Therapeutic dilemmas in the treatment of acute coronary syndrome as manifestation of essential thrombocythaemia

Abstract

Essential thrombocythemia (ET), a chronic myeloproliferative disease, is characterized by an increased number of platelets and risk of vascular thrombosis. A case of a patient treated for ET who had acute myocardial infarction (MI) and reinfarction within a month is presented. A 55-year-old male patient was hospitalized because of subacute inferolateral non-ST-segment-elevation MI, without risk factors for cardiovascular diseases. The patient has been treated for ET for the past 8 years, received anagrelide for the past two years. The first coronary-angiography did not detect significant stenosis of epicardial vessels; the patient was discharged in stable condition with anagrelide therapy. Two weeks later, the patient had an acute anterolateral ST-segment-elevation MI. Primary percutaneous coronary intervention showed thrombus in the distal part of the left anterior descending coronary artery. Percutaneous transluminal coronary angioplasty was performed and eptifibatide was administered after the procedure. There was no residual stenosis, prescribed therapy included clopidogrel and low-molecular-weight heparin. Anagrelide therapy was replaced with hydroxyurea (HU) and acetylsalicylic acid (ASA). It is necessary to treat ET in line with the standard treatment protocol for coronary diseases. In the treatment of high-risk hematology patients anagrelide proved to be a worse option than the combination of HU and ASA.

<Learning objective: It is known that the myeloproliferative disorders carry the risk of vascular thrombosis and myocardial infarction. The occurrence of vascular events is usually the first sign of the disease. A case of a patient with history of hematological disease, who was receiving active treatment and was well-regulated with oral medication, is presented here. Various approaches to treatment of such patients are possible and treatment decision-making is important for clinicians. Therefore, this article presents both our view on this issue and an overview of the literature in this area.>

Introduction

Essential thrombocythemia (ET) is a chronic myeloproliferative disease characterized by thrombocytosis with a bone marrow megakaryocyte hyperplasia and increased risk of vascular events, arterial and/or venous [1]. This heterogeneous group of diseases also includes polycythemia vera, idiopathic myelofibrosis, and chronic myelogeneous leukemia [2]. Transition from one disorder to another is possible. Acquired mutation in JAK2 gene is discovered in a high proportion in patients with Philadelphia chromosome negative myeloproliferative disease, which provides a molecular basis for integration of these entities 3, 4, 5, 6. ET affects the patient's quality of life more than their survival and thus has more favorable prognosis than other myeloproliferative disorders [7]. The challenge in treating ET is prevention of bleeding and thrombosis without increasing the risk of complications, such as paradox thrombosis, hemorrhage, or the progression of the disease into myelofibrosis or acute leukemia.

A case of a 55-year-old male patient suffering from ET for the past eight years is presented in this article. He received anagrelide therapy for the past two years. Despite active treatment, he has had acute myocardial infarction and reinfarction within one month. The aim of this article is to put greater emphasis on the problem of treating such patients.

Case report

A 55-year-old male patient was hospitalized in the coronary care unit because of subacute non-ST segment elevation myocardial infarction (NSTEMI). There was no family history of cardiovascular diseases and no major risk factors (hypertension, diabetes mellitus, dyslipidemia, smoking) for development of cardiovascular diseases in the patient's medical history. The patient has suffered from ET for the past eight years. During the first six years he was treated with hydroxyurea (HU) and acetylsalicylic acid (ASA). This therapy was discontinued and replaced with anagrelide, while the patient complained of itching of the palms, which was suspected to be related to the previous therapy. Electrocardiogram showed ischemia of the inferolateral wall of the myocardium. Table 1 presents laboratory characteristics of the patient. Calculated Grace Score was 90.6 with 3% probability of dying from admission to six months after the discharge from hospital. In consultation with the hematologist, the patient was treated with anagrelide but without ASA, low weight molecular heparin (LWMH), angiotensin-converting enzyme inhibitor (ACEI), statin, omega-3-acid, and long-acting nitrates. The coronary angiography did not detect any significant stenosis of major epicardial vessels (Fig. 1a). The patient was discharged from hospital in a stable condition with blood concentration of platelets of 706 × 10⁹/L. Two weeks after the discharge, the patient was hospitalized again because of acute anterolateral ST-segment elevation myocardial infarction (STEMI). A primary percutaneous coronary intervention (PPCI) was done and thrombus was found in the distal part of the left descending coronary artery (LAD) (Fig. 1b). Percutaneous transluminal coronary angioplasty (PTCA) was then performed to open the blocked coronary artery and to restore arterial blood flow to the heart tissue. There was no residual stenosis of the target coronary artery and no indication for stent implantation. Infusion of eptifibatide was also administered. No major complication occurred after the intervention. Echocardiographic findings after both coronary incidents indicated proper left ventricular ejection fraction with diastolic dysfunction of the first degree. The therapy included clopidogrel, ACEI, statin, omega-3-acyd, LWMH, and trimetazidim. Anagrelide was replaced with HU and ASA. Beta blocker was not given, as the patient had a low heart rate frequency.

