Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

Jérôme Rollin; Claire Pouplard; Yves Gruel

doi:10.1160/TH16-02-0109

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(05): 799-805
DOI: 10.1160/TH16-02-0109

Theme Issue Article

Schattauer GmbH

Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

Jérôme Rollin

¹Service d’Hématologie-Hémostase, Hôpital Trousseau, CHU de Tours, Tours Cedex, France

²UMR CNRS 7292 et Université François Rabelais, Tours, France

,

Claire Pouplard

¹Service d’Hématologie-Hémostase, Hôpital Trousseau, CHU de Tours, Tours Cedex, France

²UMR CNRS 7292 et Université François Rabelais, Tours, France

,

Yves Gruel

¹Service d’Hématologie-Hémostase, Hôpital Trousseau, CHU de Tours, Tours Cedex, France

²UMR CNRS 7292 et Université François Rabelais, Tours, France

› Author Affiliations

Abstract

Summary

Fcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

Keywords

Heparin - thrombocytopenia - Fcγ receptors - gene polymorphisms

Full Text

References

References
1 Bruhns P, Jonsson F. Mouse and human FcR effector functions. Immunol Rev 2015; 268: 25-51.
2 Brandsma AM. et al. Fc receptor inside-out signaling and possible impact on antibody therapy. Immunol Rev 2015; 268: 74-87.
3 Lu J, Sun PD. Structural mechanism of high affinity FcgammaRI recognition of immunoglobulin G. Immunol Rev 2015; 268: 192-200.
4 Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol 2007; 96: 179-204.
5 Clark MR. et al. Molecular basis for a polymorphism involving Fc receptor II on human monocytes. J Immunol 1989; 143: 1731-1734.
6 Ramsland PA. et al. Structural basis for Fc gammaRIIa recognition of human IgG and formation of inflammatory signaling complexes. J Immunol 2011; 187: 3208-3217.
7 Beppler J. et al. Fc Gamma receptor IIA (CD32A) R131 polymorphism as a marker of genetic susceptibility to sepsis. Inflammation 2016; 39: 518-525.
8 Bruhns P. et al. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 2009; 113: 3716-3725.
9 Dall’Ozzo S. et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res 2004; 64: 4664-4669.
10 Ternant D. et al. Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn’s Disease. Clin Pharmacokinet 2015; 54: 551-562.
11 Kelton J. et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-930.
12 Chong B. et al. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-240.
13 Reilly MP. et al. Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA. Blood 2001; 98: 2442-2447.
14 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: 4254-4260.
15 Chong B. et al. Increased expression of platelet IgG Fc receptors in immune he-parin-induced thrombocytopenia. Blood 1993; 81: 988-993.
16 Gratacap MP. et al. Phosphatidylinositol 3,4,5-trisphosphate-dependent stimulation of phospholipase C-gamma2 is an early key event in FcgammaRIIA-me-diated activation of human platelets. J Biol Chem 1998; 273: 24314-24321.
17 Yanaga F, Poole A, Asselin J. et al. Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc gamma-IIA receptor. Biochem J 1995; 311: 471-478.
18 Polgar J. et al. Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients. Blood 1998; 91: 549-554.
19 Gratacap MP. et al. FcgammaRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation. Blood 2000; 96: 3439-3446.
20 Canobbio I. et al. Platelet activation by von Willebrand factor requires coordinated signaling through thromboxane A2 and Fc gamma IIA receptor. J Biol Chem 2001; 276: 26022-26029.
21 Canobbio I. et al. A new role for FcgammaRIIA in the potentiation of human platelet activation induced by weak stimulation. Cell Signal 2006; 18: 861-870.
22 Boylan B. et al. Identification of FcgammaRIIa as the ITAM-bearing receptor mediating alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 2008; 112: 2780-2786.
23 Zhi H. et al. Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 2013; 121: 1858-1867.
24 Gardiner EE. et al. Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: de-ITAM-izing FcgammaRIIa. Blood 2008; 111: 165-174.
25 Nazi I. et al. The association between platelet activation and FcgammaRIIa pro-teolysis. J Thromb Haemost 2011; 09: 885-887.
