Letter to the Editor
Heparin-induced bullous hemorrhagic dermatosis
Dermatosis ampollosa hemorrágica inducida por heparina
Antonio Rosales-Castillo
, Antonio Bustos-Merlo, Ana Peragón Ortega
Corresponding author
Servicio de Medicina Interna, Hospital Universitario Virgen de las Nieves, Granada, Spain
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However, their use is not without adverse reactions, some of them less well known, such as distant bullous haemorrhagic dermatosis.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 68<span class="elsevierStyleHsp" style=""></span>-year-old male, admitted a week earlier for pneumonia secondary to SARS-CoV-2, who presented with haemorrhagic bullous lesions on the lower limbs secondary to treatment with enoxaparin received during admission.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A 68-year-old male with a personal history of rheumatic valve disease with mechanical aortic valve replacement, atrial fibrillation and stage 3a chronic kidney disease; anticoagulated with acenocoumarol. Two weeks earlier, he had been hospitalised for severe bilateral SARS-CoV-2 pneumonia requiring high-flow oxygen therapy. During this episode, oral anticoagulation was temporarily suspended due to moderate haemoptysis in the context of acenocoumarol overdose, and after monitoring, enoxaparin 60<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h was subsequently started due to the high combined thrombotic risk of the SARS-CoV-2 infection itself and his cardiac condition. After 4 days on enoxaparin with progressive dose increase (80<span class="elsevierStyleHsp" style=""></span>mg/12<span class="elsevierStyleHsp" style=""></span>h), it was replaced by bemiparin 10,000<span class="elsevierStyleHsp" style=""></span>UI/24<span class="elsevierStyleHsp" style=""></span>h at discharge.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Five days after being discharged from hospital, the patient came to the emergency department due to the progressive development over the previous 72<span class="elsevierStyleHsp" style=""></span>h of bullous lesions with a haemorrhagic appearance, of distal onset at malleolar and dorsal level, with pretibial extension on both lower limbs, without pain or associated pruritus. At that time the patient was being treated with bemiparin 10,000<span class="elsevierStyleHsp" style=""></span>UI daily, without the introduction of new drugs. He denied fever, arthralgias or associated myalgias.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Physical examination of the lower limbs revealed the presence of tense haemorrhagic vesicles and bullae of heterogeneous size (between 5 and 15<span class="elsevierStyleHsp" style=""></span>mm), distributed in groups, bilaterally, at the level of the medial malleolus and some isolated ones at pretibial level, with no associated signs of superinfection (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The CBC was normal and the biochemistry showed a slight worsening of renal function with prerenal cause. C-reactive protein and coagulation were also normal.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Suspecting distant bullous haemorrhagic dermatosis secondary to low molecular weight heparin, it was decided to perform a punch biopsy of one of the lesions and to start oral anticoagulation early in the following days. The lesions progressively disappeared until complete resolution two weeks later. The biopsy revealed a haemorrhagic subepidermal blister with neutrophils and underlying dermis with haematic extravasation and neutrophilic inflammatory infiltrate without signs of vasculitis, compatible with the diagnostic suspicion. After applying the Naranjo algorithm to our case, we obtained a probable causality level (7 points).</p><p id="par0035" class="elsevierStylePara elsevierViewall">As previously mentioned, low-molecular-weight heparins are widely used for both treatment and prevention of thromboembolic disease, increasing their prevalence in SARS-CoV-2 infection and their association with thromboembolic complications. Among its best-known side effects are haemorrhagic complications, osteoporosis, hypoaldosteronism, elevated transaminases and thrombocytopenia. Heparin-induced bullous haemorrhagic dermatosis was described in 2006 by Perrinaud et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and is considered a rare skin disorder, with few cases reported in the medical literature.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It is generally more common with the use of enoxaparin.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It is characterised by tense bullae, usually intraepidermal or subepidermal, hemorrhagic, without an associated vasculitis component. A mild neutrophilic infiltrate may be present and they usually occur in areas distal to the injection site, with a latency time varying between 24<span class="elsevierStyleHsp" style=""></span>h and one month, more common from 5th–7th day. Its pathogenic mechanism is not clear, and a mixed mechanism is postulated, consisting of a hypersensitivity reaction that could be enhanced by antiplatelet or excess coagulation factors.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The differential diagnosis should be made with skin necrosis and heparin-induced thrombocytopenia.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The prognosis is good, with the lesions usually disappearing after 2−3<span class="elsevierStyleHsp" style=""></span>weeks.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Treatment should be individualised, as resolution of the lesions has been observed without the need to discontinue treatment. In our case, the patient received both enoxaparin and bemiparin, deciding to maintain the latter for the switch to acenocoumarol due to the high valvular thrombotic risk, with the lesions resolving after two weeks, so the culprit factor was probably the previous administration of enoxaparin, in accordance with what is described in the medical literature.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Ethical considerations</span><p id="par0045" class="elsevierStylePara elsevierViewall">Informed consent was obtained for imaging and subsequent publication.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Funding</span><p id="par0050" class="elsevierStylePara elsevierViewall">There was no source of funding.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">There is no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Ethical considerations" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 672 "Ancho" => 1005 "Tamanyo" => 119709 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Presence of vesicles and bullae with haemorrhagic content of different sizes, tense, some confluent, distributed in groups at the level of the medial malleolus of both lower limbs.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: three cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Perrinaud" 1 => "D. Jacobi" 2 => "M.C. Machet" 3 => "C. Grodet" 4 => "Y. Gruel" 5 => "L. Machet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2005.01.098" "Revista" => array:7 [ "tituloSerie" => "J Am Acad Dermatol." "fecha" => "2006" "volumen" => "54" "numero" => "Suppl 2" "paginaInicial" => "S5" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16427995" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bullous haemorrhagic dermatitis induced by heparins and other anticoagulants: 94 cases from French pharmacovigilance centres and a literature review" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Uceda-Martin" 1 => "A. Lambert" 2 => "G. Miremont" 3 => "A. Gaiffe" 4 => "M.S. Agier" 5 => "M. 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