The unique immunological features of heparin‐induced thrombocytopenia

Abstract

Heparin-induced thrombocytopenia (HIT) is a serious drug reaction that leads to a decrease in platelet count and a high risk of thrombosis. HIT patients produce pathogenic immunoglobulin G (IgG) antibodies that bind to complexes of platelet factor-4 (PF4) and heparin. HIT immune complexes crosslink Fc-receptors resulting in platelet and monocyte activation. These events lead to the release of procoagulant chemokines and tissue factor, which together create an intensely prothrombotic state. HIT represents an atypical immune response because it has features of both T cell-dependent and T cell-independent mechanisms. The disorder is characterized by newly formed anti-PF4/heparin IgG antibodies, which are characteristic of a T cell-dependent mechanism; however, re-exposure to heparin, months after HIT, does not lead to a memory response, which is consistent with a T cell-independent mechanism. In this review, we discuss the immunobiological events that can explain these features, including the role for T cell-dependent and T cell-independent mechanisms in HIT antibody generation, the immunogenic characteristics of the PF4/heparin antigen, and the concept of a temporary loss in immune regulation contributing to the onset of HIT. We also present a novel immunobiological model to explain the atypical immune response that is characteristic of HIT.

Assessing single-stranded oligonucleotide drug-induced effects in vitro reveals key risk factors for thrombocytopenia

“…Heparin is known to activate platelets upon repeated administration [ 23 ]. It has been shown that the binding of heparin to PF4 induces a conformational change of the protein, leading to the exposure of a neo-epitope that induces the production of anti-PF4/heparin antibodies [ 24 ].…”

Use of a whole‐cell ELISA to detect additional antibodies in setting of suspected heparin‐induced thrombocytopenia

“…[1][2][3][4][5] Immunologically, type II HIT represents an atypical response with both T cell-dependent features represented by formation of antibodies to PF4-heparin complexes 6 and a T cell-independent mechanism as suggested by lack of a memory response upon heparin re-exposure. 7 For the remainder of the text, type II HIT will be referred to as HIT.…”

“…Contrary to type I, type II HIT is an immune‐mediated disorder caused by antibody formation (usually IgG) to platelet factor 4‐heparin complexes (anti–PF4‐heparin) which subsequently bind to either FcγRIIA receptor on platelets leading to their activation or on monocytes leading to tissue factor expression which facilitates platelet activation by thrombin, or to the glycosaminoglycan (GAG) molecules on the surface of platelets and endothelial cells . Immunologically, type II HIT represents an atypical response with both T cell‐dependent features represented by formation of antibodies to PF4‐heparin complexes and a T cell‐independent mechanism as suggested by lack of a memory response upon heparin re‐exposure . For the remainder of the text, type II HIT will be referred to as HIT.…”

Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin‐induced thrombocytopenia

“…The immune response in HIT is atypical: (i) anti‐PF4–heparin IgG antibodies are produced at the same time as IgM and IgA, as early as 5 days after heparin exposure ; (ii) anti‐PF4–heparin antibodies become undetectable 3 months after heparin administration ; and (iii) repeated heparin exposure does not usually elicit HIT recurrence, implying a lack of immune memory . Both T‐cell‐dependent and T‐cell‐independent immune mechanisms are probably important in HIT . Previous studies have shown HIT patients possess T cells with PF4–heparin‐specific T‐cell receptors , and murine models have demonstrated CD4 + T cells are necessary for the production of anti‐PF4–heparin antibodies .…”