Initial experience of platelet glycoprotein IIb/IIIa inhibition with abciximab during carotid stenting: a safe and effective adjunctive therapy.

BACKGROUND AND PURPOSE: Abciximab has been shown to decrease periprocedural ischemic complications after coronary intervention. However, the adjunctive use of abciximab in carotid stenting has not been adequately studied. We sought to determine the efficacy and safety of abciximab in carotid stenting. METHODS: Carotid stenting was performed in 151 consecutive patients determined to be at high surgical risk by a vascular surgeon. Of these, 128 consecutive patients received adjuvant therapy with abciximab (0.25 mg/kg bolus before the lesion was crossed with guidewire and 0.125 micro. kg(-1). min(-1) infusion for 12 hours.). A heparin bolus of 50 U/kg was given, and activated clotting time was maintained between 250 to 300 seconds. All patients received aspirin and thienopyridine. Procedural and 30-day outcomes were compared between the control (n=23) and abciximab (n=128) groups. RESULTS: The 2 groups had similar baseline characteristics. Procedural events were more frequent in the control group (8%; 1 major stroke and 1 neurological death) compared with the abciximab group (1.6%; 1 minor stroke and 1 retinal infarction; P=0.05). On 30-day follow-up, 1 patient presented with delayed intracranial hemorrhage in the abciximab group. There were no other major bleeding complications. CONCLUSIONS: Adjunctive use of abciximab for carotid stenting is safe with no increase in the risk of intracranial hemorrhage. This adjunctive therapy with potent glycoprotein IIb/IIIa inhibition may help to reduce periprocedural adverse events in patients undergoing carotid stenting.

Safety of femoral closure devices after percutaneous coronary interventions in the era of glycoprotein IIb/IIIa platelet blockade.

We compared in-hospital femoral complications of Angio-Seal, Perclose, and manual compression in consecutive patients who underwent percutaneous coronary interventions in the era of glycoprotein IIb/IIIa platelet inhibition. Femoral closure devices have a similar overall risk profile as manual compression, even in patients treated with glycoprotein IIb/IIIa platelet inhibition, although certain rare complications such as retroperitoneal hemorrhage and severe access-site infection may be more common with the use of these devices.

Intermediate outcome after carotid stenting: what should we expect?

Atherosclerosis of the extracranial carotid artery is a major public health burden. Stroke is the third leading cause of death in Western countries, after heart disease and cancer, and the leading cause of long-term disability. In the United States, there are more than 500,000 strokes annually, accounting for approximately 3 million stroke survivors with varying degrees of disability. Data from stroke registries suggest that internal carotid artery atheroembolic disease accounts for approximately 35% of all ischemic cerebral infarctions; therefore, approximately 150,000 strokes in the United States per year may be ascribed to carotid disease. Surgical endarterectomy has been shown to be superior to medical management in the management of severe carotid stenosis in both symptomatic and asymptomatic patients. Indeed, carotid endarterectomy has been one of the most heavily scrutinized operations over the past 40 years, and newer methods of revascularization are being actively explored. With the great technological advances in the endovascular treatment of both peripheral and coronary atherosclerotic disease, many of these techniques are now being applied to the extracranial circulation. We explore the rapidly expanding field of carotid artery angioplasty and stenting. The upcoming prospective randomized clinical trials of surgical endarterectomy versus carotid angioplasty and stenting also are reviewed.

Influence of a randomized clinical trial on practice by participating investigators: lessons from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). CAVEAT I and II Investigators.

