Alveolar Hemorrhage Associated with Platelet Glycoprotein IIb/IIIa Receptor Inhibitors

Bleeding into the alveoli from disruption of the pulmonary capillary lining may cause alveolar hemorrhage and can result from different mechanisms:^1–4 1. Damage secondary to immunologic mechanisms, often associated with a pulmonary capillaritis (i.e., Goodpasture’s syndrome, systemic lupus erythematosus, vasculitides); 2. Direct mechanism or toxic injury (toxin or chemical inhalation, i.e., trimellitic anhydride, isocyanate, phenytoin, penicillamine, hydralazine, mitomycin-C, crack/cocaine use, propylthiouracil); 3. Physical trauma (i.e., pulmonary contusion); 4. Coagulation defects (anticoagulation, thrombocytopenia, disseminated intravascular coagulation); 5. Increased capillary pressure (i.e., mitral stenosis/regurgitation); 6. Other (post-bone marrow transplantation, chemotherapeutic agents). Alveolar hemorrhage has been reported in the literature to be caused by various conditions, including post-bone marrow transplantation (either autologous or allogeneic), collagen vascular diseases/vasculitis, inherent bleeding disorders, iatrogenic coagulopathy, renal dysfunction, pulmonary contusion, medication/drug use, valvular heart diseases (i.e., mitral valve disorders). Among these, warfarin, clopidogrel, fibrinolytic therapy (i.e., t-PA, streptokinase), and glycoprotein (GP) IIb/IIIa inhibitors (i.e., abciximab, tirofiban) have been reported to cause alveolar hemorrhage in different settings, and are primarily associated with percutaneous coronary interventions. Monoclonal antibodies specific for platelet GP IIb/IIIa receptors, peptidomimetics and cyclic peptides have been used extensively to treat unstable angina and to improve outcomes after percutaneous transluminal coronary angioplasty (PTCA) with stent placement. The most important complications associated with these agents involve major bleeding episodes, with the rare incidence of pulmonary alveolar hemorrhage being particularly lethal.^4–6 The EPIC investigators reported the incidence of major bleeding complications at 11% when an abciximab bolus was used in the absence of concomitant low-dose, weight-adjusted unfractionated heparin administration in order to prevent ischemic complications in high-risk coronary angioplasty,⁷ while the CAPTURE trial revealed a 3.8% incidence when abciximab was used to treat unstable refractory angina.⁶ The EPILOG study found no difference in bleeding rates among the three treatment groups and showed that low-dose, weight-adjusted heparin can decrease the risk of abciximab-associated major bleeding.⁸ Aguirre et al. reviewed the cases of bleeding complications in the EPIC trial and surmised that risk factors which predict this outcome include acute myocardial infarction, low body weight, older age and complicated PTCA.⁴ Alveolar hemorrhage associated with these agents is a dire complication that has been described in association with abciximab,^5,10,11 tirofiban5 and clopidogrel use.¹² Kalra et al. performed a retrospective review of their tertiary care institution’s bronchoscopy and coronary angiography records to identify patients who experienced this complication between June 1995 and March 2000.⁹ In order to qualify for the diagnosis of pulmonary hemorrhage, the patients had to have an abnormal chest X-ray, need for a blood transfusion and evidence of impaired oxygenation. They found 7 cases of alveolar hemorrhage in a review of 2,553 records of patients receiving abciximab. With review of potential risk factors, in the absence of abciximab, no cases of pulmonary hemorrhage were identified. Therefore, they concluded that the only risk factor for pulmonary hemorrhage was infusion of abciximab. They also noted that 4 out of the 7 patients who developed alveolar hemorrhage had an initial symptom of hemoptysis, and following infusion, 2 of these patients had an early death, and 1 had a late death. Subsequent to their initial report of alveolar hemorrhage associated with abciximab, Khanlou et al. noted 6 additional patients with this complication who were described in a correspondence.