Acute Transmural Myocardial Infarction by Coronary Embolism in a Patient with JAK2 V617F-Positive Essential Thrombocythemia

Essential thrombocythemia (ET) is an acquired myeloproliferative disorder which results from malignant transformation of a multipotent hematopoietic progenitor cell. The disease is characterized by platelet count elevation (> 450 000 /µl) and augmented platelet reactivity causing thrombotic events and haemorrhages. The etiology of bleeding in ET is multifactorial and includes among others an acquired von Willebrand syndrome especially in the presence of extreme thrombocytosis (> 1 000 000 /µl). Thromboses can occur in arterial and venous vessels and are far more frequent than bleeding. Thrombotic complications are the major cause of morbidity and mortality in ET patients and do not correlate with platelet count.[1]

Herein, we report the case of a 53-year old man with low cardiovascular risk profile and untreated ET presenting with a transmural myocardial infarction (STEMI) in the territory of the left anterior descending and the right coronary artery most likely due to multiple coronary embolisation.

Case Report

A 53-year old man presented to the coronary care unit with a first episode of severe retrosternal chest pain beginning 3 hours earlier during a sauna visit. The patient reported no fever, cough, dyspnea, lower extremity edema, immobility, or trauma. He had hypercholesterolemia as a traditional risk factor for atherosclerosis. His family history was unremarkable for premature coronary artery disease. He did not use tobacco, alcohol or illicit drugs. Essential thrombocythemia had been diagnosed 5 years ago and was based on chronic non-reactive thrombocytosis and detection of Janus kinase (JAK)2 V617F mutation in the peripheral blood. A bone marrow biopsy was not performed. Without previous thrombotic or bleeding events an antiplatelet or cytoreductive therapy was not recommended by a hematologist.

On physical examination, he was afebrile and his vital signs were stable. The blood pressure was 156/103 mmHg (approximately the same in both arms), heart rate 93 /min and the oxygen saturation 98 %. Cardiac examination revealed a regular heart rhythm without extra heart sounds. Chest palpitation did not produce pain. Examination of lungs and abdomen was unremarkable.

A 12-lead electrocardiogram (ECG) showed a normal sinus rhythm and significant ST-segment elevations in leads II, III, aVF and V2-V4. Clinical presentation and ECG were characteristic of an STEMI in the territory of the left anterior descending and the right coronary artery. The patient was treated with aspirin (400 mg orally) and a 5000 U bolus of intravenous unfractionated heparin.

He was taken urgently to the catheterisation laboratory. Coronary angiography revealed a thrombus in the mid-right coronary artery (RCA, [Fig. 1A]) and thrombotic occlusions in the distal left anterior descending artery (LAD) and in the second diagonal branch (RD) ([Fig. 1B]). The patient received a loading dose of the P2Y12 inhibitor prasugrel (60 mg p.o.) and an intracoronary bolus of GPIIb/IIIa inhibitor abciximab (250 mg) followed by intravenous abciximab infusion (10 µg/min) for 12 hours.

Fig. 1 Coronary angiography of the right coronary artery (left anterior oblique view) reveals a non-occlusive, non-calcified thrombotic filling defect in the mid right coronary artery (A, inset) and distal occlusions in the left descending artery and the diagonal branch (B, circles).

Thrombus aspiration significantly reduced thrombus burden but failed to restore adequate blood flow in the RCA. Normal epicardial coronary flow (TIMI grade III) was achieved after drug-eluting stent (3.5 × 22 mm) implantation. A conservative management was opted for the occlusions in LAD and RD ([Fig. 1B]) because both were located distally and in vessels of small diameters. After percutaneous coronary intervention (PCI) ST-segment elevations in the ECG and chest pain resolved confirming that revascularisation and antithrombotic therapy had been successful.

