http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–3 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2015.1041033
CASE REPORT
Bullous hemorrhagic dermatosis induced by enoxaparin Ana Isabel Gouveia1, Leonor Lopes1, Luis Soares-Almeida1,2, and Paulo Filipe1,2 Hospital de Santa Maria, University Clinic of Dermatology, Av. Professor Egas Moniz, Lisbon, Portugal and 2Faculdade de Medicina da Universidade de Lisboa, Institute of Molecular Medicine, Research Unit of Dermatology, Lisbon, Portugal
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
1
Abstract
Keywords
The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. We report a 71-year-old man who developed hemorrhagic bullae at sites distant from subcutaneous enoxaparin injections. It is important that clinicians be aware of the different adverse reactions of these widely used drugs.
Adverse drug reaction, bullous dermatoses, enoxaparin, heparin History Received 17 February 2015 Revised 30 March 2015 Accepted 11 April 2015 Published online 5 May 2015
Introduction Heparins are used in the prophylaxis and treatment of thromboembolic diseases. Enoxaparin, a low-molecular weight heparin (LMWH) acts by binding to antithrombin III, causing inhibition of factor Xa1. Some of the most frequent adverse effects of subcutaneous heparin treatment are haemorrhagic complications, heparin-induced thrombocytopenia, osteoporosis, alopecia, elevation of serum transaminases and skin reactions2. Although uncommon, heparin-induced skin lesions are more common than previously thought2. These effects may be caused by at least five mechanisms: delayed hypersensitivity reactions (Type IV) (most common), immunemediated thrombocytopenia, Type I allergic reactions, skin necrosis and pustulosis3. Heparin-induced hemorrhagic bullous dermatosis occurring at a distance from the site of injection is a rare adverse skin reaction1, with few cases described in the literature.
Case report A 71-year-old caucasian man presented with multiple, asymptomatic vesicles and bullae on his limbs. Four weeks prior, he had been started on treatment with enoxaparin sodium (80 mg every 12 h by subcutaneous injection) after receiving the diagnosis of deep vein thrombosis (DVT) of the left leg. Two weeks after starting anticoagulant therapy the patient developed numerous tense, asymptomatic blood-filled vesicles and bullae, surrounded by a discrete erythematous
halo on the forearms, dorsum of hands (Figure 1) and knees. Mucous membranes were normal and no lesions were visible at enoxaparin injection sites. The patient had a past history of giant cell arteritis, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, benign prostatic hyperplasia, ulcerative colitis and a Scedosporium apiospermum infection on the dorsum of his left foot. His medication included prednisolone, glicazide, omeprazole, calcium carbonate, tiotropium, budesonide/formoterol, tamsolusin and voriconazole. Laboratory tests showed no alteration in complete blood count (including platelets), coagulation study (APTT, PT, INR and fibrinogen) and serum biochemistry, except for a slight increase in gamma GT 63 IU/l (reference values 9–36 IU/l). Histopathological examination of an intact lesion showed an intraepidermal vesicle filled with red blood cells, with scarce lymphocytic inflammatory infiltrate and without signs of vasculitis or intravascular thrombus (Figure 2A and B). Direct immunofluorescence showed no complement or antibody deposition. Based on the physical examination, absence of significant alterations on laboratory tests and histolopathologic findings, the diagnosis of bullous hemorrhagic dermatosis induced by enoxaparin was made. Enoxaparin treatment was maintained for 6 months required for DVT treatment and during this period the lesions waxed and waned. The complete regression of the dermatosis was achieved after discontinuation of enoxaparin, without sequelae.
