Background: Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin. Patients are at markedly increased risk of thromboembolism. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about diagnosis and management of HIT. Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 33 recommendations. The recommendations address screening of asymptomatic patients for HIT, diagnosis and initial management of patients with suspected HIT, treatment of acute HIT, and special situations in patients with acute HIT or a history of HIT, including cardiovascular surgery, percutaneous cardiovascular intervention, renal replacement therapy, and venous thromboembolism prophylaxis. Conclusions: Strong recommendations include use of the 4Ts score rather than a gestalt approach for estimating the pretest probability of HIT and avoidance of HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score. Conditional recommendations include the choice among non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) for treatment of acute HIT.

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...

Summary.  Although their central role is in the prevention of bleeding, platelets probably contribute to diverse processes that extend beyond hemostasis and thrombosis. For example, platelets can recruit leukocytes and progenitor cells to sites of vascular injury and inflammation; they release proinflammatory and anti‐inflammatory and angiogenic factors and microparticles into the circulation; and they spur thrombin generation. Data from animal models suggest that these functions may contribute to atherosclerosis, sepsis, hepatitis, vascular restenosis, acute lung injury, and transplant rejection. This article represents an integrated summary of presentations given at the Fourth Annual Platelet Colloquium in January 2009. The process of and factors mediating platelet–platelet and platelet–leukocyte interactions in inflammatory and immune responses are discussed, with the roles of P‐selectin, chemokines and Src family kinases being highlighted. Also discussed are specific disorders characterized by local or systemic platelet activation, including coronary artery restenosis after percutaneous intervention, alloantibody‐mediated transplant rejection, wound healing, and heparin‐induced thrombocytopenia.

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Heparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication of heparin therapy caused by antibodies to complexes between unfractionated heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of reactants and initiate antibody-induced platelet activation. We observed that UFH and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. These ULCs were stable and visible by electron microscopy, but they could be dissociated into smaller complexes upon addition of heparin. ULCs formed inefficiently when PF4 was incubated with low-molecular-weight heparin, and none formed with the pentasaccharide fondaparinux sodium. In addition, mutation studies showed that formation of ULCs depended on the presence of PF4 tetramers. The ULCs were more reactive as determined by their capacity to bind to a HITTlike monoclonal antibody and showed greater capacity to promote platelet activation in an antibody-and Fc␥RIIA-dependent manner than were the smaller complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH may play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with HITT.