APLASTIC ANEMIA SECONDARY TO 6-MERCAPTOPURINE INITIALLY PRESENTING WITH A HEMORRHAGIC RETINOPATHY Tania Paul, MD,* Scott Warden, MD,* Yoshihiro Yonekawa, BA,* Joseph E. Safdieh, MD,† R. V. Paul Chan, MD*
Purpose: To describe a case of hemorrhagic retinopathy secondary to aplastic anemia caused by 6-mercaptopurine. Methods: A case report of a patient who presented as an outpatient to the Ophthalmology service of the New York Presbyterian Hospital. Conclusion: To the authors’ knowledge, this is the first reported case of hemorrhagic retinopathy secondary to aplastic anemia caused by 6-mercaptopurine. RETINAL CASES & BRIEF REPORTS 3:372–375, 2009
From the *Retina Service, New York-Presbyterian Hospital, †Weill Cornell Medical College Department of Ophthalmology, New York, New York.
Over the ensuing 5 weeks the patient began to develop headaches, hearing changes, blurred vision, fatigue, shortness of breath on exertion, and began experiencing new heart palpitations. Physical examination was notable for a blood pressure of 104/52 mmHg and a pulse of 95. Otherwise, physical examination was normal. The patient underwent an MRI/MRV of the head and lumbar puncture, which were nondiagnostic. In the course of the patient’s workup he was referred to Ophthalmology for an outpatient evaluation of blurred vision. On examination, the patient’s vision was 20/30 in the right eye and 20/20 in the left. No afferent papillary defect was present and ocular motility was full in both eyes. Intraocular pressure was 7 mmHg in both eyes. Anterior segment examination was unremarkable. Dilated funduscopic examination revealed a hemorrhagic retinopathy in both eyes with scattered intraretinal hemorrhage and Roth’s spots in the posterior pole (Figure 1). Fluorescein angiogram showed blocking defects consistent with the areas of hemorrhage seen on dilated fundus examination (Figure 2). The patient was admitted to the hospital for further laboratory workup which revealed hemoglobin of 4.8, WBC of 3.4, and a platelet count of 117. On differential, poikilocytosis and HowellJowell bodies were noted. Vitamin B12 and folate were within normal limits. Iron and ferritin were high, while TIBC was low. There was no evidence of blood parasites on blood sampling. An echocardiogram was performed which showed no evidence of endocarditis. In addition, a bone marrow biopsy was performed which showed hypocellular marrow, and no evidence of lymphoproliferative or infiltrative disorders. HIV and syphilis testing were negative. Autoimmune workup and viral workup were also negative. Because 6-mercaptopurine is also associated with myelosuppression, the patient was checked for levels of thiopurine methyltransferase (an enzyme that is involved in the metabolism of purine derived medications such as 6-mercaptopurine).1 It was noted that the patient was a heterozygote for the gene responsible for gener-
A
plastic anemia is a rare hematologic disorder causing pancytopenia and hypocellular bone marrow. Ocular findings include Roth’s spots, cotton wool spots, and intraretinal, preretinal, and vitreous hemorrhage. Aplastic anemia can result from autoimmune, drug-induced, malignancy, and viral etiologies. We present a case of aplastic anemia that resulted from 6-mercaptopurine use and initially presented with blurred vision and a hemorrhagic retinopathy. Case Report A 32-year-old man with a history of ulcerative colitis being treated with 6-mercaptopurine presented to the Neurology service of the New York Presbyterian Hospital, Weill Cornell Medical Center, complaining of blurred vision and headaches. The patient reported he had been started on 6-mercaptopurine 1.5 years previously for ulcerative colitis for a total of 8 months. After a recent recurrence of colitis, the patient was restarted on 6-mercaptopurine. Support provided by the St. Giles Foundation. None of the authors has any financial interest to disclose. Reprint requests: R.V. Paul Chan, MD, St. Giles Assistant Professor of Pediatric Retina, New York-Presbyterian Hospital, Weill Cornell Medical College, Department of Ophthalmology, 1305 York Avenue, New York, NY, 10021; e-mail: roc9013@ med.cornell.edu
372
ROTH’S SPOTS AND 6-MERCAPTOPURINE
373
Fig. 1. Fundus photographs reveal scattered Roth’s spots, dot-blot hemorrhages, and flame hemorrhages over the posterior pole in both eyes.
