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.
