Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Abstract

Heparin-induced thrombocytopenia (HIT)is caused by antibodies against a "self" protein-platelet factor 4-bound to heparin. We observed an overrepresentation of the female gender in 290 patients who developed HIT after cardiac or orthopedic surgery compared with the representation found in national databases (study 1). Therefore, we investigated gender imbalance in HIT by logistic regression analysis of a randomized controlled trial of unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH) (study 2), and we analyzed individual patient data from 7 prospective studies comparing HIT frequency between UFH and LMWH, evaluating effects of gender, heparin (UFH vs LMWH), and patient type (surgical vs medical) (study 3). All 3 studies showed female overrepresentation, which for study 3 was a common odds ratio (OR) of 2.37 (95% confidence interval [95% CI], 1.37-4.09; P ‫؍‬ .0015). Study 3 also showed an interaction between gender, heparin, and patient type. Although UFH was more likely than LMWH to cause HIT (P < .0001), this effect was predominantly seen in women compared with men (common OR, 9.22 vs 1.83; P ‫؍‬ .020) and in surgical patients compared with medical patients (common OR, 13.93 vs 1.75; P ‫؍‬ .005). We conclude that females are at greater risk for HIT and that using LMWH to prevent HIT may have greatest absolute benefit in females undergoing surgical thromboprophylaxis. IntroductionHeparin-induced thrombocytopenia (HIT) is a relatively common drug-induced immune reaction affecting platelets. 1 The immunologic basis of this disorder is the transient production 2 of plateletactivating antibodies of IgG class 3-5 that recognize multimolecular complexes of platelet factor 4 (PF4) and heparin. [6][7][8] An evolving concept is that HIT resembles an autoimmune disorder 9 because the pathogenic antibodies recognize one or more neoepitopes found on the "self" protein, PF4, rather than on heparin. 10,11 Indeed, in some patients, HIT strongly resembles an autoimmune process because heparin treatment initiates the anti-PF4/heparin antibody formation but then is no longer required for the development of thrombocytopenia. [12][13][14] To date, only a minor role for patientspecific risk factors for HIT has been reported. In particular, no association with human leukocyte antigen (HLA) genes is observed, 15 and the potential role of Fc receptor polymorphisms in HIT is debated. [16][17][18] We previously observed in large retrospective studies that females constituted 56.4% 2 and 58.9% 19 of HIT patients, suggesting a possible gender imbalance. Together with the emerging concept of HIT as a drug-induced transient autoimmune disorder, we hypothesized that there might be a gender imbalance in risk for this adverse drug reaction, with a greater frequency among females, as observed in certain chronic autoimmune disorders. [20][21][22] We also examined whether the striking difference in risk for HIT between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) 23 is consistent for both genders and in ...

Anti‐PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non‐drug risk factors and evidence for a stoichiometry‐based model of immunization

“…The frequency of forming anti-PF4/heparin antibodies, as well as the risk of clinical HIT itself, varies considerably in different clinical settings [2]. One relevant factor is the type of heparin: for example unfractionated heparin (UFH) is more immunogenic, and is associated with a higher risk of HIT, compared with low-molecular weight heparin (LMWH) [3,4]. However, certain observations suggest that non-drug factors could also influence risk of HIT.…”

“…However, certain observations suggest that non-drug factors could also influence risk of HIT. For example, one meta-analysis [4] found that postsurgery patients are more likely than medical patients to develop HIT, and another study [5] reported that pregnant women are less likely than non-pregnant females to develop HIT.…”

Fondaparinux treatment in heparin induced thrombocytopenia:a case report

“…Bizim olgumuzda olduğu gibi kadın cinsiyet HBT riskini artırmaktadır. Ayrıca, dört günden fazla heparin kullanımının da 20 kata kadar HBT riskini artırmakta olduğu bildirilmektedir (10). Bizim olgumuza bakıldığında HBT gelişimi için bütün riskleri taşıdığı görülmektedir.…”

Heparin-induced thrombocytopenia

“…Specifinis gydymas taip pat nereikalingas. Šią trombocitopeniją sąlygoja tiesioginė sąveika tarp heparino ir trombocitų, sukelianti pastarųjų susigrupavimą ar suirimą (11)(12)(13).…”

“…Genetiniai trombozės rizikos veiksniai, tokie kaip faktorius V Leiden, protrombino geno mutacija, metilenetetrahidrofolato reduktazės (MTHFR) polimorfizmas ir trombocitų receptorių polimorfizmas su HIT susijusios trombozės rizikos nedidina (12,22 Trombocitopenija būna vidutinio dydžio, apie 50-60×10 9 /l. 90 proc.…”