¹⁰ Of these 6 patients, 4 were male, and 5 were smokers with chronic obstructive pulmonary disease, only 1 had an abnormal coagulation profile (INR = 1.7), and none had a history of abnormal bleeding. They had all suffered myocardial infarctions and had interstitial infiltrates noted on their chest X-rays prior to infusion of abciximab. All 6 received initial treatment with heparin, ticlopidine and aspirin, along with an abciximab bolus of 0.25 µg/kg followed by 12-hour infusion of 10 µg/kg/minute (mean activated coagulation time during the procedure was 245 seconds). The presence of alveolar hemorrhage was determined by dyspnea associated with moderate or severe hemoptysis, an increase in pulmonary infiltrates on chest X-ray and a decrease in hemoglobin. The 3 patients who died all required red cells, platelets and mechanical ventilation. Interestingly, all of the patients who developed alveolar hemorrhage had elevated pulmonary capillary wedge pressure (mean = 24 mmHg, range = 13–45) and pulmonary arterial pressures (mean systolic = 44 mmHg, mean diastolic = 28 mmHg) on right heart catheterization. These investigators suggest that underlying lung conditions are a likely risk factor for the life-threatening complication of diffuse alveolar hemorrhage associated with the use of GP IIb/IIIa inhibitors in patients with ischemic cardiac disease, and that the presence of chronic obstructive pulmonary disease, pulmonary hypertension and elevated pulmonary capillary wedge pressures may portend a potentially fatal outcome if these agents are used. We have summarized the reported alveolar hemorrhage cases in the literature in Table 1. Even though its incidence has been reported to be as low as 0.27% by Kalra et al., it is probably an underreported entity since mild cases are likely not published and are treated conservatively. Based on the summary in Table 1, abciximab, tirofiban and eptifibatide have the greatest propensity to be associated with this side effect, in descending order. Given the ubiquitous nature of coronary artery disease in the American population and the fact that platelet GP IIb/IIIa receptor inhibitors have a clear role in treating ischemic cardiac conditions and improving outcomes after revascularization, it is likely that these agents will continue to be given to a large number of patients. The extremely high morbidity and mortality rates associated with pulmonary hemorrhage which can accompany the use of these agents mandates further examination of risk factors associated with this complication, and perhaps, the presence of underlying lung disease should give clinicians a pause before administration of these agents. Patient Characteristics and Methods Hahnemann University Hospital’s pathology record database was screened for the diagnosis of “hemosiderin-laden macrophages and alveolar hemorrhage” between 1999 and 2003. The results were cross-checked with the coronary angiography and hospital record databases. Then, the matching charts of the patients were reviewed in detail for the diagnosis of alveolar hemorrhage in relationship to their GP IIb/IIIa receptor inhibitor use (pulmonary hemorrhage due to other causes is excluded by this method). A total of 6 patients who received GP IIb/IIIa inhibitors with their percutaneous coronary intervention were identified and are described below: Patient #1 was an 84-year-old female with a history of atrial fibrillation, gastrointestinal bleeding, cerebrovascular accident (CVA), hypertension, Graves’ disease with partial thyroidectomy, who developed dyspnea perioperatively following meningioma surgery at an outside hospital and was found to have inferoposterior wall myocardial infarction. She underwent cardiac catheterization which showed two-vessel coronary artery disease. This revealed 100% stenosis of the left circumflex artery, and 80% stenosis of the right coronary artery (RCA) with only luminal irregularities in the left anterior descending (LAD) artery territory. The patient was transferred to Hahnemann for further intervention. She underwent rotational atherectomy followed by percutaneous transluminal coronary angioplasty (PTCA) and stenting of the RCA. The patient received 3,500 U of weight-adjusted unfractionated heparin along with a standard dose of tirofiban during the procedure. The procedural activated clotting time (ACT) was 213 seconds, with a normal platelet count. Although the patient’s echocardiogram showed an overall normal LVEF (left ventricular ejection fraction, 55%), there were severe mitral and tricuspid regurgitation, along with moderate pulmonary hypertension with a right ventricular systolic pressure (RVSP) of 50. During hospitalization, the patient developed alveolar hemorrhage. The patient was treated with supportive care, and was later transferred to a rehabilitation facility. Patient #2 was a 74-year-old female with a history of coronary artery disease (CAD) with