Discussion Address for correspondence: Ana Isabel Gouveia, Hospital de Santa Maria, University Clinic of Dermatology, Av. Professor Egas Moniz, Lisbon, Portugal. E-mail: [email protected]
Bullous hemorrhagic dermatosis associated with heparins is rare and was first reported in 2006 by Perrinaud et al4. To the
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
2
A. I. Gouveia et al.
best of our knowledge, there were only 22 cases reported previously, 18 secondary to LMWH and 2 after unfractionated heparins1,4–14. Naveen et al.15 also described a case of hemorrhagic blisters after introduction of subcutaneous enoxaparin. However, the lesions were clinically distinct and a histopathological examination was not performed to allow exclusion of other entities, as well as comparison with previouly published cases. Within the LMWH, enoxaparin is more frequently associated with this adverse reaction, probably because it’s the most prescribed one1. This condition is characterized by development of hemorrhagic bullae at sites distant from injection sites10. The bullae typically start within 5–21 days after the initiation of heparin therapy and have been noted mostly on the limbs and abdomen10. Intraepidermal bullae with a lack of thrombotic, vasculitic or significant inflammatory changes are key histopathologic features of this disease and thus can be used to exclude other heparin-induced cutaneous reactions, including skin necrosis, contact dermatitis and urticaria10. The pathogenesis of this condition remains unknown. The presence of skin lesions at sites distant from the injection area, points to a possible systemic effect of the drug rather
Cutan Ocul Toxicol, Early Online: 1–3
than to a local reaction5. The causal link is suggested by a temporal relationship between the introduction of heparin and the beginning of lesions, by the complete resolution of the dermatosis after discontinuation of the drug, as well as the exclusion of other causes. Perrinaud et al.4 hypothesized that the mechanism may be due to an idiosyncratic reaction due to heparin because this drug was the only new drug temporarily associated with the eruption on the patients reported. The hypothesis of overdose has also been proposed since some patients were receiving concomitant warfarin or antiplatelet agents such as aspirin6. However, as in our patient, the dermatosis may occur without the use of other anticoagulants or antiplatelet therapies and without coagulation disorders. A hypersensitivity reaction was suggested by Gonzalez et al6. In their case, the histopathological examination showed an eosinophilic infiltration, however, this finding was not observed in our patient. In previous cases, the resolution of the lesions occurred despite the maintenance of the same anticoagulant regime, while in others, occurred only after patients started an alternative anticoagulant therapy4,10. The interruption or maintenance of treatment is an individual decision. In this case, it was decided to maintain the treatment. The substitution of enoxaparin by alternative anticoagulant therapy may then not be required. The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. Anticoagulants are widely used drugs, therefore clinicians must be aware of the different adverse reactions related to these therapies.
Declaration of interest The authors report no declarations of interest.
References
Figure 1. Clinical features. Vesicles and bullae surrounded by a discrete erythematous halo in the right forearm.
1. Villanueva C, Na´jera L, Espinosa P, Borbujo J. Bullous hemorrhagic dermatosis at distant sites: a report of 2 new cases due to enoxaparin injection and a review of the literature. Actas Dermosifiliogr 2012;103:816–819. 2. Schindewolf M, Lindhoff-Last E, Ludwig RJ, Boehncke W-H. Heparin-induced skin lesions. Lancet 2012;380:1867–1879.
Figure 2. Histopathological examination. Intraepidermal vesicle filled with red blood cells with scarce lymphocytic inflammatory infiltrate. No signs of vasculitis or intravascular thrombus. (A) (H&E, 25) and (B) (H&E, 100).
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
DOI: 10.3109/15569527.2015.1041033
3. Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. CMAJ 2009;181:477–481. 4. Perrinaud A, Jacobi D, Machet MC, et al. Bullous hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: three cases. J Am Acad Dermatol 2006;54:S5–S7. 5. Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases. Br J Dermatol 2009;161:191–193. 6. Gonzales UP, Scott GA, Briones AJ, Pentland AP. Remote hemorrhagic bullae occurring in a patient treated with subcutaneous heparin. Arch Dermatol 2009;145:604–605. 7. Thuillier D, Chaby G, Dadban A, et al. Dermatose bulleuse hemorragique associee a une reaction d’hypersensibilite retardee sous heparine de bas poids moleculaire. Ann Dermatol Venereol 2009;136:705–708. 8. Choudhry S, Fishman P, Hernandez C. Heparin-induced bullous hemorrhagic dermatosis. Cutis 2013;91:93–98. 9. Maldonado Cid P, Moreno Alonso de Celada R, Herranz Pinto P, et al. Bullous hemorrhagic dermatosis at sites distant from
Bullous hemorrhagic dermatosis induced by enoxaparin
10. 11.
