- Email: [email protected]
Ischemic Stroke with Essential Thrombocythemia: A Case Series
Ischemic Stroke with Essential Thrombocythemia: A Case Series Yuji Kato, MD, PhD, Takeshi Hayashi, MD, PhD, Yoshihide Sehara, MD, PhD, Ichiro Deguchi, MD, PhD, Takuya Fukuoka, MD, PhD, Hajime Maruyama, MD, PhD, Yohsuke Horiuchi, MD, Yuito Nagamine, MD, Hiroyasu Sano, MD, and Norio Tanahashi, MD, PhD
Background: Essential thrombocythemia (ET) is considered a rare cause of stroke partly because it is not detected if the platelet count is not elevated. However, early detection of ET is important because thrombosis can recur frequently, unless adequately treated. Methods: We retrospectively collected data from 10 stroke cases with ET. Clinical characteristics, location of stroke, laboratory data (platelet and leukocyte count, hemoglobin, and JAK2 V617F mutation), and treatment were reviewed. Results: The population consisted of 7 women and 3 men aged 18-83 years. Most patients had atherosclerotic risk factors. Half of the patients had a history of ischemic stroke. In 8 patients, ischemic stroke was the first manifestation of ET. Of 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. Three patients presented with watershed-type infarcts without large artery stenosis. Two patients had atherosclerotic stenosis of the large artery and experienced atherothrombotic infarction. The mean platelet count was 966 6 383 3 109/L. JAK2 V617F mutation was found in 5 of 7 patients. Despite treatment with combined antiplatelet and cytoreductive therapy in all patients, 3 experienced recurrent ischemic stroke. Conclusions: These findings suggest that ET is an adjunctive risk factor for stroke and the patients with ET are subject to watershedtype infarcts even in the absence of large artery stenosis. Early diagnosis of ET and strict management of vascular risk factors may help prevent additional cerebrovascular events. Key Words: Ischemic stroke—essential thrombocythemia—JAK2 V617F mutation—antiplatelet therapy—cytoreductive therapy. Ó 2015 by National Stroke Association
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by the overproduction of circulating platelets in the peripheral blood, caused
From the Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Japan. Received July 4, 2014; revision received August 20, 2014; accepted December 8, 2014. No grant support. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.012
890
by the excessive proliferation of megakaryocytes in the bone marrow.1 Patients with ET are at risk of disease progression to myelofibrosis or acute myeloid leukemia. However, one of the most important complications with a major effect on life expectancy is the occurrence of stroke events. Unfortunately, the clinical characteristics of ischemic stroke in patients with ET are not well understood.2 The purpose of our retrospective analysis was to assess the clinical characteristics of ischemic strokes that occur as complications in patients diagnosed with ET.
Methods We retrospectively collected data from 10 consecutive ischemic stroke patients with definitive ET treated in our hospital between April 2007 and April 2014. ET was
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 4 (April), 2015: pp 890-893
Case/age (y)/sex
Vascular risk factors
Prior stroke event
1/74/M
HT, AF
No
2/78/F
HT
No
3/83/F
HT
Lacunar infarct in the Lt. basal ganglia
4/75/F
HT
6/18/F
BAD (Rt. LSA territory infarct) HT, HL, OMI, No ASO, LV aneurysm None No
7/76/M
HT, DM, HL
8/43/M
HT, HL, smoking HT, HL
5/83/F
9/52/F
10/70/F None
JAK2 V617 Hemoglobin Leukocyte (g/dL) ( 3109/L) mutation
Treatment before current stroke
Treatment after stroke
Current stroke location
Platelet ( 3109/L)
BAD (Lt. LSA territory infarct) Rt. parasagittal watershed infarcts 1) Rt. cerebellar infarction 2) Wallenberg syndrome 1) TIA 2) TIA
1618
11.7
11.1
NE
Rt. hemiparesis
None
ASA, HU
947
10.5
10.8
Yes
Recovery
None
Clop, HU
1) 494 2) 410
1) 16.2 2) 15.9
1) 22.7 2) 21.7
Yes
1) 1185 2) 705
1) 11.0 2) 10.4
1) 6.6 2) 6.3
Yes
Recovery
NE
Severe impairment
Multiple cardiogenic shower embolism
