International Journal of Cardiology 180 (2015) 223–225
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
ST-segment elevation myocardial infarction in patient with essential thrombocythemia without associated risk Wen Gao, Wei Shen, Xinping Luo, Haiming Shi, Xiaofei Jiang, Junjie Pan ⁎ Cardiology Department, Huashan Hospital of Fudan University, Shanghai, PR China
a r t i c l e
i n f o
Article history: Received 17 November 2014 Accepted 23 November 2014 Available online 27 November 2014 Keywords: Drug therapy Essential thrombocythemia Hydroxyurea Myocardial infarction Reperfusion
1. Introduction Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by a sustained elevation of platelet count. The clinical course of untreated ET is dominated by thrombosis, constituting the major causes of morbidity and mortality. However, coronary artery thrombosis in ET patient is rare, especially those without traditional risks. A V617F mutation in the gene encoding Janus kinase 2 (JAK2) in hematopoietic progenitor cells is present in approximately 60% of patients with ET. JAK signal transducers play an important role in initiating signal transduction from hematopoietic growth factor receptors [1]. Here, we describe the case of ST-segment elevation myocardial infarction as the first clinical presentation of a previously undiagnosed ET, with positive Janus kinase 2 (JAK2) V617F gene mutation. 2. Case presentation A 61-year-old woman presented to the emergency room (ER) with chest pain as the main complaint. Her symptoms of chest distress started half an hour before arriving at ER. She reported no history of cardiac problems, diabetes mellitus and hypertension and was not taking any cardiac medications. ⁎ Corresponding author at: No. 12 Middle Urumqi Road, Jing'an District, Shanghai 200040, PR China. E-mail address: [email protected] (J. Pan).
http://dx.doi.org/10.1016/j.ijcard.2014.11.147 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Physical examination revealed low blood pressure and tachycardia. The general physical and systemic examination was normal. ECG showed peaked T wave in leads V1–V4 and then significant ST-wave elevation in the anterior leads. Serial cardiac enzymes confirmed acute myocardial infarction with troponin T peaked at 3.99 ng/mL. She was transferred to the coronary care unit where continuous infusion of tirofiban (0.4 μg/kg per min bolus followed by 0.1 μg/kg per min) and was given thrombolysis with rt-PA after the loading dose of aspirin, clopidogrel and 100 IU/kg subcutaneous heparin. She responded well to the therapy except for hypotension, and it was gradually corrected after the application of dopamine. The ST-segment in leads V1–V4 declined than 50% in 2 h and the chest pain relieved. A subsequent coronary angiography showed approximately 50% stenosis of the left anterior descending branch and 50% stenosis of the diagonal branch. Since she was absent of other risks, a platelet-mediated mechanism was considered. Her full blood counts consistently showed raised platelet count of more than 600 × 103/μL and hypercoagulability revealed by thromboelastogram (maximum amplitude, MA = 76.4 mm), while the platelet aggregation rate tested by the aggregometer was high normal. Bone marrow showed an increase of megakaryocytes, especially for the thromocytogenic ones and the biopsy showed mild degree fibrosis with plenty of megakaryocytes. There was a mild increase of the erythroid cells and no increase of neutrophil granulopoiesis. Genetic studies were positive for the JAK2V617F gene mutation. Other investigations, including erythrocyte counts, C-reactive protein, chromosomal analysis and splenic ultrasonography were normal which excluded the diagnosis of reactive thrombocytosis and polycythemia vera. A diagnosis of ET was made as per the WHO classification of the myeloid neoplasms. Since her persistent elevation of platelet, treatment with cytoreductive therapy using hydroxyurea was conducted. The doses of aspirin and clopidogrel were adjusted to achieve an ideal range of the MA (Fig. 1). Six months after the last hospitalization, she continues to do well with no further thrombotic or hemorrhagic complications and a normal platelet count. 3. Discussion Acute myocardial infarction caused by ET is often misdiagnosed because of its atypical symptoms and low incidence. We could find less than 20 cases of MI in patients with ET in the literature (Table 1). Among them, the LAD artery was occluded in most of the patients presented with MI and ET [2–7]. Only in 3 cases the platelet counts
224
W. Gao et al. / International Journal of Cardiology 180 (2015) 223–225
Fig. 1. thromboelastogram was used to test the blood coagulability of the patient after drug therapy. The inhibition rate of clopidogrel is 76.6% while the max aggregation (MA) is 52.2 mm, both within the normal range.
