Case Report
An Unusual Cause of Cerebellar Hemorrhage in a Young Patient: Essential Thrombocythemia Robert Adam, MA, MBBS, MRCP,*† Miriam Priglinger, DM,* Timothy Harrington, MBBS, FRANZCR,‡ David Gottlieb, MBBS, MD, FRACP, FRCPA,† and Martin Krause, DM, FRACP*†
Essential thrombocythemia (ET) is a risk factor for ischemic stroke and, far more rarely, hemorrhage. We report the case of an untreated 32-year-old woman with a history of JAK2 V617F–positive ET with cerebellar and subarachnoid hemorrhages without evidence of sinus vein thrombosis. She was commenced on oral cytotoxic and antiplatelet therapy. This case report discusses the underlying mechanism of hemorrhagic thrombocythemia and the management dilemma presented by the recommended treatment implications. Key words: Hemorrhagic stroke—essential thrombocythaemia— acquired von Willebrand disease—young stroke—myeloproliferative disorder— antiplatelet. Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved.
Essential thrombocythemia (ET) is a risk factor for stroke.1 However, intracerebral hemorrhage is very infrequent.2 A 32-year-old woman with a 10-year history of previously untreated Janus kinase 2 (JAK2 V617F)–positive ET presented to hospital with a 6-week history of headaches. On the day of presentation, she had acute onset of walking difficulty and altered sensation in her legs. She was drowsy, markedly ataxic, and had past-pointing bilaterally. Computed tomography and magnetic resonance imaging (MRI) of the brain (including susceptibilityFrom the *Department of Neurology, Royal North Shore Hospital; †Department of Medicine, University of Sydney; and ‡Department of Radiology, Royal North Shore Hospital, Sydney, Australia. Received September 17, 2013; revision received November 5, 2013; accepted December 9, 2013. Address correspondence to Robert Adam, MA, MBBS, MRCP, University of Sydney, Northern Clinical School, Royal North Shore Hospital, Reserve Rd, St Leonards, Sydney NSW 2065, Australia. E-mail: [email protected]. 1052-3057/$ - see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.013
weighted imaging) revealed cerebellar and subarachnoid hemorrhages without evidence of venous sinus thrombosis (Fig 1). Digital subtraction angiography, including venography, was normal. Platelets were raised at 975 3 109/L (NR [normal range] 150-400 3 109/L), activated partial thromboplastin time (APTT; 37.9 seconds [NR 26.0-35.0 seconds] was slightly raised, and prothrombin time (14.4 seconds [NR 12-15 seconds]) and international normalized ratio (INR, 1.14) were normal. Von Willebrand factor (VWF) was not measured at the time of presentation. The patient had had a high but stable platelet count (the majority of measurements were ,1000 3 109/L) for many years without any clinical problems. In the absence of any other vascular risk factor, cytoreductive therapy was not considered necessary in this young patient (,40 years old), in accordance with literature.3,4 Previous MRI studies (2002 and 2004) of her brain, including venography for the investigation of persistent headaches, were unremarkable. The patient’s neurologic symptoms were treated conservatively. She did not intend to have children in the foreseeable future and so was commenced on oral
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp e373-e374
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Figure 1. (A) Acute computed tomography scan of the cerebellum demonstrates hemorrhage. (B) Magnetic resonance susceptibility-weighted imaging of the cerebellum (axial) demonstrates that the hemorrhage is multifocal. (C) Venography was normal.
cytotoxic therapy with hydroxyurea. Within 2 weeks, she had recovered sufficiently that she could be discharged home. At follow-up, 4 months later, her platelet count had almost normalized (432 3 109/L) and her neurologic deficits had fully resolved. MRI images demonstrated partial resolution of the previously shown hemorrhage, and she was commenced on aspirin.
