HYPERCOAGULABLE STATE IN A PATIENT WITH A RETINAL VEIN OCCLUSION Apkarian O. Alexandra, MD, Kimberly A. Drenser, MD, PhD
Purpose: The purpose of this study was to report unusual findings from a hypercoagulability workup of a patient with a retinal vein occlusion and to suggest the importance of investigating hypercoagulability in patients with similar presentations. Methods: This is a retrospective case report of a patient seen in the clinic during a several-month period. Results: The laboratory evaluation of the patient showed decreased antithrombin III activity and a prothrombin mutation, and platelet evaluation was consistent with sticky platelet syndrome. Conclusion: It is important to take a detailed history and pursue the possibility of hypercoagulability as an etiology for retinal vein occlusion in patients outside the classic, younger age group. This can lead to prompt intervention and possible prevention of future thrombotic events. RETINAL CASES & BRIEF REPORTS 5:76–78, 2011
From the Associated Retinal Consultants and William Beaumont Hospital, Royal Oak, Michigan.
Case Report Our patient was a 59-year-old woman who was referred by her general ophthalmologist for further evaluation. She reported seeing flashes, without floaters, and transient blurring of vision in her right eye during the week before presentation. Her medical history was only remarkable for multiple miscarriages. She had no surgical history. Her only medication was Lipitor. On examination, her best-corrected vision was 20/302 in the right eye and 20/25+ in the left eye. Pressures by applanation were 17 and 19 in the right and the left eyes, respectively. External and slit-lamp examinations were unremarkable. Fundus examination in the right eye demonstrated a slightly erythematous disk with ,0.1 cup-to-disk ratio and a small RVO in the superonasal arcade (Figures 1 and 2). There were small punctate dot/blot hemorrhages in the macular region and an occasional peripheral intraretinal hemorrhage. The left fundus was remarkable for a cup-to-disk ratio of 0.1 to 0.2, some arteriosclerosis, and mild arterio-venous (AV) nicking. The patient was sent for fluorescein angiography, which showed mildly delayed venous blood flow and a hyperfiuorescent disk (Figures 3 and 4). The patient also had an erythrocyte sedmentation rate (ESR) and C-reactive protein sent to assess active inflammation, which returned within the normal range. Given the patient’s history and examination, we recommended that the patient be seen by her primary care physician for further workup of blood dyscrasias and hypercoagulability, as well as to ensure normal blood pressure, glucose, and lipids. She underwent a thorough hypercoagulability workup. Homocysteine level, protein S activity, anticardiolipin antibodies, factor V Leiden, protein immunofixation, and phospholipid level all returned normal. Protein C activity was actually 150%, slightly above the
R
etinal vein occlusion (RVO) represents an important cause of ocular morbidity, commonly affecting patients older than 65 years. Risk factors for RVO include systemic hypertension, diabetes, hyperlipidemia, glaucoma, smoking, and atherosclerosis.1 In younger patients, this condition has also been associated with systemic inflammatory conditions and hypercoagulable states.2 Management of RVO is aimed at preventing vision-threatening complications. It consists of regular follow-up visits and laser photocoagulation (if neovascularization is present).3,4 Medical management is often targeted at underlying risk factors, such as hypertension and diabetes.5 Given a demonstrated association between hypercoagulable states and retinal vein thrombosis,6,7 it is important to initiate a hypercoagulability workup in younger patients, as well as older patients without hypertension or other common risk factors who present with RVO. The authors have no conflicts of interest to disclose. Reprint requests: Kimberly A. Drenser, MD, PhD, Associated Retinal Consultants, 555 William Beaumont Medical Building, 3535 West 13 Mile Road, Royal Oak, MI 48073; e-mail: [email protected]
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Fig. 1. Fundus photograph of the right eye at the time of diagnosis.
