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Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin‐induced thrombocytopenia
Author(s) -
Nazy I.,
Clare R.,
Staibano P.,
Warkentin T. E.,
Larché M.,
Moore J. C.,
Smith J. W.,
Whitlock R. P.,
Kelton J. G.,
Arnold D. M.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14132
Subject(s) - platelet factor 4 , heparin , heparin induced thrombocytopenia , platelet , platelet activation , medicine , immune system , immunology , peripheral blood mononuclear cell , cd14 , growth factor , pharmacology , chemistry , biochemistry , receptor , in vitro
SummaryEssentials The immunogenesis of Heparin‐induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)‐heparin occurs early in life, before any heparin exposure. PF4 and PF4‐heparin complexes induce the proliferation of CD14 + cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT.Summary Background Heparin‐induced thrombocytopenia ( HIT ) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 ( PF 4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF 4–heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF 4–heparin complexes in patients with HIT . Patients/Methods Peripheral blood mononuclear cells ( PBMC s) from healthy controls ( n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass ( CPB ) ( n = 17) and patients with confirmed HIT ( n = 41) were cultured with PF 4 and PF 4–heparin complexes. Cellular proliferation was assessed by [ 3 H]thymidine uptake and 5‐ethynyl‐2′‐deoxyuridine detection. Results and Conclusions PBMC s proliferated in the presence of PF 4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen‐specific, depended on the presence of platelets, and only CD 14 + cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin‐10 and transforming growth factor‐β1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF 4–heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT .