Journal of Thrombosis and Thrombolysis

, 25:193

Challenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome


    • Department of Cardiology and Cardiovascular Disease
  • Björn Krämer
    • Department of Cardiology and Cardiovascular Disease
  • Tobias Geisler
    • Department of Cardiology and Cardiovascular Disease
  • Andreas E. May
    • Department of Cardiology and Cardiovascular Disease
  • Stefan-Martin Kroeber
    • Institute of Pathology Koblenz
  • Reinhard Kandolf
    • Institute of Molecular Pathology
  • Meinrad Gawaz
    • Department of Cardiology and Cardiovascular Disease

DOI: 10.1007/s11239-007-0082-0

Cite this article as:
Doesch, C., Krämer, B., Geisler, T. et al. J Thromb Thrombolysis (2008) 25: 193. doi:10.1007/s11239-007-0082-0


Essential thrombocythemia (ET) is an acquired clonal hematological stem-cell disorder that is characterized by a persistent increase in platelet count over 600,000/μl and elevated megakaryocyte levels in the bone marrow. Patients with ET are on the one hand at risk of thrombosis and on the other hand of hemorrhagic events especially in patients with very high platelet accounts. We report two illustrative cases with ET and acute coronary syndrome from our recent clinical experience illustrating the challenges in the antithrombotic treatment of these patients.


Essential thrombocythemiaThrombosisAcute coronary syndromeCytoreductive treatmentAntiplatelet therapy


Essential thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) that is characterized by an increase in platelet count over 600,000/μl, elevated hyperploid megakaryocyte levels in bone marrow and clumping giant platelets [1]. Thrombotic events predominantly in the arterial system are the major complications. However, there are only a few reports on angina and myocardial infarction in patients with ET [25]. As hemorrhagic events also occur especially in patients with very high platelet counts, the optimal treatment with antiplatelet and cytoreductive therapy is a challenge in these patients requiring individualized dose adjustment depending on platelet count and function tests. We present two cases of patients with ET and acute coronary syndrome illustrating the challenges and possible complications in the treatment of these patients with an altered hemostatic response.

Case 1

A 48 year old man was referred to our hospital by his general practitioner with symptoms of acute onset of chest pain radiating to the back that have started the day before his admission. The patient did not have cardiovascular risk factors apart from tobacco abuse and his past medical history did not reveal evidence of hematological disease. ECG showed a Q, discrete ST-segment elevations and negative T waves in II, III, aVF suggestive of an acute inferior infarction (Fig. 1). Laboratory data showed an increase of creatine kinase (CKmax 884 U/l, CK-MB 77 U/l) with a positive troponin T (12.8 U/l) and a raised platelet count of 1270,000/μl. Before coronary angiography the patient was administered 500 mg aspirin and 5,000 IE heparin intravenously. Additionally, he receive a loading dose of 600 mg clopidogrel. Coronary angiography revealed subtotal occlusion of the proximal right coronary artery (TIMI 0-1). After wire passage and initial treatment with glycoprotein IIb/IIIa receptor antagonist coronary blood flow was restored (TIMI 2-3). The right coronary artery showed extensive thrombotic material at the site of a ruptured proximal RCA plaque (Fig. 2) so that angioplasty and bare metal stenting (Zeta 4.0 × 23 mm/mm) was performed. The rest of the coronary artery system did not reveal atherosclerotic lesions. After the coronary intervention a glycoprotein IIb/IIIa receptor antagonist infusion was continued over 12 h combined with the standard therapy of aspirin 100 mg per day and clopidogrel 75 mg per day. As ADP-induced aggregometry revealed a low responsiveness (platelet inhibition <30%) to clopidogrel the daily dose was increased to 150 mg to prevent adverse cardiac advents in the future. In the week after the myocardial infarction the platelet count rose to a maximum of 1858,000/μl (Fig. 3). Bone marrow examination (Fig. 4) showed numerous large hyperploid megakaryocytes with heterogenous morphology. Normal myelopoiesis and erythropoieses were present and no Philadelphia chromosome was detected. PCR for JAK2 V617F mutation was positive. Under the cytoreductive therapy with hydroxyurea platelet count fell. As soon as a stable reduction of the platelet count was achieved, the clopidogrel dose was reduced to 75 mg per day. Aggregometry under cytoreductive treatment revealed an adequate response to clopidogrel so that the maintenance dose of 75 mg was administered for another two months. For more than 1 year no major cardiovascular events and no hemorrhage occurred under the continued therapy with hydroxyurea and aspirin.
Fig. 1
Case 1: ECG with Q, discrete ST segment elevations and negative T waves in II, III, aVF (
Fig. 2