coronary artery bypass graft surgery (CABG), chronic obstructive pulmonary disease (COPD), tobacco use, interstitial lung disease, hypothyroidism, and hypertrophic obstructive cardiomyopathy. She underwent PTCA and stenting of the proximal left internal mammary artery (LIMA) graft and developed postprocedural dyspnea and chest pain for which she was taken back to the catheterization laboratory on the next day and underwent PTCA of the distal LIMA. The patient had hemoptysis 2 days later. She was noted to have a pulmonary artery (PA) pressure of 50/20 mmHg, with a mean pulmonary capillary wedge pressure (PCWP) of 20 mmHg. The patient received 7,500 U of heparin in addition to a standard dose of abciximab, clopidogrel and aspirin periprocedurally. Her platelet count was normal, and her ACT was 263 seconds at the time of the procedure. The echocardiography showed severe cardiac dysfunction, with a LVEF of 20%, moderate mitral and tricuspid regurgitation, and moderate pulmonary hypertension, with a RVSP of 45. After recovery with supportive care, the patient was discharged 4 days later. Patient #3 was a 50-year-old female with a history of coronary artery disease, hypertension, chronic bronchitis, tobacco use, hypercholesterolemia, and myocardial infarction with PTCA and stenting. She was admitted to the hospital with chest pain and underwent PTCA and stenting of the right coronary artery. During the procedure, the patient received 4,000 U of heparin in addition to abciximab, clopidogrel and aspirin. At the time of the procedure, her platelet count was normal, and her ACT was 156 seconds. The patient was noted to have dyspnea and hemoptysis postprocedure. Her echocardiography showed a LVEF of 25–35% and mild mitral and tricuspid regurgitation. The patient’s PA pressure was 44/22 mmHg, with a PCWP of 24 mmHg on a previous catheterization report. The patient was later discharged from the hospital after recovery with supportive care. Patient #4 was a 64-year-old male with a history of coronary artery disease, myocardial infarction, congestive heart failure/cardiomyopathy, hypertension, diabetes mellitus, COPD and tobacco use. He was admitted with inferior wall myocardial infarction and underwent PTCA and stenting of the RCA. The patient received 5,000 U of heparin in addition to a standard dose of abciximab, clopidogrel and aspirin. At the time of the procedure, his platelet count was normal, and his ACT was 319 seconds. Although the patient’s PA pressures were noted to be only 24/14 and his PCWP was 13, he was initially hypotensive, which was resolved with intravenous fluids later on. The patient developed alveolar hemorrhage that required intubation during hospitalization. He was treated with optimal supportive care. The echocardiography from the same admission showed moderate-to-severe LV dysfunction, with a PA systolic pressure of 43. The patient was transferred to rehabilitation after supportive medical therapy. Patient #5 was a 62-year-old male with a history of myocardial infarction, coronary artery disease and CABG, ischemic cardiomyopathy with multiple coronary interventions, tobacco use, congestive heart failure, hypertension, diabetes mellitus, hypercholesterolemia, atrial fibrillation, and renal artery stenosis with stenting. He was admitted with dyspnea and underwent PTCA and stenting of the saphenous vein graft to the obtusus marginal artery, using 6,000 U of heparin in addition to a standard dose of abciximab, clopidogrel and aspirin. The patient’s PA pressure was 70/30 mmHg, with a PCWP of 28 mmHg. He developed alveolar hemorrhage and required intubation during the hospital course, and expired during the same hospitalization. Patient #6 was an 80-year-old male with a history of diabetes mellitus, hypertension, tobacco use, hypercholesterolemia, carotid stenosis, myocardial infarction, CABG, PTCA with stenting of the left circumflex and left main coronary arteries, PTCA and brachytherapy for in-stent restenosis of the left main coronary artery with development of subacute thrombosis (the patient had cardiorespiratory arrest and was successfully resuscitated and discharged from the hospital at that time, with appropriate percutaneous coronary intervention). In the past, the patient was readmitted with myocardial infarction. The ECG showed left bundle branch block with left axis deviation. He underwent cardiac catheterization which showed 70% in-stent restenosis of the left main coronary artery, an occluded left anterior descending coronary