Eptifibatide-induced profound thrombocytopaenia: a rare complication

Abstract

Drug-induced immune thrombocytopaenia (DITP) is a type of thrombocytopaenia caused by medications. It is one of the common causes of unexplained thrombocytopaenia. It is caused by the formation of autoantibodies against a particular drug and is commonly observed with medications like heparin and beta-lactam antibiotics. One of the rare causes of DITP is eptifibatide, a widely used antiplatelet agent for pretreatment in cardiac catheterisation. These patients can be asymptomatic or develop complications like skin bruising, epistaxis and even intracranial haemorrhage. We present a case of a 64-year-old man who developed eptifibatide-induced profound thrombocytopaenia leading to extensive skin bruising. He was treated with platelet transfusions followed by prompt improvement in platelet count.

Background

Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor inhibitors like abciximab and eptifibatide inhibit fibrinogen binding to this receptor on the surface of platelets, thus preventing platelet aggregation. These drugs are used in acute coronary syndrome when percutaneous coronary intervention (PCI) is undertaken.^1–3 A common adverse effect of these drugs is bleeding. Drug-induced immune thrombocytopaenia (DITP) is a rare complication that happens due to autoantibody formation against these drugs. The incidence of eptifibatide-induced DITP is 1%.^{1 4} If not detected urgently, it can lead to life-threatening complications like intracranial haemorrhage. It is usually managed with platelet transfusions and close monitoring.

Case presentation

A 64-year-old man with a medical history of hypertension and coronary artery disease presented to the hospital with complaints of pressure-like retrosternal chest pain, which was 8/10 in intensity and radiating to his left arm. He took three nitroglycerin tablets causing minimal relief, and reported no associated symptoms. He was hospitalised 2 months ago with a similar episode of chest pain when he underwent cardiac catheterisation for non-ST elevation myocardial infarction, showing 70%–80% stenosis of proximal right coronary artery (RCA), 100% distal RCA stenosis and moderate stenosis of the left anterior descending (LAD) artery. He had subsequently undergone PCI with four drug-eluting stents (DES) placed in RCA. Eptifibatide was administered during PCI and continued for 5 hours post-PCI. He was then discharged, and aspirin 81 mg daily, ticagrelor 90 mg every 12 hours, lisinopril 5 mg daily, rosuvastatin 5 mg daily, isosorbide mononitrate 30 mg daily and metoprolol succinate 25 mg daily were prescribed. Ticagrelor was later switched to clopidogrel 75 mg daily.

During the initial presentation, the temperature was 36.6°C, blood pressure 114/75 mm Hg, heart rate 55 beats/min, respiratory rate 18 breaths/min and oxygen saturation 95% breathing room air. He did not have any abnormal findings on physical examination. Troponin I level was elevated, and serial ECG showed nonspecific ST and T wave abnormalities. Left heart catheterisation was subsequently performed, which showed significant coronary artery disease and patent RCA stents. Four DES LAD stents were placed, and a bolus dose of eptifibatide 17 000 μg was given. He tolerated the procedure well, but within 7 hours of PCI and eptifibatide infusion, he started experiencing severe chest pain and profuse sweating with generalised spontaneous bruising predominantly on the left lateral chest (figure 1).

Figure 1.

Bruising on left lateral chest and left flank.

Investigations

Initial complete blood count (CBC) showed platelet count 227 x 10⁹/L, white cell count 5.45 x 10⁹/L and haemoglobin 1.53 g/L. His electrolytes and creatinine level were within normal limits. Troponin I level was elevated and increased from 0.10 ng/mL to 0.17 ng/mL within 2 hours. Serial electrocardiograms (ECG) showed nonspecific ST and T wave abnormalities in leads V3, V4 and V5. Left heart catheterisation was then performed, which showed 99% mid-LAD stenosis, 50% mid-distal LAD stenosis and 60%–70% distal LAD stenosis, with patent RCA stents. Four DES LAD stents were placed. When the patient developed chest pain and bruising postprocedure, his platelet count dropped from a previous value of 227 000/μL–2000/μL, confirmed by repeated testing. Heparin-dependent platelet factor 4 (PF4) antibodies were not detected. Transthoracic echocardiogram showed a left ventricular ejection fraction of 35%–39% (55%–60% two months ago) with trace pericardial effusion, while the chest X-ray did not reveal any abnormality. ECG did not show any significant change from prior ECG.

Differential diagnosis

The differential diagnosis for acute thrombocytopaenia includes immune thrombocytopaenia, chronic liver disease, hypersplenism, viral infections like hepatitis C, parvovirus, mumps, rubella or bacterial sepsis leading to disseminated intravascular coagulation. Other possibilities include nutritional deficiencies like vitamin B₁₂ and folate deficiency, malignancies, bone marrow disorders, autoimmune disorders like systemic lupus erythematosus, alcohol or drug-induced thrombocytopaenia by medications like heparin, chemotherapeutic agents, beta-lactam antibiotics and GpIIb/IIIa inhibitors like eptifibatide. In this case, the primary differential diagnoses included drug-induced thrombocytopaenia due to eptifibatide, especially given the prior exposure and heparin-induced thrombocytopaenia.