Cardiac biomarkers were elevated and confirmed myocardial injury. The initial high-sensitive troponin-T level of 0.071 ng/ml peaked at 1.33 ng/ml within 18 hours (normal value, < 0.009 ng/ml). Peak serum creatine kinase (CK) concentration was 1140 U/l 18 hours after admission (normal value, < 180 U/l) with an MB isoenzyme level of 121 U/l (normal value, < 25 U/l). Laboratory data showed a leukocyte count of 18 000 /µl (reference range 4600–10 200 /µl), a platelet count of 482 000 /µl (reference range 150 000–400 000 /µl), and a haematocrit of 41.8 % (reference range 43–49 %). The lipid panel revealed total cholesterol of 268 mg/dl (normal value, < 200 mg/dl), high density lipoprotein (HDL) 40 mg/dl (normal value, > 55 mg/dl), and low density lipoprotein (LDL) 203 mg/dl (normal value, < 130 mg/dl). To reach the LDL cholesterol goal of < 70 mg/dl after STEMI high-intensity statin therapy with atorvastatin 80 mg daily was initiated. The results of other blood chemical and liver-function tests were unremarkable.

After PCI transthoracic echocardiography showed a reduction of the left ventricular ejection fraction (EF) to 40 % with akinesia of the anterior, inferobasal and inferoseptal wall. Given the impaired EF after STEMI treatment with beta blocker bisoprolol 2.5 mg and ACE inhibitor ramipril 2.5 mg daily was started.

Occlusion of multiple coronary vessels can be caused by embolisation. A diagnostic work-up to detect sources of emboli was undertaken. To detect atrial fibrillation, a 24-hour Holter ECG monitoring was performed and showed continuous sinus rhythm without arrhythmias. The transoesopheal echocardiography (TOE) revealed a patent foramen ovale (PFO) allowing rapid and extensive passage of microbubbles from the right to the left atrium even without valsalva manoeuver. In the presence of a PFO paradoxical embolism is a potential mechanism that caused embolic STEMI. However, deep vein thrombosis of lower extremities was excluded by compression ultrasound. Another potential source of coronary embolism are aortic thrombi. A thrombus (1.5 × 1.5 cm) attached to the aortic arch was seen in the TOE and was confirmed by a contrast-enhanced multidetector computed tomography (MDCT) ([Fig. 2]). Moreover, MDCT of the aorta visualised multiple mural non-occlusive thrombi in the aortic arch and in the abdominal aorta. Infarction areas in spleen and kidneys due to arterial embolisation were ruled out. The patient̀s history was unremarkable for acute lower extremity or abdominal pain due to arterial occlusion.

Fig. 2 Multidetector computed tomography (MDCT) revealed several mural thrombi in the abdominal aorta (A, sagittal scan) and in the aortic arch (B, axial scan).

In regard to the thrombotic risk and the coronary embolism the patient received an antithrombotic triple therapy to prevent recurrent paradoxical embolism or stent thrombosis. According to recent expert recommendations prasugrel was replaced by clopidogrel 75 mg/d. Rivaroxaban 15 mg/d was started in addition to aspirin and clopidogrel. Four days after the STEMI the patient was discharged in a good condition and attended cardiac rehabilitation.

After 4 weeks the PFO was effectively occluded with an Amplatzer® PFO occluder device. The TOE confirmed the complete resolution of the thrombus in the aortic arch. After PFO closure, it was considered safe to discontinue anticoagulation with rivaroxaban. In addition to rivaroxaban clopidogrel was stopped. The patient received acetylsalicylic acid and ticagrelor (90 mg bidaily for 12 months, then 60 mg bidaily on a long-term basis).

After 6 month, coronary angiography revealed complete restoration of coronary blood flow (TIMI III). The TOE confirmed a correct position of the PFO closure device. The leukocyte count was normal (9.270 /µl) and the thrombocyte count had increased to 580 000 /µl. Testing of peripheral blood for the JAK2 V617F mutation was positive again. A new bone marrow biopsy revealed hypercellularity with trilineage hematopoiesis ([Fig. 3A], [B]). Megakaryocytes were increased in number and showed large, atypical forms ([Fig. 3B]). The histological features confirmed a myeloproliferative neoplasm consistent with either myelofibrosis or ET. Results of karyotypic analysis were normal. Treatment with pegylated interferon alpha (pegINFα) was recommended at a dose of 90 mg s. c. weekly.