Fig. 3. Fluorescein angiography of the right eye at diagnosis.
normal range of 70% to 140%. She also had a borderline antinuclear antibody (ANA), with a titer ,l:160. However, portions of the patient’s hypercoagulability workup were abnormal. First, she was found to have significantly reduced antithrombin III activity at 3% (normal range is 80-120%). Second, she was found to be heterozygous for the prothrombin G202210A mutation. Finally, evaluation of her platelets was consistent with sticky platelet syndrome.
Our patient’s workup revealed multiple hematologic abnormalities. Antithrombin III deficiency is usually inherited as an autosomal dominant trait.8 Because antithrombin normally acts to inhibit thrombin (factor Ha) and other serine proteinases in the clotting cascade, its deficiency results in the prolonged circulation of clotting factors. Antithrombin III
deficiency is therefore associated with increased risk of thrombus formation.9 Prothrombin G20210A mutation is associated with a single nucleotide polymorphism in a gene coding for blood coagulation factors, which causes increased production of a procoagulant protein. It is associated with an increased incidence of thrombosis, especially when present together with other thrombotic risk factors.10 Finally, sticky platelet syndrome is a congenital, autosomal dominant disorder characterized by hyperaggregability of platelets in response to adenosine phosphate (ADP), epinephrine, or both. Clinically, it is associated with arterial and venous thromboembolic events, including retinal thrombosis. Low-dose aspirin treatment (80-100 mg) alleviates symptoms and decreases platelet hyperaggregability.11
Fig. 2. Fundus photograph of the right eye at the time of diagnosis.
Fig. 4. Fluorescein angiography of the right eye at diagnosis.
Discussion
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RETINAL CASES & BRIEF REPORTS´ 2011 VOLUME 5 NUMBER 1
The coexistence and synergistic effect of these prothrombotic hematologic alterations placed our patient at significant risk for another thrombotic event. She therefore started and has been maintained on coumadin therapy. Given the possibility of recurrent thrombosis with oral anticoagulant therapy alone in patients with sticky platelet syndrome, she was concurrently maintained on low-dose aspirin therapy. On initial follow-up examination, the patient’s intraretinal hemorrhages remained stable, and there was no evidence of macular edema. She continues to deny any new visual symptoms or any decrease in visual acuity since that time. Our patient’s history of multiple miscarriages was an important factor in prompting a hypercoagulability workup. Prothrombin mutation, antithrombin III deficiency, and sticky platelet syndrome represent likely etiologies for her ophthalmologic condition and obstetric history. Most importantly, they indicate the need for adequate anticoagulation to prevent future thrombotic events. This case emphasizes the importance of considering hypercoagulability as a possible etiology for RVO in patients who may be in an older, more classic age group but who do not have hypertension or other common risk factors. These patients may have milder hematologic abnormalities, which have not previously caused appreciable morbidity. However, these patients will likely have a lower threshold for thrombosis, with the addition of risk factors associated with advancing age. Identifying these patients can lead to prompt medical intervention and possible prevention of both ocular and nonocular thrombotic events.
Key words: vein occlusion, retina, hypercoagulation, autoimmune, clotting, dyscrasia, inflammatory. References 1. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 2. Fong AC, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol 1993;38:88. 3. Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. Arch Ophthalmol 1986;104:34–41. 4. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol 1997;115:486–491. 5. Phillips S, Fekrat S, Finkelstein D. Branch Retinal Vein Occlusion. Retina 2006;2:1348–1354. 6. Lahey JM, Tune M, Kearney J, et al. Laboratory evaluation of hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology 2002;109:126–131. 7. Cahill MT, Stinnett SS, Fekrat S. Meta-analysis of plasma homocysteine, serum folate, serum vitamin B12, and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease. Am J Ophthalmol 2003;136:1136–1150. 8. Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism [review]. Clin Hematol 1981;10:369–390. 9. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67:1429–1440. 10. Aznar J, Vaya A, Estelles A, et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000;85:1271–1276. 11. Mammen EF. Sticky platelet syndrome. Semin Thromb He most 1999;25:361–365.