Treatment

The patient was subsequently transferred to the intensive care unit for close monitoring. PF4 antibodies were not detected. Haematology service was consulted. Per their recommendations, prothrombin time, partial thromboplastin time and fibrinogen level were checked, which were normal. Aspirin, clopidogrel and eptifibatide were discontinued. Two units of platelets were transfused, and the platelet count increased to 82 000/μL the next day. Nitroglycerin infusion was started due to persistently elevated blood pressure but was discontinued within a few hours. He was then given a bolus dose of clopidogrel 300 mg orally due to a high risk of in-stent thrombosis. Daily doses of aspirin 81 mg and clopidogrel 75 mg were also resumed. The patient was subsequently discharged following the normalisation of his platelet count and was recommended to continue his prior medications, along with cardiac rehabilitation.

Outcome and follow-up

The patient’s skin bruising had entirely resolved by 1 week. There was no evidence of thrombocytopaenia in CBC checked 1 week later. He continued taking the prescribed medications without any complications. He has now completed cardiac rehabilitation and returned to prior functional status.

Discussion

The normal platelet count in adults ranges from 150 000 to 4 50 000/μL.⁵ Thrombocytopaenia is defined as a platelet count below the lower limit of normal (ie, <150 000/μL for adults). It can be divided as mild (platelet count 100 000–150 000/μL), moderate (50 000–99 000/μL), severe (<50 000/μL) and profound (<20 000/μL) thrombocytopaenia.⁶ It can have multiple aetiologies, including infections, nutritional deficiencies, malignancies, liver or spleen disorders, toxins or medications.^{1 5} More than 300 medications have been implicated in causing DITP, the common ones being heparin and beta-lactam antibiotics.1 4 5 7 Rarely, it can be caused by Gp IIb/IIIa receptor inhibitors like abciximab and eptifibatide.^{1 2}

DITP is a serious complication that is often overlooked as a cause of thrombocytopaenia.^{7 8} Incidence of DITP can be as high as 10 cases per million population per year, with a prevalence of about 25% in critically ill patients as reported in international pharmacovigilance literature.^{7 9 10} Pharmacovigilance is the practice of monitoring the effects of medications after being licensed for use, especially to identify and evaluate previously unreported adverse reactions. It involves clinical trials that provide risk and benefit data of drugs to determine if the benefits outweigh the risks. Several clinical trials have been conducted in the past as part of pharmacovigilance to ensure proper monitoring of the DITP associated with these drugs.⁹

These drugs inhibit fibrinogen binding to the receptors on the surface of platelets, thus preventing platelet aggregation. Integrins are transmembrane proteins that bind with other proteins like fibronectin, collagen and laminin to mediate cell-cell and cell-matrix interaction. Gp IIb/IIIa is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor, causing platelet activation and irreversible aggregation. Gp IIb/IIIa receptor inhibitors are used in acute coronary syndrome when PCI is undertaken.^{1 3 11} They reduce the thrombotic complications associated with percutaneous transluminal coronary angioplasty by inhibition of platelet aggregation, thereby significantly reducing the incidence of myocardial infarction and urgent revascularisation before-and-after angioplasty. Inhibition of platelet aggregation starts within thirty minutes of giving the bolus dose of these medications intravenously. A common adverse effect of these drugs is bleeding, while a rare but potentially life-threatening complication is thrombocytopaenia, which culminates from the autoantibody formation against these drugs, and a timely diagnosis is pivotal to prevent worse outcomes.^{1 12}

Drug-induced immune thrombocytopaenia (DITP) can manifest as a broad spectrum of signs and symptoms, including fever, diaphoresis, ecchymoses and hypotension within the first 24 hours of drug administration, in about 0.1%–0.5% of patients. Drug-induced acute, profound thrombocytopaenia, a predictor of grave prognosis in ACS, is defined as a decrease in platelet count to below 20 000/mm³ within 24 hours of exposure to the drug.^{1 3 4}

