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Calcium-heparinate induced skin necrosis without thrombocytopenia
European Geriatric Medicine 2 (2011) 375–376
EGM clinical case
Calcium-heparinate induced skin necrosis without thrombocytopenia P. Gibert a,*, S. Logerot b, D. Bourneau b, A. Desbois c, S. Amiard c, M. Mallaret b, J. Calop a, G. Gavazzi c a b c
UF pharmacie clinique, poˆle pharmacie, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France Centre re´gional de pharmacovigilance, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France Clinique universitaire de me´decine ge´riatrique, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France
A R T I C L E I N F O
Article history: Received 11 April 2011 Accepted 15 June 2011 Available online 31 August 2011
Heparin-induced skin necrosis is a rare but potentially severe drug adverse effect. We describe a case of skin necrosis induced by calcium-heparinate subcutaneous injections. An 82-year-old woman was hospitalized for digestive disorders, confusing state and acute renal failure related to dehydration. On her admission, preventive anticoagulation by calcium heparinate was started with subcutaneous injections into the abdominal wall. A subsequent haematoma was observed. Six days after starting heparin therapy, a large inflammatory plaque around the haematoma appeared. It changed into a painful necrotic wound on the abdomen measuring 10 5 cm (Fig. 1). There was no induration. Injections of calcium heparinate could not be stopped because of auricular fibrillation, with dosages raised up to a curative posology. Platelet values were
normal. In the hypothesis of immunoallergic mechanism, heparinplatelet factor-4 antibodies were assessed by enzyme-linked immunosorbent assay (Elisa) and were negative. No histological exam was realized. Diagnoses of erysipelas and necrotizing vasculitis were rejected. Calcium heparinate was stopped with a relay by oral anticoagulant (warfarin). Evolution was favorable with occlusive dressings and surgical removal of necrotic tissue was conducted for a complete recovery. 1. Discussion Heparin can cause different types of cutaneous reactions. Haematoma, at the point of injection, is the most frequent complication observed but erythema, urticaria or eczema is also well known [1,2]. Skin necrosis induced by heparin is rare and seems to be more frequent with subcutaneous low molecular weight heparin injections. While heparin is frequently prescribed, the incidence of such adverse event remains low with two cases for 8000 patients but is probably underestimated [3]. Cutaneous signs begin from 2 days to 2 weeks after the first injection. It is generally located at the injection points with subcutaneous administration but can be disseminated, in particular with the intravenous route
Fig. 1. Evolution of the skin necrosis after one week of subcutaneous low molecular weight heparin injections: dermatologic signs began with an haematoma subsequent to the first injections, with a large inflammatory plaque around the haematoma. It changed into a painful necrotic wound on the abdomen measuring 10 5 cm without induration.
* Corresponding author. E-mail address: [email protected] (P. Gibert). 1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.06.005
376
P. Gibert et al. / European Geriatric Medicine 2 (2011) 375–376
[4]. The diameter of necrotic lesion varies from 3 cm to 15 cm or more enlarged [5]. The pathogenesis seems to involve several mechanisms since the presence of thrombopenia and heparinplatelet factor-4 antibody is not systematically found [3]. The role of antibodies platelet-heparin complex is mostly incriminated, leading to an activation of the coagulation cascade. Another immunologic hypothesis has been proposed, involving fibrosing vasculitis of dermal vessels induced by a type III hypersensitivity reaction [6]. In addition, skin necrosis may be the result of local trauma at the injection site or poor absorption of heparin due to adipose tissue. For calcium heparinate specifically, abnormal calcium deposition is hypothesized [7]. Diagnosis can be difficult since the presence of concomitant thrombocytopenia is not systematic and may be associated with thrombocytosis [8]. Recognition of the diagnosis and discontinuation of heparin therapy is the key point in the management of this adverse event. Switch for other types of heparin remains at risk without excluding a concomitant type II heparin induced thrombocytopenia. Outcome is usually favorable with a switch for danaparoid or oral anticoagulant. In severe cases, surgical therapy may be necessary. 2. Conclusion We describe a case of severe skin necrosis induced by calcium heparinate without thrombocytopenia and without heparinplatelet antibodies detectable. Despite the severity of the reaction, calcium-heparinate injections were not stopped and no other organ systems were affected. Clinicians should be aware of this