Table 1.

Laboratory characteristic.

RBC 3.76 × 1012/L (4.34–5.72 × 1012/L), Hb 114 g/L (138–175 g/L), Hct 0.337 (0.415–0.530)

WBC 15.5 × 109/L (3.4–9.7 × 109/L)

Plts 840 × 109/L (158–424 × 109/L)

PT 1.18 1 (0.70–1.27 1), APTT 0.97 (0.8–1.2), TT 15.8 s (14–21 s), BT 0.07 s (0.06–0.24 s), protein C 1.40 (0.69–1.56), vWF 0.72 1 (0.50–1.50 1), thrombocyte aggregation to ristocetin 2 U (90–201 U), LAC 1.27 aCL screen, anti-β2GPI negative, JAK2 mutation negative

TnI 88.000 μg/L (0.000–0.056 μg/L), CK 1247 U/L (0–177 U/L), CK-MB 123 U/L (0–24 U/L)

Na 134 mmol/L (137–146 mmol/L), K 4.3 mmol/L (3.9–5.1 mmol/L), urea 5.4 mmol/L (2.8–8.3 mmol/L), creatinine 78 μmol/L (42–80 μmol/L)

LDH 224 U/L (130–241 U/L), cholesterol 3.03 mmol/L (<5 mmol/L), LDL-C 1.19 mmol/L (<3 mmol/L), HDL-C 0.92 mmol/L (>1 mmol/L), triglyceride 2.03 mmol/L (<1.7 mmol/L)

RBC, red blood cell; Hb, hemoglobin; Hct, hematocrit; WBC, white blood cell; Plts, platelets; PT, prothrombin time; APTT, activated partial thromboplastin time; TT, thrombotic time; BT, bleeding time; vWF, von Wilebrand factor; LAC, lupus anticoagulant; aCL, anticardiolipin; anti-β2GPI, anti-beta2 glycoprotein I.

Fig. 1.

(a) Normal angiogram of left anterior descending artery (LAD) and left circumflex artery after first myocardial infarction and (b) distal occlusion of LAD during second myocardial infarction.