12. 13. 14. 15.
3
subcutaneous injections of heparin: a report of 5 cases. J Am Acad Dermatol 2012;67:e220–e222. Pen˜a ZG, Suszko JW, Morrison LH. Hemorrhagic bullae in a 73-year-old man. Bullous hemorrhagic dermatosis related to enoxaparin use. JAMA Dermatol 2013;149:871–872. Loidi Pascual L, Valcayo Pen˜alba A, Yerani Ruiz de Azu´a Ciria A, Yanguas Bayona I. Dermatosis ampollosa hemorra´gica a distancia inducida por heparina: descripcio´n de 2 nuevos casos. Med Clin (Barc) 2014;143:516–517. Oztu¨rk S, Can I, Erden I, et al. Enoxaparin-induced hemorrhagic bullous dermatosis in a leprosy patient. Cutan Ocul Toxicol 2014; 9527:1–3. Concha-Garzon M, Sotomayor-Lopez E, Solano-Lopez G, et al. Bullous hemorrhagic dermatosis distant from the site of heparin injection. Dermatol Online J 2014;15:20. Roux J, Duong TA, Ingen-Housz-Oro S, et al. Heparin-induced hemorrhagic blisters. Eur J Dermatol 2013;23:105–107. Naveen K, Rai V. Bullous hemorrhagic dermatosis: a case report. Indian J Dermatol 2014;59:423.
CASE REPORT
Bullous hemorrhagic dermatosis induced by enoxaparin Ana Isabel Gouveia1, Leonor Lopes1, Luis Soares-Almeida1,2, and Paulo Filipe1,2 Hospital de Santa Maria, University Clinic of Dermatology, Av. Professor Egas Moniz, Lisbon, Portugal and 2Faculdade de Medicina da Universidade de Lisboa, Institute of Molecular Medicine, Research Unit of Dermatology, Lisbon, Portugal
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
1
Abstract
Keywords
The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. We report a 71-year-old man who developed hemorrhagic bullae at sites distant from subcutaneous enoxaparin injections. It is important that clinicians be aware of the different adverse reactions of these widely used drugs.
Adverse drug reaction, bullous dermatoses, enoxaparin, heparin History Received 17 February 2015 Revised 30 March 2015 Accepted 11 April 2015 Published online 5 May 2015
Introduction Heparins are used in the prophylaxis and treatment of thromboembolic diseases. Enoxaparin, a low-molecular weight heparin (LMWH) acts by binding to antithrombin III, causing inhibition of factor Xa1. Some of the most frequent adverse effects of subcutaneous heparin treatment are haemorrhagic complications, heparin-induced thrombocytopenia, osteoporosis, alopecia, elevation of serum transaminases and skin reactions2. Although uncommon, heparin-induced skin lesions are more common than previously thought2. These effects may be caused by at least five mechanisms: delayed hypersensitivity reactions (Type IV) (most common), immunemediated thrombocytopenia, Type I allergic reactions, skin necrosis and pustulosis3. Heparin-induced hemorrhagic bullous dermatosis occurring at a distance from the site of injection is a rare adverse skin reaction1, with few cases described in the literature.