Fig. 3 Bone marrow aspirate smear showing hypercellular bone marrow with proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes (A). Two enlarged megakaryocytes with hyperlobulated nuclei (B).

Discussion

In general, a STEMI occurs after complete occlusion of a coronary artery and is mostly caused by rupture of an unstable atherosclerotic plaque with subsequent occlusive thrombosis.[2] Approximately 50 % of STEMI patients present with significant multi-vessel disease.[3] Most of these patients had several risk factors for coronary artery disease including smoking, arterial hypertension, diabetes mellitus, hyperlipidemia and family history of coronary artery disease.[4] This STEMI patient had only mild hypercholesterolemia but showed several focal occlusions in otherwise normal-appearing coronary arteries ([Fig. 1]).

If multiple occlusions occur in coronary arteries with smooth contours, other causes than simultaneous rupture of atherosclerotic plaques should be considered. Alternative etiologies include

• severe coronary inflammation,

• coronary embolism,

• or vasospasm provoked by cocaine, cigarettes, cannabis or alcohol.[5]

Moreover, coronary thrombus formation may be promoted by coagulation disorders such as heparin-induced thrombocytopenia and antithrombin III deficiency or by other thrombophilic conditions such as essential thrombocythaemia.[4]

In this case, the patient had an untreated essential thrombocythemia (ET) with JAK2 V617F mutation. Compared with the general population the incidence of thrombosis in ET patients is significantly elevated.[1] In a study of 891 patients with essential thrombocythemia, 13 % of these patients experienced arterial (9 %) or venous (4 %) thrombosis within a median follow-up of 6.2 years.[6] Clinical presentations of arterial thrombosis are stroke, myocardial infarction and peripheral arterial occlusion.[1] Predictors of arterial thrombosis include

• age > 60 years,

• history of thrombotic events,

• leukocytosis,

• presence of cardiovascular risk factors,

• and the JAK2 V617F mutation.[1]

An acquired gain-of-function mutation (V617F) in the JAK2 gene can be found in approximately 55 % of the ET patients.[1] The presence of JAK2 V617F mutation increases the risk for thrombotic events through alterations in platelet and mega–karyocyte biology by increasing expression of P-selectin and tissue factor on platelets and exhibiting hypersensitive signaling through the thrombopoietin receptor in mega–karyocytes.[7] [8] [9] Other mechanisms of thrombosis in ET comprise platelet activation by neutrophils through the release of proteolytic enzymes (elastase and cathepsin G) and reactive oxygen species or endothelial dysfunction with upregulation of adhesion receptors.[10]

Drug therapy is based on effective platelet inhibition and cytoreduction. Low-dose aspirin is recommended for all low-risk ET patients with a JAK2 V617F mutation.[1] Since ET is associated with abnormal megakaryopoiesis, increased platelet turnover and faster renewal of platelet cyclooxygenase (COX)-1 low-dose acetylsalicylic acid dosing once daily may not be adequate. A crossover study showed efficient platelet inhibition in ET patients with a twice-daily regimen of low-dose aspirin.[11]

Cytoreductive therapy requires risk stratification into a low risk (age < 40 years, no history of thrombosis), intermediate (age 40–60 years, no history of thrombosis) or high risk group for thrombotic events and is recommended for all high-risk patients (age > 60 years, prior thrombosis, history of hemorrhage, platelet count > 1500 × 10⁹/l).[12] Hydroxycarbamid is the first line therapy for the majority of ET patients and has proven efficacy in the prevention of thrombosis.[1] [12] Since results of preclinical and clinical studies are still conflicting regarding the leukemogenic potential of hydroxycarbamid,[13] treatment with interferon alpha (IFNα) may be preferable in younger patients (i.e. in those < 40 years of age).[14] [15] [16] [17] In addition, IFNα reduces the allele burden in JAK2 V617F-positive patients and may induce a response that persists even after discontinuation of treatment. However, the toxicity associated with IFNα treatment should always be considered. In this regard pegylated IFNα has been shown to be better tolerated.[18]

