygous patients in the LA/TE+ cohort (odds ratio 6.76, 95% confidence interval 1.55 – 62.03, p< 0.008). For the first time, heterozygosity, rather than homozygosity, can be linked to disease, which may be explained by the dual function of the FcγRIIa, namely binding of antibodies to platelets and thereby their activation, and, on the other hand, clearance of antibody coated platelets by the phagocyte system. There was no correlation between the presence of anti-FcγRIIa or anti GPIbα autoantibodies and the FcγRIIa -R/H131 polymorphism, nor the incidence of TE, nor HLA class II alleles.

Keywords

Lupus anticoagulant - FcγRIIa receptor - GPIbα - thromboembolic disease

Volltext

Referenzen

References
1 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112: 682-98.
2 Levine JS. et al. The anti-phospholipid syndrome. N Engl J Med 2002; 346: 752-63.
3 Joseph JE, Harrison P, Mackie IJ. et al. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001; 115: 451-9.
4 Cassel DL, Keller MA, Surrey S. et al. Differential expression of Fc gamma RIIA, Fc gamma RIIB and Fc gamma RIIC in hematopoietic cells: analysis of transcripts. Mol Immunol 1993; 30: 451-60.
5 Sullam PM. et al. Physical proximity and functional interplay of the glycoprotein Ib-IX-V complex and the Fc receptor Fcγ RIIA on the platelet plasma membrane. J Biol Chem 1998; 273: 5331-6.
6 Clark MR, Clarkson SB, Ory PA. et al. Molecular Basis for a Polymorphism Involving Fc Receptor II on Human Monocytes. J Immunol 1989; 143: 1731-4.
7 Warmerdam PA, Van de Winkel JGJ, Gosselin EJ. et al. Molecular basis for a polymorphism of human Fcγ receptor II (CD32). J Exp Med 1990; 172: 19-25.
8 Warmerdam PA, Van de Winkel JG, Vlug A. et al. 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.
9 Parren PW, Warmerdam PA, Boeije LC. et al. On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 1992; 90: 1537-46.
10 Sammaritano LR. et al. Anticardiolipin IgG Subclasses. Arthritis Rheum 1997; 40: 1998-2006.
11 Out HJ, de Groot PG, van Vliet M. et al. Antibodies to platelets in patients with anti-phospholipid antibodies. Blood 1991; 77: 2655-9.
12 Fabris F. et al. Specific antiplatelet autoantibodies in patients with antiphospholipid antibodies and thrombocytopenia. Eur J Haematol 1994; 53: 232-6.
13 Galli M. et al. Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1994; 71: 571-5.
14 Panzer S, Pabinger I, Gschwandtner ME. et al. Lupus anticoagulants: strong association with the major histocompatibility complex class II and platelet antibodies. Br J Haematol 1997; 98: 342-5.
15 Panzer S, Gschwandtner ME, Hütter D. et al. Specificities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome. Ann Hematol 1997; 74: 239-42.
16 Niessner H, Clemetson KJ, Panzer S. et al. Acquired thrombasthenia due to GPIIb/IIIa-specific platelet autoantibodies. Blood 1986; 68: 571-76.
17 Olsson A, Andersson PO, Tengborn L. et al. Serum from patients with chronic idiopathic thrombocytopenic purpura frequently affect the platelet function. Thromb Res 2002; 15 107: 135-9.
18 Kekomaki R. Platelet function and immune response. J Pediatr Hematol Oncol 2003; 25: 19-23.
19 Boylan B, Chen H, Rathore V. et al. Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRγ - chain complex from the human platelet surface. Blood 2004; 104: 1350-55.
20 Canobbio I, Bertoni A, Lova P. et al. Platelet activation by von Willebrand factor requires coordinated signaling through thromboxane A2 and Fc gamma IIA receptor. J Biol Chem 2001; 276: 26022-9.
21 Cauwenberghs N. et al. Fc-receptor dependent platelet aggregation induced by monoclonal antibodies against platelet glycoprotein Ib or von Willebrand factor. Thromb Haemost 2001; 85: 679-85.
22 Brandt JT, Triplett DA, Alving B. et al. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/ Antiphospholipid Antibody of the SSC of the ISTH. Thromb Haemost 1995; 74: 1185-90.
23 Wenzel C, Stoiser B, Locker GJ. et al. Frequent development of lupus anticoagulants in critically ill patients treated under intensive care conditions. Crit Care Med 2002; 30: 763-70.
24 Carlsson LE. et al. Heparin-induced thrombocytopenia: new insights into the impact of the Fc γ RIIa- R-H131 polymorphism. Blood 1998; 92: 1526-31.
25 Flesch BK, Bauer F, Neppert J. Rapid typing of the human Fc gamma receptor IIA polymorphism by polymerase chain reaction amplification with allelespecific primers. Transfusion 1998; 38: 174-76.
26 Kiefel V, Santoso S, Weisheit M. et al. Monoclonal antibody-specific immobilization of platelet antigens (MAIPA): a new tool for the identification of plateletreactive antibodies. Blood 1987; 70: 1722-6.
27 Fischer GF, Faé I, Pickl WF. Distribution of polymorphic HLA-DR and –DQ alleles as determined by restriction fragment length polymorphism analysis in an Austrian population. Vox Sang 1992; 62: 236-41.
28 De Haas M. IgG-Fc receptors and the clinical relevance of their polymorphisms. Wien Klin Wochenschr 2001; 113: 825-31.
29 Macchi L, Rispal P, Clofent-Sanchez G. et al. Antiplatelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia. Br J Haematol 1997; 98: 336-41.
30 Arnett FC. et al. Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups. Arthritis Rheum 1999; 42: 268-74.
31 Bertolaccini ML. et al. Association of antiphosphatidylserine/ prothrombin autoantibodies with HLA class II genes. Arthritis Rheum 2000; 43: 683-8.
32 Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin- induced thrombocytopenia. Thromb Haemost 1996; 75: 536-41.
33 Taylor SM. et al. Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor. Blood 2000; 96: 4254-60.
34 Duits AJ. et al. Skewed distribution of IgG Fc Receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995; 39: 1832-6.
35 Salmon JE, Millard S. et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996; 97: 1348-54.
36 Kiefel V, Spaeth P, Mueller-Eckhardt C. Immune thrombocytopenic purpura: autoimmune or immune complex disease?. Br J Haematol 1986; 64: 57-68.
37 Karassa FB, Bijl M, Davies KA. et al. Role of the Fcgamma receptor IIA polymorphism in the antiphospholipid syndrome: an international meta-analysis. Arthritis Rheum 2003; 48: 1930-8.
38 Blasini AM. et al. 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.
39 Rascu A. et al. Clinical relevance of Fcγ receptor polymorphisms. Ann NY Acad Sci 1997; 815: 282-95.
40 Miescher S, Spycher MO, Amstutz H. et al. A single recombinant anti-RhD IgG prevents RhD immunization: association of RhD-positive red blood cell clearance rate with polymorphisms in the Fc γ RIIA and Fcγ IIIA genes. Blood, 2004; 103: 4028-35.
41 Carcao MD. et al. Fcγ receptor IIa and IIIa polymorphisms in childhood immune thrombocytopenic purpura. Br J Haematol 2003; 120: 135-41.