more than a million. In fact, patients with markedly elevated platelet counts (N1.5 million), usually seen in the setting of a myeloproliferative disorder, have an increased risk of bleeding. We did not find incidence difference between the sexes, although there is an unexplained female predominance of ET. JAK2V617F mutation was presented in 6 cases. This mutation increases the risk of thrombosis by approximately 2fold in ET patients. JAK2V617F positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide than those negative ones [8]. Screening for this mutation may be useful in patients presenting with unexplained thrombotic disorders [5]. Coronary artery thrombosis is the main pathogenesis of AMI with ET instead of atherosclerosis. The LAD artery is burdened with big systolic pressure and high shear stress of blood flow which makes it susceptible to endothelial damage, according to the retrieved results. Other theories include: (1) prolonged spasm and subsequent thrombosis, (2) increased procoagulant activity of thrombocytes, (3) possible deficiency of selective lipoxygenase, and (4) altered platelet granule glycoprotein [9]. We also find cigarette smoking as a risk factor of thrombosis in ET patients [3] probably by causing coronary vasoconstriction and endothelial dysfunction. Patients should be advised to stop smoking and other traditional cardiovascular risk factors.
No writing regulations of the treatment of AMI with ET were found in the literature. Primary angioplasty [3], thrombolytic therapy [10] and coronary artery bypass surgery [2] are of choice. In our case, tirofiban was used to break continuing platelet activation considering the pathophysiology of the disease. Clinical improvement following GPIIb/IIIa inhibitor treatments was also observed in other cases [4–6]. Treatment with hydroxyurea has been shown to reduce the risk of thrombosis in high-risk (age N 60 or history of thrombosis) ET patients. Another cytoreductive medicine anagrelide was reported to be associated with an excess rate of arterial thrombosis and myelofibrotic transformation [3,10]. Since ET treatment is a compromise balancing preventing thrombotic and hemorrhagic complications, we tested the platelet aggregation activity and used thromboelastogram to get the right doses of aspirin and clopidogrel in case of hemorrhage.
4. Conclusion Patients with high platelet counts should be evaluated carefully. A platelet-mediated mechanism should be considered in myocardial infarction without traditional risk factors. Tirofiban could be used as a
Table 1 Patient characteristics and clinical therapies in the case reports. Author
Age Sex Lesions
Platelet counts Other risks (×109/L)
Wang D.W. et al. Schaaf M. et al. Singla A. et al.
48 44 68
F F M
LAD LAD LAD
889 600 539
Cheng C.W. et al. Lim Y.H. et al. Zhang Z. et al. Pande S. et al. Lata K. et al. Camacho F.J. et al. Alioglu E. et al. Bildirici U. et al. Ozbe B. et al. Watanabe T. et al. Mizuta E. et al.
30 30 63 29 45 52 68 30 54 67 65
F F M M M M F F F M F
Inferior wall LAD Inferior wall LAD & LM RCA RCA RCA LAD LAD & LCX LM RCA
1277 388 1092 1200–1400 529 569 1243 982 676 678 469
Navati A. et al.
33
M
RCA & LAD
648
Reperfusion method
PCI & CABG PCI Percutaneous aspiration thrombectomy Drug therapy Anagrelide history PCI Smoking & hyperlipidemia Drug therapy Thrombolysis PCI S protein (SP) deficiency Thrombolysis & rescue PCI Diabetes Drug therapy PCI HTN & oral analgesics history Drug therapy Smoking history PCI Smoking, HTN & CRF Intra-right coronary injection of urokinase PCI
Anagrelide history A heterozygous mutation for Factor V Leiden,
Anti-platelet medicines
Cytoreductive JAK2 mutation therapy positive
DAPT Hydroxyurea DAPT DAPT & eptifibatide DAPT DAPT DAPT & tirofiban Aspirin DAPT & eptifibatide Unclear DAPT & tirofiban DAPT & tirofiban DAPT DAPT DAPT DAPT & eptifibatide
Y Y
Hydroxyurea Hydroxyurea Hydroxyureaa
Hydroxyurea Hydroxyurea Hydroxyurea
Y Y Y
b
Hydroxyurea Y
Abbreviations: F: female; M: male; LAD, left anterior descending; RCA: right coronary artery; LM: left main coronary artery; LCX: left circumflex; HTN: hypertension; CRF: chronic renal failure; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; DAPT: dual anti platelet therapy. a This was later changed to interferon α, to avoid any possible side effects on fertility. b Chemotherapy with hydroxyurea for ET was not initiated because of interstitial pneumonia and pulmonary aspergillosis.
