Case Report and Brief Review

Acute Stent Thrombosis Associated with Heparin-Induced Thrombocytopenia and Abciximab-Induced Profound Thrombocytopenia

Tarun W. Dasari, MD, MPH, Reji Pappy, MD, Thomas A. Hennebry, MB BCh BAO
Tarun W. Dasari, MD, MPH, Reji Pappy, MD, Thomas A. Hennebry, MB BCh BAO

ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a well-known complication after exposure to heparin products. Profound thrombocytopenia has also been reported with the use of abciximab, a glycoprotein IIb/IIIa receptor antagonist, which is used during percutaneous coronary intervention. Acute stent thrombosis is a rare but serious complication of HIT. We report an unusual case of acute stent thrombosis with concomitant heparin- and abciximab-induced profound thrombocytopenia and discuss the subsequent treatment strategies. Prompt identification and management of this disorder is critically important to avoid devastating complications.

Key words: abciximab-induced thrombocytopenia, acute stent thrombosis, heparin-induced thrombocytopenia and thrombosis, thrombocytopenia

Drug-induced thrombocytopenia has been reported with several agents that are used in the treatment of acute coronary syndromes (ACS).1–3 Unfractionated heparin and, less commonly, low-molecular-weight heparin are associated with the development of heparin-induced thrombocytopenia.1–3 In addition, glycoprotein IIb/IIIa receptor blockers have been implicated in the development of thrombocytopenia, often within hours of exposure.4–6 We report an unusual case of suspected heparin-induced thrombocytopenia and thrombosis (HIT/HITT) resulting in acute profound thrombocytopenia within hours of re-exposure to abciximab (c7E3 Fab; Reopro, Eli Lilly, Indianapolis, Indiana) and unfractionated heparin after emergent percutaneous coronary intervention (PCI) for acute stent thrombosis. We discuss the subsequent treatment strategies of HITT in the setting of acute stent thrombosis.

Case Report. A 42-year-old African American male with a history of coronary artery disease, hypertension and hyperlipidemia presented with anterior ST-segment elevation myocardial infarction. Two weeks prior, he underwent PCI in the setting of non-ST elevation myocardial infarction at an outside hospital. This resulted in the placement of 4 Multilink® Minivision stents (Abbott Laboratories, Abbott Park, Illinois) — 2 in the proximal left anterior descending (LAD) artery and 2 kissing stents in the mid-LAD and proximal first diagonal artery. Three days later, he presented again with unstable angina but with normal electrocardiogram and cardiac biomarkers. A repeat angiogram revealed malapposition of the first diagonal stent with a residual stenosis of 60%. A repeat angioplasty (2.5 x 12 mm balloon at 14 atm) of the first diagonal was performed and the patient was discharged home on dual anti-platelet therapy with aspirin and clopidogrel. During both of these procedures, intravenous unfractionated heparin bolus and abciximab bolus (0.25 mg/kg) followed by an infusion (0.125 mcg/kg/min) were administered. The platelet count was within normal range prior to discharge on both occasions.