ating thiopurine methyltransferase, and as a result had low levels of functional thiopurine methyltransferase. As a result of the laboratory workup, the patient received several blood transfusions and the 6-mercaptopurine was discontinued. The patient’s hematologic counts improved and stabilized, and after 5 days in the hospital, the patient was discharged home in good condition. Over the next month the patient’s blood counts continued to improve and the retinal hemorrhages gradually resolved.
Discussion There have been several case reports of patients developing aplastic anemia with purine antimetabolites such as azathioprine and 6-mercaptopurine.2 Azathioprine is also a purine antimetabolite and is metabolized in the body to 6-mercaptopurine and to 6-thioinosinic acid. Purine antimetabolites are used to treat autoimmune conditions such as graft rejection, leukemia, lymphoma, rheumatoid arthritis, and in-
Fig. 2. Fluorescein angiogram reveals blocking defects from the intraretinal hemorrhages in both eyes.
flammatory bowel disease. To our knowledge, we present the first case of aplastic anemia associated with 6-mercaptopurine use that initially presented with blurred vision and a hemorrhagic retinopathy. A rare side effect of antimetabolite medications is myelosuppression. Patients with a deficiency of thiopurine methyltransferase are much more susceptible to developing toxic levels of purine antagonists which places them at greater risk of side effects from these medications. Our patient’s deficiency in thiopurine methyltransferase likely resulted in elevated levels of available 6-mercaptopurine creating a relatively toxic
374
RETINAL CASES & BRIEF REPORTSℜ
environment for the hematopoietic stem cells resulting in aplastic anemia. Aplastic anemia is a disease that occurs in all ages, but is especially prevalent between ages 15 and 25 years.3 The most common etiology is autoimmune, but aplastic anemia can also be inherited, drug-induced, and caused by viral illnesses. The histocompatibility locus HLA DR2 is especially associated with a predisposition to acquiring aplastic anemia.4 Aplastic anemia can present quickly or slowly over weeks to months. Patients can present with shortness of breath, easy bruising, petechiae, epistaxis, gingival bleeding, headache, fever, heavy menstrual periods, and fatigue.3 Workup should include CBC, differential, reticulocyte count, bone marrow aspirate and biopsy, flow cytometry, and karyotyping of bonemarrow aspirate.3 Aplastic anemia develops as a result of damage to the bone marrow stem cells or to the cellular microenvironment of the stem cells. Patients with aplastic anemia will have hypocellular bone marrow on bone marrow biopsy and pancytopenia.3 Patients with mild aplastic anemia rarely need treatment and rarely result in death, whereas patients with severe aplastic anemia have a mortality rate that is close to 80%.3,5 Drug-induced aplastic anemia, which was the etiology of the anemia in the case we present, is thought to be related to an autoimmune phenomenon, though no clear mechanism has been elucidated to explain how or why certain drugs (such as chloramphenicol and penicillamine) are more frequently associated with aplastic anemia. It is believed that either the initial exposure to a drug causes an abnormal immune response which produces cytotoxic T cells that destroy hematopoietic stem cells which then leads to aplastic anemia, or the drug generates a toxic microcellular environment for the marrow stem cells. Interestingly, there have been case reports linking ulcerative colitis and aplastic anemia— both potentially autoimmune processes.6,7 This association between ulcerative colitis and aplastic anemia is very rare, thus it is more likely that our patient developed a drug-induced aplastic anemia rather than a primary autoimmune aplastic anemia. There are three main modalities of treatment for severe aplastic anemia: allogenic bone-marrow transplantation (for all types of aplastic anemias), immunosuppressive therapy such as antithymocyte globulin and cyclosporin (for immune related aplastic anemia), and high-dose cyclophosphamide.3 Hemorrhagic retinopathy in patients with blood dyscrasias including leukemia, anemia, and thrombocytopenia has been well described. In general, most cases are asymptomatic even though up to 50% of