Case 1: Coronary angiography: Stenosis (arrow ←) of the RCA before (Panel a) and after stenting (Panel b)
Fig. 3

Case 1: Time course of blood platelet count after myocardial infarction and combined cytoreductive and antiplatelet therapy
Fig. 4

Case 1: Cytology of bone marrow aspiration with numerous megakaryocytes (Panel a) and histology (Giemsa stain) with atypical megakarycytes (Panel b)

Case 2

A 67 year old woman was transferred to our hospital for coronary angiogram. Six days ago, she had been supplied with a DDD-R pacemaker system because of symptomatic sick sinus syndrome. She had had episodes of chest pain on exertion over the last weeks and reported a predisposition for hematomas and increased episodes of nose bleeding during the last weeks. The night before her admission to our hospital she had suffered from acute chest pain associated with increasing troponin T levels but without ECG alterations. Laboratory findings also revealed an elevated blood count of 989,000/μl. Suspecting an acute coronary syndrome the patient was administered 500 mg aspirin, 5,000 IE heparin and a loading dose of 600 mg clopidogrel before cardiac catherization. Coronary angiography ruled out significant stenotic coronary artery disease or a culprit lesion. However, the night after coronary angiography the patient developed a painful pocket haematoma expanding in size so that surgical drainage was required. Because of her raising platelet count the patient underwent a bone marrow aspiration and biopsy, which showed marked, isolated megakaryocytic expansion, which was consistent with ET. Besides, tests of hemostasis were performed to detect clinically relevant platelet dysfunction with an increased bleeding risk. In our patient the in vivo collagen/epinephrine and collagen/ADP in vitro bleeding time (PFA-100 Dade-Behring) were normal. However, the pathological CBA/WF ratio revealed an acquired Von Willebrand’s deficiency in this patient. ADP-induced aggregometry showed a platelet inhibition >60% 5 days after clopidogrel loading. PCR for JAK2 V517F mutation was negative. As the combination of an acquired VWF syndrome and the treatment with antiplatelet drugs for a suspected coronary artery syndrome may have increased the bleeding risk, antiplatelet therapy was not continued to prevent further hemorrhagic complications. However, due to the high platelet count and the bleeding complication a cytoreductive treatment was started. The therapy with hydroxyurea reduced the platelet count under 450,000/μl within 1 month (Fig. 5).
Fig. 5

Case 2: Time course of blood platelet count after acute coronary syndrome, pocket haematoma and cytoreductive therapy


ET is an acquired MPD characterized by a sustained elevation of the platelet number with a tendency to thrombosis and hemorrhage. According to the new WHO classification, ET is diagnosed by a platelet count threshold over 600,000/μl, characteristic bone marrow findings, exclusion of a reactive thrombocytosis or other myeloproliferative disorders like polycythemia vera (PV), chronic idiopathic myelofibrosis (IMF), and chronic myeloic leukemia (CML) [6]. The JAK2 V617F mutation is confirmed in more than 50% of ET patients and is associated with a longer duration of disease and a higher rate of complications (fibrosis, hemorrhage and thrombosis) [7].

ET is often diagnosed accidentally. However, 20% of patients with ET are diagnosed due to thrombembolic or hemorrhagic complications [8]. Pathophysiologically, the persistant elevated platelet count in ET arises from the pathological expansion of the megakaryocytic elements in the bone marrow and is considered a clonal disorder of a multipotent myeloid stem cell. The increased number of functionally altered thrombocytes leads to thrombembolic complications in the arterial and venous system as well as platelet-mediated microvascular disturbances. But at the same time especially patients with very high platelet counts can also present with bleeding symptoms. The bleeding diathesis in these patients does not occur due to an impaired platelet function but is more likely caused by an acquired Von Willebrand’s disease that can be explained by the proteolytic reduction of Von Willebrand Factor (VWF) multimers. The VWF large mulitmer deficiency appears at platelet counts of 1000,000/μl to 1500,000/μl and increases thereafter [9].