26 Nazi I. et al. FcgammaRIIa proteolysis as a diagnostic biomarker for heparin-in-duced thrombocytopenia. J Thromb Haemost 2013; 11: 1146-1153.
27 Qiao J. et al. The platelet Fc receptor, FcgammaRIIa. Immunol Rev 2015; 268: 241-252.
28 Senis YA. et al. The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis. Blood 2009; 113: 4942-4954.
29 Mancini F. et al. The low-molecular-weight phosphotyrosine phosphatase is a negative regulator of FcgammaRIIA-mediated cell activation. Blood 2007; 110: 1871-1878.
30 Ragab A. et al. The tyrosine phosphatase 1B regulates linker for activation of T-cell phosphorylation and platelet aggregation upon FcgammaRIIa cross-linking. J Biol Chem 2003; 278: 40923-40932.
31 Pasquet JM. et al. Evidence of a role for SHP-1 in platelet activation by the collagen receptor glycoprotein VI. J Biol Chem 2000; 275: 28526-28531.
32 Weng Z. et al. PTEN regulates collagen-induced platelet activation. Blood 2010; 116: 2579-2581.
33 Thomas DH. et al. A novel histidine tyrosine phosphatase, TULA-2, associates with Syk and negatively regulates GPVI signaling in platelets. Blood 2010; 116: 2570-2578.
34 Zhou Y. et al. Anti-miR-148a regulates platelet FcgammaRIIA signaling and decreases thrombosis in vivo in mice. Blood 2015; 126: 2871-2881.
35 Yeung J. et al. Platelet 12-LOX is essential for FcgammaRIIa-mediated platelet activation. Blood 2014; 124: 2271-2279.
36 Senis YA. et al. A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b–B, a novel immunoreceptor tyrosine-based inhibitory motif protein. Mol Cell Proteomics 2007; 06: 548-564.
37 Thai le M. et al. Physical proximity and functional interplay of PECAM-1 with the Fc receptor Fc gamma RIIa on the platelet plasma membrane. Blood 2003; 102: 3637-3645.
38 Mori J. et al. G6b–B inhibits constitutive and agonist-induced signaling by glyco-protein VI and CLEC-2. J Biol Chem 2008; 283: 35419-35427.
39 Warkentin T. et al. 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.
40 Hughes M. et al. Morphological analysis of microparticle generation in heparin-induced thrombocytopenia. Blood 2000; 96: 188-194.
41 Cines D. et al. Immune endothelial-cell injury in heparin-associated throm-bocytopenia. N Engl J Med 1987; 316: 581-589.
42 Pouplard C. et al. Induction of monocyte tissue factor expression by antibodies to heparin- platelet factor 4 complexes developed in heparin-induced throm-bocytopenia. Blood 2001; 97: 3300-3302.
43 Arepally GM, Mayer IM. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8. Blood 2001; 98: 1252-1254.
44 Xiao Z. et al. Immune complexes formed following the binding of anti-platelet factor 4 (CXCL4) antibodies to CXCL4 stimulate human neutrophil activation and cell adhesion. Blood 2008; 112: 1091-1100.
45 Rauova L. et al. Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood 2010; 116: 5021-5031.
46 Kasthuri RS. et al. PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcgammaRI. Blood 2012; 119: 5285-5293.
47 Tutwiler V. et al. Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia. Blood 2016; 127: 464-472.
48 Khairy M. et al. Polymorphonuclear leukocyte and monocyte activation induced by plasma from patients with heparin-induced thrombocytopenia in whole blood. Thromb Haemost 2004; 92: 1411-1419.
49 Khairy M. et al. A new approach in the study of the molecular and cellular events implicated in heparin-induced thrombocytopenia. Formation of leukocyte-platelet aggregates. Thromb Haemost 2001; 85: 1090-1096.
50 Blank M. et al. Anti-platelet factor 4/heparin antibodies from patients with he-parin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002; 14: 121-129.
51 Clynes R, Ravetch JV. Cytotoxic antibodies trigger inflammation through Fc receptors. Immunity 1995; 03: 21-26.
52 Mancardi DA. et al. The high-affinity human IgG receptor FcgammaRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immuno-therapy. Blood 2013; 121: 1563-1573.
53 McKenzie SE. et al. The role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model. J Immunol 1999; 162: 4311-4318.
