Essential thrombocythemia complicated with simultaneous two-vessel acute myocardial infarction in the subacute phase of takotsubo cardiomyopathy: A case report

Abstract

We report the case of a 79-year-old woman with essential thrombocythemia who presented with simultaneous two-vessel acute myocardial infarction (AMI) in the subacute phase of takotsubo cardiomyopathy. Despite sufficient anticoagulation therapy with warfarin to prevent thrombus formation in the left ventricle, the patient developed simultaneous two-vessel AMI in the right and left circumflex coronary arteries 16 days after the onset of takotsubo cardiomyopathy. Thromboembolism from the left ventricle associated with takotsubo cardiomyopathy was considered a potential cause of this event. However, macroscopic and pathological findings of the aspirated thrombi revealed that the primary cause of AMI was non-organized white platelet thrombi associated with essential thrombocythemia. In addition to oral anticoagulation therapy with warfarin, low-dose aspirin was started. The patient was discharged without any symptoms, and the clinical course has been uneventful for >5 years. This case highlights the potential risk of fatal complications associated with essential thrombocythemia, including simultaneous multivessel AMI. Additionally, pathological findings of the thrombi may play a crucial role in clarifying the etiology in such complicated cases. Appropriate antithrombotic therapy should be selected according to the pathogenesis of the condition.

Learning objective

We describe a 79-year-old woman with essential thrombocythemia complicated with simultaneous two-vessel acute myocardial infarction (AMI) in the subacute phase of takotsubo cardiomyopathy. Although patients with essential thrombocythemia are highly predisposed to thrombotic events including AMI, the appropriate antithrombotic regimen remains controversial. The macroscopic and pathological findings of the thrombi play a pivotal role in clarifying the etiology, which may lead to the appropriate antithrombotic therapy.

Introduction

Takotsubo cardiomyopathy is characterized by transient left ventricular dysfunction with akinesis and systolic expansion of the apical segment in combination with basal hyperkinesis and generally has a good prognosis [1]. In-hospital mortality among patients with takotsubo cardiomyopathy reportedly ranges from 0 % to 5 %; however, it can lead to serious complications, such as thrombus formation in the left ventricle and subsequent systemic thromboembolism [1]. Essential thrombocythemia is a chronic myeloproliferative neoplasm that is characterized by clonal thrombocytosis and platelet dysfunction. Patients with essential thrombocythemia are at high risk of thrombosis as well as hemorrhage [2].

We herein describe a 79-year-old woman with essential thrombocythemia who presented with simultaneous two-vessel acute myocardial infarction (AMI) in the subacute phase of takotsubo cardiomyopathy. In general, simultaneous multivessel AMI is rare and usually associated with a poor prognosis [3]. In this case, macroscopic and pathological findings of the aspirated thrombi indicated that the primary cause of AMI was multiple non-organized white platelet thrombi associated with essential thrombocythemia rather than simultaneous thromboembolism from the left ventricle associated with takotsubo cardiomyopathy.

Case report

A 79-year-old woman presented with sudden-onset chest pain while on antibiotic therapy for tonsilitis. She had no history of smoking or drinking but had a history of hypertension, cerebral infarction, and essential thrombocythemia with the JAK2 mutation. She had undergone treatment for these conditions with 40 mg of nifedipine, 100 mg of cilostazol, and 1.0 mg of anagrelide, respectively. She had recently experienced psychological stress from joining a choral society and physical stress due to tonsilitis.

In the emergency room, electrocardiography revealed ST-segment elevation in leads II, III, aVF, and V2–V4, with ST-segment depression in leads I and aVL (Fig. 1A). Transthoracic echocardiography revealed apical hypokinesis, systolic bulging, and basal hyperkinesis. Laboratory testing revealed thrombocytosis with a platelet count of 651 × 10³/μL and mild elevation of troponin-T levels (0.304 ng/mL); other cardiac markers, such as creatinine phosphokinase (98 U/L) and its MB isozyme (22 U/L), were not significantly elevated. We immediately performed coronary angiography and found no significant stenosis in both coronary arteries (Fig. 1B–D). Additionally, left ventriculography revealed systolic apical ballooning and basal hyperkinesis (Fig. 1E, F). Based on these findings, she was diagnosed with takotsubo cardiomyopathy. We opted to perform conservative medical therapy with 10 mg of furosemide and 0.625 mg of bisoprolol for mild heart failure symptoms along with anticoagulation therapy with intravenous heparin followed by warfarin to avoid thrombus formation in the left ventricle. Follow-up transthoracic echocardiography performed on days 2 and 7 of admission indicated improved left ventricular systolic function and no clear findings of thrombus formation in the left ventricle. On day 12, the prothrombin time-international normalized ratio (PT-INR) was 1.7 with warfarin at 2 mg/day. She was subsequently discharged with well-controlled anticoagulation.

