Cutaneous adverse events associated with heparin

Abstract

SummaryHeparin use is associated with various cutaneous reactions, with the most common being immune-mediated skin lesions and bleeding complications. In this review, we compile the dermatological side-effects of heparin reported in the literature, and provide a clear approach to their adequate management. Heparin use and mechanism of actionHeparin (and its analogues) and warfarin are the traditional anticoagulants used for the prevention and treatment of thromboembolic disease. Table 1 shows a simplified classification of anticoagulants.Heparin is an indirect thrombin inhibitor that binds to anti-thrombin, converting this cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa and IXa. Lowmolecular weight heparin (LMWH) drugs have less anti-thrombin activity than does unfractionated heparin (UFH). 1 Unfractionated heparin is used intravenously, and requires monitoring using the activated partial thromboplastin time (APTT). By contrast, LMWH is administered by subcutaneous injection, and the dose can be weightadjusted without monitoring. 1 Epidemiology of cutaneous adverse events associated with heparinOwing to under-reporting, the real incidence of heparininduced skin lesions is unknown.2 However, AEs are reported less often with LMWH than with UFH.3 In a recent prospective study, 2 the incidence and causes of heparin-induced skin lesions were evaluated in a large cohort of patients. An incidence of 7.5% was found, much higher than the 1-2% previously estimated. Delayed-type hypersensitivity reactions were found to be the commonest cutaneous side-effect related to heparin use. Most patients enrolled in the study received LMWH. Classification, aetiology and managementSkin lesions related to heparin use can be classified as: immune-mediated reactions, which covers (i) type I immediate hypersensitivity reactions; (ii) type IV delayed hypersensitivity reactions: (iii) skin necrosis; and non-immune-mediated reactions, covering (iv) bleeding diathesis and (iv) other, less common reactions (Table 2). Immune-mediated reactions Type I immediate hypersensitivity reactionsImmediate hypersensitivity reactions to heparins, 3-5 e.g. pruritus (including palmoplantar pruritus), urticaria ( Fig. 1), angio-oedema, conjunctivitis, rhinitis, bronchial asthma and anaphylaxis, are probably IgE-mediated. These reactions were first reported in the 1940s, after the introduction of heparin for clinical use, and were attributed to contaminant proteins and preservatives. They are now rare because of improved purification procedures.

Skin tests in patients with delayed and immediate hypersensitivity to heparins: A case series

“…1 Risk factors for hypersensitivity include obesity, female sex, pregnancy, and prolonged treatment. 6 Our case series confirms literature data regarding sex and obesity, as all of our patients were female, and four of them had a body mass index of >30. These data suggest that hormonal and metabolic features are predisposing factors for heparin hypersensitivity.…”

“…The incidence of heparin‐induced skin lesions is reported to be up to 7.5% in treated patients, with DTH being the main cause . Risk factors for hypersensitivity include obesity, female sex, pregnancy, and prolonged treatment . Our case series confirms literature data regarding sex and obesity, as all of our patients were female, and four of them had a body mass index of >30.…”

Complementary Use of U.S. FDA’s Adverse Event Reporting System and Sentinel System to Characterize Direct Oral Anticoagulants‐Associated Cutaneous Small Vessel Vasculitis

“…However, CSVV associated with warfarin and heparin has been described and attributed to immune-complex deposition. 15,16 In the pivotal DOAC trials, vasculitis adverse events including CSVV were reported in patients treated with DOACs. For example, in the ROCKET-AF trial (7111 patients treated with rivaroxaban) the incidence of cutaneous vasculitis in the rivaroxaban arm was low (0.01%).…”

“…Research exploring the pathogenesis of DOAC‐associated CSVV is lacking. However, CSVV associated with warfarin and heparin has been described and attributed to immune‐complex deposition 15,16 …”

A Case Report of Henoch–Schonlein Purpura and IgA Nephropathy Associated With Rivaroxaban

“…Literature exploring the pathophysiology of rivaroxaban‐associated vasculitis is lacking. However, IgA cutaneous vasculitis associated with heparin has been described and attributed to immune‐complex deposition . Rivaroxaban‐associated immune‐complex formation and deposition in the glomerulus is a potential mechanism for IgA nephropathy observed in this case.…”