While acute coronary syndromes inclusive of ST-elevation myocardial infarction (STEMI) have been described in patients with polycythemia vera (PCV), optimal pharmacologic and interventional management strategies in the setting of drastically elevated platelet counts remain unclear.1 To our knowledge this is the first reported case of STEMI with massive thrombus burden in a patient with PCV treated successfully with high-dose tirofiban bolus and infusion followed by staged aspiration thrombectomy and drug-eluting stent implantation.
A 54-year-old female with a history of hypertension, diabetes, and polycythemia vera (platelet counts ranging from 700,000–1,000,000/l over the preceding year with normal leukocyte count and normal hemoglobin) treated in the past with hydroxyurea, presented to our institution with a several hour history of persistent retrosternal chest pain that began at rest and was associated with nausea and diaphoresis. The patient had a history of episodic chest pain in the past prompting a coronary angiography two years prior that revealed moderate one-vessel non-obstructive coronary artery disease with luminal irregularities of the left anterior descending (LAD) artery and mild disease of all three vessels. The patient was taking baby enteric-coated aspirin, hydroxyurea, hydrochlorothiazde, glipizide, and enalapril at the time of presentation. The initial electrocardiogram (ECG) obtained in the emergency department demonstrated 2–3mm of ST-segment elevation in the anterolateral and inferior leads and the patient’s chest pain was rated an eight out of 10 at presentation, improving to two out of 10 after receiving two sublingual nitroglycerin (NTG) tabs and NTG infusion, IV metoprolol, unfractionated heparin bolus, and aspirin 325mg. Initial laboratory data were notable for cardiac troponin I 3.8ng/ml, hemoglobin 15.4g/dl, and platelet count 727,000/l. The patient was immediately brought to the cardiac catheterization laboratory, where she was hemodynamically stable and nearly free of chest pain.
Coronary angiography revealed significant one-vessel coronary artery disease with a very large, subocclusive thrombus in the proximal LAD associated with 70–80% proximal LAD stenosis (see Figure 1). The thrombus was noted to extend well into the left main coronary artery (LMCA), as well as into the S1 and D1 branches, and Thrombolysis in yocardial infarction (TIMI) 2 flow was observed in the LAD and side branches. During angiography, the patient became free from chest pain with complete resolution of ST-segment elevation on 12-lead ECG.
After careful consideration of the various pharmacologic and interventional options available, the patient was admitted to the cardiac care unit with the arterial sheath left in place. High-dose tirofiban was started in the catheterization laboratory (25mcg/kg bolus and 0.15mcg/kg/minute infusion) along with unfractionated heparin bolus and infusion (target PTT 40–60 seconds). Clopidogrel 600mg was given orally. After approximately 24 hours of antiplatelet/antithrombotic pre-treatment (during which time the patient remained free of chest pain), the patient returned to the catheterization laboratory and underwent repeat angiography. Subsequent angiography demonstrated flow improvement to TIMI 3 in the LAD and decrease in the thrombus burden, which now appeared organized, well circumscribed, and limited to the LAD with no side branch or LMCA extension. Percutaneous coronary intervention (PCI) was performed with aspiration thrombectomy using a 6 French (Fr) Medtronic Export catheter, with resultant removal of a significant amount of atherothrombotic debris and progressive angiographic improvement after 10 aspiration passes (see Figures 2 and 3). Histopathologic analysis of the aspirate subsequently demonstrated abundant aggregates of neutrophils, necrotic and degenerated cells, and fibrin, but notably, scant platelet aggregates. The residual 70% lesion was addressed with the implantation of a 3 x 32mm Taxus paclitaxel-eluting stent, deployed at 18ATM. Excellent results were noted in the treated segment of LAD by angiography and by intravascular ultrasound with no sidebranch compromise or evidence of distal embolization. (see Figure 4). Cardiac biomarkers drawn post-PCI, continued to decline. A pre-discharge transthoracic echocardiogram demonstrated a small area of hypokinesis at the apex, with normal overall left ventricular systolic function. Clinically, the patient did well for the remainder of the hospital course and was maintained on enteric-coated acetylsalicylic acid (ECASA) 325mg and clopidogrel 75mg daily following discharge. The patient has remained asymptomatic and free of cardiovascular events including stent thrombosis for over one year on dual antiplatelet therapy.