Discussion

ET is the most common among chronic myeloproliferative monoclonal neoplasms [8]. The disease appears at all ages and is prevalent in women [9]. Most patients are asymptomatic at presentation. Vascular events are the most common clinical manifestation of the disease and arterial thromboses are more often than venous 10, 11, 12. Acute coronary syndrome occurs in 9.4% of patients with essential thrombocytosis [13]. Smoking and hypertension are the risk factors for ischemic arterial complications in patients with essential thrombocytosis [14]. The pathogenesis of thrombosis in ET has not been clarified. Along with smoking and hypertension, advanced age and previous history of thrombosis are the most important factors for vascular manifestation in ET 8, 10, 15. There is no correlation between platelet blood level and the risk of thrombosis [16]. The possible importance of leukocytes and JAK2 mutation in development of thrombosis in monoclonal neoplasm has been researched in many studies 7, 17. The results of these studies tend to support a contributory role of higher leukocyte counts and JAK2 mutation status and allele burden for development of thrombosis [16]. Leukocytes in ET patients have an activated phenotype with increased phagocytosis, overexpression of the membrane CD11b antigen and leukocyte alkaline phosphatase, and increased plasmatic and cellular elastase content [18]. Overexpression of monocyte tissue factor, currently considered the main trigger of the coagulation cascade in vivo, has been demonstrated in ET patients with thrombosis, and an increased number of platelets expressing P-selectin has also been found. The link between leukocyte and platelet activation and thrombosis in ET has been confirmed by the finding of increased concentrations of markers for coagulation and endothelial activation in patients with increased blood cell activation 18, 19. A vascular event represents the most frequent complication of ET. That affects the patients’ quality of life more than their survival rate. Prognostic stratification of ET must be dictated by the patients’ risk of developing such complications and therefore the treatment goal should be to prevent thrombosis and bleeding without increasing the risk of transformation of the disease [20]. Recent diagnostic criteria for ET have lowered the platelet threshold from 600 × 10⁹/L to 450 × 10⁹/L [15]. A risk-adapted treatment strategy is an option in the choice of therapy. Bearing in mind the possible complications in patients who suffer from ET (thrombotic events or hemorrhage), there are a few drugs available for treatment. A young, asymptomatic patient with a platelet count of less than 1500 × 10⁹/L should be considered at a low risk of thrombosis and hemorrhagic events, and does not need cytoreductive drugs, only ASA 12, 21. By contrast, advanced age of 60 years or more, a history of serious bleeding or thrombosis, or a platelet level over 1500 × 10⁹/L, are indications for cytoreductive drugs [21]. The myelosuppressive agent of choice in patients who suffer from ET and have risk of vascular thrombosis or bleeding is HU [19]. This drug was found to be effective in reducing the incidence of thrombosis [22]. The biggest concern is whether HU carries the risk of development of leukemia. There is no strong scientific evidence for this, but the putative risk of leukemia associated with HU prompted researchers to test some new drugs that lack this potential, such as anagrelide. Anagrelide is an imidazoquinazoline derivate that reduces the platelet count in ET [23]. It selectively inhibits maturation of megakaryocytes, with either minimal or no effect on the other blood cell precursors. This might be a solution to our problem, and it may explain why this patient had a myocardial infarction twice. Furthermore, according to the results obtained by Harrison and colleagues, HU plus ASA therapy was superior to anagrelide plus ASA in patients with ET at high risk of vascular events [24]. Their trial showed that control of platelet count alone should not be taken as an appropriate surrogate end point to judge the efficiency of treatment for ET. There were more vascular events in the group of patients with anagrelide therapy, despite a reduction in the platelet count that was similar in the HU group. A likely explanation for this finding is the myelosuppressive effect of HU which affects thrombocytes, leukocytes, and erythrocytes [25]. Anagrelide and ASA act synergistically, which increases the risk of bleeding complications due to inhibited platelet function when these two drugs are administered simultaneously. However, the combination of HU and ASA does not have such an effect. A similar result was obtained in a patient treated with HU and ASA because of polycythemia vera [26]. Evolution into myelofibrosis is a part of the natural history of ET and it occurs in about 3% of patients after 5 years, in 8% after 10 years, and in 15% after 15 years of the illness [27]. The study by Harrison et al. showed that progression to myleofibrosis was about three times as frequent in the anagrelide group as it was in the HU group. Transformation into acute leukemia was similar in both groups [28].

Treatment of a myocardial infarction as a manifestation of ET is a great challenge for clinicians. There are some important facts to be considered in treatment decision-making. Mechanical opening of a blood vessel–by angioplasty, aspiration, or stent placement does not present a problem, but there is a question of choosing adequate antiaggregation therapy for treatment of MI, but also of ET. The gold standard in long-term treatment of acute coronary syndrome is a dual antiplatelet therapy (DAT) with clopiodgrel and ASA [29]. ASA is not the optimal choice in patients who were treated with anagrelide due to increased risk of hemorrhage. By substituting anagrelide with HU, the treatment is optimized. PPCI is still the best option in treatment of acute MI – opening of the occluded blood vessel. When catheterization laboratory is not available, administration of a fibrinolytic therapy is an alternative. Introduction of unfractionated or LMWH and glycoprotein IIb/IIIa receptor inhibitors are also recommended therapies [29].

Conclusion

The treatment of patients with ET and myocardial infarction includes PPCI, elective PCI, emergency coronary artery bypass graft, or infusion of fibrinolytic agent. The treatment of myocardial infarction based on myeloproliferative monoclonal diseases requires special consideration. Standard protocol of treatment for acute coronary syndrome is effective in most cases, but we must know that it is crucial to treat the underlying disease as well. According to new data, the combination of HU and ASA provides the greatest benefit for the patients with ET and myocardial infarction. There is much less bleeding and fewer vascular events, and progression to myelofibrosis and leukemia in the HU/ASA group is lower than in the anagrelide group. However, there is no simple answer to the question of how to treat patients with ET and myocardial infarction. There are insufficient data on the most appropriate way of treating these patients, which requires further studies with a larger number of patients.