To date approximately 30 cases of patients with ET and acute myocardial infarction due to coronary occlusion have been published. Only 4 cases report multi-vessel thrombosis and acute myocardial infarction in ET patients.[19] [20] [21] [22] Treatment strategies of ET patients with STEMI are mostly derived from case reports. In general, reperfusion should be performed as early as possible.[3] In a systematic review comprising 56 patients the management of coronary thrombosis was evaluated. 14 % received aspiration thrombectomy and stent implantation was performed in 91 %.[4] If coronary flow is unsatisfactory after thrombus aspiration implantation of drug-eluting stents represents the method of choice. Ultimately, the individual risk of haemorrhagic and thrombotic complications must be weighed up.

In the absence of obstructive atherosclerosis myocardial infarction, especially in younger patients with no or low cardiovascular risk factors, STEMI may be caused by coronary embolization.[23] After exclusion of cardio-embolic sources we detected multiple mural aortic thrombi in this patient ([Fig. 2]). In general, embolisation of aortic thrombi into the coronary artery is an uncommon finding and occurs more often in women without a preference concerning RCA or LAD.[24] [25] [26] An association between ET and aortic thrombi has been previously described.[27] [28] [29] [30] [31] [32] [33] [34] [35] However, this is the first case report of an ET patient with myocardial infarction and simultaneous detection of aortic thrombi. Options to treat aortic thrombi include medical treatment with antithrombotic therapy or surgical treatment with aortic thrombectomy or endovascular repair.[32] [33] [36] [37]

In the presence of a PFO the possibility that myocardial infarction results from paradoxical embolism should also be considered. Paradoxical coronary embolism is a rare cause of myocardial infarction and is reported to account for 10–15 % of all paradoxical emboli.[38] The association of ET with the suspicion of paradoxical embolism is very uncommon.[39] Therapeutic approaches include administration of anticoagulants or closure of the PFO.[40] Trials assessing whether these patients benefit from medical or interventional treatments are lacking.

However, an individualised approach to PFO closure may be recommended and after careful consideration interventional PFO occlusion maybe justified as a valuable therapeutic option.

In regard to the increased thrombotic risk of this patient with ET and JAK2 V617F mutation the PFO was occluded. Subsequently, it was considered safe to stop anticoagulation with rivaroxaban and dual antiplatelet therapy with acetylsalicylic acid and ticagrelor (90 mg bidaily) was continued.[41] After 12 month ticagrelor dose reduction to 60 mg bidaily was recommended. Long term addition of ticagrelor to low-dose acetylsalicylic acid not only reduces the risk of cardiovascular death, myocardial infarction, or stroke in patients with prior myocardial infarction, but also increases the risk of TIMI major bleeding.[42] This has to be taken into consideration especially in ET patients with extreme thrombocytosis. In this case efficacious cytoreductive therapy, as described above, is necessary to prevent bleeding complications when antithrombotics are administered.

Conclusion

When coronary occlusions are unexplained and occur in patients with low cardiovascular risk and normal appearing coronary arteries, screening for alternative etiologies may be considered. In this patient with untreated ET, myocardial infarction resulted most likely from thrombi that embolised to the coronary arteries. Sources of emboli were detected in the aorta, but in the presence of a patent foramen ovale myocardial infarction due to paradoxical embolism should also be considered.

In the absence of evidence-based clinical practice guidelines an individualized and risk-adapted approach to interventional, cytoreductive and antithrombotic therapy is recommended in ET patients with myocardial infarction due to coronary embolism.