Discussion
Polycythemia vera is a myeloproliferative disorder characterized by the overproduction of various cell lines including leukocytes, erythrocytes, and platelets. Thrombotic complications, including MI, remain the primary cause of mortality and have been attributed to increased whole blood viscosity, quantitative, and perhaps qualitative platelet abnormalities, and to the presence of leukocytosis.2,3,4 While coronary thrombosis is the predominant mechanism of MI in patients with PCV, there is evidence that marked intimal proliferation may also play a role.5
Cardiac catheterization and percutaneous coronary intervention in patients with PCV has reportedly been associated with acute total aortic occlusion and recurrent stent thrombosis.6,7 Other complications of PCV that have been reported include splenic rupture in the setting of peri-PCI use of glycoprotein IIb/IIIa inhibition, as well as ventricular septal rupture as a complication of a small anteroseptal MI in a patient with only minimal ectasia in the LAD.8,9 Varying degrees of thrombus burden have also been described in PCV patients presenting with acute coronary syndromes and acute MI. Angiographically evident intracoronary thrombus may be quantified via the TIMI scoring system and is divided into five grades.10 Per this schema, thrombus grade zero (G0) represents the absence of thrombus. In grade one (G1), possible thrombus is present with such angiographic characteristics as reduced contrast density, haziness, irregular lesion contour, or a smooth convex meniscus at the site of total occlusion suggestive, but not diagnostic of thrombus. In thrombus grade two (G2), there is definite thrombus with greatest dimensions less than or equal to half the vessel diameter. In thrombus grade 3 (G3), there is definite thrombus with greatest linear dimension greater than half but <2 vessel diameters and in thrombus grade four (G4) there is definite thrombus with the largest dimension ≥2 vessel diameters. In thrombus grade five (G5) there is total thrombotic occlusion. A thrombus grade ≥4 as encountered in the case described implies a large thrombus burden. Contrast angiography has a sensitivity of 20% and a specificity approaching 100%.11 Percutaneous interventions of thrombotic lesions may be associated with such complications as distal embolization, no reflow, side branch occlusion, and abrupt vessel closure. Intracoronary infusions of fibrinolytic agents, adenosine, and verapamil have all been demonstrated in case reports and small studies to diminish no-reflow, however, few definitive data currently exist in support of these adjunctive therapies.12,13 Other pharmacologic therapies that have been studied include systemic, intracoronary, and site-specific delivery of glycoprotein IIb/IIIa inhibitors.
The central role of platelet activation and aggregation in the pathogenesis of vascular thrombosis has been extensively studied. The glycoprotein (Gp) IIb/IIIa (integrin α2bβ3) receptor mediates the final common pathway for platelet aggregation via its interaction with soluble fibrinogen. Three parenteral Gp IIb/IIa inhibitors (GPIs) are currently available for clinical use. Abciximab (c7E3) is a chimeric humanized murine monoclonal antibody fragment directed against the Gp IIb/IIIa receptor, but also binds vitronectin and Mac-1 receptors.
Tirofiban and eptifibatide are high-affinity, semi-synthetic inhibitors that are often grouped together as ‘small-molecule GPIs’ in deference to their low molecular weights relative to abciximab.14 The small-molecule GPIs are associated with high levels of steady-state platelet inhibition especially during longer infusion periods.15 In contrast, Abciximab evidences excellent acute inhibition of platelet aggregation with a slow downward drift during the recommended 12-hour infusion period, with longer infusions rarely used today given data from Global utilization of strategies to open occluded arteries (GUSTO) IV ACS, suggesting higher rates of adverse events when abciximab is used in this capacity.16,17 The clinical benefits of the small-molecule inhibitors are most pronounced in patients undergoing early percutaneous intervention after a period of pre-treatment.14 In the Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban—thrombolysis In myocardial infarction (TACTICS-TIMI) 18 trial, routine angiography and selective early revascularization after medical stabilization with tirofiban for a period of four to 48 hours in patients with non-ST elevation acute coronary syndromes resulted in reduced incidence of major adverse cardiac events.18 The conjunctive use of tirofiban and unfractionated heparin is also effective at reducing angiographic thrombus burden and improving distal perfusion in patients with ACS.19 In patients with massive angiographic intracoronary thrombus, longer duration of tirofiban infusion prior to PCI has been shown to reduce thrombus burden and lower no-reflow rates.20 Extended infusions of tirofiban also seem to yield improvement in pre- and post-PCI myocardial perfusion, an angiographic finding that has been associated with improved clinical outcomes independent of achievement of TIMI grade three epicardial flow.21