Discussion ET frequently causes platelet-mediated thrombosis.1 In high-risk patients, both hydroxyurea and aspirin are considered standard therapy to reduce this complication. Hemorrhagic thrombocythemia affects less than 10% of all patients with ET and is, paradoxically, related to very high platelet counts (above 1500 3 109/L).1 Intracerebral hemorrhage is rarely reported in ET.5,6 Focal cerebellar hemorrhage has not previously been reported. Hemorrhage in ET with high platelet count may be because of acquired von Willebrand Syndrome (AVWS), though platelet counts usually exceed those found here. The prolonged APTT in this case is consistent with that diagnosis. In addition to the APTT, appropriate investigation for AVWS includes measurement of VWF antigen and function, specifically ristocetin cofactor activity and collagen binding for the latter.7 VWF multimer analysis may also be of value but is performed only in highly specialized laboratories. The patient responded to cytoreductive therapy with hydroxyurea. This drug has previously been reported to result in remission of AVWS in 12 of 14 patients.8 Treatment with hydroxyurea has also been reported to reduce the risk of hemorrhage in high-risk patients with ET9 and is more effective than other myelosuppressive agents like anagrelide in preventing arterial thrombotic events and major hemorrhage.10 Hydroxyurea is the treatment of choice in all patients except during pregnancy when it is contraindicated, and interferon alpha is the preferred agent. Interferon is more difficult to tolerate, less convenient, and more expensive. During active hemorrhage,
cytoreductive treatment is not immediately effective and additional treatment with Desmopressin or recombinant factor VIIa may be required.11 Although there is broad agreement that ET patients with vascular risk factors benefit from aspirin, the timing and use of antiplatelet agents in ET following major hemorrhage are uncertain.1,12
References 1. Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005;128:275-290. 2. Millard FE, Hunter CS, Anderson M, et al. Clinical manifestations of essential thrombocythemia in young adults. Am J Hematol 1990;33:27-31. 3. Beer PA, Erber WN, Campbell PJ, et al. How I treat essential thrombocythemia. Blood 2011;117:1472-1482. 4. Alvarez-Larr an A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia 2007;21:1218-1223. 5. Kondlapudi J, O’Connor RJ, Mawer S. Cerebral haemorrhage as the presenting feature of myeloproliferative disorder. BMJ Case Rep 2009; http://dx.doi.org/10.1136/ bcr.08.2008.0720, published online 26 March 2009. 6. Kase CS, Williams JP, Wyatt DA, et al. Lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology 1982;32:1146-1150. 7. Tefferi A, Nichols L. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med 1997;103:536-540. 8. Mohri H, Motomura S, Kanamori H, et al. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998;91:3623-3629. 9. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N. Engl. J. Med 1995;332:1132-1137. 10. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N. Engl. J. Med 2005;353:33-45. 11. Tiede A, Rand JH, Budde U, et al. How I treat the acquired von Willebrand syndrome. Blood 2011;117:6777-6785. 12. Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood Rev 2012;26:205-211.
An Unusual Cause of Cerebellar Hemorrhage in a Young Patient: Essential Thrombocythemia Robert Adam, MA, MBBS, MRCP,*† Miriam Priglinger, DM,* Timothy Harrington, MBBS, FRANZCR,‡ David Gottlieb, MBBS, MD, FRACP, FRCPA,† and Martin Krause, DM, FRACP*†
Essential thrombocythemia (ET) is a risk factor for ischemic stroke and, far more rarely, hemorrhage. We report the case of an untreated 32-year-old woman with a history of JAK2 V617F–positive ET with cerebellar and subarachnoid hemorrhages without evidence of sinus vein thrombosis. She was commenced on oral cytotoxic and antiplatelet therapy. This case report discusses the underlying mechanism of hemorrhagic thrombocythemia and the management dilemma presented by the recommended treatment implications. Key words: Hemorrhagic stroke—essential thrombocythaemia— acquired von Willebrand disease—young stroke—myeloproliferative disorder— antiplatelet. Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved.
Essential thrombocythemia (ET) is a risk factor for stroke.1 However, intracerebral hemorrhage is very infrequent.2 A 32-year-old woman with a 10-year history of previously untreated Janus kinase 2 (JAK2 V617F)–positive ET presented to hospital with a 6-week history of headaches. On the day of presentation, she had acute onset of walking difficulty and altered sensation in her legs. She was drowsy, markedly ataxic, and had past-pointing bilaterally. Computed tomography and magnetic resonance imaging (MRI) of the brain (including susceptibilityFrom the *Department of Neurology, Royal North Shore Hospital; †Department of Medicine, University of Sydney; and ‡Department of Radiology, Royal North Shore Hospital, Sydney, Australia. Received September 17, 2013; revision received November 5, 2013; accepted December 9, 2013. Address correspondence to Robert Adam, MA, MBBS, MRCP, University of Sydney, Northern Clinical School, Royal North Shore Hospital, Reserve Rd, St Leonards, Sydney NSW 2065, Australia. E-mail: [email protected]. 1052-3057/$ - see front matter Crown Copyright Ó 2014 Published by Elsevier Inc. on behalf of National Stroke Association. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.013
weighted imaging) revealed cerebellar and subarachnoid hemorrhages without evidence of venous sinus thrombosis (Fig 1). Digital subtraction angiography, including venography, was normal. Platelets were raised at 975 3 109/L (NR [normal range] 150-400 3 109/L), activated partial thromboplastin time (APTT; 37.9 seconds [NR 26.0-35.0 seconds] was slightly raised, and prothrombin time (14.4 seconds [NR 12-15 seconds]) and international normalized ratio (INR, 1.14) were normal. Von Willebrand factor (VWF) was not measured at the time of presentation. The patient had had a high but stable platelet count (the majority of measurements were ,1000 3 109/L) for many years without any clinical problems. In the absence of any other vascular risk factor, cytoreductive therapy was not considered necessary in this young patient (,40 years old), in accordance with literature.3,4 Previous MRI studies (2002 and 2004) of her brain, including venography for the investigation of persistent headaches, were unremarkable. The patient’s neurologic symptoms were treated conservatively. She did not intend to have children in the foreseeable future and so was commenced on oral
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 5 (May-June), 2014: pp e373-e374