Conflicts of interest

CB has received speaker's fees from Merck, AstraZeneca, Sanofi und Bayer; MM has received speaker's fees from Bayer Vital GmbH, AstraZeneca GmbH, Daiichi Sankyo Deutschland GmbH, Pfizer/Bristol-Myers Squibb, Berlin Chemie AG, Lilly Deutschland GmbH, Boehringer Ingelheim Pharma GmbH & Co. and KG Sanofi-Aventis Deutschland GmbH; JRDL, JR, TK and TH declare that there are no conflicts of interest.

• References

• 1 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90 (02) 162-173
• 2 Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006; 47 (8 Suppl): C7-12
• 3 Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), Steg PG, James SK et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33 (20) 2569-2619
• 4 Mahmoud A, Saad M, Elgendy YI. Simultaneous multi-vessel coronary thrombosis in patients with ST-elevation myocardial infarction: a systematic review. Cardiovasc Revasc Med 2015; 16 (03) 163-166
• 5 Roule V, Sabatier R, Lognoné T. , et al. Thrombus in normal coronary arteries: retrospective study and review of case reports. Arch Cardiovasc Dis 2011; 104 (04) 216-226
• 6 Carobbio A, Thiele J, Passamonti F. , et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 2011; 117 (22) 5857-5859
• 7 Landolfi R, Di Gennaro L. Prevention of thrombosis in polycythemia vera and essential thrombocythemia. Haematologica 2008; 93 (03) 331-335
• 8 Hobbs CM, Manning H, Bennett C. , et al. JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia. Blood 2013; 122 (23) 3787-3797
• 9 Fleischman AG, Tyner JW. Causal role for JAK2 V617F in thrombosis. Blood 2013; 122 (23) 3705-3706
• 10 Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood 2013; 122 (13) 2176-2184
• 11 Pascale S, Petrucci G, Dragani A. , et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119 (15) 3595-3603
• 12 Beer PA, Erber WN, Campbell PJ, Green AR. How I treat essential thrombocythemia. Blood 2011; 117 (05) 1472-1482
• 13 Björkholm M, Hultcrantz M, Derolf ÅR. Leukemic transformation in myeloproliferative neoplasms: therapy-related or unrelated?. Best Pract Res Clin Haematol 2014; 27 (02) 141-153
• 14 Pai SG, Kaplan JB, Giles FJ. Long-acting interferon for myeloproliferative neoplasms – an update. Expert Rev Hematol 2016; 9 (10) 915-917
• 15 Kovacsovics-Bankowski M, Kelley TW, Efimova O. , et al. Changes in peripheral blood lymphocytes in polycythemia vera and essential thrombocythemia patients treated with pegylated-interferon alpha and correlation with JAK2(V617F) allelic burden. Exp Hematol Oncol 2015; 5: 28
• 16 Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia 2008; 22 (11) 1990-1998
• 17 Kiladjian JJ, Cassinat B, Chevret S. , et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008; 112 (08) 3065-3072
• 18 Besses C, Alvarez-Larrán A. How to Treat Essential Thrombocythemia and Polycythemia Vera. Clin Lymphoma Myeloma Leuk 2016; 16 (Suppl): S114-S123
• 19 Hamada Y, Matsuda Y, Fujii B. , et al. Multiple coronary thrombosis in a patient with thrombocytosis. Clin Cardiol 1989; 12 (12) 723-724
• 20 Michaels AD, Whisenant B, MacGregor JS. Multivessel coronary thrombosis treated with abciximab (ReoPro) in a patient with essential thrombocythemia. Clin Cardiol 1998; 21 (02) 134-138
• 21 Terada H, Satoh H, Uehara A. Multivessel coronary thrombosis, acute myocardial infarction, and no reflow in a patient with essential thrombocythaemia. Heart 2000; 83 (06) E10
