Diagnosis and management of heparin-induced thrombocytopenia: Third edition

This guideline updates and widens the scope of the previous British Society for Haematology (BSH) Clinical guidelines for Diagnosis and Management of Heparin-Induced Thrombocytopenia: Second Edition¹ to include functional assays in the diagnosis of heparin-induced thrombocytopenia (HIT), when to use direct-acting oral anti-coagulants, and the role of intravenous (IV) immunoglobulins and plasma exchange in the management of HIT and spontaneous HIT.

HIT is an immune-mediated, highly pro-thrombotic disorder of platelet activation caused by pathogenic antibodies against a platelet factor 4 (PF4)–heparin complex. It is the most frequent drug-induced immune thrombocytopenia and may lead to life-threatening thrombosis. There are two distinct forms of HIT: type I, also known as heparin-associated thrombocytopenia, which is a non-immunological response to heparin treatment, mediated by a direct interaction between heparin and circulating platelets causing platelet clumping or sequestration, and type II, which is immune mediated.

Type I HIT is more frequent than type II, affects around 10%–30% of patients and occurs early, within the first 48–72 h following heparin exposure.² It generally causes transient, mild thrombocytopenia, and the platelet count returns to normal within 4 days of heparin discontinuation. Type I HIT is benign and is not associated with thrombosis. In contrast, type II HIT is much less frequent, and its incidence ranges from 0.1% to 7% depending on the type of heparin, duration of heparin exposure and patient population. Unfractionated heparin (UFH) is associated with ~10-fold greater risk of HIT than low molecular weight heparin (LMWH).^3, 4 HIT typically occurs within 5–14 days of first exposure to heparin and is associated with a significantly increased risk of thrombosis.⁵ Unlike type I HIT, thrombosis is more frequent in type II HIT and occurs in around 25%–50% of patients.^6, 7 When used hereafter in this guideline, ‘HIT’ refers to type II HIT.

The complex formed by the binding of heparin to PF4 acts as an immunogen, leading to immunoglobulin (Ig)G antibody production by B cells. Although IgG is the main driver in the pathogenesis of HIT, there is some evidence to suggest IgM and IgA may also have a pathogenic role.^8, 9 The antibodies form a heparin–PF4-IgG molecular complex that binds to platelets via platelet FcγRIIa causing platelet activation and aggregation with the release of more PF4 and microparticles, leading to complement and coagulation activation. Furthermore, activation of monocytes through FcγRIIa leads to the expression of tissue factor and binding of HIT antibodies to PF4/glycosaminoglycan complexes on the surface endothelial cells (ECs) causing their activation, creating a pro-coagulant state.¹⁰

Platelet activation, aggregation and the activation of complement, monocytes and ECs all lead to thrombosis with thrombocytopenia. Removal of immune complex-coated platelets by the reticuloendothelial system contributes further to thrombocytopenia.¹¹ Anti-PF4–heparin immune complexes are able to induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil–platelet interactions. In a microfluidic system and mouse model, it has been shown that HIT immune complexes are able to induce thrombi containing neutrophils, extra-cellular DNA, citrullinated histone H3 and platelets, whereas depletion of neutrophils abolished thrombus formation.¹² Thrombosis in HIT may be venous, arterial, microvascular or a combination and can affect virtually any tissue or organ.^10, 13, 14 The immunogenicity of PF4–heparin complexes is affected by heparin chain length and the level of sulphation.¹⁵ This may explain the higher incidence of HIT following exposure to UFH compared to LMWH and the near absence of risk with fondaparinux.^16, 17 The diagnosis of HIT is based on the key aspects of the clinical history combined with confirmation of PF4-heparin antibodies presence by laboratory tests. Final confirmation can come from a demonstration that the antibodies can mediate platelet activation.

In these disorders, the antigen site(s) on PF4 that support anti-PF4 antibodies with heparin-independent reactivity are distinct from those with heparin-dependent reactivity seen in classical HIT.

This guideline was compiled according to the BSH process at (https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature search was carried out using the terms given in Appendix until August 2022.