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Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.
Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.
Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al
Case Report
An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.
Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.
Upon further questioning, the patient revealed a history of similar oral lesions 1 year prior, following exposure to subcutaneous enoxaparin. At that time, formal evaluation by dermatology was deferred due to the rapid resolution of the blisters. Despite these new oral lesions, the patient was continued on a heparin drip for the next 48 hours because of the mortality benefit of heparin in non–ST-segment elevation MI. The patient was discharged from the hospital on a regimen of aspirin, warfarin, and clopidogrel. At 2-week follow-up, the oral lesions had resolved (Figure, C and D).
Comment
Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.
Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.
Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.
Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.
Differential Diagnosis
Our patient’s lesions appeared morphologically similar to
Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.12
Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.
Conclusion
We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.
- Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G, et al. Discovery of anticoagulant drugs: a historical perspective. Curr Drug Discov Technol. 2012;9:83-104.
- Noti C, Seeberger PH. Chemical approaches to define the structure-activity relationship of heparin-like glycosaminoglycans. Chem Biol. 2005;12:731-756.
- Bakchoul T. An update on heparin-induced thrombocytopenia: diagnosis and management. Expert Opin Drug Saf. 2016;15:787-797.
- Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. Can Med Assoc J. 2009;181:477-481.
- 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(2 suppl):S5-S7.
- Naveen KN, Rai V. Bullous hemorrhagic dermatosis: a case report. Indian J Dermatol. 2014;59:423.
- Choudhry S, Fishman PM, Hernandez C. Heparin-induced bullous hemorrhagic dermatosis. Cutis. 2013;91:93-98.
- Villanueva CA, Nájera L, Espinosa P, et al. 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.
- Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83:575-582.
- Horie N, Kawano R, Inaba J, et al. Angina bullosa hemorrhagica of the soft palate: a clinical study of 16 cases. J Oral Sci. 2008;50:33-36.
- Rai S, Kaur M, Goel S. Angina bullosa hemorrhagica: report of 2 cases. Indian J Dermatol. 2012;57:503.
- Lawson W. Bullous oral lesions: clues to identifying—and managing—the cause. Consultant. 2013;53:168-176.
Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.
Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.
Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al
Case Report
An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.
Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.
Upon further questioning, the patient revealed a history of similar oral lesions 1 year prior, following exposure to subcutaneous enoxaparin. At that time, formal evaluation by dermatology was deferred due to the rapid resolution of the blisters. Despite these new oral lesions, the patient was continued on a heparin drip for the next 48 hours because of the mortality benefit of heparin in non–ST-segment elevation MI. The patient was discharged from the hospital on a regimen of aspirin, warfarin, and clopidogrel. At 2-week follow-up, the oral lesions had resolved (Figure, C and D).
Comment
Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.
Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.
Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.
Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.
Differential Diagnosis
Our patient’s lesions appeared morphologically similar to
Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.12
Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.
Conclusion
We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.
Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.
Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.
Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al
Case Report
An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.
Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.
Upon further questioning, the patient revealed a history of similar oral lesions 1 year prior, following exposure to subcutaneous enoxaparin. At that time, formal evaluation by dermatology was deferred due to the rapid resolution of the blisters. Despite these new oral lesions, the patient was continued on a heparin drip for the next 48 hours because of the mortality benefit of heparin in non–ST-segment elevation MI. The patient was discharged from the hospital on a regimen of aspirin, warfarin, and clopidogrel. At 2-week follow-up, the oral lesions had resolved (Figure, C and D).
Comment
Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.
Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.
Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.
Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.
Differential Diagnosis
Our patient’s lesions appeared morphologically similar to
Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.12
Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.
Conclusion
We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.
- Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G, et al. Discovery of anticoagulant drugs: a historical perspective. Curr Drug Discov Technol. 2012;9:83-104.
- Noti C, Seeberger PH. Chemical approaches to define the structure-activity relationship of heparin-like glycosaminoglycans. Chem Biol. 2005;12:731-756.
- Bakchoul T. An update on heparin-induced thrombocytopenia: diagnosis and management. Expert Opin Drug Saf. 2016;15:787-797.
- Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. Can Med Assoc J. 2009;181:477-481.
- 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(2 suppl):S5-S7.
- Naveen KN, Rai V. Bullous hemorrhagic dermatosis: a case report. Indian J Dermatol. 2014;59:423.
- Choudhry S, Fishman PM, Hernandez C. Heparin-induced bullous hemorrhagic dermatosis. Cutis. 2013;91:93-98.
- Villanueva CA, Nájera L, Espinosa P, et al. 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.
- Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83:575-582.
- Horie N, Kawano R, Inaba J, et al. Angina bullosa hemorrhagica of the soft palate: a clinical study of 16 cases. J Oral Sci. 2008;50:33-36.
- Rai S, Kaur M, Goel S. Angina bullosa hemorrhagica: report of 2 cases. Indian J Dermatol. 2012;57:503.
- Lawson W. Bullous oral lesions: clues to identifying—and managing—the cause. Consultant. 2013;53:168-176.
- Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G, et al. Discovery of anticoagulant drugs: a historical perspective. Curr Drug Discov Technol. 2012;9:83-104.
- Noti C, Seeberger PH. Chemical approaches to define the structure-activity relationship of heparin-like glycosaminoglycans. Chem Biol. 2005;12:731-756.
- Bakchoul T. An update on heparin-induced thrombocytopenia: diagnosis and management. Expert Opin Drug Saf. 2016;15:787-797.
- Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. Can Med Assoc J. 2009;181:477-481.
- 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(2 suppl):S5-S7.
- Naveen KN, Rai V. Bullous hemorrhagic dermatosis: a case report. Indian J Dermatol. 2014;59:423.
- Choudhry S, Fishman PM, Hernandez C. Heparin-induced bullous hemorrhagic dermatosis. Cutis. 2013;91:93-98.
- Villanueva CA, Nájera L, Espinosa P, et al. 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.
- Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83:575-582.
- Horie N, Kawano R, Inaba J, et al. Angina bullosa hemorrhagica of the soft palate: a clinical study of 16 cases. J Oral Sci. 2008;50:33-36.
- Rai S, Kaur M, Goel S. Angina bullosa hemorrhagica: report of 2 cases. Indian J Dermatol. 2012;57:503.
- Lawson W. Bullous oral lesions: clues to identifying—and managing—the cause. Consultant. 2013;53:168-176.
Practice Points
- It is important for physicians to recognize the clinical appearance of cutaneous adverse reactions to heparin, including bullous hemorrhagic dermatosis.
- Heparin-induced bullous hemorrhagic dermatosis tends to self-resolve, even with continuation of unfractionated heparin.