artery and right coronary artery, and a diffusely diseased/ectatic left circumflex coronary artery. Bypass graft injection revealed a patent left internal mammary graft to the left anterior descending artery, an occluded sequential saphenous vein graft (SVG) to the first and second obtuse marginal branches, and a 50% ostial and 90% proximal stenosis of the saphenous vein graft to a diagonal branch. The patient had 2 stents placed to the SVG to the diagonal graft, and received 5,000 U of heparin along with tirofiban, in addition to aspirin and clopidogrel. An echocardiogram performed the same day showed moderate LV dysfunction with mild tricuspid regurgitation. The patient later developed further chest discomfort for which he was taken back to the cardiac catheterization laboratory the next day and underwent cutting balloon angioplasty with stenting of the left main coronary artery, along with intra-aortic balloon pump placement. The patient again received 4,800 U of heparin along with tirofiban during this procedure. The ACT was 244 seconds at that time. His pulmonary artery mean pressure was 64 mmHg, and his pulmonary capillary wedge pressure was 50 mmHg. Later in his hospitalization, the patient developed respiratory distress and hemoptysis for which he had to be intubated. He was diagnosed with alveolar hemorrhage at this time. The patient’s initial platelet count was 196,000, but decreased at the time of diagnosis to 99,000. After a prolonged hospitalization course, patient care was withdrawn per his family’s wishes, and he expired. Results The recognition of alveolar hemorrhage requires a high degree of suspicion because hemoptysis is not always present. Cough and shortness of breath are usually common symptoms. A high DLCO or hemosiderin-laden macrophages in bronchoalveolar lavage fluid or sputum may suggest the diagnosis in the appropriate clinical setting. Although it is difficult to outline certain risk factors for alveolar hemorrhage, there appear to be a few common underlying comorbid conditions we have to mention based on the available data from these patients; 1. Chronic obstructive pulmonary disease with at least a moderate degree of pulmonary hypertension, and/or history of tobacco use; 2. Left ventricular dysfunction; 3. Congestive heart failure; 4. Elevated LVEDP/PCWP; 5. Valvular regurgitation (especially acute, or acute on chronic); 6. Acute myocardial stunning related to acute myocardial infarction with a sudden and abrupt rise in LVEDP/PCWP; 7. The level and duration of anticoagulation (excessive anticoagulation with multiple anticoagulants, including in a facilitated percutaneous coronary intervention); 8. History of multiple interventions in a patient with a history of CAD; 9. Old age; 10. History of autoimmune/collagen vascular disorders with capillaritis or allergic disorders (especially patients with active inflammatory disease and probably with increased TNFa or IgE levels). Although the overall incidence of alveolar hemorrhage associated with GP IIb/IIIa receptor inhibitor use is rare, the mortality rate associated with it is higher, approximately 33% in our patient series. The presence of COPD/severe pulmonary hypertension and LV dysfunction/CHF in a patient with a history of CAD/multiple interventions, as well as protracted intense anticoagulation, appears to be associated with the worst outcomes in these patients. In our patients, the mean age was 69 years. Patient gender was equally distributed, although mortality appeared to be higher in males. In our series, most of these cases were associated with either RCA or SVG graft interventions, in which mortality occurred in males with SVG graft intervention when these agents were used (more with abciximab than tirofiban). At least half of the patients required intubation, and two-thirds of these intubated patients died in the hospital course. The survivors had prolonged hospitalization with optimal supportive care including discontinuation of anticoagulation, transfusion of blood/platelet products and positive end-expiratory pressure mechanical ventilation, along with aggressive pulmonary care, when needed, in order to maintain the lung reserve and necessary oxygenation. Because of its rare occurrence, our study is limited to being a retrospective case review study. Therefore, it is possible that some of the clustered characteristics of these patients are due to chance alone. It should also be noted that not all the patients with these characteristics developed alveolar