Purpose: The purpose of this study was to report unusual findings from a hypercoagulability workup of a patient with a retinal vein occlusion and to suggest the importance of investigating hypercoagulability in patients with similar presentations. Methods: This is a retrospective case report of a patient seen in the clinic during a several-month period. Results: The laboratory evaluation of the patient showed decreased antithrombin III activity and a prothrombin mutation, and platelet evaluation was consistent with sticky platelet syndrome. Conclusion: It is important to take a detailed history and pursue the possibility of hypercoagulability as an etiology for retinal vein occlusion in patients outside the classic, younger age group. This can lead to prompt intervention and possible prevention of future thrombotic events. RETINAL CASES & BRIEF REPORTS 5:76–78, 2011
From the Associated Retinal Consultants and William Beaumont Hospital, Royal Oak, Michigan.
Case Report Our patient was a 59-year-old woman who was referred by her general ophthalmologist for further evaluation. She reported seeing flashes, without floaters, and transient blurring of vision in her right eye during the week before presentation. Her medical history was only remarkable for multiple miscarriages. She had no surgical history. Her only medication was Lipitor. On examination, her best-corrected vision was 20/302 in the right eye and 20/25+ in the left eye. Pressures by applanation were 17 and 19 in the right and the left eyes, respectively. External and slit-lamp examinations were unremarkable. Fundus examination in the right eye demonstrated a slightly erythematous disk with ,0.1 cup-to-disk ratio and a small RVO in the superonasal arcade (Figures 1 and 2). There were small punctate dot/blot hemorrhages in the macular region and an occasional peripheral intraretinal hemorrhage. The left fundus was remarkable for a cup-to-disk ratio of 0.1 to 0.2, some arteriosclerosis, and mild arterio-venous (AV) nicking. The patient was sent for fluorescein angiography, which showed mildly delayed venous blood flow and a hyperfiuorescent disk (Figures 3 and 4). The patient also had an erythrocyte sedmentation rate (ESR) and C-reactive protein sent to assess active inflammation, which returned within the normal range. Given the patient’s history and examination, we recommended that the patient be seen by her primary care physician for further workup of blood dyscrasias and hypercoagulability, as well as to ensure normal blood pressure, glucose, and lipids. She underwent a thorough hypercoagulability workup. Homocysteine level, protein S activity, anticardiolipin antibodies, factor V Leiden, protein immunofixation, and phospholipid level all returned normal. Protein C activity was actually 150%, slightly above the
R
etinal vein occlusion (RVO) represents an important cause of ocular morbidity, commonly affecting patients older than 65 years. Risk factors for RVO include systemic hypertension, diabetes, hyperlipidemia, glaucoma, smoking, and atherosclerosis.1 In younger patients, this condition has also been associated with systemic inflammatory conditions and hypercoagulable states.2 Management of RVO is aimed at preventing vision-threatening complications. It consists of regular follow-up visits and laser photocoagulation (if neovascularization is present).3,4 Medical management is often targeted at underlying risk factors, such as hypertension and diabetes.5 Given a demonstrated association between hypercoagulable states and retinal vein thrombosis,6,7 it is important to initiate a hypercoagulability workup in younger patients, as well as older patients without hypertension or other common risk factors who present with RVO. The authors have no conflicts of interest to disclose. Reprint requests: Kimberly A. Drenser, MD, PhD, Associated Retinal Consultants, 555 William Beaumont Medical Building, 3535 West 13 Mile Road, Royal Oak, MI 48073; e-mail: [email protected]
76
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HYPERCOAGULABLE STATE IN AN RVO PATIENT
Fig. 1. Fundus photograph of the right eye at the time of diagnosis.
