Activation of platelets by sera containing IgG1 heparin-dependent antibodies: An explanation for the predominance of the Fc gamma RIIa ''low responder'' (his(131)) gene in patients with heparin-induced thrombocytopenia

被引:72
作者
Denomme, GA
Warkentin, TE
Horsewood, P
Sheppard, JAI
Warner, MN
Kelton, JG
机构
[1] HAMILTON HLTH SCI CORP,DEPT LAB MED,HAMILTON,ON L8L 2X2,CANADA
[2] HAMILTON HLTH SCI CORP,DEPT MED,HAMILTON,ON L8L 2X2,CANADA
[3] MCMASTER UNIV,DEPT PATHOL,HAMILTON,ON L8S 4L8,CANADA
[4] MCMASTER UNIV,DEPT MED,HAMILTON,ON L8S 4L8,CANADA
[5] HEART & STROKE FDN,OTTAWA,ON,CANADA
来源
JOURNAL OF LABORATORY AND CLINICAL MEDICINE | 1997年 / 130卷 / 03期
关键词
D O I
10.1016/S0022-2143(97)90022-6
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by heparin-dependent IgG (HIT-IgG) that recognizes a complex of heparin and platelet factor 4 (PF4), leading to platelet activation via the platelet Fc gamma IIa receptors (Fc gamma RIIa). Not all patients who generate HIT-IgG in response to heparin develop HIT, however, possibly because of observed differences in the ability of platelets from healthy individuals to be activated by HIT sera. It is known that a polymorphism in the platelet Fc gamma RIIa plays an important role in determining platelet reactivity to murine platelet-activating monoclonal antibodies of the IgG1 subclass: homozygous arg(131) (''high responder'' or HR) platelets respond well, and homozygous his(131) (''low responder'' or LR) platelets respond poorly, respectively, to these murine monoclonal antibodies. We sought to determine whether the differing risk for HIT among patients who receive heparin, as well as the variable platelet reactivity to HIT sera, could be explained by preferential activation by HIT-IgG of platelets bearing a particular Fc gamma RIIa phenotype. We found that the LR Fc gamma RIIa gene frequency was significantly overrepresented among 84 HIT patients, compared with that of 264 control subjects (0.565 versus 0.471; p = 0.03). We studied the subclass distribution of HIT-IgG against its major antigen, heparin/PF4 complexes, and found that 55 of 61 (90%) HIT sera expressed IgG1 antibodies either alone (n = 47) or in combination with IgG2 (n = 5) or IgQ (n = 3). We then compared the platelet-activating profile of HIT sera with murine platelet-activating monoclonal antibodies. As expected, the murine IgG1 monoclonal antibodies preferentially activated platelets from homozygous HR individuals. In contrast, however, the LR homozygous platelets exhibited the greatest reactivity to HIT sera that contained predominantly anti-heparin/PF4 antibodies of the IgG1 subclass. We conclude that the significant overrepresentation of the LR (his(131)) gene among patients with HIT may be explained by the preferential activation of LR Fc gamma RIIa platelets by HIT antibodies of the IgG1 subclass, which is the predominant immunoglobulin subclass generated in HIT.
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收藏
页码:278 / 284
页数:7
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