W. Gao et al. / International Journal of Cardiology 180 (2015) 223–225
treatment by breaking the continuing chain of aggregation and activation. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] F. Cervantes, A. Pereira, Advances in the understanding and management of primary myelofibrosis, Curr. Opin. Oncol. 23 (6) (2011) 665–671 (2011-11-01). [2] D.W. Wang, Y. Zhang, J.M. Yao, Z.B. Xiao, Surgical treatment of a ventricular aneurysm in a patient with essential thrombocythemia complicated by acute myocardial infarction: A case report, Exp. Ther. Med. 7 (1) (2014) 267–269 (2014-01-01). [3] M. Schaaf, F. Sibellas, Acute myocardial infarction and anagrelide, Int. J. Cardiol. 168 (2) (2013) e50–e52 (2013-09-30).
225
[4] A. Singla, D. Jagasia, M. Garg, P.A. Lowry, D. Stapleton, Acute ST-segment elevation myocardial infarction: a rare initial presentation of previously undiagnosed essential thrombocythemia, Platelets 23 (6) (2012) 463–466 (2012-01-20). [5] K. Lata, N. Madiraju, L. Levitt, JAK2 mutations and coronary ischemia, N. Engl. J. Med. 363 (4) (2010) 396–397 (2010-07-22). [6] U. Bildirici, U. Celikyurt, E. Ural, Essential thrombocythemia: a case of acute STsegment elevation myocardial infarction in a young female, Clin. Cardiol. 32 (2) (2009) 104–105 (2009-02-01). [7] B. Ozben, A. Ekmekci, Z. Bugra, S. Umman, M. Meric, Multiple coronary thrombosis and stent implantation to the subtotally occluded right renal artery in a patient with essential thrombocytosis: a case report with review, J. Thromb. Thrombolysis 22 (1) (2006) 79–84 (2006-08-01). [8] P.J. Campbell, et al., Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study, Lancet 366 (9501) (2005) 1945–1953. [9] P. Douste-Blazy, M.J. Taudou, M. Delay, J. Pris, P. Sie, L. Ribaut, et al., Essential thrombocythaemia and recurrent myocardial infarction, Lancet 2 (8409) (1984) 992 (1984-10-27). [10] S. Pande, R. Joshi, R. Pande, Essential thrombocythemia in a young man treated for myocardial infarction, BMJ Case Rep. (2010) 2010 (2010-01-20).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
ST-segment elevation myocardial infarction in patient with essential thrombocythemia without associated risk Wen Gao, Wei Shen, Xinping Luo, Haiming Shi, Xiaofei Jiang, Junjie Pan ⁎ Cardiology Department, Huashan Hospital of Fudan University, Shanghai, PR China
a r t i c l e
i n f o
Article history: Received 17 November 2014 Accepted 23 November 2014 Available online 27 November 2014 Keywords: Drug therapy Essential thrombocythemia Hydroxyurea Myocardial infarction Reperfusion
1. Introduction Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by a sustained elevation of platelet count. The clinical course of untreated ET is dominated by thrombosis, constituting the major causes of morbidity and mortality. However, coronary artery thrombosis in ET patient is rare, especially those without traditional risks. A V617F mutation in the gene encoding Janus kinase 2 (JAK2) in hematopoietic progenitor cells is present in approximately 60% of patients with ET. JAK signal transducers play an important role in initiating signal transduction from hematopoietic growth factor receptors [1]. Here, we describe the case of ST-segment elevation myocardial infarction as the first clinical presentation of a previously undiagnosed ET, with positive Janus kinase 2 (JAK2) V617F gene mutation. 2. Case presentation A 61-year-old woman presented to the emergency room (ER) with chest pain as the main complaint. Her symptoms of chest distress started half an hour before arriving at ER. She reported no history of cardiac problems, diabetes mellitus and hypertension and was not taking any cardiac medications. ⁎ Corresponding author at: No. 12 Middle Urumqi Road, Jing'an District, Shanghai 200040, PR China. E-mail address: [email protected] (J. Pan).
