Letter to the Editor
Heparin hemorrhagic bullae induced by enoxaparin
Bullas hemorrágicas por enoxeparina
Ignacio Torres-Navarro, Blanca de Unamuno-Bustos
, Conrad Pujol-Marco
Corresponding author
Dermatology Department, Hospital Universitario y Politécnico la Fe, Valencia, Spain
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Subcorneal bullae of hematic content (black arrows). No vasculitis or small vessels thrombosis is seen in HHB.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Heparin-induced cutaneous lesions are a frequent adverse effect/event usually seen in non-surgical patients. Local injection-site reactions are the most common one, appearing as hematoma, skin necrosis, contact dermatitis and urticaria.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Recently, a new entity characterized by hemorrhagic intraepidermal bullae that appear on distant areas from the heparin injection sites has been defined, called heparin hemorrhagic bullae (HHB).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Herein, we present a three-case series of patients with prophylactic treatment with enoxaparin that developed HHB, and resolved after switching to bemiparin.</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 1</span>. A 68-year-old male was admitted for pneumonia due to influenza B, and required treatment in the intensive care unit due to respiratory distress syndrome. He had a history of chronic obstructive pulmonary disease (COPD) and was anticoagulated with acenocumarol due to atrial fibrillation. On admission, his oral anticoagulation was changed to subcutaneous enoxaparin. Four days after admission, he presented with hemorrhagic lesions in the arms, proximal area of the thighs, and as well as in the abdomen (in the areas of enoxeparin injection, <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). A peripheral blood test was carried out revealing no alterations on the hemogram, and coagulation including <span class="elsevierStyleSmallCaps">d</span>-dimer. Urea, electrolytes, and liver function also showed normal values. Anticoagulant treatment was changed to bemiparin sodium with resolution of the lesions after 2 weeks. One month later, the patient showed no recurrence of the lesions and died two months later due to a cardiac arrest.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 2</span>. A 64-year-old man was admitted to our hospital for evaluation of cardiac transplantation. He had a history of COPD and chronic atrial fibrillation, so he was anticoagulated with acenocumarol. On admission, his anticoagulation was changed to subcutaneous enoxaparin. After 5 days of admission, asymptomatic hemorrhagic bullae appeared in abdomen, forearms (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B) and the back of the right hand. Peripheral blood test did not show any alterations. Treatment was changed to bemiparin sodium with resolution of the lesions after 10 days. The patient showed no recurrence of the lesions after twelve years.</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Case 3</span>. A 57-year-old male was admitted for subarachnoid hemorrhage. He had a history of diabetes mellitus type II and arterial hypertension. After the resolution of the acute phase of his disease, as was a patient with mechanical in the mitral position, anticoagulation with enoxaparin was initiated. Seven days after admission, he presented with hemorrhagic blisters in the distal area of both forearms. Peripheral blood test did not show significant results. Treatment was changed to bemiparin sodium with resolution of the lesions after 13 days. The patient did not shown recurrence of the lesions after ten years.</p><p id="par0030" class="elsevierStylePara elsevierViewall">HHB have been reported with different doses of heparin (both, primary and prophylactic treatment).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–4</span></a> Its pathogenesis is unknown, although it seems to be a non-immune mechanism that differs from that found in heparin cutaneous necrosis, which is due to thrombosis of the dermal capillaries, and is associated with the presence of antibodies against platelet-factor 4 related to heparin.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It has also been speculated that HHB appear in the extremities of the elderly due to existing vessel damage<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>; however, all of our patients were under 70-years-old. In addition, HHB have been related to various low molecular-weight heparins, especially enoxaparin,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> as its use is widely extended in Spain, where most of the cases have been reported.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3,4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">HHB are more frequent in males (ratio 7:1).<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> They usually appear as tense blisters in areas of non-inflamed skin, distal to the injection site.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Nevertheless, as our case two, HHB can rise also on the injection area.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Histologically, the majority of cases show constant findings (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C, corresponds to patient three), with vesicles and intra-epidermal or subcorneal bullae of hematic content, without vasculitis or cutaneous vessels thrombosis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Differential diagnosis should be made with porphyria cutanea tarda, atypical bullous pemphigoid and epidermolysis bullosa acquisita, as well as friction and neurological blisters.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> Resolution with replacement of enoxaparin treatment by other anticoagulants is usually seen within two weeks<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3,5</span></a>; however, also self-resolution with no treatment changes has been described.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3,4</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, HHB is an infrequent adverse effect of anticoagulant treatment with low molecular weight heparins. Clinicians should be aware of this entity with self-limiting nature that it is probably under-recognized, in order to do the differential diagnosis with other skin diseases that require active treatment. Switching to bemiparin may be a safe alternative in patients that develop HHB with enoxaparin.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding sources</span><p id="par0045" class="elsevierStylePara elsevierViewall">None.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">None to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Funding sources" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 2 => array:2 [ "identificador" => "xack504936" "titulo" => "Acknowledgments" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 436 "Ancho" => 1750 "Tamanyo" => 196701 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Hemorrhagic blisters at heparin-injection site in abdomen (note that some had surrounding purpura while others did not, green arrows); (B) hemorrhagic bullae in forearms, distal to the heparin-injection site (some had more inflammatory base than others, green arrows); (C) histological findings in HHB (H&E 200×, original magnification). Subcorneal bullae of hematic content (black arrows). No vasculitis or small vessels thrombosis is seen in HHB.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dermatosis ampollosa hemorrágica a distancia; dos nuevos casos por enoxaparina y revisión de la literatura" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "C.A. Villanueva" 1 => "L. Nájera" 2 => "P. Espinosa" 3 => "J. 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Golitz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ced.13327" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Dermatol" "fecha" => "2018" "volumen" => "43" "paginaInicial" => "393" "paginaFinal" => "398" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29282761" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack504936" "titulo" => "Acknowledgments" "texto" => "<p id="par0055" class="elsevierStylePara elsevierViewall">To Gemma Llavador-Ros MD, Jon Ortiz-Carrera MD and Rafael Botella-Estrada MD, PhD for their value help.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015600000001/v1_202101070942/S2387020620305830/v1_202101070942/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015600000001/v1_202101070942/S2387020620305830/v1_202101070942/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620305830?idApp=UINPBA00004N" ]