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leukemic patients will have ocular findings.8 Ocular findings in aplastic anemia include nerve fiber layer hemorrhages, cotton wool spots, preretinal hemorrhages, Roth’s spots, vitreous hemorrhage, eyelid hematomas, subconjunctival hemorrhage, conjunctival blanching, premacular hemorrhage, and disk edema. These findings stem from vascular changes that occur with anemia. Blood vessels in an anemic patient become dilated and tortuous.9 It is hypothesized that in severe anemia, vessel wall dilation, increased blood flow, and decreased endothelial cellular integrity permit easy passage of erythrocytes through vessels. This occurs because platelet counts are also low, and there are insufficient numbers of platelets to block areas of vessel leakage.10 Severe anemia can also cause retinal ischemia (seen as cotton wool spots). Cotton wool spots occur when hemoglobin is below 7.8/100 mL.10,11 Retinal hemorrhages occur when hemoglobin is less than 7 g/100 mL, and also when the platelet count is low (below 50,000/mm3).10 –12 Roth’s spots, as seen in the case presented, are found both in bacterial endocarditis and in blood dyscrasias. These white centered hemorrhages represent capillary rupture with a central area of fibrin deposition with extravasated blood surrounding the white fibrin.8 This case is just another example of how lifethreatening medical illnesses can initially present with ocular findings, and prompt referral to the appropriate medical subspecialist is important in preventing morbidity and mortality. In addition, to our knowledge this case is the first presentation of aplastic anemia caused by 6-mercaptopurine that initially presented with blurred vision and a hemorrhagic retinopathy. This case was also important in highlighting the importance of assessing levels of thiopurine methyltransferase in patients who present with hemorrhagic retinopathy and who are taking purine antagonists. This assessment can be done in conjunction with hematology to measure levels of thiopurine methyltransferases as well as investigating possible development of aplastic anemia.
References 1.
2.
3.
Al Hadithy AF, de Boer NK, Derijks LJ, et al. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 2005;37:282–297. Sudhir RR, Rao SK, Shanmugam MP, Padmanabhan P. Bilateral macular hemorrhage caused by azathioprine-induced aplastic anemia in a corneal graft recipient. Cornea 2002;21: 712–714. Brodsky RA, Jones RJ. Aplastic anemia. Lancet 2005;365: 1647–1656.
375
ROTH’S SPOTS AND 6-MERCAPTOPURINE 4.
5.
6.
7.
Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood 1994;84:923–927. Camitta BM, Thomas ED, Nathan DG, et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 1979;53:504–514. Kishikawa H, Nishida J, Nakano M, et al. Ulcerative colitis associated with aplastic anemia. Dig Dis Sci 2003;48:1376– 1379. Sharma BC, Yachha SK, Mishra RN, Gupta D. Hypoplastic anemia associated with ulcerative colitis in a child. J Pediatr Gastroenterol Nutr 1996;23:326–328.
8. 9.
10. 11. 12.
Duane TD, Osher RH, Green WR. White centered hemorrhages: their significance. Ophthalmology 1980;87:66–69. Aisen ML, Bacon BR, Goodman AM, Chester EM. Retinal abnormalities associated with anemia. Arch Ophthalmol 1983;101:1049–1052. Mansour AM, Salti HI, Han DP, et al. Ocular findings in aplastic anemia. Opthalmogica 2000;214:399 – 402. Holt JM, Gordon-Smith EC. Retinal abnormalities in diseases of the blood. Br J Ophthalmol 1969;53:145–160. Rubenstein RA, Yanoff M, Albert DM. Thrombocytopenia, anemia, and retinal hemorrhage. Am J Ophthalmol 1968;65: 435–439.