Eptifibatide is one of the three GPIIb/IIIa antagonists associated with drug-induced thrombocytopaenia, the other two being abciximab and tirofiban.^{1 12} In the PURSUIT (Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial (eptifibatide vs placebo in 10 948 patients with acute coronary syndrome), eptifibatide was not associated with an increased incidence of thrombocytopaenia.^{2 13} However, the incidence of profound thrombocytopaenia in a small subset of patients (n=9) was more than double that of the placebo group (0.2% vs <0.1%; relative risk, 5.0; 95% CI 1.3 to 32.4), which suggests a possible immunological basis for platelet destruction in those patients.^{1 13} In the PRISM (Platelet Receptor inhibition for Ischaemic Syndrome Management) trial (aspirin plus tirofiban vs aspirin plus heparin in 3232 patients with unstable angina), the incidence of thrombocytopaenia in the tirofiban group was more than double the heparin group, 1.1% vs 0.4 %, respectively.^{1 14} However, a subsequent pooled analysis, which reviewed the data from eight randomised trials involving GP IIb/IIIa inhibitors, including the PURSUIT and PRISM trials, concluded abciximab as the only GP IIb/IIIa inhibitor with an increased incidence of mild and severe thrombocytopaenia.¹² This conclusion was confirmed by a follow-up analysis of data from the TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Trial) study, which directly compared abciximab and tirofiban.¹¹

Several pathophysiological mechanisms have been identified in explaining GP IIb/IIIa inhibitors induced acute, profound thrombocytopaenia. The most common mechanism mentioned in the literature shows an association between the pre-existing drug-dependent antibodies to platelet surfaces in patients with prior usage of that particular drug and thrombocytopaenia development.^{1 11} One hypothesis is that the glycoprotein inhibitors may induce a change in the conformation in the GP IIb/IIIa receptors on the platelet surface, leading to the expression of neoepitopes, which are recognised by pre-existing serum antibodies. Another possible mechanism would be the formation of a receptor-antagonist complex by the recognised neoepitopes. In our patient, the physiological platelet count and all other haematological parameters (PT, aPTT, red blood cells, white cell count) ruled out bone marrow dysfunction, non-immune and immune thrombocytopaenia as a cause of thrombocytopaenia. It is also essential to rule out pseudothrombocytopaenia by manual examination of blood film and rechecking the platelet count to rule out a laboratory error.¹

Early recognition and prompt discontinuation of the causative agent is the key to a quick recovery. Platelet transfusion is sometimes required to prevent the development of life-threatening complications. Still, the risk vs benefit assessment needs to be performed since platelet transfusion poses a risk of thrombosis in a newly placed coronary stent in patients who have undergone PCI.^{1 2}

Our case is one of the rare instances of eptifibatide-induced profound thrombocytopaenia reported in the literature thus far and endorses the importance of constant clinical and serial platelet monitoring after this agent’s initiation.

Patient’s perspective.

Doctor,

I thought it best to re-broadcast all of my recollections of the event, even down to the minute detail.

• As the PCI procedure was progressing, I experienced an increasing sense of coldness and muscle quivering throughout my body. These abnormal symptoms relented on completion of the PCI procedure. In addition, I experienced unusual swelling of the uvula in my throat. No spontaneous bruising was observed after the initial PCI.

• I again sustained the progressive and peculiar sense of coldness and muscle quivering similar to what I had experienced with the initial PCI 2 months previously. In a similar fashion, those unusual symptoms relented on completion of the PCI procedure.

• I also experienced difficulties with unexpected minor haemorrhage events in the right wrist at the point of the incision used for insertion of the catheter. Twice the nursing staff had to take additional measures to cease the haemorrhages, which included adding a second hard plastic cuff at the incision. These peculiar events had raised concerns among the attending nursing staff since the cuff seemed to be properly installed.

• The second and most critical value of low platelet count (which could have been viewed as a seemingly ‘outlier’ value) was properly confirmed by the hospital via a second blood draw and test.

• I did not experience any symptoms that would indicate the formation of intracranial haemorrhage. At the time that the symptoms of chest pain and bruising had manifested themselves, I did not have any adverse effects on my vision, no severe headaches, nor any red colour in my vision spectrum.

• Shortly after transfusion of the first unit of platelets, my chest pain and sweating abruptly ceased.

• I have now successfully completed cardiac rehabilitation and returned to a fully functioning lifestyle, which has included physical and recreational activities that one would consider as being normal for a typical 64-year-old male. I have not experienced any shortness of breath, no excessive bleeding, nor any skin bruising beyond what could be normally expected with a daily 75 mg clopidogrel intake.

Our goals are similar in that we just hope that this technical paper helps other medical professionals to deal with this strange anomaly that cardiologists at Heart and Vascular Institute had to face with me last October. I feel very fortunate that, given the grave circumstances that we all encountered together, I have survived and flourished—under this hospital’s care.

Thanks.

Learning points.

• Serial platelet counts must be monitored for at least 24 hours after eptifibatide initiation for urgent diagnosis and prevention of life-threatening complications like intracranial haemorrhage.

• Risk versus benefit analysis needs to be performed in cases of glycoprotein IIb/IIIa inhibitor-induced profound thrombocytopaenia since stopping the medication and transfusing platelets can potentially lead to in-stent thrombosis.

• It is highly imperative to review the results of published and ongoing trials as part of pharmacovigilance, to decrease the incidence and prevalence of drug-induced immune thrombocytopaenia.

Ethics statements

Patient consent for publication

Obtained.