Case report A 71-year-old caucasian man presented with multiple, asymptomatic vesicles and bullae on his limbs. Four weeks prior, he had been started on treatment with enoxaparin sodium (80 mg every 12 h by subcutaneous injection) after receiving the diagnosis of deep vein thrombosis (DVT) of the left leg. Two weeks after starting anticoagulant therapy the patient developed numerous tense, asymptomatic blood-filled vesicles and bullae, surrounded by a discrete erythematous
halo on the forearms, dorsum of hands (Figure 1) and knees. Mucous membranes were normal and no lesions were visible at enoxaparin injection sites. The patient had a past history of giant cell arteritis, diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, benign prostatic hyperplasia, ulcerative colitis and a Scedosporium apiospermum infection on the dorsum of his left foot. His medication included prednisolone, glicazide, omeprazole, calcium carbonate, tiotropium, budesonide/formoterol, tamsolusin and voriconazole. Laboratory tests showed no alteration in complete blood count (including platelets), coagulation study (APTT, PT, INR and fibrinogen) and serum biochemistry, except for a slight increase in gamma GT 63 IU/l (reference values 9–36 IU/l). Histopathological examination of an intact lesion showed an intraepidermal vesicle filled with red blood cells, with scarce lymphocytic inflammatory infiltrate and without signs of vasculitis or intravascular thrombus (Figure 2A and B). Direct immunofluorescence showed no complement or antibody deposition. Based on the physical examination, absence of significant alterations on laboratory tests and histolopathologic findings, the diagnosis of bullous hemorrhagic dermatosis induced by enoxaparin was made. Enoxaparin treatment was maintained for 6 months required for DVT treatment and during this period the lesions waxed and waned. The complete regression of the dermatosis was achieved after discontinuation of enoxaparin, without sequelae.
Discussion Address for correspondence: Ana Isabel Gouveia, Hospital de Santa Maria, University Clinic of Dermatology, Av. Professor Egas Moniz, Lisbon, Portugal. E-mail: [email protected]
Bullous hemorrhagic dermatosis associated with heparins is rare and was first reported in 2006 by Perrinaud et al4. To the
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
2
A. I. Gouveia et al.
best of our knowledge, there were only 22 cases reported previously, 18 secondary to LMWH and 2 after unfractionated heparins1,4–14. Naveen et al.15 also described a case of hemorrhagic blisters after introduction of subcutaneous enoxaparin. However, the lesions were clinically distinct and a histopathological examination was not performed to allow exclusion of other entities, as well as comparison with previouly published cases. Within the LMWH, enoxaparin is more frequently associated with this adverse reaction, probably because it’s the most prescribed one1. This condition is characterized by development of hemorrhagic bullae at sites distant from injection sites10. The bullae typically start within 5–21 days after the initiation of heparin therapy and have been noted mostly on the limbs and abdomen10. Intraepidermal bullae with a lack of thrombotic, vasculitic or significant inflammatory changes are key histopathologic features of this disease and thus can be used to exclude other heparin-induced cutaneous reactions, including skin necrosis, contact dermatitis and urticaria10. The pathogenesis of this condition remains unknown. The presence of skin lesions at sites distant from the injection area, points to a possible systemic effect of the drug rather
Cutan Ocul Toxicol, Early Online: 1–3
than to a local reaction5. The causal link is suggested by a temporal relationship between the introduction of heparin and the beginning of lesions, by the complete resolution of the dermatosis after discontinuation of the drug, as well as the exclusion of other causes. Perrinaud et al.4 hypothesized that the mechanism may be due to an idiosyncratic reaction due to heparin because this drug was the only new drug temporarily associated with the eruption on the patients reported. The hypothesis of overdose has also been proposed since some patients were receiving concomitant warfarin or antiplatelet agents such as aspirin6. However, as in our patient, the dermatosis may occur without the use of other anticoagulants or antiplatelet therapies and without coagulation disorders. A hypersensitivity reaction was suggested by Gonzalez et al6. In their case, the histopathological examination showed an eosinophilic infiltration, however, this finding was not observed in our patient. In previous cases, the resolution of the lesions occurred despite the maintenance of the same anticoagulant regime, while in others, occurred only after patients started an alternative anticoagulant therapy4,10. The interruption or maintenance of treatment is an individual decision. In this case, it was decided to maintain the treatment. The substitution of enoxaparin by alternative anticoagulant therapy may then not be required. The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. Anticoagulants are widely used drugs, therefore clinicians must be aware of the different adverse reactions related to these therapies.
