Tirofiban-Induced Diffuse Alveolar Hemorrhage

Abstract

Platelets play an important role in the development of acute coronary syndromes. Evidence indicates that platelet-inhibiting drugs, such as glycoprotein IIb/IIIa inhibitors, can be beneficial when they are administered at the time of primary percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction. However, an associated increase in the risk of bleeding is well documented. Diffuse alveolar hemorrhage is a rare but life-threatening and underdiagnosed complication of therapy with glycoprotein IIb/IIIa inhibitors.

Diffuse alveolar hemorrhage can easily be mistaken for acute pulmonary edema, a condition commonly seen in patients with acute coronary syndrome. Physicians need to be aware of this diagnostic dilemma, because early treatment increases the chance that the patients will survive.

Herein, we report the fatal outcome of diffuse alveolar hemorrhage in a 73-year-old man who presented with acute ST-segment-elevation myocardial infarction and was treated with tirofiban in conjunction with primary percutaneous coronary intervention. In addition, we review the medical literature pertaining to the sequelae of glycoprotein IIb/IIIa inhibitor therapy in the presence of diffuse alveolar hemorrhage.

The administration of glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors provides additional benefit to the mechanical reperfusion treatment of patients with ST-segment-elevation myocardial infarction (STEMI).^1–4 This therapy is included as a class IIa recommendation in the Guidelines for Percutaneous Coronary Intervention (PCI).⁵

However, a well-documented increase in bleeding risk is associated with the use of GPIIb/IIIa inhibitors. Several types of bleeding have been described, including intracranial, gastrointestinal, pulmonary, and inguinal.⁶ Diffuse alveolar hemorrhage is a rare but potentially life-threatening complication that is often misidentified and confused with other respiratory syndromes. Herein, we report the case of a patient who developed diffuse alveolar hemorrhage after being given tirofiban, and we review the relevant medical literature.

Case Report

In July 2009, a 73-year-old man emergently presented with retrosternal chest discomfort, diaphoresis, nausea, and vomiting for 4 hours after the onset of chest symptoms. His medical history included hypertension and acute STEMI; a bare-metal stent had been implanted in his left anterior descending coronary artery 4 years previously. He had been prescribed clopidogrel (75 mg/d) for 1 month and aspirin (100 mg/d) indefinitely. A chest radiograph at that time showed atelectasis in the left-lung fields and right-lung emphysema (Fig. 1A). The patient had had tuberculosis and had undergone left pulmonary bubble resections 30 years previously. He reported no history of bleeding or hematologic disorders.

Fig. 1 In a 73-year-old man with acute inferior myocardial infarction, chest radiographs (anteroposterior view) show A) atelectasis in the left-lung fields and right-lung emphysema upon the patient's hospital admission 4 years earlier, and B) widespread new alveolar bilateral infiltrates 2.5 hours after tirofiban administration during the current admission.

Upon arrival at our hospital, the patient had chest pain, blood pressure of 80/60 mmHg, and a heart rate of 40 beats/min. Physical examination revealed no rhonchi in the lungs and no heart murmur. Hemodynamic support was provided with intravenous fluids and a dopamine drip. An electrocardiogram showed a 2-mm ST-segment elevation in the inferior leads and 3rd-degree atrioventricular block. Results of a laboratory test for troponin T were positive. After being given 300 mg of aspirin and 600 mg of clopidogrel, the patient was transferred to the catheterization laboratory.

A transvenous temporary pacemaker was inserted immediately. Coronary angiography revealed subtotal thrombotic occlusion of the proximal segment of the left circumflex coronary artery with Thrombolysis in Myocardial Infarction (TIMI)-1 flow, a 50% in-stent restenosis of the left anterior descending coronary artery, and 2 tandem stenoses (40%–50%) in the right coronary artery.

An intra-aortic balloon pump (IABP) was inserted, and 5,000 units of unfractionated heparin and a 25-µg/kg tirofiban bolus were administered over 3 minutes, followed by a 0.15-µg/kg/min tirofiban infusion. A drug-eluting stent was deployed in the left circumflex coronary artery, resulting in TIMI-3 flow. The patient's arterial pressure was brought to at least 100 mmHg. The temporary pacemaker was removed, with normal rhythm thereafter; the left ventricular end-diastolic pressure (LVEDP) was 25 mmHg. The maximum activated clotting time (ACT) was 255 seconds during the procedure. The tirofiban drip was continued during this time, and no additional heparin was given.

Approximately 2 hours after the tirofiban bolus, the patient remained hemodynamically stable but developed paroxysms of coughing without sputum, and his oxygen saturation fell from 95% to 60%. Auscultation of the lungs revealed bilateral rhonchi; however, results of a cardiac examination remained unchanged, except for an increase in the patient's heart rate. Intravenous furosemide (40 mg) was administered for presumed pulmonary edema, and supplemental oxygen was provided through a facemask. Two and a half hours after the tirofiban administration, the patient experienced massive hemoptysis of bright red blood. A bedside chest radiograph revealed bilateral diffuse alveolar infiltrates (Fig. 1B), and diffuse alveolar hemorrhage was diagnosed. The tirofiban was stopped immediately. The patient's hemoglobin level fell from 136 to 108 g/L. The platelet count was 203/L, and the activated partial thromboplastin time (APTT) was 71 seconds.

