Heparin-induced thrombocytopenia

Abstract

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. This chapter will summarize our diagnostic approach to HIT by underscoring critical elements of the clinical and laboratory evaluation. Keywordsplatelet factor 4; PF4; heparin; PF4/H complexes; HIT Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening immune complication which occurs after exposure to unfractionated heparin (UFH) or less commonly, to low-molecular weight heparins (LMWHs). 1 It is characterized by declining platelet counts beginning 5-14 days after heparin exposure occurring in isolation (isolated HIT) or concurrent with new arterial and venous thrombotic complications. 2 HIT is caused by antibodies directed against complexes formed by a platelet protein, platelet factor 4, and heparin (PF4/H). Circulating immune complexes containing IgG and PF4/H complexes bind to platelet and monocyte Fc receptors and promote cellular activation leading to procoagulant microparticle release and thrombin generation. 3,4 Historically, the challenge associated with HIT was lack of awareness of the syndrome and its pursuant complications; the challenge now is in over-diagnosis and treatment of HIT. With the widespread availability of screening immunoassays and the desire of clinicians to avoid the thrombotic consequences associated with true disease, many patients without HIT Correspondence to: Gowthami M. Arepally, arepa001@mc.duke.edu. now suffer needless morbidity due to bleeding complications from use of alternative anticoagulants. To avoid a reflexive diagnosis of HIT in the heparinized thrombocytopenic patient, clinicians must have a sound understanding of the clinical and laboratory diagnostic elements essential for a diagnosis of HIT. This paper reviews our diagnostic and management strategy in evaluating the common presentation of thrombocytopenia in a heparinized patient. NIH Public Access Diagnosing HIT: the clinical challengeHIT is a challenging clinical diagnosis. The increasing use of UFH/LMWH for thromboprophylaxis in hospitalized patients 5 coupled with the frequency of thrombocytopenia, particularly among critically ill patients, 6 results in a significant overlap of patients suspected of HIT. In a recent registry of ~1000 patients treated with thromboprophylactic dosed heparin, 19% (n = 190) met thrombocytopenia criteria compatible with a diagnosis of HIT (as defined by a platelet count < 150 × 10 9 /L or > 50% drop in platelet counts), but only 5% of patients were diagnosed with HIT. 6 This study and clinical experience suggest that other causes of thrombocytopenia, such as infection, medi...

The complex functioning of the complement system in xenotransplantation

“…Platelets interact with both the complement and coagulation systems. Immune complexes may bind to FcγRIIA on the platelets, thus activating them, and also bind to C1q to activate the complement system . The activated platelets may bind ficolin‐1, ficolin‐2, and ficolin‐3, and activate mannose‐binding lectin‐associated serine proteases (MASP‐1 and MASP‐2) .…”

“…Immune complexes may bind to FcγRIIA on the platelets, thus activating them, and also bind to C1q to activate the complement system . The activated platelets may bind ficolin‐1, ficolin‐2, and ficolin‐3, and activate mannose‐binding lectin‐associated serine proteases (MASP‐1 and MASP‐2) . Activated platelets bind to plasma proteins, initiating contact activation (factors XIIa and XIa, and kallikrein), and may induce C3 and factor XI phosphorylation, which may enhance their activities…”

“…Immune complexes may bind to FcγRIIA on the platelets, thus activating them, and also bind to C1q to activate the complement system. 42 The activated platelets may bind ficolin-1, ficolin-2, and ficolin-3, and activate mannose-binding lectin-associated serine proteases (MASP-1 and MASP-2). 42 may decrease expression of vascular endothelial growth factor in a graft, resulting in endothelial injury and complement activation, 52 leading to thrombotic microangiopathy and consumptive coagulopathy.…”

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

“…1 Its etiology is not precisely known but it may result from a direct effect of heparin on platelet activity that leads to agglutination and does not involve an immune response. 1 Type II HIT normally takes 5-14 days to develop after heparin administration. 2 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.…”

“…2 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. [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.…”