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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