1) Bilateral parasagittal watershed infarcts 2) TIA AT with Lt. ICA AT in the Lt. MCA stenosis territory AT with Rt. Crescendo TIA MCA stenosis No Lt. MCA territory infarct due to dissection Lt. parasagittal Lt. parasagittal watershed watershed infarcts infarcts
757
1) 1512 2) 465
12.7
6.8
Outcomes
1) Recovery 2) Impaired sensation
1) Clop* 2) Clop, HU
ISCHEMIC STROKE WITH ET
Table 1. The main characteristics of the patients
1) Clop, HU 2) Clop, HU
1) Clop, Cilo 1) Clop, Cilo 2) Clop, Cilo, 2) Clop, Cilo, HU HU Sarp, HU ASA, warfarin, Sarp, HU
1) 10.5 2) 12.1
1) 22.4 2) 3.6
No
Recovery
1) None 2) Clop, HU
1) Clop, HU 2) Clop, HU
645
11.4
10.7
NE
Clop, Cilo
Clop, Cilo, HU
912
16.2
6.7
No
Rt. hemiparesis, dementia Recovery
Clop, Cilo
Clop, Cilo, HU
554
15.5
10.2
Yes
Mild aphasia
None
Clop, HU
1032
12.6
10.0
Yes
Recovery
Dipy
Dipy, HU
Abbreviations: AF, atrial fibrillation; AT, atherothrombotic infarction; ASA, aspirin; ASO, arteriosclerosis obliterans; BAD, branch atheromatous disease; Cilo, cilostazol; Clop, clopidogrel; Dipy, dipyridamole; HL, hyperlipidemia; HT, hypertension; HU, hydroxyurea; ICA, internal carotid artery; LSA, lenticulostriate artery; Lt, left; LV, left ventricular; MCA, middle cerebral artery; NE, not examined; OMI, old myocardial infarction; Rt, right; Sarp, sarpogrelate; TIA, transient ischemic attack. *During clopidogrel withdrawal endoscopic submucosal dissection for gastric cancer. 891
Y. KATO ET AL.
892
diagnosed according to World Health Organization criteria, which include sustained platelet count $450 3 109/L; bone marrow biopsy specimen showing increased numbers of enlarged, mature megakaryocytes; not meeting the criteria for other chronic myeloid neoplasms; and JAK2 617V mutation or no evidence of reactive thrombocytosis.3 Clinical characteristics, location of ischemic stroke, laboratory data (platelet count, hemoglobin level, leukocyte count, and JAK2 V617F mutation), outcomes, and treatment were reviewed. The study was approved by the institutional ethics committee. No informed consent was required.
Results Data from 10 cases (13 events), 7 women and 3 men, were collected (Table 1). The patients included in this study represent .5% of the total number of patients (n 5 2538) with ischemic stroke admitted to our institution. Mean patient age was 65 6 21 years (range, 18-83 years), with only 2 patients aged younger than 45 years (cases 6 and 8). Only 2 patients had no vascular risk factors (cases 6 and 9). Two patients (cases 5 and 10) were previously diagnosed with ET, and the other patients (cases 1-4 and 6-9) were diagnosed after stroke occurred. ET was diagnosed by hematologists according to World Health Organization criteria.3 Five patients had a history of ischemic stroke and were treated with antiplatelet drugs before the onset of the current stroke (cases 3, 4, 7, 8, and 10). Three patients presented with watershed-type infarcts without large artery stenosis (cases 2, 6, and 10; representative case is shown in Fig 1). Two patients presented with atherosclerotic steno-
Figure 2. Case 9: 3-dimensional computed tomographic angiography showing irregular dilatation distal (arrowheads) to segmental narrowing (arrow) at the left middle cerebral artery, indicative of arterial dissection.
sis of the relevant large artery and experienced atherothrombotic infarction (cases 7 and 8). One patient experienced ischemic stroke caused by middle cerebral artery dissection (case 9; Fig 2). Infratentorial lesions occurred in 1 patient alone (in case 3 only). The mean platelet count was 966 6 383 3 109/L (range, 410-1618 3 109/L) at the time of stroke. The number of leukocytes was more than 11 3 109/L in 5 patients. JAK2 V617F mutation was confirmed in 5 of 7 cases (71%). All patients were treated with combined antiplatelet and cytoreductive therapy after stroke. Three patients experienced ischemic stroke after treatment (cases 3, 4, and 6). The interval to recurrence of ischemic stroke was 7 months (range, 1-16 months). The mean followup period of patients after current stroke was 42 6 31 months.
Discussion
Figure 1. Case 6: diffusion-weighted magnetic resonance image showing bilateral high-intensity lesions in the border zone of the middle cerebral artery.
Ischemic stroke associated with ET was diagnosed in .5% of cases, which is similar to the .25%-.5% incidence reported previously.4,5 Most patients with ET in our study who experienced ischemic stroke presented with one or more conventional vascular risk factors that may have influenced radiologic appearance and the clinical course. These findings suggest that ET is an adjunctive risk factor for stroke in most cases, but is rarely the sole risk factor. The risk factors for thrombotic events in patients with ET include cardiovascular risk factors and JAK2 V617F mutation as well as patient age and history of thrombosis.6 However, leukocytosis correlated with a higher thrombotic risk, even in low-risk ET patients (age ,60 years with no previous thrombosis).7,8 Our results are in accordance with this risk profile. Half of the patients had a history of ischemic stroke in our study, which suggests that ET is frequently underdiagnosed.
ISCHEMIC STROKE WITH ET
Of the 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. This high incidence of transient ischemic attack is consistent with microcirculatory disturbances found in ET.4 It is reported that the most frequent stroke subtype is lacunar infarcts in ET,9 but these occurred in few patients in our series. Instead, watershed-type infarcts were noted. Patients with ET should be subject to watershed-type infarcts even in the absence of large artery stenosis. We found no correlation between platelet count and stroke type. Factors contributing to the prothrombotic state in ET include platelet activation and increased turnover, alterations of coagulation and inhibition, endothelial activation, and leukocyte activation.2,9–11 It is possible that ET induces arteriosclerosis because of platelet activation. One patient presented with middle cerebral artery dissection, suggesting endothelial damage caused by ET.5,12 Early diagnosis of ET is important because of the high risk of recurrent thrombosis. Antiplatelet treatment is important, but combination with cytoreductive treatment is more effective and results in a 50% reduction in the risk of recurrent thrombosis.13 However, at very high platelet counts, aspirin is associated with a bleeding risk that may be attributed to aggravation of platelet dysfunction.14 Despite combined treatment with clopidogrel and hydroxyurea, ischemic stroke recurred in a few patients, which suggests the need for a new antiplatelet therapeutic strategy for ET. Early diagnosis and treatment of ET may help prevent cerebral vascular events. Suspected ET (persistent elevation in the platelet count above the threshold value of 450 3 109/L) should be confirmed by a hematologist, and cytoreductive treatment should be administered. Elimination of modifiable risk factors such as cardiovascular risk factors may greatly facilitate the complex management of patients with ET.
References 1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health
893
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22. Landolfi R, Cipriani MC, Novarese L. Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Haematol 2006;19:617-633. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110: 1092-1097. Arboix A, Besses C, Acın P, et al. Ischemic stroke as first manifestation of essential thrombocythemia. Report of six cases. Stroke 1995;26:1463-1466. Richard S, Perrin J, Baillot PA, et al. Ischaemic stroke and essential thrombocythemia: a series of 14 cases. Eur J Neurol 2011;18:995-998. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013;88:507-516. Carobbio A, Finazzi G, Guerini V, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007;109:2310-2313. Palandri F, Polverelli N, Catani L, et al. Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. Ann Hematol 2011;90:933-938. Marton I, Sz} P osfai E, oke A, et al. Stroke in essential thrombocythemia. J Neurol Sci 2014;336:260-262. Arellano-Rodrigo E, Alvarez-Larr an A, Reverter JC, et al. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol 2009;84:102-108. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2012;2012:571-581. D’Ambrosio D, Della-Morte D, Gargiulo G, et al. Intrapetrous internal carotid artery dissection and essential thrombocythemia: what relationship? A case report. Cases J 2008;1:354. De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008;93:372-380. van Genderen PJ, Michiels JJ. Erythromelalgic, thrombotic and haemorrhagic manifestations of thrombocythaemia. Presse Med 1994;23:73-77.