Purpose: To describe a case of hemorrhagic retinopathy secondary to aplastic anemia caused by 6-mercaptopurine. Methods: A case report of a patient who presented as an outpatient to the Ophthalmology service of the New York Presbyterian Hospital. Conclusion: To the authors’ knowledge, this is the first reported case of hemorrhagic retinopathy secondary to aplastic anemia caused by 6-mercaptopurine. RETINAL CASES & BRIEF REPORTS 3:372–375, 2009
From the *Retina Service, New York-Presbyterian Hospital, †Weill Cornell Medical College Department of Ophthalmology, New York, New York.
Over the ensuing 5 weeks the patient began to develop headaches, hearing changes, blurred vision, fatigue, shortness of breath on exertion, and began experiencing new heart palpitations. Physical examination was notable for a blood pressure of 104/52 mmHg and a pulse of 95. Otherwise, physical examination was normal. The patient underwent an MRI/MRV of the head and lumbar puncture, which were nondiagnostic. In the course of the patient’s workup he was referred to Ophthalmology for an outpatient evaluation of blurred vision. On examination, the patient’s vision was 20/30 in the right eye and 20/20 in the left. No afferent papillary defect was present and ocular motility was full in both eyes. Intraocular pressure was 7 mmHg in both eyes. Anterior segment examination was unremarkable. Dilated funduscopic examination revealed a hemorrhagic retinopathy in both eyes with scattered intraretinal hemorrhage and Roth’s spots in the posterior pole (Figure 1). Fluorescein angiogram showed blocking defects consistent with the areas of hemorrhage seen on dilated fundus examination (Figure 2). The patient was admitted to the hospital for further laboratory workup which revealed hemoglobin of 4.8, WBC of 3.4, and a platelet count of 117. On differential, poikilocytosis and HowellJowell bodies were noted. Vitamin B12 and folate were within normal limits. Iron and ferritin were high, while TIBC was low. There was no evidence of blood parasites on blood sampling. An echocardiogram was performed which showed no evidence of endocarditis. In addition, a bone marrow biopsy was performed which showed hypocellular marrow, and no evidence of lymphoproliferative or infiltrative disorders. HIV and syphilis testing were negative. Autoimmune workup and viral workup were also negative. Because 6-mercaptopurine is also associated with myelosuppression, the patient was checked for levels of thiopurine methyltransferase (an enzyme that is involved in the metabolism of purine derived medications such as 6-mercaptopurine).1 It was noted that the patient was a heterozygote for the gene responsible for gener-
A
plastic anemia is a rare hematologic disorder causing pancytopenia and hypocellular bone marrow. Ocular findings include Roth’s spots, cotton wool spots, and intraretinal, preretinal, and vitreous hemorrhage. Aplastic anemia can result from autoimmune, drug-induced, malignancy, and viral etiologies. We present a case of aplastic anemia that resulted from 6-mercaptopurine use and initially presented with blurred vision and a hemorrhagic retinopathy. Case Report A 32-year-old man with a history of ulcerative colitis being treated with 6-mercaptopurine presented to the Neurology service of the New York Presbyterian Hospital, Weill Cornell Medical Center, complaining of blurred vision and headaches. The patient reported he had been started on 6-mercaptopurine 1.5 years previously for ulcerative colitis for a total of 8 months. After a recent recurrence of colitis, the patient was restarted on 6-mercaptopurine. Support provided by the St. Giles Foundation. None of the authors has any financial interest to disclose. Reprint requests: R.V. Paul Chan, MD, St. Giles Assistant Professor of Pediatric Retina, New York-Presbyterian Hospital, Weill Cornell Medical College, Department of Ophthalmology, 1305 York Avenue, New York, NY, 10021; e-mail: roc9013@ med.cornell.edu
372
ROTH’S SPOTS AND 6-MERCAPTOPURINE
373
Fig. 1. Fundus photographs reveal scattered Roth’s spots, dot-blot hemorrhages, and flame hemorrhages over the posterior pole in both eyes.