Angiography during the current hospitalization revealed extensive stent thrombus in the proximal and mid-LAD and proximal diagonal (Figure 1). Unfractionated heparin 2,500 U and 2 boluses of abciximab (0.25 mg/kg) were given followed by a continuous infusion (0.125 mcg/kg/min). The LAD was crossed with a Pilot 50 wire (Abbott Laboratories). Pronto® thrombectomy (Vascular Solutions, Inc., Minneapolis, Minnesota) was performed and a 3.0 x 18 mm PROMUS® stent (Boston Scientific, Natick, Massachusetts) was deployed at 18 atm in the mid-LAD. A BMW® guidewire (Abbott Laboratories) was advanced into the first diagonal and a 2.0 x 16 mm MiniVision® stent was deployed at 18 atm. Kissing balloon inflations were performed across the LAD and diagonal at 12 atm. The activated clotting time was 219 seconds at the end of the intervention with Thrombolysis In Myocardial Infarction (TIMI)-3 flow in both culprit arteries (Figure 2). The patient had resolution of both chest pain and ST-segment elevation. However, upon transfer to the intensive care unit, he experienced an abrupt return of symptoms within 30 minutes, with new ST-segment elevation in the lateral leads and right bundle branch block. Emergent angiogram showed complete occlusion of the mid-LAD stent immediately distal to the first diagonal along with moderate thrombus in the first diagonal with TIMI-3 flow (Figure 3). The occluded LAD lesion was passed with a BMW® wire and Pronto thrombectomy was repeated. Next, after passing a Run-through® guidewire (Terumo Interventional Systems, Somerset, New Jersey), an aspiration thrombectomy was performed in the diagonal. Kissing balloon was done both in the LAD (3.5 x 20 mm noncompliant balloon) and diagonal (2.0 x 20 mm) at 18 atm. A lesion was also noted in the proximal LAD. Due to the patient’s propensity to repeatedly form large amounts of thrombus, a bolus of bivalirudin (0.75 mg/kg) was given as he had just received 2,500 U of unfractionated heparin in addition to continuing abciximab (0.125 mcg/kg/min). The LAD was then stented just beyond the first diagonal with a 3.5 x 12 mm VISION® stent (Abbott Laboratories) and post-dilated with a 3.5 mm noncompliant balloon at 18–20 atm. We then stented the diagonal at the distal edge of the prior stent with a 2.75 x 16 mm Liberte bare-metal stent (Boston Scientific) and post-dilated the other stent to 2.75 mm. Finally, the intervention was completed with kissing balloons (2.5 x 20 mm in the LAD diagonal and 3.5 x 20 mm balloon in the proximal LAD), both inflated at 15 atm. The final result was excellent, with TIMI-3 flow and good myocardial blush (Figure 4). As compared to admission platelet count of 166,000/mm3, a repeat platelet count 6 hours after the second PCI showed profound thrombocytopenia with a platelet count of 3,000/mm3. Abciximab, aspirin and prasugrel were discontinued after a repeat count in an EDTA-free citrate tube confirmed the finding. A peripheral smear ruled out clumping. Enzyme-linked immunosorbent assay for heparin-dependent platelet factor 4 antibody in addition to serotonin release assay were requested to rule out HIT. Subsequently, 2 units of platelets were transfused due to bleeding concerns and profound thrombocytopenia. Post-transfusion (2 hours) platelet count was 57,000/mm3 and a few hours later dropped to 37,000/mm3, but stabilized at 51,000/mm3 within 1 hour, at which time aspirin and prasugrel were re-initiated.

The platelet count trend through hospitalization is summarized in Figure 5. The antibody test for HIT returned positive on day 3 (1.775 with > 1 suggestive of probable HIT). The direct thrombin inhibitor argatroban was started at a dose of 2 mcg/kg/min to target aPTT to 60–90 seconds. The goal was to achieve an INR close to 3 prior to initiation of warfarin therapy (as argatroban can lead to elevation of INR by itself). The serotonin-release assay returned several days later at 16%, which is positive. The patient was subsequently discharged with a platelet count of 215,000/mm3. Although there are concerns of increased bleeding risk from triple therapy, our patient was discharged on aspirin, prasugrel and warfarin.

Discussion. This case highlights an interesting challenge in the diagnosis and management of patients with profound thrombocytopenia in the setting of acute stent thrombosis. To our knowledge, there are only a few case reports on this phenomenon,7–11 and ours is the first to report an acute stent thrombosis within 30 minutes of PCI in the setting of HITT.

The most clinically significant form of HIT is type II, caused by IgG antibodies directed against a complex of heparin and platelet factor 4 (PF4).12 The onset of thrombocytopenia following heparin administration varies based on a patient’s prior history of exposure. It usually occurs 5–10 days after the initial exposure to heparin.13 A rapid decline in platelet count, often within hours, can occur in patients with a recent exposure to heparin and with measurable levels of PF4-heparin antibodies.14–16 In addition to thrombocytopenia, both venous and arterial thrombotic complications have been reported with HIT, with the former being much more common.18