Background: Essential thrombocythemia (ET) is considered a rare cause of stroke partly because it is not detected if the platelet count is not elevated. However, early detection of ET is important because thrombosis can recur frequently, unless adequately treated. Methods: We retrospectively collected data from 10 stroke cases with ET. Clinical characteristics, location of stroke, laboratory data (platelet and leukocyte count, hemoglobin, and JAK2 V617F mutation), and treatment were reviewed. Results: The population consisted of 7 women and 3 men aged 18-83 years. Most patients had atherosclerotic risk factors. Half of the patients had a history of ischemic stroke. In 8 patients, ischemic stroke was the first manifestation of ET. Of 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. Three patients presented with watershed-type infarcts without large artery stenosis. Two patients had atherosclerotic stenosis of the large artery and experienced atherothrombotic infarction. The mean platelet count was 966 6 383 3 109/L. JAK2 V617F mutation was found in 5 of 7 patients. Despite treatment with combined antiplatelet and cytoreductive therapy in all patients, 3 experienced recurrent ischemic stroke. Conclusions: These findings suggest that ET is an adjunctive risk factor for stroke and the patients with ET are subject to watershedtype infarcts even in the absence of large artery stenosis. Early diagnosis of ET and strict management of vascular risk factors may help prevent additional cerebrovascular events. Key Words: Ischemic stroke—essential thrombocythemia—JAK2 V617F mutation—antiplatelet therapy—cytoreductive therapy. Ó 2015 by National Stroke Association
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by the overproduction of circulating platelets in the peripheral blood, caused
From the Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Japan. Received July 4, 2014; revision received August 20, 2014; accepted December 8, 2014. No grant support. Address correspondence to Yuji Kato, MD, PhD, Department of Neurology and Cerebrovascular Medicine, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.12.012
890
by the excessive proliferation of megakaryocytes in the bone marrow.1 Patients with ET are at risk of disease progression to myelofibrosis or acute myeloid leukemia. However, one of the most important complications with a major effect on life expectancy is the occurrence of stroke events. Unfortunately, the clinical characteristics of ischemic stroke in patients with ET are not well understood.2 The purpose of our retrospective analysis was to assess the clinical characteristics of ischemic strokes that occur as complications in patients diagnosed with ET.
Methods We retrospectively collected data from 10 consecutive ischemic stroke patients with definitive ET treated in our hospital between April 2007 and April 2014. ET was
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 4 (April), 2015: pp 890-893
Case/age (y)/sex
Vascular risk factors
Prior stroke event
1/74/M
HT, AF
No
2/78/F
HT
No
3/83/F
HT
Lacunar infarct in the Lt. basal ganglia
4/75/F
HT
6/18/F
BAD (Rt. LSA territory infarct) HT, HL, OMI, No ASO, LV aneurysm None No
7/76/M
HT, DM, HL
8/43/M
HT, HL, smoking HT, HL
5/83/F
9/52/F
10/70/F None
JAK2 V617 Hemoglobin Leukocyte (g/dL) ( 3109/L) mutation
Treatment before current stroke
Treatment after stroke
Current stroke location
Platelet ( 3109/L)
BAD (Lt. LSA territory infarct) Rt. parasagittal watershed infarcts 1) Rt. cerebellar infarction 2) Wallenberg syndrome 1) TIA 2) TIA
1618
11.7
11.1
NE
Rt. hemiparesis
None
ASA, HU
947
10.5
10.8
Yes
Recovery
None
Clop, HU
1) 494 2) 410
1) 16.2 2) 15.9
1) 22.7 2) 21.7
Yes
1) 1185 2) 705
1) 11.0 2) 10.4
1) 6.6 2) 6.3
Yes
Recovery
NE
Severe impairment
Multiple cardiogenic shower embolism
1) Bilateral parasagittal watershed infarcts 2) TIA AT with Lt. ICA AT in the Lt. MCA stenosis territory AT with Rt. Crescendo TIA MCA stenosis No Lt. MCA territory infarct due to dissection Lt. parasagittal Lt. parasagittal watershed watershed infarcts infarcts