Although arterial thromboembolism is common in ET, coronary artery involvement leading to acute myocardial infarction is rare compared with other MPDs like PV [10]. Rossi et al. [10] have followed 170 patients with ET for 10 years. Only 9.4% of these patients had a MI during the follow-up period and 75% of the ET patients who suffered a myocardial infarction had additionally cardiovascular risk factors. There are a lot of theories about the factors contributing to myocardial infarction in ET patients. However, the underlying pathophysiological mechanisms still remains unclear. Platelet number does not seem to be a good predictor of thrombembolic events. This is clearly illustrated by our two patient examples. Nearly the same platelet count led to coronary thrombembolism with low responsivness to antiplatelet therapy with clopidogrel in case 1 and bleeding complications the day after loading with antiplatelet drugs for suspected acute coronary syndrome in the second patient presenting with a secondary VWF syndrome.

In patients with ET circulating platelets and megakaryocytes in the bone marrow are morphologically altered and functional studies have proved that these anatomically altered platelets function abnormally. Proteomic analysis of platelets of ET patients have revealed individual differences but not yet led to the identification of disease-specific proteins. Furthermore, no biomarkes allowing to estimate the risk of thrombosis or bleeding have been identified so far [11]. There is no doubt that the individual hemostatic response is determined by the number and functionality of the platelet surface receptors. In patients with MPDs a variety of platelet surface membrane protein and receptor abnormalities have been demonstrated but could not be used to identify patients at risk of bleeding or thrombosis [8].

In general, patients with ET have a thrombembolic risk for arterial or venous thrombosis of 3.4%. If a previous thrombembolic event had occurred, the annual risk of thrombosis raises up to 31.4% [12]. In our case 1 the dual antiplatelet therapy with asprin and 75 mg clopidogrel per day was not effective so that the daily dose was increase to 150 mg per day until the a stable reduction of platelet number was achieved by cytoreductive therapy.

The study by Geisler et al. [13] showed that patients with a low-responsiveness to clopidogrel after symptomatic CAD and stent implantation have a significant elevated risk for adverse cardiovascular events and death. In diabetics with acute coronary syndrome who also suffer from an altered platelet function, the inadequate to response to clopidogrel is discussed as one major contributor to recurrent atherothrombotic events in this patient subgroup. Therefore, these patients also might profit from an intensified platelet therapy [14].

These studies suggest that in patients with ET and cardiovascular events the adequate response to clopidogrel by ADP-induced platelet aggregation [15] seems to be crucial to prevent future cardiovascular events.


If thrombembolic events and bleeding can be avoided life expectancy in patients with ET is not altered. Regardless of prior thrombembolic complications, patients with ET under 60 year and no risk of bleeding diathesis are recommended a low-dose asprin therapy with 100 mg per day in order to prevent arterial thrombosis [16, 17]. An additional cytoreductive therapy with hydroxyurea is recommended in patients with additional risk factors like an increased age (over 60 years), previous thrombembolic or hemorrhagic complication as well as a platelet count over 1000,000/μl [18]. Anagrelide was recommended in patients who do not respond to a cytoreductive therapy with hydroxyurea. In patients over 60 years but without additional risk factors cytoreductive therapy is controversial [17].

Especially patients with a pronounced thrombocytosis and previous myocardial infarction may, due to an impaired platelet function, not respond adequately to a standardized antiplatelet therapy and therefore may benefit from an individual dose adjustment by point-of-care testing.

On the other hand, antiplatelet drugs also increase the risk of bleeding complication in these patients often suffering from an acquired VWF syndrome.

Therefore, the adequate antiplatelet drug therapy and dose adjustment should be decided based on clotting tests and aggregometry results on each single patient.

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© Springer Science+Business Media, LLC 2007