Declaration of interest The authors report no declarations of interest.
References
Figure 1. Clinical features. Vesicles and bullae surrounded by a discrete erythematous halo in the right forearm.
1. Villanueva C, Na´jera L, Espinosa P, Borbujo J. Bullous hemorrhagic dermatosis at distant sites: a report of 2 new cases due to enoxaparin injection and a review of the literature. Actas Dermosifiliogr 2012;103:816–819. 2. Schindewolf M, Lindhoff-Last E, Ludwig RJ, Boehncke W-H. Heparin-induced skin lesions. Lancet 2012;380:1867–1879.
Figure 2. Histopathological examination. Intraepidermal vesicle filled with red blood cells with scarce lymphocytic inflammatory infiltrate. No signs of vasculitis or intravascular thrombus. (A) (H&E, 25) and (B) (H&E, 100).
Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by Nyu Medical Center on 05/25/15 For personal use only.
DOI: 10.3109/15569527.2015.1041033
3. Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. CMAJ 2009;181:477–481. 4. Perrinaud A, Jacobi D, Machet MC, et al. Bullous hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: three cases. J Am Acad Dermatol 2006;54:S5–S7. 5. Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases. Br J Dermatol 2009;161:191–193. 6. Gonzales UP, Scott GA, Briones AJ, Pentland AP. Remote hemorrhagic bullae occurring in a patient treated with subcutaneous heparin. Arch Dermatol 2009;145:604–605. 7. Thuillier D, Chaby G, Dadban A, et al. Dermatose bulleuse hemorragique associee a une reaction d’hypersensibilite retardee sous heparine de bas poids moleculaire. Ann Dermatol Venereol 2009;136:705–708. 8. Choudhry S, Fishman P, Hernandez C. Heparin-induced bullous hemorrhagic dermatosis. Cutis 2013;91:93–98. 9. Maldonado Cid P, Moreno Alonso de Celada R, Herranz Pinto P, et al. Bullous hemorrhagic dermatosis at sites distant from
Bullous hemorrhagic dermatosis induced by enoxaparin
10. 11.
12. 13. 14. 15.
3
subcutaneous injections of heparin: a report of 5 cases. J Am Acad Dermatol 2012;67:e220–e222. Pen˜a ZG, Suszko JW, Morrison LH. Hemorrhagic bullae in a 73-year-old man. Bullous hemorrhagic dermatosis related to enoxaparin use. JAMA Dermatol 2013;149:871–872. Loidi Pascual L, Valcayo Pen˜alba A, Yerani Ruiz de Azu´a Ciria A, Yanguas Bayona I. Dermatosis ampollosa hemorra´gica a distancia inducida por heparina: descripcio´n de 2 nuevos casos. Med Clin (Barc) 2014;143:516–517. Oztu¨rk S, Can I, Erden I, et al. Enoxaparin-induced hemorrhagic bullous dermatosis in a leprosy patient. Cutan Ocul Toxicol 2014; 9527:1–3. Concha-Garzon M, Sotomayor-Lopez E, Solano-Lopez G, et al. Bullous hemorrhagic dermatosis distant from the site of heparin injection. Dermatol Online J 2014;15:20. Roux J, Duong TA, Ingen-Housz-Oro S, et al. Heparin-induced hemorrhagic blisters. Eur J Dermatol 2013;23:105–107. Naveen K, Rai V. Bullous hemorrhagic dermatosis: a case report. Indian J Dermatol 2014;59:423.