• 22 Ozben B, Ekmekci A, Bugra Z. , et al. 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 2006; 22 (01) 79-84
• 23 Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015; 36 (08) 475-481
• 24 Nader RG, Barr F, Rubin R. , et al. Aortic degenerative changes and thrombus formation: an unusual cause of massive myocardial infarction with normal coronary arteries. Am J Med 1989; 86 (6 Pt 1): 718-722
• 25 Ito H, Takahashi K, Sasaki H. , et al. Large thrombus in the ascending aorta successfully treated by thrombolysis – an unusual cause of acute massive myocardial infarction. Jpn Circ J 2001; 65 (06) 572-574
• 26 Knoess M, Otto M, Kracht T, Neis P. Two consecutive fatal cases of acute myocardial infarction caused by free floating thrombus in the ascending aorta and review of literature. Forensic Sci Int 2007; 171 (01) 78-83
• 27 Oki M, Moriuchi M, Kawada H. , et al. A case of essential thrombocythemia presenting with aortic thrombosis. Tokai J Exp Clin Med 2008; 33 (04) 135-137
• 28 Morata Barrado PC, Blanco Cañibano E, García Fresnillo B, Guerra Requena M. Acute lower limb ischemia in a patient with aortic thrombus and essential thrombocytosis. Int J Hematol 2009; 90 (03) 343-346
• 29 Lorelli DR, Shepard AD. Aortic mural thrombus embolization: an unusual presentation of essential thrombocytosis. Ann Vasc Surg 2002; 16 (03) 375-379
• 30 Bachmeyer C, Elalamy I. [Aortic thrombus and splenic infarcts indicating essential thrombocythemia]. Rev Med Intern 2011; 32 (09) e102-104
• 31 Hino H, Terasaki T, Hashimoto Y. , et al. [Cerebral infarction associated with mobile thoracic ascending aortic thrombus in a patient with essential thrombocythemia]. Rinsho Shinkeigaku 1999; 39 (07) 705-710
• 32 Fang M, Agha S, Lockridge L. , et al. Medical management of a large aortic thrombus in a young woman with essential thrombocythemia. Mayo Clin Proc 2001; 76 (04) 427-431
• 33 Sohn V, Arthurs Z, Andersen C, Starnes B. Aortic thrombus due to essential thrombocytosis: strategies for medical and surgical management. Ann Vasc Surg 2008; 22 (05) 676-680
• 34 Johnson M, Gernsheimer T, Johansen K. Essential thrombocytosis: underemphasized cause of large-vessel thrombosis. J Vasc Surg 1995; 22 (04) 443-449
• 35 Campos Franco J, Martínez Lesquereux L, Seoane Pose C, Pazos González G. [Aortic thrombosis in a patient with essential thrombocythemia]. Cir Esp 2013; 91 (02) e9
• 36 Choukroun EM, Labrousse LM, Madonna FP, Deville C. Mobile thrombus of the thoracic aorta: diagnosis and treatment in 9 cases. Ann Vasc Surg 2002; 16 (06) 714-722
• 37 Böckler D, von Tengg-Kobligk H, Schoebinger M. , et al. An unusual cause of peripheral artery embolism: floating thrombus of the thoracic aorta surgically removed. VASA 2007; 36 (02) 121-123
• 38 Wachsman DE, Jacobs AK. Paradoxical coronary embolism: a rare cause of acute myocardial infarction. Rev Cardiovasc Med 2003; 4 (02) 107-111
• 39 Ahmed S, Sadiq A, Siddiqui AK. , et al. Paradoxical arterial emboli causing acute limb ischemia in a patient with essential thrombocytosis. Am J Med Sci 2003; 326 (03) 156-158
• 40 Meier B, Kalesan B, Mattle HP. , et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368 (12) 1083-1091
• 41 Wallentin L, Becker RC, Budaj A. , et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 42 Bonaca MP, Bhatt DL, Cohen M. , et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800