Contemporary dose-ranging experiences have suggested that more rapid and complete abolishment of platelet aggregation may safely be attained with more aggressive dosing regimens of tirofiban than those implemented in the aforementioned studies.22 In The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary artery angioplasty (ADVANCE) trial, high-dose tirofiban (25mcg/kg bolus +0.15mcg/kg/minute infusion) was found to significantly improve clinical outcomes in thienopyridine-pretreated patients undergoing high-risk PCI compared with placebo.23
Mardikar et al. compared the same high-dose strategy of tirofiban with double-bolus eptifibitide in patients undergoing PCI and found higher degrees of platelet inhibition with high-dose tirofiban both early and late in the course of treatment.24 More recently still, the Ongoing tirofiban in myocardial infarction evaluation (On-TIME) 2 trial found pre-hospital initiation of high-dose tirofiban in STEMI patients being transferred for primary PCI to result in more rapid resolution of ST segment elevation and lower rates of adverse cardiac events including thrombotic bailout and abrupt vessel closure.25
Various mechanical strategies targeting thrombus removal have also been evaluated in high-risk PCI. While coronary thrombectomy has generally been regarded as a safe and feasible family of techniques, historically, there has been little evidence of a clear clinical benefit with its routine use in STEMI intervention.26 A recent meta-analysis confirmed that the use of adjunctive mechanical devices to prevent distal embolization during primary PCI for STEMI improved myocardial perfusion and lessened distal embolization, but did so without any apparent improvement in survival.27 However, emerging data suggest that manual thrombus aspiration during PCI improves angiographic as well as long-term clinical outcomes.28–31 Furthermore, in a randomized controlled trial of 1,071 patients, aspiration thrombectomy during primary PCI for STEMI resulted in superior reperfusion and clinical outcomes than conventional PCI irrespective of clinical and angiographic baseline characteristics.32
In the case described, the choice of high-dose tirofiban was deliberate and predicated on the previously detailed clinical and platelet inhibition data as well as on specific stoichiometric considerations. While the current abciximab bolus and infusion dosing strategy was developed to provide ≥80% inhibition of stimulated platelet aggregation in individuals with normal platelet counts, the ratio of abciximab molecules to glycoprotein receptor is relatively low (estimated at 2:1) and, therefore, may not provide adequate platelet inhibition in the setting of elevated platelet count or super-normal receptor expression.33–36 In contrast, the analogous ratio with small-molecule GPIs has been estimated to be at least 50:1 but perhaps as high as several hundred to one.37 Therefore, it was postulated, that a small molecule GPI used in the capacity of an aggressive dosing strategy and extended pre-PCI infusion might be a more attractive choice than abciximab in this setting.
The near-absence of platelet aggregates upon histologic analysis of the aspirate ostensibly confirms the validity of this strategy. The aggressive use of aspiration thrombectomy facilitated retrieval of a considerable amount of atherothrombotic material with no side branch compromise by angiography and no vessel trauma by angiography and intravascular ultrasound (IVUS). Furthermore, little or no embolization was seen on the angiographic images or evidenced by biomarker release post-PCI.
Long-term management of patients with PCV includes use of low-dose aspirin, which has been shown to reduce the rate of major thrombosis and cardiovascular death and is therefore recommended in all PCV patients in the absence of contraindications.38 However, no data exist with respect to dual antiplatelet therapy with aspirin plus a thienopyridine. There are also no established guidelines for treating patients with ACS or STEMI in the setting of PCV. Phlebotomy with volume replacement and close hemodynamic monitoring has been suggested as an adjunctive approach to standard treatments.1 Whether a strategy of antiplatelet and antithrombotic pre-treatment prior to PCI with or without thrombectomy will consistently yield satisfactory outcomes in PCV patients presenting with ACS or STEMI, remains a matter for speculation. Nevertheless, based on the relevant pathobiologic considerations and a review of the available literature, we feel the strategy employed in this case to be a reasonable one when clinical circumstances render it feasible. However, we acknowledge that the window of freedom from chest pain encountered in our patient was a fortunate, if uncommon occurrence in STEMI, which allowed us to extend the antiplatelet/antithrombotic pre-treatment regimen for 24 hours prior to definitive mechanical therapy for the infarct-related vessel.