e373
R. ADAM ET AL.
e374
Figure 1. (A) Acute computed tomography scan of the cerebellum demonstrates hemorrhage. (B) Magnetic resonance susceptibility-weighted imaging of the cerebellum (axial) demonstrates that the hemorrhage is multifocal. (C) Venography was normal.
cytotoxic therapy with hydroxyurea. Within 2 weeks, she had recovered sufficiently that she could be discharged home. At follow-up, 4 months later, her platelet count had almost normalized (432 3 109/L) and her neurologic deficits had fully resolved. MRI images demonstrated partial resolution of the previously shown hemorrhage, and she was commenced on aspirin.
Discussion ET frequently causes platelet-mediated thrombosis.1 In high-risk patients, both hydroxyurea and aspirin are considered standard therapy to reduce this complication. Hemorrhagic thrombocythemia affects less than 10% of all patients with ET and is, paradoxically, related to very high platelet counts (above 1500 3 109/L).1 Intracerebral hemorrhage is rarely reported in ET.5,6 Focal cerebellar hemorrhage has not previously been reported. Hemorrhage in ET with high platelet count may be because of acquired von Willebrand Syndrome (AVWS), though platelet counts usually exceed those found here. The prolonged APTT in this case is consistent with that diagnosis. In addition to the APTT, appropriate investigation for AVWS includes measurement of VWF antigen and function, specifically ristocetin cofactor activity and collagen binding for the latter.7 VWF multimer analysis may also be of value but is performed only in highly specialized laboratories. The patient responded to cytoreductive therapy with hydroxyurea. This drug has previously been reported to result in remission of AVWS in 12 of 14 patients.8 Treatment with hydroxyurea has also been reported to reduce the risk of hemorrhage in high-risk patients with ET9 and is more effective than other myelosuppressive agents like anagrelide in preventing arterial thrombotic events and major hemorrhage.10 Hydroxyurea is the treatment of choice in all patients except during pregnancy when it is contraindicated, and interferon alpha is the preferred agent. Interferon is more difficult to tolerate, less convenient, and more expensive. During active hemorrhage,
cytoreductive treatment is not immediately effective and additional treatment with Desmopressin or recombinant factor VIIa may be required.11 Although there is broad agreement that ET patients with vascular risk factors benefit from aspirin, the timing and use of antiplatelet agents in ET following major hemorrhage are uncertain.1,12
References 1. Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005;128:275-290. 2. Millard FE, Hunter CS, Anderson M, et al. Clinical manifestations of essential thrombocythemia in young adults. Am J Hematol 1990;33:27-31. 3. Beer PA, Erber WN, Campbell PJ, et al. How I treat essential thrombocythemia. Blood 2011;117:1472-1482. 4. Alvarez-Larr an A, Cervantes F, Bellosillo B, et al. Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Leukemia 2007;21:1218-1223. 5. Kondlapudi J, O’Connor RJ, Mawer S. Cerebral haemorrhage as the presenting feature of myeloproliferative disorder. BMJ Case Rep 2009; http://dx.doi.org/10.1136/ bcr.08.2008.0720, published online 26 March 2009. 6. Kase CS, Williams JP, Wyatt DA, et al. Lobar intracerebral hematomas: clinical and CT analysis of 22 cases. Neurology 1982;32:1146-1150. 7. Tefferi A, Nichols L. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med 1997;103:536-540. 8. Mohri H, Motomura S, Kanamori H, et al. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998;91:3623-3629. 9. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N. Engl. J. Med 1995;332:1132-1137. 10. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N. Engl. J. Med 2005;353:33-45. 11. Tiede A, Rand JH, Budde U, et al. How I treat the acquired von Willebrand syndrome. Blood 2011;117:6777-6785. 12. Barbui T, Finazzi MC, Finazzi G. Front-line therapy in polycythemia vera and essential thrombocythemia. Blood Rev 2012;26:205-211.
