Acute Coronary Syndromes in Patients with Thrombocytopenia

Abstract

Antiplatelet drugs are fully approved in the current guidelines for the treatment of acute coronary syndromes, however they are potentially fatal considering their bleeding effect related to their antiplatelet action. Therefore, the bleeding risk associated with the use of antiplatelet drugs in patients with thrombocytopenia is crucial. Over the next years we will see more patients with thrombocytopenia and appropriate clinical practice guidelines are still required for these patients.

Keywords: Innovative biotechnologies; Personalized medicine; Acute coronary syndromes; Thrombocytopenia; Antiplatelet therapy

Abbreviations

ACS: Acute Coronary Syndromes; AMI: Acute Myocardial Infarction; DAPT: Dual Antiplatelet Therapy; PCI: Percutaneous Coronary Intervention

Introduction

Platelets play a pivotal role in the pathogenesis of Acute Coronary Syndromes (ACS) and thrombocytosis has been demonstrated to be an important risk factor for Acute Myocardial Infarction (AMI); indeed, in patients with essential thrombocythemia the incidence of AMI is about 9.4% [1]. Nevertheless, AMI has been reported also in patients who suffer from thrombocytopenia that could be associated with several conditions [2,3].

Thrombocytopenia is defined as a platelet count of <150 x 10^9/L and it is classified as mild (100-150 x 10^9/L), moderate (50-100 x 10^9/L) or severe (<50 x 10^9/L). Thrombocytopenia is generally expected in 13% of patients, whereas this condition is present in 5% of ACS patients suffering from thrombocytopenia. It is more frequent in several conditions such as older patients, diabetes, renal insufficiency, heart failure and sometimes is considered as a risk factor of AMI, for example in patients with Kawasaki disease [4-6].

As reported in autoptic samples, the pathogenesis of an occlusive thrombus in these patients share similarities with classic atherosclerotic plaque rupture, shedding light on hidden aspects that go beyond platelet count [7]. Indeed, likewise of rodent models, patients with thrombocytopenia may be predisposed to coronary thrombosis because their platelets are larger and more adhesive to the vascular surface [8,9]. Furthermore a higher platelet microparticles activation has been shown in ACS patients with idiopathic thrombocytopenic purpura and middle-aged patients than in control groups [10,11].

The American Heart Association (AHA) and the European Society of Cardiology (ESC) strongly recommend in ACS the Dual Antiplatelet Therapy (DAPT) consisting of aspirin and a P2Y12 receptor antagonist [12,13]. Although DAPT reduces the incidence of stent thrombosis an increased bleeding risk is present. Hence, the management of antiplatelet therapy in ACS patients with thrombocytopenia turn out to be challenging both for the concomitant higher risk of bleeding and ischaemic events in this group [14,15]. In ACS, actual scores such as the PRECISE-DAPT score, might evaluate the usefulness of DAPT duration balancing the ischemic protection and minimizing bleeding risks in the individual patient on the basis of hemoglobin value, white blood cells count, age of the patient, creatinine clearance and a general history of prior bleeding without specific indications (type of bleeding, platelet count, platelet function, secondary predisposing hemorrhagic conditions) [16].

Unfortunately the safety of DAPT and Percutaneous Coronary Intervention (PCI) in patients who have ACS and thrombocytopenia is unknown, and there are no guidelines to suggest a treatment approach in such patients. Indeed, despite representing a substantial proportion of ACS patients, these patients have been underrepresented in important clinical trials evaluating antiplatelet strategies [17-20].

Other considerations beyond the platelet count

In addiction, the evaluation of both DAPT and PCI in ACS patients with thrombocytopenia should not only consider the platelet count but also the platelet function and the condition causing thrombocytopenia [21,22].

Older patients or patients with a platelet counts <30 x 10^9/L are associated with an increased risk of bleeding, thus authors have proposed DAPT in ACS patients with a threshold platelet count of > 30 x 10^9/L, choosing a type of stent that allows shortening the therapy duration with the smallest risk of stent thrombosis [23].

An interesting condition that clinicians have to overcome in the future is thrombocytopenia in ACS patients associated with chronic liver disease because of the increased prevalence of metabolic syndrome which can progress to cirrhosis; interestingly, a deficiency of thrombopoietin has been mentioned as a possible cause of the thrombocytopenia of individuals with nonalcoholich fatty liver disease [24]. Nowadays, there are not available recommendations on the most appropriate DAPT in this context and, probably, the perceived bleeding risk in these patients is higher than the real one and lead to less intense antiplatelet therapy, with consequent increased risk of thrombosis. Indeed, the reduction in procoagulant factors is offset by a parallel decrease in anticoagulant factors and an increased concentration of von Willebrand factor which can compensate for the low platelet count and ensure primary hemostasis [25].

Two other common conditions are chemotherapy-related thrombocytopenia and myelodysplastic syndromes. Chemotherapyrelated thrombocytopenia is transitory and with a predictable recovery period and a low risk of bleeding in patients with platelet counts >10 x 10^9/L [26].

Thrombocytopenia associated with myelodysplastic syndromes usually has a chronic course and it is associated with a higher bleeding risk than chemotherapy-induced one [27]. Infact in myelodysplastic syndromes, platelets often have abnormally low concentrations of cell surface procoagulant markers or lack intracellular granules, and bleeding is common even with a platelet count >100 x 10^9/L [28].

In the setting of cancer and hematologic malignancies, some small-sized retrospective studies have shown that aspirin may be beneficial in thrombocytopenic ACS patients [29,30].

Outcomes of ACS patients presenting with thrombocytopenia

The presence of thrombocytopenia in ACS patients predicts significantly worse outcomes. Yadav et al. [5] retrospectively examined 10.603 patients who underwent PCI for non-ST-elevation ACS or ST-elevation myocardial infarction and showed that the presence of thrombocytopenia (<150 x 10^9/L) at baseline (607 patients, 5.7%) was an independent predictor of mortality at 1 year (6.7% vs 3.6%; P < 0.0001), ischaemic target lesion revascularization (HR, 1.37; 95% CI, 1.04-1.81; P = 0.03), and major adverse cardiac events (HR, 1.39; 95% CI, 1.09-1.79; P = 0.009). Any association between baseline thrombocytopenia and major or minor bleeding rates at 30 days was found; nevertheless, their cohort of patients included patients with mild thrombocytopenia.

Wang et al. examined 36.182 patients with non-ST-segment elevation ACS [4]. Risks of inpatient mortality and bleeding correlated directly with severity of thrombocytopenia and even mild thrombocytopenia (at least 100-149 x 10^9/L) was associated with increased risks of mortality (adjusted OR, 2.01; 95% CI: 1.69 to 2.38) and bleeding (adjusted OR, 3.76; 95% CI: 3.43 to 4.12). Even mild thrombocytopenia or a platelet count drop >/=50% in the setting of normal baseline values identifies a population of ACS patients at higher risk of mortality and major bleeding.

It hase been suggested that thrombocytopenia in ACS may reflect a greater burden of atherosclerosis or clinically significant thrombosis predisposing platelet consumption; consequently, its presence might be considered a marker of disease severity [31].

The current management of ACS patients presenting with thrombocytopenia

As there are not strong evidence-based recommendations, we might suggest that a proper approach should begin with the identification of the eziology (Table 1) [32] and the correction of any reversible causes of thrombocytopenia or medications such as unfractionated heparin, glycoprotein IIb/IIIa inhibitors, furosemide, NSAIDs and penicillin based antibiotics.

TABLECREATED

Table 1: Etiologies of thrombocytopenia.