http://dx.doi.org/10.1016/j.ijcard.2014.11.147 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Physical examination revealed low blood pressure and tachycardia. The general physical and systemic examination was normal. ECG showed peaked T wave in leads V1–V4 and then significant ST-wave elevation in the anterior leads. Serial cardiac enzymes confirmed acute myocardial infarction with troponin T peaked at 3.99 ng/mL. She was transferred to the coronary care unit where continuous infusion of tirofiban (0.4 μg/kg per min bolus followed by 0.1 μg/kg per min) and was given thrombolysis with rt-PA after the loading dose of aspirin, clopidogrel and 100 IU/kg subcutaneous heparin. She responded well to the therapy except for hypotension, and it was gradually corrected after the application of dopamine. The ST-segment in leads V1–V4 declined than 50% in 2 h and the chest pain relieved. A subsequent coronary angiography showed approximately 50% stenosis of the left anterior descending branch and 50% stenosis of the diagonal branch. Since she was absent of other risks, a platelet-mediated mechanism was considered. Her full blood counts consistently showed raised platelet count of more than 600 × 103/μL and hypercoagulability revealed by thromboelastogram (maximum amplitude, MA = 76.4 mm), while the platelet aggregation rate tested by the aggregometer was high normal. Bone marrow showed an increase of megakaryocytes, especially for the thromocytogenic ones and the biopsy showed mild degree fibrosis with plenty of megakaryocytes. There was a mild increase of the erythroid cells and no increase of neutrophil granulopoiesis. Genetic studies were positive for the JAK2V617F gene mutation. Other investigations, including erythrocyte counts, C-reactive protein, chromosomal analysis and splenic ultrasonography were normal which excluded the diagnosis of reactive thrombocytosis and polycythemia vera. A diagnosis of ET was made as per the WHO classification of the myeloid neoplasms. Since her persistent elevation of platelet, treatment with cytoreductive therapy using hydroxyurea was conducted. The doses of aspirin and clopidogrel were adjusted to achieve an ideal range of the MA (Fig. 1). Six months after the last hospitalization, she continues to do well with no further thrombotic or hemorrhagic complications and a normal platelet count. 3. Discussion Acute myocardial infarction caused by ET is often misdiagnosed because of its atypical symptoms and low incidence. We could find less than 20 cases of MI in patients with ET in the literature (Table 1). Among them, the LAD artery was occluded in most of the patients presented with MI and ET [2–7]. Only in 3 cases the platelet counts
224
W. Gao et al. / International Journal of Cardiology 180 (2015) 223–225
Fig. 1. thromboelastogram was used to test the blood coagulability of the patient after drug therapy. The inhibition rate of clopidogrel is 76.6% while the max aggregation (MA) is 52.2 mm, both within the normal range.
more than a million. In fact, patients with markedly elevated platelet counts (N1.5 million), usually seen in the setting of a myeloproliferative disorder, have an increased risk of bleeding. We did not find incidence difference between the sexes, although there is an unexplained female predominance of ET. JAK2V617F mutation was presented in 6 cases. This mutation increases the risk of thrombosis by approximately 2fold in ET patients. JAK2V617F positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide than those negative ones [8]. Screening for this mutation may be useful in patients presenting with unexplained thrombotic disorders [5]. Coronary artery thrombosis is the main pathogenesis of AMI with ET instead of atherosclerosis. The LAD artery is burdened with big systolic pressure and high shear stress of blood flow which makes it susceptible to endothelial damage, according to the retrieved results. Other theories include: (1) prolonged spasm and subsequent thrombosis, (2) increased procoagulant activity of thrombocytes, (3) possible deficiency of selective lipoxygenase, and (4) altered platelet granule glycoprotein [9]. We also find cigarette smoking as a risk factor of thrombosis in ET patients [3] probably by causing coronary vasoconstriction and endothelial dysfunction. Patients should be advised to stop smoking and other traditional cardiovascular risk factors.
No writing regulations of the treatment of AMI with ET were found in the literature. Primary angioplasty [3], thrombolytic therapy [10] and coronary artery bypass surgery [2] are of choice. In our case, tirofiban was used to break continuing platelet activation considering the pathophysiology of the disease. Clinical improvement following GPIIb/IIIa inhibitor treatments was also observed in other cases [4–6]. Treatment with hydroxyurea has been shown to reduce the risk of thrombosis in high-risk (age N 60 or history of thrombosis) ET patients. Another cytoreductive medicine anagrelide was reported to be associated with an excess rate of arterial thrombosis and myelofibrotic transformation [3,10]. Since ET treatment is a compromise balancing preventing thrombotic and hemorrhagic complications, we tested the platelet aggregation activity and used thromboelastogram to get the right doses of aspirin and clopidogrel in case of hemorrhage.
4. Conclusion Patients with high platelet counts should be evaluated carefully. A platelet-mediated mechanism should be considered in myocardial infarction without traditional risk factors. Tirofiban could be used as a
Table 1 Patient characteristics and clinical therapies in the case reports. Author
Age Sex Lesions
Platelet counts Other risks (×109/L)
Wang D.W. et al. Schaaf M. et al. Singla A. et al.