54 Huang ZY. et al. Human platelet FcgammaRIIA and phagocytes in immune-complex clearance. Mol Immunol 2011; 48: 691-696.
55 Clarkson SB. et al. Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N Engl J Med 1986; 314: 1236-1239.
56 Soubrane C. et al. Biologic response to anti-CD16 monoclonal antibody therapy in a human immunodeficiency virus-related immune thrombocytopenic pur-pura patient. Blood 1993; 81: 15-19.
57 Lu J. et al. Structural recognition and functional activation of FcgammaR by innate pentraxins. Nature 2008; 456: 989-992.
58 Stein MP. et al. C-reactive protein binding to FcgammaRIIa on human mono-cytes and neutrophils is allele-specific. J Clin Invest 2000; 105: 369-376.
59 Marjon KD. et al. Macrophages activated by C-reactive protein through Fc gamma RI transfer suppression of immune thrombocytopenia. J Immunol 2009; 182: 1397-1403.
60 Kapur R. et al. C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia. Blood 2015; 125: 1793-1802.
61 Trikalinos TA. et al. Meta-analysis of the association between low-affinity Fcgamma receptor gene polymorphisms and hematologic and autoimmune disease. Blood 2001; 98: 1634-1635.
62 Rollin J. et al. Increased risk of thrombosis in FcgammaRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2. Blood 2015; 125: 2397-2404.
63 Carlsson LE. et al. Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism. Blood 1998; 92: 1526-1531.
64 Scaparro P. et al. Heparin-induced thrombocytopenia: The role of platelets genetic polymorphisms. Platelets 2013; 24: 362-365.
65 Winder A. et al. High-dose intravenous gamma-globulins for heparin-induced thrombocytopenia: A prompt response. J Clin Immunol 1998; 18: 330-334.
66 Ben Mkaddem S. et al. Shifting FcgammaRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. J Clin Invest 2014; 124: 3945-3959.
67 Zwicker JI. et al. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost 2004; 02: 2133-2137.
68 Lee GM, Arepally GM. Diagnosis and management of heparin-induced throm-bocytopenia. Hematol Oncol Clin North Am 2013; 27: 541-563.
69 Greinacher A. et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94: 132-135.
70 Ellison S. et al. CD148 enhances platelet responsiveness to collagen by maintaining a pool of active Src family kinases. J Thromb Haemost 2010; 08: 1575-1583.
71 Rollin J. et al. Polymorphisms of protein tyrosine phosphatase CD148 influence FcgammaRIIA-dependent platelet activation and the risk of heparin-induced thrombocytopenia. Blood 2012; 120: 1309-1316.
72 Arepally G. et al. Fc gamma RIIA H/R(131) polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 1997; 89: 370-375.
73 Pouplard C. et al. Differences in specificity of heparin-dependent antibodies developed in heparin-induced thrombocytopenia and consequences on cross-reactivity with danaparoid sodium. Br J Haematol 1997; 99: 273-280.
74 Gruel Y. et al. The homozygous FcgammaRIIIa-158V genotype is a risk factor for heparin-induced thrombocytopenia in patients with antibodies to heparin-platelet factor 4 complexes. Blood 2004; 104: 2791-2793.
75 Papagianni A. et al. FcγRIIa and FcγRIIIa polymorphisms in childhood primary immune thrombocytopenia: implications for disease pathogenesis and outcome. Blood Coagul Fibrinolysis 2013; 24: 35-39.
76 Carcao MD. et al. Fcγ receptor IIa and IIIa polymorphisms in childhood immune thrombocytopenic purpura. Br J Haematol 2003; 120: 135-141.
77 Meyer T. et al. CD32a antibodies induce thrombocytopenia and type II hyper-sensitivity reactions in FCGR2A mice. Blood 2015; 126: 2230-2238.
78 Gratacap MP. et al. The new tyrosine-kinase inhibitor and anticancer drug da-satinib reversibly affects platelet activation in vitro and in vivo. Blood 2009; 114: 1884-1892.
79 Reilly MP. et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood 2011; 117: 2241-2246.
80 Lhermusier T. et al. The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies. J Thromb Haemost 2011; 09: 2067-2076.
81 Bachelot-Loza C. et al. Importance of the FcγRIIa-Arg/His-131 polymorphism in heparin-induced thrombocytopenia diagnosis. Thromb Haemost 1998; 79: 523-528.