hemorrhage, and perhaps other factors, including genetic predisposition, play a role in this regard. Discussion Many reported cases with this rare complication have been noted to have COPD/asthma/reactive airway disease along with pulmonary hypertension, all of which raise the question of what underlying possible mechanisms could play a role in this setting. It also appears from the published literature that the degree of pulmonary hypertension may be a prognostic factor in these patients. The clinical picture somewhat resembles pulmonary infarction, which occurs when the two conditions are simultaneously present: the presence of a large occlusive pulmonary emboli (with an increase in pulmonary artery pressures), and severe LV dysfunction. It is possible that severe pulmonary hypertension, which is one of the indications for chronic anticoagulation, increases the likelihood of developing a local thrombotic process in pulmonary beds and causes a preconditioning similar to pulmonary infarction. The use of GP IIb/IIIa inhibitors may play a critical triggering role in further propagation of bleeding into the lungs in the setting of underlying inflammatory lung disease. Since there are different situations which can lead to alveolar hemorrhage, it appears that there must be more than one concurrent precipitating factor present to cause alveolar hemorrhage. Pathophysioloy is complex and involves platelets, other inflammatory cells and cytokines. Despite being anucleate, platelets share many characteristics of inflammatory cells, and can undergo chemotaxis, express adhesion molecules, release a variety of pro-inflammatory mediators, enzymes, cationic proteins, and can become activated by mediators released by other cell types involved in the inflammation process. Platelets, along with other blood cells like eosinophils and monocytes, have been observed to be attached to the vascular endothelium and undergo diapedesis in asthmatics, an event that is accompanied by extensive inflammatory changes to the airways. The adhesive events that occur between platelets and leukocytes may be induced by up-regulation of the adhesion molecule, P-selectin (platelet selectin is found in a-granules of platelets and is released to the surface upon activation), thus making it possible that leukocytes could adhere to platelets and endothelium through a specific ligand. Activated platelets can bind to many cells including monocytes, PMN (polymorphonuclear) cells, eosinophils, basophils, and a subpopulation of T4 and T8 cells, all of which is dependent on divalent cations and is completely inhibited by monoclonal antibodies to P-selectin or PSGL-1 (P-selectin glycoprotein ligand-1). Once platelets are activated (i.e., vascular damage, PMN cathepsin G, thrombin), P-selectin expressed on the platelet surface binds to its ligand, PSGL-1, on PMN leukocytes. This starts a signalling mechanism involving tyrosine phosphorylation and activation/up-regulation of b2 integrin (CD11b/18), also called Mac-1 receptor (found in granulocytes, moncytes, and natural killer cells and contribute to the process of neutrophil adhesion, leukocyte transmigration across endothelium/epithelium, neutrophil aggregation, chemotaxis, phagocytosis, and leukocyte-platelet interaction). The Mac-1 receptor becomes able to bind to platelet counter-receptors (including fibrinogen via IIb/IIIa receptors) or to other b2 integrin ligands that allow stable multicellular interaction — all of which promotes tethering and rolling of leukocytes on the vascular surface. Cathepsin G, released by activated PMN leukocytes, may also facilitate further platelet and PMN recruitment at the vascular injury site. Platelet rosetting around leukocytes with subsequent attachment and transmigration across the endothelium may be a critical process that is further enhanced by the release of platelet lysosomal enzymes (these contain matrix metalloproteinases which degrade glycoproteins, glycolipids, and glycoseaminoglycans), degrading glycolipids attached to cell membranes, facilitating the movement/extravasation of leukocytes (diapedesis) across the tissue, along with the release of membrane-bound growth factors for wound repair in this regard.^13,14 Production of antigen-specific IgE in response to allergen provocation is a fundamental hallmark of atopic diseases by definition.^15,16 The cross-linking of IgE by antigen is believed to provide the stimulus for mast cell degranulation in early-phase reactions, an event that precipitates a cascade of inflammatory events in response to allergens.