Discussion
Relatively young patients (age 30–45) with ET who do not exhibit
traditional coronary risk factors (i.e., dyslipidemia, hypertension,
smoking, diabetes, and older age) have also been reported to have acute
myocardial infarction (AMI)14-17; however, there is
little information on the incidence of AMI among patients younger than
20 years, with few reports on such cases.18
The mechanisms underlying acute coronary syndrome are considered to be
multifactorial. Increased blood cells numbers and increased blood
viscosity in ET promote the formation of platelet–leukocyte aggregates,
with concomitant release of proteases from the activated leukocytes into
circulation, and consequent intravascular
hypercoagulability.19 Besides the hyperviscosity,
chronic endothelial cell damage provoked by activated platelets and
chronic high shear stress on the vessel wall are potential causative
factors for acute coronary syndrome.19 Most patients
with ET (approximately 60%) harbor the JAK2 V617F mutation in
their hematopoietic cells.2, 20 This somatic
mutation causes constitutive activation of the kinase, resulting in
myeloproliferative disorders, and is also known as a significant risk
factor for cardiovascular events.2-6, 16Pathophysiologically, platelets from patients with ET carrying theJAK2 V617F mutation increased their capacity to generate thrombin
associated with platelet activation.3 Additionally,
megakaryocytes from the JAK2 V617F knocked-in model mice showed
accelerated maturation and increased proplatelet
formation,21 indicating that the JAK2 V617F
mutation alters the intrinsic characters of both megakaryocytes and
platelets beyond merely increasing in cell numbers. In our case,
coronary endothelial cell dysfunction lasted for a year after STEMI
onset and was confirmed by a positive acetylcholine provocation test
result. We suggest that the presence of the JAK2 V617F mutation
and hyperviscosity since childhood, may have contributed to the
persistent chronic coronary pathology.
Anagrelide is a selective inhibitor of thrombopoiesis and is effective
for lowering the platelet count.9, 22-24 Although the
precise mechanism underlying the attenuation of platelet overproduction
remains ambiguous, anagrelide’s effect may be based on the repression of
transcriptional factors related to the megakaryopoiesis including GATA-1
and FOG-1.25 Furthermore, anagrelide inhibits cyclic
adenosine monophosphate phosphodiesterase III pharmacologically, and has
inotropic and vasodilator properties; thus, the most common
cardiovascular adverse events associated anagrelide include
tachycardia/palpitations.9, 12 However, acute coronary
syndrome including AMI and angina have been reported as adverse events
of anagrelide.23, 25 Typically, patients with ET are
middle-aged or older2 and often have the traditional
cardiovascular risk factors. Therefore, observation of AMI pathogenesis
in our very young patient without any conventional risk factors, except
for ET itself and anagrelide administration, was
unusual.13
The biological effects of anagrelide on the coronary artery are
controversial, and both vasospasm25 and
vasodilation26 have been reported. Theoretically, the
inhibition of phosphodiesterase III by anagrelide should induces
vasodilatation, but not vasospasm. However, a mouse model study revealed
that phosphodiesterase inhibitors increased the release of sympathetic
neurotransmitters.27 A report speculated that
depending on the expression patterns of alpha- and beta- adrenergic
receptors in particular vessels cause vasoconstriction and
vasodilatation, respectively.25 In addition to the
long-lasting endothelial cell damage caused by ET itself, the complex
distribution of adrenergic receptors may induce the deterioration of
coronary vessel function, eventually resulting in STEMI. In our case,
the negative effects of thrombocytosis due to ET on the maintenance of
coronary artery integrity, as shown by abnormal findings, together with
the pharmacological effects anagrelide on the artery led to the
exacerbation of chest symptoms such as palpitations and vague
sensations, which finally led to STEMI.
In conclusion, our patient with ET developed STEMI as a consequence of
anagrelide administration and persistent coronary endothelial
dysfunction caused by the ET itself.
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