ating thiopurine methyltransferase, and as a result had low levels of functional thiopurine methyltransferase. As a result of the laboratory workup, the patient received several blood transfusions and the 6-mercaptopurine was discontinued. The patient’s hematologic counts improved and stabilized, and after 5 days in the hospital, the patient was discharged home in good condition. Over the next month the patient’s blood counts continued to improve and the retinal hemorrhages gradually resolved.
Discussion There have been several case reports of patients developing aplastic anemia with purine antimetabolites such as azathioprine and 6-mercaptopurine.2 Azathioprine is also a purine antimetabolite and is metabolized in the body to 6-mercaptopurine and to 6-thioinosinic acid. Purine antimetabolites are used to treat autoimmune conditions such as graft rejection, leukemia, lymphoma, rheumatoid arthritis, and in-
Fig. 2. Fluorescein angiogram reveals blocking defects from the intraretinal hemorrhages in both eyes.
flammatory bowel disease. To our knowledge, we present the first case of aplastic anemia associated with 6-mercaptopurine use that initially presented with blurred vision and a hemorrhagic retinopathy. A rare side effect of antimetabolite medications is myelosuppression. Patients with a deficiency of thiopurine methyltransferase are much more susceptible to developing toxic levels of purine antagonists which places them at greater risk of side effects from these medications. Our patient’s deficiency in thiopurine methyltransferase likely resulted in elevated levels of available 6-mercaptopurine creating a relatively toxic
374
RETINAL CASES & BRIEF REPORTSℜ
environment for the hematopoietic stem cells resulting in aplastic anemia. Aplastic anemia is a disease that occurs in all ages, but is especially prevalent between ages 15 and 25 years.3 The most common etiology is autoimmune, but aplastic anemia can also be inherited, drug-induced, and caused by viral illnesses. The histocompatibility locus HLA DR2 is especially associated with a predisposition to acquiring aplastic anemia.4 Aplastic anemia can present quickly or slowly over weeks to months. Patients can present with shortness of breath, easy bruising, petechiae, epistaxis, gingival bleeding, headache, fever, heavy menstrual periods, and fatigue.3 Workup should include CBC, differential, reticulocyte count, bone marrow aspirate and biopsy, flow cytometry, and karyotyping of bonemarrow aspirate.3 Aplastic anemia develops as a result of damage to the bone marrow stem cells or to the cellular microenvironment of the stem cells. Patients with aplastic anemia will have hypocellular bone marrow on bone marrow biopsy and pancytopenia.3 Patients with mild aplastic anemia rarely need treatment and rarely result in death, whereas patients with severe aplastic anemia have a mortality rate that is close to 80%.3,5 Drug-induced aplastic anemia, which was the etiology of the anemia in the case we present, is thought to be related to an autoimmune phenomenon, though no clear mechanism has been elucidated to explain how or why certain drugs (such as chloramphenicol and penicillamine) are more frequently associated with aplastic anemia. It is believed that either the initial exposure to a drug causes an abnormal immune response which produces cytotoxic T cells that destroy hematopoietic stem cells which then leads to aplastic anemia, or the drug generates a toxic microcellular environment for the marrow stem cells. Interestingly, there have been case reports linking ulcerative colitis and aplastic anemia— both potentially autoimmune processes.6,7 This association between ulcerative colitis and aplastic anemia is very rare, thus it is more likely that our patient developed a drug-induced aplastic anemia rather than a primary autoimmune aplastic anemia. There are three main modalities of treatment for severe aplastic anemia: allogenic bone-marrow transplantation (for all types of aplastic anemias), immunosuppressive therapy such as antithymocyte globulin and cyclosporin (for immune related aplastic anemia), and high-dose cyclophosphamide.3 Hemorrhagic retinopathy in patients with blood dyscrasias including leukemia, anemia, and thrombocytopenia has been well described. In general, most cases are asymptomatic even though up to 50% of