^17–19 There is compelling evidence that platelets are also activated via IgE, perhaps initiating an important pathway to platelet activation, independent of mediator release from other inflammatory cells. Numerous studies have revealed an alteration in the character and function of platelets in patients with allergic diseases (i.e., asthma), and these alterations may be dissociated from the well-characterized involvement of platelets in thrombosis and hemostasis, illustrating a dichotomy (Table 3) in platelet function.^20–24 Platelets from allergic patients are found to be refractory to a variety of stimuli ex vivo, a phenomenon possibly resulting from platelet “exhaustion”, where platelets are overstimulated in vivo and thereby subsequently respond poorly to stimuli in vitro.^25,26 In support of this concept, the ability of proinflammatory mediators such as noradrenaline and ADP to induce platelet aggregation is seen to be impaired in asthmatic patients, with no second-phase aggregation, an occurrence that has been correlated with increased serum IgE in asthmatic patients.^27,28 Platelets from allergic patients produce free radical oxygen species in response to IgE stimulation via specific allergens or antibodies.²⁹ This platelet activation process can be inhibited by antibodies specific for the low-affinity receptor for IgE,^30,31 thus revealing a negative feedback response of platelets to IgE stimulation, governed by differential up-regulation of IgE receptors. Platelets from asthmatic patients have also been observed to undergo chemotaxis in response to allergen exposure, perhaps via platelet-bound, antigen-specific IgE.³² In response to IgE stimulation, platelets produce free radical oxygen species in allergic patients, which was demonstrated to be inhibited by drugs such as nedocromil sodium or disodium chromoglycate,^33,34 resulting in a decrease in the generation of cytotoxic mediators, the inhibition of oxidative metabolism, increased survival time of platelets and increased monoamine uptake.³⁵ Inhibition of eosinophil chemotaxis by cetirizine (H1 receptor antagonist) may be linked to the inhibition of IgE-dependent platelet activation.³⁶ Observations have been made of decreased platelet survival time, decreased arachidonic acid metabolism (but an increase in lypoxygenase products), increased levels of mediators (i.e., beta thromboglobulin, PAF, platelet factor 4), and second messengers (phosphatidyl inositol, inositol triphosphate, calcium) accompanied by prolonged bleeding time, increased platelet mass, and altered sensitivity to PAF in stable atopic asthmatics, perhaps as a result of desensitization due to chronic platelet activation.^37–43 These phenomena can be corrected by treating patients with medications such as glucocorticoids,⁴⁴ or with platelets treated with disodium chromoglycate in vitro before reinfusion.⁴⁵ The rise in PAF levels may be related to a deficiency state in PAF acetylhydrolase, an enzyme that inactivates PAF in children studied with asthma.^46–51 As a drug, nedocromil sodium has also been shown to inhibit platelet activation induced by PAF in ex vivo studies.⁵² After thromboxane stimulation, the increased release of CD62 (P-selectin), RANTES (regulated upon activation normally T-cell expressed and secreted), and intracellular free calcium have been observed in asthmatics, and the release of these products have been correlated to a rise in the level of b-thromboglobulin in vivo, all of which also can be suppressed with the administration of medications such as theophylline.^53,54 These explained changes may increase the likelihood of bleeding complications, especially with the use of multiple anticoagulants. In this article, we tried to summarize the cellular aspect of this complex interaction between platelets and other mediators that may have an effect on coagulation. Conclusions Before GP IIb/IIIa receptor inhibitors became widely available, pulmonary hemorrhage had been reported by Brown et al. in 4 out of 88 patients (1 died) in whom anticoagulation included warfarin, heparin, aspirin, dypiridamole and dextran.