Fig. 3. Fluorescein angiography of the right eye at diagnosis.
normal range of 70% to 140%. She also had a borderline antinuclear antibody (ANA), with a titer ,l:160. However, portions of the patient’s hypercoagulability workup were abnormal. First, she was found to have significantly reduced antithrombin III activity at 3% (normal range is 80-120%). Second, she was found to be heterozygous for the prothrombin G202210A mutation. Finally, evaluation of her platelets was consistent with sticky platelet syndrome.
Our patient’s workup revealed multiple hematologic abnormalities. Antithrombin III deficiency is usually inherited as an autosomal dominant trait.8 Because antithrombin normally acts to inhibit thrombin (factor Ha) and other serine proteinases in the clotting cascade, its deficiency results in the prolonged circulation of clotting factors. Antithrombin III
deficiency is therefore associated with increased risk of thrombus formation.9 Prothrombin G20210A mutation is associated with a single nucleotide polymorphism in a gene coding for blood coagulation factors, which causes increased production of a procoagulant protein. It is associated with an increased incidence of thrombosis, especially when present together with other thrombotic risk factors.10 Finally, sticky platelet syndrome is a congenital, autosomal dominant disorder characterized by hyperaggregability of platelets in response to adenosine phosphate (ADP), epinephrine, or both. Clinically, it is associated with arterial and venous thromboembolic events, including retinal thrombosis. Low-dose aspirin treatment (80-100 mg) alleviates symptoms and decreases platelet hyperaggregability.11
Fig. 2. Fundus photograph of the right eye at the time of diagnosis.
Fig. 4. Fluorescein angiography of the right eye at diagnosis.
Discussion
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The coexistence and synergistic effect of these prothrombotic hematologic alterations placed our patient at significant risk for another thrombotic event. She therefore started and has been maintained on coumadin therapy. Given the possibility of recurrent thrombosis with oral anticoagulant therapy alone in patients with sticky platelet syndrome, she was concurrently maintained on low-dose aspirin therapy. On initial follow-up examination, the patient’s intraretinal hemorrhages remained stable, and there was no evidence of macular edema. She continues to deny any new visual symptoms or any decrease in visual acuity since that time. Our patient’s history of multiple miscarriages was an important factor in prompting a hypercoagulability workup. Prothrombin mutation, antithrombin III deficiency, and sticky platelet syndrome represent likely etiologies for her ophthalmologic condition and obstetric history. Most importantly, they indicate the need for adequate anticoagulation to prevent future thrombotic events. This case emphasizes the importance of considering hypercoagulability as a possible etiology for RVO in patients who may be in an older, more classic age group but who do not have hypertension or other common risk factors. These patients may have milder hematologic abnormalities, which have not previously caused appreciable morbidity. However, these patients will likely have a lower threshold for thrombosis, with the addition of risk factors associated with advancing age. Identifying these patients can lead to prompt medical intervention and possible prevention of both ocular and nonocular thrombotic events.
Key words: vein occlusion, retina, hypercoagulation, autoimmune, clotting, dyscrasia, inflammatory. References 1. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 2. Fong AC, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol 1993;38:88. 3. Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. Arch Ophthalmol 1986;104:34–41. 4. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol 1997;115:486–491. 5. Phillips S, Fekrat S, Finkelstein D. Branch Retinal Vein Occlusion. Retina 2006;2:1348–1354. 6. Lahey JM, Tune M, Kearney J, et al. Laboratory evaluation of hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology 2002;109:126–131. 7. Cahill MT, Stinnett SS, Fekrat S. Meta-analysis of plasma homocysteine, serum folate, serum vitamin B12, and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease. Am J Ophthalmol 2003;136:1136–1150. 8. Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism [review]. Clin Hematol 1981;10:369–390. 9. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67:1429–1440. 10. Aznar J, Vaya A, Estelles A, et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000;85:1271–1276. 11. Mammen EF. Sticky platelet syndrome. Semin Thromb He most 1999;25:361–365.