Abciximab, a chimeric (murine/human) monoclonal antibody fragment (c7E3 Fab) against a platelet glycoprotein IIb/IIIa, is a potent inhibitor of platelet aggregation. Abciximab-induced thrombocytopenia has been well studied and usually occurs within 24 hours of first exposure. The mechanism of action may be through drug-dependant antibodies binding to ligand-induced binding sites (LIBS) that are exposed when the IIb/IIIa antagonists bind to the IIb/IIIa receptor, inducing conformational changes in the receptor, the so-called “LIBS effect.”17 Profound thrombocytopenia, defined as a rapid decline in platelet counts to 3, often within 24 hours, has been shown to occur in 0.5–2.4% of patients on initial or re-exposure to abciximab.19,20 Tcheng et al, in a 500 patient Reopro readministration registry report, found that the rates of thrombocytopenia (4.6%) were comparable to prior randomized controlled clinical trials of initial abciximab exposure; however, there was a higher incidence (2.4%) of profound thrombocytopenia (3) upon re-exposure.20 The final report from this registry reported an incidence of 2%, but the risk was substantially higher at 12% if re-exposure was within 1 month.21 A subsequent report from Duke reported an 8% incidence of profound thrombocytopenia if re-exposure was within 2 weeks.22

The management of HITT in a setting of profound thrombocytopenia from abciximab can be complicated. There is no consensus on the treatment in such scenarios. The best initial strategy would be to hold all offending agents and transfuse platelets in case of bleeding or if platelet counts are 3. Although there are no convincing data to prove the harmful effects of platelet transfusion in the setting of HITT, this is the norm in current practice. The only available evidence is from a case series of 4 patients with confirmed HIT who had no subsequent complications after platelet transfusions.23 Pseudo-thrombocytopenia and thrombotic thrombocytopenic purpura should always be ruled out by examining the peripheral smear and obtaining count in an EDTA-free tube. There are no established guidelines on when to resume antiplatelet agents, but it is safe to resume both aspirin and thienopyridines once platelet counts are > 40,000–50,000/mm3. HITT should be ruled out by obtaining the antibody test and the serotonin-release assay. It is reasonable to delay treatment with agents such as argatroban or lepirudin until confirmatory tests are available unless platelet counts continue to decline. These agents are usually continued until the counts are > 150,000/mm3 followed by oral anticoagulation for at least 3–6 months. It is worthwhile commenting on the subsequent management strategies in case such patients present with acute coronary syndromes or a need for repeat PCI. There does not appear to be a cross-sensitivity among the various IIb/IIIa receptor antagonists. Thus, tirofiban or eptifibatide may be preferable over repeat abciximab, particularly if it is within 2 months.24,25 Avoidance of glycoprotein IIb/IIIa receptor antagonists in such patients might be the best strategy. Bivalirudin is another potent thrombin inhibitor that can be used in a setting of HIT, although it is currently not approved by the Food and Drug Administration.

While profound thrombocytopenia could have been an effect of abciximab, an acute stent thrombosis with thrombus formation manifest during the final intervention argues for HITT, although acute stent thrombosis by itself is reported in up to 0.5–0.7% of the cases in the first 24 hours post PCI (with either drug-eluting or bare-metal stents).26 During both interventional procedures, we were able to aspirate white clot suggestive of platelet rich white thrombus, which may indicate HITT. Several risk factors implicated in acute stent thrombosis were present in our patient, such as low ejection fraction, presence of disease proximal to the culprit lesion, multivessel disease, PCI in the setting of acute coronary syndrome, bifurcation lesions, younger age, non-white race and suspected clopidogrel resistance.27,28

Conclusion. In patients with multiple recent exposures to anticoagulants and intravenous antiplatelet agents, there is an increased risk of development of profound thrombocytopenia and HITT. The management of HITT with concomitant profound thrombocytopenia from abciximab is challenging. Our treatment strategy was predicated on the observance of acute stent thrombosis. HITT could be a potentially dangerous complication and prompt identification and treatment is of paramount importance.


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From the Section of Cardiovascular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. The authors report no conflicts of interest regarding the content herein. Manuscript submitted May 3, 2010, provisional acceptance given June 2, 2010, final version accepted June 4, 2010. Address for correspondence: Tarun W. Dasari, MD, MPH, 920 Stanton L. Young Blvd., WP 3010, Cardiovascular Section, OUHSC, Oklahoma City, OK 73190. E-mail: