Article

ST-segment Elevation Myocardial Infarction in a Patient with Polycythemia Vera Managed with High-dose Tirofiban Pre-treatment, Aspiration Thrombectomy, and Paclitaxel-eluting Stent Implantation

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare: ReprintsWarehouse@springernature.com.

For permissions and non-commercial reprint enquiries, please visit Copyright.com to start a request.

For author reprints, please email rob.barclay@radcliffe-group.com.
Average (ratings)
No ratings
Your rating

Abstract

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. 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. 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 acute coronary syndrome (ACS) or STEMI, remains a matter of speculation. Nevertheless, based on the relevant pathobiologic considerations and review of the available literature, we feel the strategy employed in this case to be a reasonable one when clinical circumstances render it feasible.

Disclosure:Sandeep Nathan, MD, MSc, has provided consultancy services for sanofi-aventis. The remaining authors have no conflicts of interest to declare.

Received:

Accepted:

Correspondence Details:Steve Attanasio, DO, Rush University Medical Center, Adult Section of Cardiology, 10 Jelke, 1653 West Congress Parkway, Chicago, IL. E: steve_attanasio@rush.edu

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

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.

References

  1. Wu CF, Armstrong GP, Henderson R, Ruygrok P, Polycythemia Vera Presenting as ST-Elevation Myocardial Infarction, Heart, Lung and Circulation, 2005;14:51–3.
    Crossref | PubMed
  2. Gruppo Italiano Studio Policitemia, Polycythemia Vera: The Natural History of 1213 patients followed for 20 years, Ann Intern Med, 1995;123:656–64.
    Crossref | PubMed
  3. Schafer A, Molecular basis of the diagnosis and treatment of polycythemia and essential thrombocytosis, Blood, 2006;109:2446.
  4. Landolfi R, Di Gennaro L, Barbui T, et al., Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera, Blood, 2007;109(6):2446–52.
    Crossref | PubMed
  5. Hermanns B, Handt S, Kindler J, Fuzesi L, Coronary vasculopathy in Polycythemia Vera, Pathology Oncology Research, 1998;4(1):37–9.
    Crossref | PubMed
  6. Zinn P, Applegate RJ, Walsh RA, Acute total aortic occlusion during cardiac catheterization associated with polycythemia vera, Cathet Cardiovasc Diagn, 1998;14(2):108–10.
    Crossref | PubMed
  7. Friedrich EB, Kinderman M, Link A, Bohm M, Splenic rupture complicating periinterventional glycoprotein IIb/IIIa antagonist therapy for myocardial infarction in polycythemia vera, Z Kardiol, 2005;94(3):200–4.
    Crossref | PubMed
  8. Goethals P, Evrard S, Dubois C, Recurrent coronary stent thrombosis, Acta Cardiol, 2005;55(6):371–3.
    Crossref | PubMed
  9. Choy JB, Burton JR, Penkoske PA, Taylor DA, Myocardial infarction complicated by ventricular septal rupture in a patient with polycythemia vera and minimal coronary ectasia, Can J Cardiol, 1998;14(9):1161–4.
    PubMed
  10. Gibson CM, de Lemos JA, Murphy SA, et al., Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy, Circulation, 2001;103:2550–4.
    Crossref | PubMed
  11. den Heijer P, Foley DP, Escaned J, et al., Angioscopic versus angiographic detection of intimal dissection and intracoronary thrombus, J Am Coll Cardiol, 1994;24:649–54.
    Crossref | PubMed
  12. Marzilli M, Orsini E, Marraccini P, Testa R, Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction, Circulation, 2000;101(18):2154–9.
    Crossref | PubMed
  13. Taniyama Y, Ito H, Iwakura K, et al., Beneficial effect of intracoronary verapmail on microvascular and myocardial salvage in patients with acute myocardial infarction, J Am Coll Cardiol, 1997;30(5):1193–9.
    Crossref | PubMed
  14. Stone GW, Glycoprotein IIb/IIIa inhibitors:more different than alike?, Catheter Cardiovasc Interv, 2001;53:304–7.
    Crossref | PubMed
  15. Cannon CP, Small molecule glycoprotein IIb/IIIa receptor inhibitors as upstream therapy in acute coronary syndromes: Insights from the TACTICS TIMI-18 trial, J Am Coll Cardiol, 2003;41:43S–8S.
    Crossref | PubMed
  16. Tcheng JE, Ellis SG, George BS, et al., Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty, Circulation, 1994;90:1757–64.
    Crossref | PubMed
  17. The GUSTO IV-ACS Investigators, Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial, Lancet, 001;357(9272):1915–24.
    Crossref | PubMed
  18. Cannon CP, Weintraub WS, Demopoulos LA, et al., for the (TACTICS) TIMI-18 Investigators. Comparison of early invasive versus early conservative strategies in patients with unstable angina and non-ST elevation myocardial infarction treated with early glycoprotein IIb/IIIa inhibition, N Engl J Med, 2001;344(25):1879–87.
    Crossref | PubMed
  19. Zhao XQ, Theroux P, Snapinn SM, Sax FL, Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS investigators, Circulation, 1999;100(15):1609–15.
    Crossref | PubMed
  20. Timurkaynak T, Arslan U, Balcioglu S, Turkoglu S, Long term tirofiban infusion before percutaneous coronary intervention in patients with angiographically massive intracoronary thrombus, Saudi Med J, 2008;29(1):42–7.
    PubMed
  21. Gibson CM, Singh KP, Murphy SA, et al., Association between duration of Tirofiban therapy before percutaneous intervention and tissue level perfusion (A TACTICS-TIMI 18 Substudy), Am J Cardiol, 2004;94:492–4.
    Crossref | PubMed
  22. Schneider D, Herrmann H, Lakkis N, et al., Increased concentrations of tirofiban in blood and their correlation with inhibition of platelet aggregation after greater bolus doses of tirofiban, AJC, 2003;91(3):334–6.
    Crossref | PubMed
  23. Valgimigli M, Percoco G, Barbieri D, et al., The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial, J Am Coll Cardiol, 2004;44(1):14–9.
    Crossref | PubMed
  24. Mardikar HM, Hiremath MS, Moliterno DJ, et al., Optimal platelet inhibition in patients undergoing PCI: Data from the Multicenter Registry of High-Risk Percutaneous Inhibition (MR PCI) study, AHJ, August 2007;344.e1–5.
    Crossref | PubMed
  25. Van’t Hof AW, Ten Berg J, Heestermans T, et al., Prehospital Initiation of Tirofiban in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Angioplasty (On-TIME 2): A Multicentre, Double-Blind, Randomized Controlled Trial, Lancet, 2008;372:537–46.
    Crossref | PubMed
  26. Margheri M, Vittori G, Chechi T, et al., Thrombus aspiration with export catheter in ST elevation myocardial infarction, J Interv Cardiol, 2007;20(1):38–43.
    Crossref | PubMed
  27. De Luca G, Suryapranata H, Stone GW, et al., Adjunctive mechanical devices to prevent distal Embolization in patients undergoing mechanical revascularization for acute myocardial infarction: A meta-analysis of randomized trials, AHJ, 2007;343–53.
    Crossref | PubMed
  28. Sardella G, Mancone M, Nguyen BL, et al., The effect of thrombectomy on myocardial blush in primary angioplasty: the randomized evaluation of thrombus aspiration by two thrombectomy devices in acute myocardial infarction (RETAMI) trial, Catheter Cardiovasc Interv, 2008;71(1):84–91.
    Crossref | PubMed
  29. Ali A, Cox D, Dib N, et al., Angiojet in acute myocardial infarction trial: the AIMI trial, J Am Coll Cardiol, 2006;48:244–52.
    Crossref | PubMed
  30. Pate G, Lowe R, Kuchela A, et al., Procedural efficacy and complications of X-Sizer thrombectomy in de novo and stented lesions, Catheter Cardiovasc Interv, 2004;63(2):177–82.
    Crossref | PubMed
  31. De Rosa S, Cirillo P, De Luca G, et al., Rheolytic thrombectomy during percutaneous coronary intervention improves long-term outcome in high-risk patients with acute myocardial infarction, J Interv Cardiol, 2007;20(4):292–8.
    Crossref | PubMed
  32. Svilaas T, Vlaar P, Van der Horst I, et al., Thrombus aspiration during primary percutaneous coronary intervention, N Engl J Med, 2008;358(6):557–67.
    Crossref | PubMed
  33. Jordan RE, Wagner CL, Mascelli M, et al., Preclinical development of c7E3 Fab; a mouse/human chimeric monoclonal antibody fragment that inhibits platelet function by blockade of GPIIb/IIIa receptors with observations on the immunogenicity of c7E3 Fab inhumans. In: Horton MD, ed., Adhesion Receptors as Therapeutic Targets, CRC, FL: CRC, Boca Raton, 1996;281–305.
  34. Simoons ML, de Boer MJ, van den Brand MJ, et al., Randomized trial of GPIIb/IIIa platelet receptor blocker in refractory unstable angina, Circulation, 1994;89:596–603.
    Crossref | PubMed
  35. Kohl DW, Slavik KJ, Kamath G, et al., High-dose abciximab during coronary angioplasty in a patient with essential thrombocytosis, J Invasive Cardiol, 1998;10:173–6.
    PubMed
  36. Michaels AD, Whisenant B, MacGregor JS, Multivessel coronary thrombosis treated with abciximab (ReoPro) in a patient with essential thrombocythemia, Clin Cardiol, 1998;21:134–8.
    Crossref | PubMed
  37. Tcheng JE, Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: bleeding, reversal, thrombocytopenia, and retreatment, Am Heart J, 2000;139:S38–45.
    Crossref | PubMed
  38. Landolfi R, Marchioli R, Kutti J, et al., Efficacy and safety of low-dose aspirin in polycythemia vera, N Engl J Med, 2004;350:114.
    Crossref | PubMed