⁵⁵ Since it was first described with GP IIb/IIIa inhibitors by Sitges et al.,⁵⁶ the treatment of alveolar hemorrhage has not changed much, and supportive care has been the mainstay of therapy in addition to withholding anticoagulation. Although alveolar hemorrhage is a rare complication related to GP IIb/IIIa inhibitor use during percutaneous coronary intervention, its high morbidity and mortality rates require specific attention to possible risk factors and/or pre-existing comorbid conditions. Clinical diagnosis requires a high degree of suspicion since patients can present with only dyspnea, hypoxemia and/or chest X-ray abnormalities without hemoptysis. Because of its relatively low incidence, it would be difficult to test a specific drug efficacy in this particular setting. It is probably an underreported entity since mild cases are likely to be treated conservatively. The treatment involves holding the anticoagulation, supportive care with platelet and packed red blood cell transfusions (fresh frozen plasma/cryoprecipitate, epsilon aminocaproic acid if fibrinolytic agents were used), high positive end-expiratory pressure ventilation (if the patient requires mechanical ventilation), and aggressive respiratory care. In the drug-eluting stent era, the need for holding anticoagulation adds additional risk for subacute stent thrombosis, and may further increase overall morbidity and mortality. Although alveolar hemorrhage in our patient series was related to abciximab and tirofiban, eptifibatide is not excluded in relationship to this entity.⁵⁷ More recently, other monoclonal antibodies (i.e., rituxan, gemtuzumab ozogamicin, gefitinib, bevacizumab) used in hematology/oncology as chemotherapeutic agents have also been reported to cause this rare complication.^58–60 Most interestingly, sirolimus, an immunosuppressive medication used in transplant recipients, has been associated with interstitial pneumonitis and diffuse alveolar hemorrhage.^61–62 It is important since this compound is also currently used in stent chemotherapy to prevent restenosis. Whether this minute amount of sirolimus in drug-eluting stents will likely increase this complication risk remains to be seen. The efficacy of other therapies for either prophylaxis or for the treatment of this disorder needs further confirmation (i.e., glucocorticoids, disodium chromoglycate, nedocromil sodium, theophylline, cetirizine). It should also be noted that although some of these medications are relatively safe in the setting of acute myocardial infarction, systemic glucocorticoids are relatively contraindicated and therefore should not be used empirically. Antihistamines may be beneficial in high-risk populations as part of the initial sedation regimen in the cardiac catheterization laboratory if physical examination and history are suggestive of active inflammatory/allergic disorders. Therapy should be individualized based on antecedent history and presentation. Finally, activated factor VII has recently been recommended by some authors for the treatment of diffuse alveolar hemorrhage.⁶³ We suggest that consultation with hematology should be obtained before using this drug since serious side effects are being reported with its use in recent literature. There are also a few other points to keep in mind. Activated clotting time during coronary intervention is a significant correlate of bleeding complications, and therefore, use of weight-adjusted heparin to maintain an ACT of 200–250 seconds will likely reduce bleeding, especially with concomitant use with GP IIb/IIIa receptor inhibitors. In addition, although operators in our patient series have used GP IIb/IIIa receptor inhibitors in vein graft interventions, careful weighing of the risk-to-benefit ratio is warranted before using these agents since they are not routinely recommended in this setting at present. Excessive fluid resuscitation should be avoided, if at all possible, in patients with elevated left-sided filling pressures and/or abnormal LV function. In the setting of LV dysfunction with markedly high biventricular filling pressures (especially those with chronic/active lung disease), patients should be treated aggressively in the cardiac catheterization laboratory with appropriate preload and afterload reducing agents/diuretics, as blood pressure allows, while emergency percutaneous coronary intervention takes place for acute myocardial infarction. In elective cases, the patient’s medical condition should be optimized in this regard before a percutaneous coronary intervention is considered. Interventional cardiologists should familiarize themselves with these patient characteristics when they are planning percutaneous coronary interventions with GP IIb/IIIa receptor inhibitor use. Acknowledgement. We dedicate this article to our families.

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