Fig. 1.

Electrocardiography, coronary angiography, and left ventriculography at first admission. (A) Electrocardiography showed ST-segment elevation in leads II, III, aVF, and V2–V4, with ST-segment depression in leads I and aVL. (B, C, D) Coronary angiography revealed no significant stenosis in the left circumflex artery (B: right anterior oblique caudal view), left anterior descending artery (C: right anterior oblique cranial view), and right coronary artery (D: left anterior oblique cranial view). (E, F) Left ventriculography of the end-diastolic (E) and end-systolic (F) phases showed akinesia and systolic bulging of apical segments (red arrows) and hyperkinesis of basal segments (green arrows).

However, on day 16 after takotsubo cardiomyopathy onset, she experienced severe chest pain once more and was brought to our hospital. Laboratory testing revealed slightly elevated troponin-T levels (0.063 mg/mL) and a significantly increased platelet count of 948 × 10³/μL. Other laboratory tests revealed normal levels of creatinine phosphokinase (26 U/L) and well-controlled PT-INR (2.10) with warfarin therapy. Electrocardiography revealed ST-segment elevation in leads I and aVL, with ST-segment depression in leads II, III, aVF, and V2–V4 (Fig. 2A). Emergent coronary angiography revealed subtotal occlusive lesions in the mid-portion of the left circumflex artery (LCX) (Fig. 2B) as well as in the proximal portion of the right coronary artery (RCA) (Fig. 2D), with filling defects indicating the presence of thrombi. Accordingly, she was diagnosed with simultaneous two-vessel AMI. Subsequently, a 6-Fr JL-4 guiding catheter was inserted in the left coronary artery, and thrombus aspiration with a 6-Fr Eliminate 3 (Terumo, Tokyo, Japan) was repeatedly performed, resulting in excellent coronary blood flow (Fig. 2C). Upon visual inspection, the aspirated thrombi were whitish, delicate, and not organized (Fig. 3A). Intravascular ultrasound confirmed that only a negligibly small thrombus remained in the LCX with no clear findings of plaque rupture. Consequently, we did not use a stent for the lesion. Thereafter, a 6-Fr JR-4 guiding catheter was inserted in the RCA and thrombus aspiration was performed again. Similar whitish and brittle thrombi were removed. As with the LCX, we did not perform stent implantation. The procedure was successful (Fig. 2C, E) and her symptoms were resolved.

Fig. 2.

Electrocardiography and coronary angiography at second admission. (A) Electrocardiography showed ST-segment elevation in leads I and aVL, with ST-segment depression in leads II, III, aVF, and V2–V4. (B) Left coronary angiography revealed a subtotal occlusive lesion with filling defects in the mid-left circumflex artery (anteroposterior caudal view; yellow arrows). (C) Left coronary angiography after thrombus aspiration revealed improved coronary flow without filling defects. (D) Right coronary angiography revealed a subtotal occlusive lesion with filling defects in the proximal right coronary artery (left anterior oblique view; purple arrows). (E) Right coronary angiography after thrombus aspiration revealed improved coronary flow without filling defects.

Fig. 3.

Macroscopic and pathological findings of the aspirated thrombi. (A) Macroscopically, the aspirated thrombi were whitish and delicate. (B, C, D) Histopathology analyses revealed that these thrombi predominantly comprised CD42b-positive platelets [B, C: hematoxylin-eosin (HE) stain, D: CD42b stain].

After readmission, aspirin (81 mg) was started along with warfarin because the pathological findings of the aspirated thrombi clearly showed CD42b-positive white platelet thrombi potentially associated with essential thrombocythemia (Fig. 3B–D). Transthoracic echocardiography revealed an improved ejection fraction (52 %) of the left ventricle with mild apical hypokinesis on day 23. Follow-up coronary angiography revealed no significant stenosis and no clear findings of intracoronary thrombi on day 29. On day 31, she was discharged and continued antithrombotic therapy with 81 mg of aspirin, 2 mg of warfarin, and 1 mg of anagrelide. Her clinical course has been uneventful for >5 years after the second hospital discharge.