757
1) 1512 2) 465
12.7
6.8
Outcomes
1) Recovery 2) Impaired sensation
1) Clop* 2) Clop, HU
ISCHEMIC STROKE WITH ET
Table 1. The main characteristics of the patients
1) Clop, HU 2) Clop, HU
1) Clop, Cilo 1) Clop, Cilo 2) Clop, Cilo, 2) Clop, Cilo, HU HU Sarp, HU ASA, warfarin, Sarp, HU
1) 10.5 2) 12.1
1) 22.4 2) 3.6
No
Recovery
1) None 2) Clop, HU
1) Clop, HU 2) Clop, HU
645
11.4
10.7
NE
Clop, Cilo
Clop, Cilo, HU
912
16.2
6.7
No
Rt. hemiparesis, dementia Recovery
Clop, Cilo
Clop, Cilo, HU
554
15.5
10.2
Yes
Mild aphasia
None
Clop, HU
1032
12.6
10.0
Yes
Recovery
Dipy
Dipy, HU
Abbreviations: AF, atrial fibrillation; AT, atherothrombotic infarction; ASA, aspirin; ASO, arteriosclerosis obliterans; BAD, branch atheromatous disease; Cilo, cilostazol; Clop, clopidogrel; Dipy, dipyridamole; HL, hyperlipidemia; HT, hypertension; HU, hydroxyurea; ICA, internal carotid artery; LSA, lenticulostriate artery; Lt, left; LV, left ventricular; MCA, middle cerebral artery; NE, not examined; OMI, old myocardial infarction; Rt, right; Sarp, sarpogrelate; TIA, transient ischemic attack. *During clopidogrel withdrawal endoscopic submucosal dissection for gastric cancer. 891
Y. KATO ET AL.
892
diagnosed according to World Health Organization criteria, which include sustained platelet count $450 3 109/L; bone marrow biopsy specimen showing increased numbers of enlarged, mature megakaryocytes; not meeting the criteria for other chronic myeloid neoplasms; and JAK2 617V mutation or no evidence of reactive thrombocytosis.3 Clinical characteristics, location of ischemic stroke, laboratory data (platelet count, hemoglobin level, leukocyte count, and JAK2 V617F mutation), outcomes, and treatment were reviewed. The study was approved by the institutional ethics committee. No informed consent was required.
Results Data from 10 cases (13 events), 7 women and 3 men, were collected (Table 1). The patients included in this study represent .5% of the total number of patients (n 5 2538) with ischemic stroke admitted to our institution. Mean patient age was 65 6 21 years (range, 18-83 years), with only 2 patients aged younger than 45 years (cases 6 and 8). Only 2 patients had no vascular risk factors (cases 6 and 9). Two patients (cases 5 and 10) were previously diagnosed with ET, and the other patients (cases 1-4 and 6-9) were diagnosed after stroke occurred. ET was diagnosed by hematologists according to World Health Organization criteria.3 Five patients had a history of ischemic stroke and were treated with antiplatelet drugs before the onset of the current stroke (cases 3, 4, 7, 8, and 10). Three patients presented with watershed-type infarcts without large artery stenosis (cases 2, 6, and 10; representative case is shown in Fig 1). Two patients presented with atherosclerotic steno-
Figure 2. Case 9: 3-dimensional computed tomographic angiography showing irregular dilatation distal (arrowheads) to segmental narrowing (arrow) at the left middle cerebral artery, indicative of arterial dissection.
sis of the relevant large artery and experienced atherothrombotic infarction (cases 7 and 8). One patient experienced ischemic stroke caused by middle cerebral artery dissection (case 9; Fig 2). Infratentorial lesions occurred in 1 patient alone (in case 3 only). The mean platelet count was 966 6 383 3 109/L (range, 410-1618 3 109/L) at the time of stroke. The number of leukocytes was more than 11 3 109/L in 5 patients. JAK2 V617F mutation was confirmed in 5 of 7 cases (71%). All patients were treated with combined antiplatelet and cytoreductive therapy after stroke. Three patients experienced ischemic stroke after treatment (cases 3, 4, and 6). The interval to recurrence of ischemic stroke was 7 months (range, 1-16 months). The mean followup period of patients after current stroke was 42 6 31 months.
Discussion
Figure 1. Case 6: diffusion-weighted magnetic resonance image showing bilateral high-intensity lesions in the border zone of the middle cerebral artery.
