Shortly after the discovery of heparin in 1916, it was proven to be a valuable anticoagulant, and after its initial clinical use in the late 1930s Citation[1], still is the mainstay of prophylactic and therapeutic anticoagulant therapy Citation[2]. Due to this long history of clinical use, most adverse events of heparin are well known. Among these are bleeding, immune- and non-immune heparin-induced thrombocytopenia (HIT), osteoporosis and hair loss Citation[3,4]. In addition, heparin has also been noted to induce skin lesions. Several causes for heparin-induced skin lesions – for example, immediate and delayed-type hypersensitivity responses, immune HIT, recall urticaria and others Citation[5] – have been noted. However, while believed to be ‘underestimated’ Citation[6], no data on the incidence and causes of heparin-induced skin lesions were available until recently.
To obtain data on the incidence and causes of heparin-induced skin lesions, over 300 medical patients were prospectively investigated for the presence of heparin-induced skin lesions. Overall, 7.5% of the patients presented with heparin-induced skin lesions, far exceeding the expected incidence. In all cases, a delayed-type hypersensitivity response was identified as the underlying cause by histology, allergologic testing or both. By regression analysis, female sex, obesity and long duration of heparin therapy were identified as risk factors for heparin-induced cutaneous hypersensitivity (HIHS). Interestingly, patients anticoagulated with nadroparin developed HIHS more often than those treated with enoxaparin, indicating a diverse profile of different low-molecular-weight heparin. In contrast to several previous studies Citation[6–10], a low cross-reactivity among other heparins was noted Citation[11]. Detailed analysis of the diagnostic procedures for HIHS showed that, with the exception of subcutaneous provocation tests, allergologic testing has a low sensitivity and specificity. On the contrary, histology together with the medical history and clinical presentation proved a valid diagnostic tool [Schindewolf M, Ludwig RJ. Evaluation of procedures for the diagnosis of heparin-induced delayed type hypersensitivity. Manuscript submitted].
In our opinion, this study has several clinical implications. Firstly, immune HIT needs to be ruled out. Despite HIHS being the main cause for heparin-induced skin lesions, these may be the only clinical presentation of immune-mediated HIT Citation[12], and the initial clinical presentation of both diseases may be similar. Furthermore, one of our patients with HIHS was also diagnosed with immune-mediated HIT, indicating that HIHS does not rule out HIT. As therapeutic options for HIT and HIHS are diametrically opposed – for example, intravenous heparin administration is a safe therapeutic option in HIHS Citation[13], but is contraindicated in HIT – rapid and valid diagnosis of heparin-induced skin lesions is essential for patient management. Therefore, in each patient with heparin-induced skin lesions, the underlying cause has to be defined by the appropriate investigations.
Secondly, allergologic testing should only be used for the identification of alternative anticoagulants. Due to the low sensitivity and specificity of allergologic testing (with the exception of subcutaneous provocation) we do not recommend to routinely perform allergologic testing. Furthermore, allergologic testing cannot be performed when therapeutic decisions have to be made. We hence propose to diagnose heparin-induced skin lesions based on the history, clinical presentation and histology. This allows diagnosis within 1–2 days after identification of skin lesions.
Finally, the study implicated that heparin-induced skin lesions should be routinely checked for. From our experience, heparin-induced skin lesions are still underdetected, and if detected, one low-molecular-weight heparin preparation is mostly replaced by another Citation[14]. This prolonged exposure to various heparins may lead to the high cross-reactivity among the heparin preparations, which has been noted in past studies Citation[5,15,16]. This hypothesis is supported by the notion of a low cross-reactivity in our prospective study Citation[11]. In this study, patients with heparin-induced skin lesions were immediately changed to suitable alternatives. As a consequence, exposure to allergy-inducing anticoagulants was limited to a relatively short period. Hence, early detection of heparin-induced skin lesions, followed by appropriate changes of anticoagulant therapy, will prevent development of cross-reactivity.
In addition, the results also challenge the concept that an increasing molecular weight of heparin preparations is associated with an increased risk of developing sensitization Citation[16–18]. In our study, nadroparin and enoxaparin were most frequently used. Despite a similar anticoagulatory profile and a similar molecular weight, the incidence of HIHS was 3.9% for enoxaparin and 17.1% for nadroparin. However, final conclusions cannot be drawn, as heparin preparations with other molecular weights were not administered in sufficient numbers for respective calculations. However, a recently accomplished study shows a low incidence of skin lesions in patients treated with the pentasaccharide fondaparinux [Schindewolf M, Ludwig RJ. Fondaparinux exhibits a low allergenic potential and a favourable safety profile – results of a prospective investigation. Manuscript submitted]. This indicates that a low molecular weight is associated with a reduced risk of developing a delayed-type hypersensitivity response to subcutaneous anticoagulants.
However, anticoagulation should not only be selected from an allergologic perspective, but should also take into account the needs of each individual patient. Heparin is not only a potent anticoagulant, but also possesses strong anti-inflammatory and antimetastatic activities Citation[19–21]. For example, heparin inhibits experimental metastasis formation Citation[22,23] and prolongs the survival of tumor patients Citation[24–26]. However, both anti-inflammatory and antimetastatic effects are independent of the anticoagulatory activity, and seem to correlate with the inhibition of selectin adhesion molecules. Unfractionated heparin and nadroparin, in contrast to enoxaparin and the pentasaccharide fondaparinux, are potent inhibitors of P- and L-selectin Citation[27,28]. Therefore, the heparin preparation should be selected based on the activities of the respective heparin preparations and the individual needs of the patient. For patients with known heparin allergy, or with risk factors to develop heparin allergy, fondaparinux or pentosan polysulfate are suitable alternatives.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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