Centre régional de pharmacovigilance de Strasbourg, HUS, 1, place de l'Hôpital, 67000 Strasbourg, France.
Pôle de santé publique, pharmacologie médicale, centre de pharmacovigilance de Bordeaux, CHU de Bordeaux, Bordeaux, France.
Ann Dermatol Venereol. 2022 Mar;149(1):45-50. doi: 10.1016/j.annder.2021.05.003. Epub 2021 Jun 24.
Bullous haemorrhagic dermatitis (BHD) is an uncommon and highly particular side effect of various forms of heparins.
To better characterise the disease, we collected all cases from French Pharmacovigilance centres recorded over a 20-year period (37 cases) and performed a Medline literature search up to June 2020 (57 cases).
In all, 94 patients were identified (male/female ratio: 2.2) of mean age 73.5±12.1 years (31-94). Patients were treated with enoxaparin (n=66), unfractionated heparin (n=11), fondaparinux (n=10), tinzaparin (n=4), bemiparin (n=1), reviparin (n=1), dalteparin (n=1), and 4 with other anticoagulants: warfarin (n=3) and rivaroxaban (n=1). All cases presented with 1 to more than 100 haemorrhagic vesicles and bullae, distant from the injection sites, located mainly on the lower (75%) or upper limbs (69%). The lesions were asymptomatic, except in 5 patients who had pruritic or painful lesions. The interval between treatment initiation and BHD ranged from 6 hours to 30 days (mean: 8.4±7 days). Biopsy (n=53) showed intraepidermal or subcorneal cavity with red cells (n=39) or junctional blisters (n=10), with eosinophilic infiltrate only rarely. Direct immuno-fluorescence was negative in 19/20 cases and indirect immunofluorescence was negative in 8/8. The outcome was favourable in all cases, including in 12 patients for whom heparin was maintained. A 93-year-old patient died of compressive haematomas unrelated to BHD. We found 5 cases similar to BHD due to other anticoagulants.
This is the largest comprehensive series of this adverse effect due to heparins or, more rarely, to other anticoagulants. Dermatologists must be aware of BHD, since this benign side effect does not necessarily require interruption of treatment. It is rare, considering the large-scale prescription of heparins, and occurs mainly in male patients aged over 70. Although the presentation is highly typical, the physiopathology is difficult to understand, as coagulation parameters are usually normal. Aging, skin fragility or mechanical factors might play a role.
大疱性出血性皮炎（BHD）是各种形式肝素的一种罕见且高度特殊的副作用。
为了更好地描述这种疾病，我们收集了法国药物警戒中心在 20 年期间记录的所有病例（37 例），并进行了截至 2020 年 6 月的 Medline 文献检索（57 例）。
共发现 94 例患者（男女比例为 2.2），平均年龄为 73.5±12.1 岁（31-94 岁）。患者接受了依诺肝素（n=66）、未分级肝素（n=11）、磺达肝素（n=10）、亭扎肝素（n=4）、贝米肝素（n=1）、瑞肝素（n=1）、达肝素（n=1）和其他 4 种抗凝剂：华法林（n=3）和利伐沙班（n=1）。所有患者均表现为 1 个或 100 多个远离注射部位的出血性水疱和大疱，主要位于下肢（75%）或上肢（69%）。病变无症状，仅 5 例患者出现瘙痒或疼痛病变。从治疗开始到 BHD 的时间间隔为 6 小时至 30 天（平均：8.4±7 天）。活检（n=53）显示表皮内或表皮下腔红细胞（n=39）或交界性水疱（n=10），仅偶尔有嗜酸性粒细胞浸润。19/20 例直接免疫荧光阴性，8/8 例间接免疫荧光阴性。所有病例的结局均良好，包括 12 例继续使用肝素的患者。一名 93 岁患者死于与 BHD 无关的压迫性血肿。我们发现了 5 例与其他抗凝剂相关的类似于 BHD 的病例。
这是由于肝素或更罕见的其他抗凝剂引起的这种不良反应的最大综合系列。皮肤科医生必须意识到 BHD，因为这种良性副作用不一定需要中断治疗。考虑到大范围肝素的处方，它很少见，主要发生在 70 岁以上的男性患者中。尽管表现高度典型，但发病机制难以理解，因为凝血参数通常正常。衰老、皮肤脆弱或机械因素可能起作用。