Discussion

Left ventricular thrombi accompanied by takotsubo cardiomyopathy has been reported in 2 % to 9 % of people, and approximately one-third may develop systemic thromboembolism [1]. Therefore, anticoagulation therapy is generally recommended, especially in the acute phase. Although our patient underwent sufficient anticoagulation therapy, she developed simultaneous two-vessel AMI. Notably, multiple white platelet thrombi were the primary cause of multivessel AMI. Our findings suggest that platelet thrombi in patients with essential thrombocythemia differ from the left ventricular thrombi secondary to takotsubo cardiomyopathy. The latter forms red thrombi mainly comprising fibrin and red blood cells caused by the accelerating coagulation cascade explained by the Virchow's triad [4]. In this case, the aspirated thrombi were not organized, which implied that thrombus formation in the left ventricle was not a primary cause of AMI. Conversely, patients with essential thrombocythemia are at a high risk of thrombosis owing to platelet thrombi, and the precise mechanisms of thrombophilia are considered multifactorial. Hyperviscosity due to increased blood cell counts, inflammatory cytokines, high levels of neutrophil extracellular traps, and microvesicles from erythrocytes are the potential explanations [5].

The incidence of AMI associated with essential thrombocythemia reportedly ranges from 2 % to 9.4 % [6]. In patients with essential thrombocythemia, treatment strategy is generally based on the thrombotic and bleeding risk scale [2], [7]. Because our patient was aged over >60 years and had a history of stroke and hypertension in addition to the JAK2 mutation, she should have been considered at high risk of thrombosis. Our patient had been prescribed cilostazol instead of low-dose aspirin because of her stroke history. According to previous reports recommending low-dose aspirin for thrombosis prophylaxis [2], [7], aspirin might have been appropriate for our patient, although the optimal antithrombotic regimen for patients with essential thrombocythemia complicated with AMI remains controversial. Additionally, previous reports have shown that anagrelide is less effective than hydroxyurea [2], [8]. However, in our case, anagrelide was prescribed instead of hydroxyurea before takotsubo cardiomyopathy onset, mainly because of the side effects of hydroxyurea. In general, platelet levels should be maintained below 400–600 × 10³/μL to reduce the risk of thrombosis in patients with essential thrombocythemia, although the most appropriate target platelet count remains unclear [2]. In our case, the platelet count increased to 651 × 10³/μL at first admission and escalated to 948 × 10³/μL at readmission due to AMI, although it had been maintained between 400 and 600 × 10³/μL with hydroxyurea before exchanging the drug to anagrelide. These conditions might be associated with the occurrence of multivessel AMI. Because our case was at high risk for thrombosis due to essential thrombocythemia with the JAK 2 mutation, advanced age, and a history of stroke [2], [7], and still had impaired contractility of the left ventricle at second hospital discharge owing to takotsubo cardiomyopathy and AMI, we continuously prescribed warfarin in addition to low-dose aspirin. However, considering the risk of bleeding complications due to the combination use of antiplatelet agent and anticoagulant, warfarin should have been discontinued once the improvement of left ventricular contractility was confirmed.

To our knowledge, there are only four reported cases of simultaneous multivessel AMI in patients with essential thrombocythemia [3], [9], [10]. All patients had thrombocytosis with a platelet count of >600 × 10³/μL at AMI onset, as was the case with our patient, suggesting a causal relationship between the increased platelet count and multiple thromboses. Initial treatment for multivessel AMI was successfully performed and all patients in these cases were discharged alive [3], [9], [10]. Compared with these previous cases, ours had several unique findings. This is the first case of simultaneous multivessel AMI in a patient with essential thrombocythemia in the subacute phase of takotsubo cardiomyopathy. Activated sympathetic nerves, microvascular dysfunction, and increased platelet activity might have caused simultaneous multivessel AMI, although the contribution of takotsubo cardiomyopathy to this event remains uncertain. Additionally, the macroscopic and pathological findings of the thrombi suggest novel clinical implications for the etiology and optimal management of such patients.

Conclusion

Simultaneous multivessel AMI is one of the most serious complications to occur in association with essential thrombocythemia. Pathological findings of the thrombi play a pivotal role in clarifying the etiology, which may lead to the application of appropriate antithrombotic therapy.

Declaration of competing interest

The authors declare that there is no conflict of interest.