●
2009
●
VOLUME 3
●
NUMBER 4
leukemic patients will have ocular findings.8 Ocular findings in aplastic anemia include nerve fiber layer hemorrhages, cotton wool spots, preretinal hemorrhages, Roth’s spots, vitreous hemorrhage, eyelid hematomas, subconjunctival hemorrhage, conjunctival blanching, premacular hemorrhage, and disk edema. These findings stem from vascular changes that occur with anemia. Blood vessels in an anemic patient become dilated and tortuous.9 It is hypothesized that in severe anemia, vessel wall dilation, increased blood flow, and decreased endothelial cellular integrity permit easy passage of erythrocytes through vessels. This occurs because platelet counts are also low, and there are insufficient numbers of platelets to block areas of vessel leakage.10 Severe anemia can also cause retinal ischemia (seen as cotton wool spots). Cotton wool spots occur when hemoglobin is below 7.8/100 mL.10,11 Retinal hemorrhages occur when hemoglobin is less than 7 g/100 mL, and also when the platelet count is low (below 50,000/mm3).10 –12 Roth’s spots, as seen in the case presented, are found both in bacterial endocarditis and in blood dyscrasias. These white centered hemorrhages represent capillary rupture with a central area of fibrin deposition with extravasated blood surrounding the white fibrin.8 This case is just another example of how lifethreatening medical illnesses can initially present with ocular findings, and prompt referral to the appropriate medical subspecialist is important in preventing morbidity and mortality. In addition, to our knowledge this case is the first presentation of aplastic anemia caused by 6-mercaptopurine that initially presented with blurred vision and a hemorrhagic retinopathy. This case was also important in highlighting the importance of assessing levels of thiopurine methyltransferase in patients who present with hemorrhagic retinopathy and who are taking purine antagonists. This assessment can be done in conjunction with hematology to measure levels of thiopurine methyltransferases as well as investigating possible development of aplastic anemia.
References 1.
2.
3.
Al Hadithy AF, de Boer NK, Derijks LJ, et al. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 2005;37:282–297. Sudhir RR, Rao SK, Shanmugam MP, Padmanabhan P. Bilateral macular hemorrhage caused by azathioprine-induced aplastic anemia in a corneal graft recipient. Cornea 2002;21: 712–714. Brodsky RA, Jones RJ. Aplastic anemia. Lancet 2005;365: 1647–1656.
375
ROTH’S SPOTS AND 6-MERCAPTOPURINE 4.
5.
6.
7.
Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood 1994;84:923–927. Camitta BM, Thomas ED, Nathan DG, et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 1979;53:504–514. Kishikawa H, Nishida J, Nakano M, et al. Ulcerative colitis associated with aplastic anemia. Dig Dis Sci 2003;48:1376– 1379. Sharma BC, Yachha SK, Mishra RN, Gupta D. Hypoplastic anemia associated with ulcerative colitis in a child. J Pediatr Gastroenterol Nutr 1996;23:326–328.
8. 9.
10. 11. 12.
Duane TD, Osher RH, Green WR. White centered hemorrhages: their significance. Ophthalmology 1980;87:66–69. Aisen ML, Bacon BR, Goodman AM, Chester EM. Retinal abnormalities associated with anemia. Arch Ophthalmol 1983;101:1049–1052. Mansour AM, Salti HI, Han DP, et al. Ocular findings in aplastic anemia. Opthalmogica 2000;214:399 – 402. Holt JM, Gordon-Smith EC. Retinal abnormalities in diseases of the blood. Br J Ophthalmol 1969;53:145–160. Rubenstein RA, Yanoff M, Albert DM. Thrombocytopenia, anemia, and retinal hemorrhage. Am J Ophthalmol 1968;65: 435–439.