The patient was intubated due to increasing dyspnea, and a large amount of bloody material was aspirated from the bronchi. Treatment for diffuse alveolar hemorrhage was attempted by means of continuous infusion of carbazocrome and tranexamic acid, and 2 units of packed red cells were transfused. Despite intensive supportive care, the patient's respiratory condition failed to improve, and he died on postprocedural day 7.

Discussion

Diffuse alveolar hemorrhage associated with platelet GPIIb/IIIa inhibitors is a severe and rare complication that has been described in various case reports. In 1997, Sitges and Villa⁷ reported a case of diffuse alveolar hemorrhage after abciximab use. In 2000, Ali and colleagues⁸ reported diffuse alveolar hemorrhage in a patient who was given tirofiban. Cases of diffuse alveolar hemorrhage have been reported sporadically for all 3 GPIIb/IIIa inhibitors, so the true incidence of the condition remains unknown. In a study by Ali and associates,⁹ the prevalence of pulmonary hemorrhage was 0.5% for eptifibatide, 0.7% for abciximab, and 0.9% for tirofiban.

Multivariable predictors of major bleeding in patients undergoing PCI included IABP use, the administration of GPIIb/IIIa inhibitors, older age, female sex, chronic renal insufficiency, and the administration of low-molecular-weight heparin within 48 hours preprocedurally.¹⁰ Only limited data are available on specific risk factors for diffuse alveolar hemorrhage.^11–13 According to 1 trial,^12,14 the increased risk of the condition in patients treated with GPIIb/IIIa inhibitors could be associated with female sex, a history of acute myocardial infarction, low body weight, older age, a prolonged or complicated angioplasty procedure, and the presence of underlying lung conditions such as chronic obstructive pulmonary disease, pulmonary hypertension, or high pulmonary capillary wedge pressure. Our patient had elevated LVEDP, and the factors of old age, chronic pulmonary disease, IABP use, and the administration of tirofiban could have increased his risk of developing diffuse alveolar hemorrhage. Of note, our patient had a prolonged ACT (>250 s) during PCI, and he had an elevated APTT at the time of the complication.

It is unclear whether our patient bled as the result of tirofiban alone or because of superimposed anticoagulation with aspirin, heparin, and clopidogrel, or IABP insertion. Diffuse alveolar hemorrhage is not usually associated with aspirin and heparin when these medications are administered alone. Different loading doses of clopidogrel might affect the hemorrhagic complications of GPIIb/IIIa inhibitors. We could not find a study that compared diffuse alveolar hemorrhage rates after the loading of 300 versus 600 mg of clopidogrel in patients who were undergoing primary PCI with GPIIb/IIIa inhibitors. In our patient, these drugs and the IABP might have amplified the effects of tirofiban on the hemostatic mechanism.

Compared with other hemorrhagic syndromes, diffuse alveolar hemorrhage is difficult to diagnose. The presenting signs (including dyspnea and hemoptysis) and the radiologic signs are quite nonspecific.^6,15,16 Hemoptysis can be absent in as many as one third of all cases of diffuse alveolar hemorrhage, which further complicates the diagnosis.¹⁷ Our patient developed severe dyspnea and hypoxemia with hemoptysis that was initially misdiagnosed as pulmonary edema, and this delayed appropriate treatment by at least 30 minutes.

Although no guidelines are established for the treatment of diffuse alveolar hemorrhage induced by GPIIb/IIIa inhibitors, treatment for the condition typically includes the discontinuation of antiplatelet and anticoagulant agents as soon as possible and the institution of mechanical ventilation.^6,13 Blood transfusion is performed and is closely monitored. Platelet transfusion can be considered in patients who have been given abciximab, but transfusion might not effectively reverse the effects of tirofiban. Despite all these measures, the potential sequelae of GPIIb/IIIa inhibitor therapy can be life-threatening, and physician awareness is required to ensure early diagnosis.¹⁸

Although alveolar hemorrhage associated with GPIIb/IIIa inhibitor use is rare, the associated mortality rate is high, ranging from 29% to 50%.^11–13,19 Table I summarizes the reported cases of diffuse alveolar hemorrhage associated with GPIIb/IIIa inhibitor therapy.6–9,13,19–26 In association with tirofiban, 7 of 10 patients required intubation, and 6 of the 7 died in the hospital. The survivors underwent prolonged hospitalization with optimal supportive care, including the discontinuation of anticoagulation, the transfusion of blood and platelet products, and positive end-expiratory-pressure mechanical ventilation, along with aggressive pulmonary care when needed, to maintain lung reserves and necessary oxygenation.¹³

TABLE I. Published Reports of Diffuse Alveolar Hemorrhage after Therapy with Glycoprotein IIb/IIIa Inhibitors

In conclusion, diffuse alveolar hemorrhage is a rare but life-threatening and underdiagnosed complication of treatment with GPIIb/IIIa inhibitors. Clinical findings that should alert the physician to the possibility of the condition in patients receiving tirofiban therapy while undergoing PCI are respiratory distress, worsening alveolar infiltrates, and a sudden drop in the hemoglobin level accompanied by hemoptysis.