adverse effect and the safest course would be the substitution for alternative oral anticoagulants. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Ethical statement: This manuscript has not been published elsewhere and not currently under consideration for publication by another journal. References [1] Gruel Y, Pouplard C. Allergies aux he´parines. Rev Fr Allergol Immunol Clin 2002;42:97–103. [2] Roussel S, Tennstedt D, Lachapelle JM. Re´actions cutane´es induites par les anticoagulants. Louvain Med 2001;120:192–8. [3] Handschin AE, Trentz O, Kock HJ, Wanner GA. Low molecular weight heparininduced skin necrosis: a systematic review. Langenbecks Arch Surg 2005;390: 249–54. [4] Tietge UJF, Schmidt HHJ, Ja¨ckel E, Trautwein C, Manns MPM. Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia. J Intern Med 1998;243:313–5. [5] Drew PJ, Smith MJ, Milling MAP. Heparin-induced skin necrosis and low molecular weight heparins. Ann R Coll Surg Engl 1999;81:266–9. [6] Wu¨ttschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 1999;20: 515–25. [7] Bonnecarre`re L, Templier I, Carron PL, Maurizi J, Salameire D, Beani JC, et al. Two cases of iatrogenic cutis and subcutis calcinosis after calcium-containing heparin injection. J Mal Vasc 2009;34:366–71. [8] Perbet S, Trouiler P, Paugam-Burtz C, Denninger MH, Mantz J. Heparin-induced skin necrosis then thrombocytosis in intensive care unit: difficulty in diagnosis. Ann Fr Anesth Reanim 2007;26:791–4.
EGM clinical case
Calcium-heparinate induced skin necrosis without thrombocytopenia P. Gibert a,*, S. Logerot b, D. Bourneau b, A. Desbois c, S. Amiard c, M. Mallaret b, J. Calop a, G. Gavazzi c a b c
UF pharmacie clinique, poˆle pharmacie, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France Centre re´gional de pharmacovigilance, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France Clinique universitaire de me´decine ge´riatrique, hoˆpital A.-Michallon, BP217, 38043 Grenoble cedex 9, France
A R T I C L E I N F O
Article history: Received 11 April 2011 Accepted 15 June 2011 Available online 31 August 2011
Heparin-induced skin necrosis is a rare but potentially severe drug adverse effect. We describe a case of skin necrosis induced by calcium-heparinate subcutaneous injections. An 82-year-old woman was hospitalized for digestive disorders, confusing state and acute renal failure related to dehydration. On her admission, preventive anticoagulation by calcium heparinate was started with subcutaneous injections into the abdominal wall. A subsequent haematoma was observed. Six days after starting heparin therapy, a large inflammatory plaque around the haematoma appeared. It changed into a painful necrotic wound on the abdomen measuring 10 5 cm (Fig. 1). There was no induration. Injections of calcium heparinate could not be stopped because of auricular fibrillation, with dosages raised up to a curative posology. Platelet values were
normal. In the hypothesis of immunoallergic mechanism, heparinplatelet factor-4 antibodies were assessed by enzyme-linked immunosorbent assay (Elisa) and were negative. No histological exam was realized. Diagnoses of erysipelas and necrotizing vasculitis were rejected. Calcium heparinate was stopped with a relay by oral anticoagulant (warfarin). Evolution was favorable with occlusive dressings and surgical removal of necrotic tissue was conducted for a complete recovery. 1. Discussion Heparin can cause different types of cutaneous reactions. Haematoma, at the point of injection, is the most frequent complication observed but erythema, urticaria or eczema is also well known [1,2]. Skin necrosis induced by heparin is rare and seems to be more frequent with subcutaneous low molecular weight heparin injections. While heparin is frequently prescribed, the incidence of such adverse event remains low with two cases for 8000 patients but is probably underestimated [3]. Cutaneous signs begin from 2 days to 2 weeks after the first injection. It is generally located at the injection points with subcutaneous administration but can be disseminated, in particular with the intravenous route
Fig. 1. Evolution of the skin necrosis after one week of subcutaneous low molecular weight heparin injections: dermatologic signs began with an haematoma subsequent to the first injections, with a large inflammatory plaque around the haematoma. It changed into a painful necrotic wound on the abdomen measuring 10 5 cm without induration.