Ischemic stroke associated with ET was diagnosed in .5% of cases, which is similar to the .25%-.5% incidence reported previously.4,5 Most patients with ET in our study who experienced ischemic stroke presented with one or more conventional vascular risk factors that may have influenced radiologic appearance and the clinical course. These findings suggest that ET is an adjunctive risk factor for stroke in most cases, but is rarely the sole risk factor. The risk factors for thrombotic events in patients with ET include cardiovascular risk factors and JAK2 V617F mutation as well as patient age and history of thrombosis.6 However, leukocytosis correlated with a higher thrombotic risk, even in low-risk ET patients (age ,60 years with no previous thrombosis).7,8 Our results are in accordance with this risk profile. Half of the patients had a history of ischemic stroke in our study, which suggests that ET is frequently underdiagnosed.
ISCHEMIC STROKE WITH ET
Of the 13 acute cerebrovascular events, 4 were transient ischemic attacks and 9 were cerebral infarctions. This high incidence of transient ischemic attack is consistent with microcirculatory disturbances found in ET.4 It is reported that the most frequent stroke subtype is lacunar infarcts in ET,9 but these occurred in few patients in our series. Instead, watershed-type infarcts were noted. Patients with ET should be subject to watershed-type infarcts even in the absence of large artery stenosis. We found no correlation between platelet count and stroke type. Factors contributing to the prothrombotic state in ET include platelet activation and increased turnover, alterations of coagulation and inhibition, endothelial activation, and leukocyte activation.2,9–11 It is possible that ET induces arteriosclerosis because of platelet activation. One patient presented with middle cerebral artery dissection, suggesting endothelial damage caused by ET.5,12 Early diagnosis of ET is important because of the high risk of recurrent thrombosis. Antiplatelet treatment is important, but combination with cytoreductive treatment is more effective and results in a 50% reduction in the risk of recurrent thrombosis.13 However, at very high platelet counts, aspirin is associated with a bleeding risk that may be attributed to aggravation of platelet dysfunction.14 Despite combined treatment with clopidogrel and hydroxyurea, ischemic stroke recurred in a few patients, which suggests the need for a new antiplatelet therapeutic strategy for ET. Early diagnosis and treatment of ET may help prevent cerebral vascular events. Suspected ET (persistent elevation in the platelet count above the threshold value of 450 3 109/L) should be confirmed by a hematologist, and cytoreductive treatment should be administered. Elimination of modifiable risk factors such as cardiovascular risk factors may greatly facilitate the complex management of patients with ET.
References 1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health
893
2.
3.
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22. Landolfi R, Cipriani MC, Novarese L. Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: pathogenetic mechanisms and prevention. Best Pract Res Clin Haematol 2006;19:617-633. Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110: 1092-1097. Arboix A, Besses C, Acın P, et al. Ischemic stroke as first manifestation of essential thrombocythemia. Report of six cases. Stroke 1995;26:1463-1466. Richard S, Perrin J, Baillot PA, et al. Ischaemic stroke and essential thrombocythemia: a series of 14 cases. Eur J Neurol 2011;18:995-998. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013;88:507-516. Carobbio A, Finazzi G, Guerini V, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007;109:2310-2313. Palandri F, Polverelli N, Catani L, et al. Impact of leukocytosis on thrombotic risk and survival in 532 patients with essential thrombocythemia: a retrospective study. Ann Hematol 2011;90:933-938. Marton I, Sz} P osfai E, oke A, et al. Stroke in essential thrombocythemia. J Neurol Sci 2014;336:260-262. Arellano-Rodrigo E, Alvarez-Larr an A, Reverter JC, et al. Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: relationship with thrombosis occurrence and JAK2 V617F allele burden. Am J Hematol 2009;84:102-108. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2012;2012:571-581. D’Ambrosio D, Della-Morte D, Gargiulo G, et al. Intrapetrous internal carotid artery dissection and essential thrombocythemia: what relationship? A case report. Cases J 2008;1:354. De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments. Haematologica 2008;93:372-380. van Genderen PJ, Michiels JJ. Erythromelalgic, thrombotic and haemorrhagic manifestations of thrombocythaemia. Presse Med 1994;23:73-77.