48 44 68
F F M
LAD LAD LAD
889 600 539
Cheng C.W. et al. Lim Y.H. et al. Zhang Z. et al. Pande S. et al. Lata K. et al. Camacho F.J. et al. Alioglu E. et al. Bildirici U. et al. Ozbe B. et al. Watanabe T. et al. Mizuta E. et al.
30 30 63 29 45 52 68 30 54 67 65
F F M M M M F F F M F
Inferior wall LAD Inferior wall LAD & LM RCA RCA RCA LAD LAD & LCX LM RCA
1277 388 1092 1200–1400 529 569 1243 982 676 678 469
Navati A. et al.
33
M
RCA & LAD
648
Reperfusion method
PCI & CABG PCI Percutaneous aspiration thrombectomy Drug therapy Anagrelide history PCI Smoking & hyperlipidemia Drug therapy Thrombolysis PCI S protein (SP) deficiency Thrombolysis & rescue PCI Diabetes Drug therapy PCI HTN & oral analgesics history Drug therapy Smoking history PCI Smoking, HTN & CRF Intra-right coronary injection of urokinase PCI
Anagrelide history A heterozygous mutation for Factor V Leiden,
Anti-platelet medicines
Cytoreductive JAK2 mutation therapy positive
DAPT Hydroxyurea DAPT DAPT & eptifibatide DAPT DAPT DAPT & tirofiban Aspirin DAPT & eptifibatide Unclear DAPT & tirofiban DAPT & tirofiban DAPT DAPT DAPT DAPT & eptifibatide
Y Y
Hydroxyurea Hydroxyurea Hydroxyureaa
Hydroxyurea Hydroxyurea Hydroxyurea
Y Y Y
b
Hydroxyurea Y
Abbreviations: F: female; M: male; LAD, left anterior descending; RCA: right coronary artery; LM: left main coronary artery; LCX: left circumflex; HTN: hypertension; CRF: chronic renal failure; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; DAPT: dual anti platelet therapy. a This was later changed to interferon α, to avoid any possible side effects on fertility. b Chemotherapy with hydroxyurea for ET was not initiated because of interstitial pneumonia and pulmonary aspergillosis.
W. Gao et al. / International Journal of Cardiology 180 (2015) 223–225
treatment by breaking the continuing chain of aggregation and activation. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] F. Cervantes, A. Pereira, Advances in the understanding and management of primary myelofibrosis, Curr. Opin. Oncol. 23 (6) (2011) 665–671 (2011-11-01). [2] D.W. Wang, Y. Zhang, J.M. Yao, Z.B. Xiao, Surgical treatment of a ventricular aneurysm in a patient with essential thrombocythemia complicated by acute myocardial infarction: A case report, Exp. Ther. Med. 7 (1) (2014) 267–269 (2014-01-01). [3] M. Schaaf, F. Sibellas, Acute myocardial infarction and anagrelide, Int. J. Cardiol. 168 (2) (2013) e50–e52 (2013-09-30).
225
[4] A. Singla, D. Jagasia, M. Garg, P.A. Lowry, D. Stapleton, Acute ST-segment elevation myocardial infarction: a rare initial presentation of previously undiagnosed essential thrombocythemia, Platelets 23 (6) (2012) 463–466 (2012-01-20). [5] K. Lata, N. Madiraju, L. Levitt, JAK2 mutations and coronary ischemia, N. Engl. J. Med. 363 (4) (2010) 396–397 (2010-07-22). [6] U. Bildirici, U. Celikyurt, E. Ural, Essential thrombocythemia: a case of acute STsegment elevation myocardial infarction in a young female, Clin. Cardiol. 32 (2) (2009) 104–105 (2009-02-01). [7] B. Ozben, A. Ekmekci, Z. Bugra, S. Umman, M. Meric, Multiple coronary thrombosis and stent implantation to the subtotally occluded right renal artery in a patient with essential thrombocytosis: a case report with review, J. Thromb. Thrombolysis 22 (1) (2006) 79–84 (2006-08-01). [8] P.J. Campbell, et al., Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study, Lancet 366 (9501) (2005) 1945–1953. [9] P. Douste-Blazy, M.J. Taudou, M. Delay, J. Pris, P. Sie, L. Ribaut, et al., Essential thrombocythaemia and recurrent myocardial infarction, Lancet 2 (8409) (1984) 992 (1984-10-27). [10] S. Pande, R. Joshi, R. Pande, Essential thrombocythemia in a young man treated for myocardial infarction, BMJ Case Rep. (2010) 2010 (2010-01-20).