* Corresponding author. E-mail address: [email protected] (P. Gibert). 1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.06.005
376
P. Gibert et al. / European Geriatric Medicine 2 (2011) 375–376
[4]. The diameter of necrotic lesion varies from 3 cm to 15 cm or more enlarged [5]. The pathogenesis seems to involve several mechanisms since the presence of thrombopenia and heparinplatelet factor-4 antibody is not systematically found [3]. The role of antibodies platelet-heparin complex is mostly incriminated, leading to an activation of the coagulation cascade. Another immunologic hypothesis has been proposed, involving fibrosing vasculitis of dermal vessels induced by a type III hypersensitivity reaction [6]. In addition, skin necrosis may be the result of local trauma at the injection site or poor absorption of heparin due to adipose tissue. For calcium heparinate specifically, abnormal calcium deposition is hypothesized [7]. Diagnosis can be difficult since the presence of concomitant thrombocytopenia is not systematic and may be associated with thrombocytosis [8]. Recognition of the diagnosis and discontinuation of heparin therapy is the key point in the management of this adverse event. Switch for other types of heparin remains at risk without excluding a concomitant type II heparin induced thrombocytopenia. Outcome is usually favorable with a switch for danaparoid or oral anticoagulant. In severe cases, surgical therapy may be necessary. 2. Conclusion We describe a case of severe skin necrosis induced by calcium heparinate without thrombocytopenia and without heparinplatelet antibodies detectable. Despite the severity of the reaction, calcium-heparinate injections were not stopped and no other organ systems were affected. Clinicians should be aware of this
adverse effect and the safest course would be the substitution for alternative oral anticoagulants. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Ethical statement: This manuscript has not been published elsewhere and not currently under consideration for publication by another journal. References [1] Gruel Y, Pouplard C. Allergies aux he´parines. Rev Fr Allergol Immunol Clin 2002;42:97–103. [2] Roussel S, Tennstedt D, Lachapelle JM. Re´actions cutane´es induites par les anticoagulants. Louvain Med 2001;120:192–8. [3] Handschin AE, Trentz O, Kock HJ, Wanner GA. Low molecular weight heparininduced skin necrosis: a systematic review. Langenbecks Arch Surg 2005;390: 249–54. [4] Tietge UJF, Schmidt HHJ, Ja¨ckel E, Trautwein C, Manns MPM. Low molecular weight heparin-induced skin necrosis occurring distant from injection sites and without thrombocytopenia. J Intern Med 1998;243:313–5. [5] Drew PJ, Smith MJ, Milling MAP. Heparin-induced skin necrosis and low molecular weight heparins. Ann R Coll Surg Engl 1999;81:266–9. [6] Wu¨ttschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 1999;20: 515–25. [7] Bonnecarre`re L, Templier I, Carron PL, Maurizi J, Salameire D, Beani JC, et al. Two cases of iatrogenic cutis and subcutis calcinosis after calcium-containing heparin injection. J Mal Vasc 2009;34:366–71. [8] Perbet S, Trouiler P, Paugam-Burtz C, Denninger MH, Mantz J. Heparin-induced skin necrosis then thrombocytosis in intensive care unit: difficulty in diagnosis. Ann Fr Anesth Reanim 2007;26:791–4.