OBJECTIVES: We sought to determine whether the results of the first Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) influenced subsequent practice patterns among the investigators. BACKGROUND: CAVEAT-I demonstrated that directional coronary atherectomy (DCA) resulted in higher rates of early complications at a higher cost and with no clinical benefit. We sought to determine whether these results influenced subsequent use of procedures among CAVEAT-I investigators. METHODS: We compared the results of a week-long registry of all coronary interventions performed at 35 CAVEAT-I sites in 1994 with those of a similar registry obtained in 1992 before the trial, the results of which were published in 1993. For control purposes, the use of procedures was studied at 24 additional sites to provide insight into practice at hospitals not participating in the trial. A total of 1,465 interventions were analyzed. RESULTS: Ninety-four percent of CAVEAT-I sites responded. Utilization rates differed between CAVEAT-I and CAVEAT-I follow-up (p < 0.001). Balloon angioplasty decreased from 83.8% to 68.5%, DCA increased slightly from 10.7% to 14.1%, and the use of other devices increased from 5.4% to 17.5%. Stand-alone balloon use was more prevalent at nonparticipating control sites than at sites that took part in CAVEAT-I (p < 0.001). CONCLUSIONS: Paradoxically, despite the negative findings of CAVEAT-I, there was a noteworthy trend toward an increase in the use of DCA and other devices at CAVEAT-I sites. Our findings suggest that among investigators in the trial, there may have been a lack of influence of trial data on clinical practice patterns 1 year after publication of the results. Ethics of protocol: Both CAVEAT I and II were approved by the Institutional Review Board at each study site.

Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model.

BACKGROUND: An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. METHODS AND RESULTS: A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. CONCLUSIONS: Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.

Reduction of blood loss from diagnostic sampling in critically ill patients using a blood-conserving arterial line system.

STUDY OBJECTIVE: To demonstrate the utility of a new blood-conserving arterial line system in reducing blood loss associated with blood drawing in the critical care setting. DESIGN: Prospective, randomized, crossover comparison between two arterial line systems. SETTING: Medical intensive care unit (ICU); tertiary care teaching institution. PATIENTS: Thirty-one patients who required invasive arterial blood pressure monitoring throughout their ICU course. INTERVENTIONS: For ICU days 1 to 2, patients were randomized to receive either a conventional arterial line system or a new blood-conserving arterial line system. On ICU days 3 to 7, patients with a conventional arterial line were crossed over to the blood-conserving arterial line, and vice versa. Laboratory blood volumes, mixed discard volumes, and blood discard volumes were then recorded to document how much blood loss is associated with each aspect of the blood sampling process. RESULTS: The mean total volume of blood sent to the laboratory for testing was 257.4 ml. As a result of "clearing the line" over the 7-day period, patients with the conventional arterial line system lost a mean volume of 340.2 ml of blood mixed with heparinized saline solution more than patients with the blood-conserving arterial line. In terms of the blood component of the blood-heparinized saline solution mixture, use of the conventional arterial line was associated with an average of 156.8 ml more blood discarded than with the blood-conserving arterial line. CONCLUSION: The new blood-conserving arterial line system provides a simple and effective method for reducing blood loss related to diagnostic sampling in the critical care setting.

Acute noncardiogenic pulmonary edema due to polymer fume fever.

BACKGROUND: Certain fluorocarbon polymers can produce a clinical syndrome called polymer fume fever when the products of pyrolysis are inhaled. SUMMARY: A previously healthy 21-year-old white man presented with severe chest tightness, difficulty in breathing, pyrexia, nausea, vomiting, and a dry irritating cough. These symptoms occurred suddenly while smoking a cigarette 2 hours after leaving his place of work, where he is a plastics machinist. A chest roentgenogram revealed a bilateral patchy alveolar air space filling pattern involving the mid and lower lung fields. The diagnosis of polymer fume fever was established on the basis of the symptom complex, the association with cigarette smoking, and the occupational exposure to micronized polytetrafluoroethylene. CONCLUSIONS: A thorough occupational and smoking history is necessary to recognize polymer fume disease, which may resemble influenza.

Evaluation of a new blood-conserving arterial line system for patients in intensive care units.

OBJECTIVE: To evaluate blood samples obtained from a new blood-conserving arterial line system for the presence of hemodilution or heparin contamination. DESIGN: Prospective, clinical trial. SETTING: A coronary intensive care unit in a tertiary-care teaching hospital. PATIENTS: Cardiovascular patients in whom invasive arterial blood pressure monitoring was indicated. INTERVENTIONS: Paired blood samples were obtained from a conventional arterial line system and a new blood-conserving arterial line system for the measurement of hematocrit and partial thromboplastin time, and compared to evaluate for the presence of either hemodilution or heparin contamination. MEASUREMENTS AND MAIN RESULTS: A Bland-Altman bias analysis of the variability between the two blood draw methods was performed. The analysis indicated that a) a randomly determined partial thromboplastin time obtained from the blood-conserving arterial line would lie between 3.32 and -5.11 of the partial thromboplastin time taken from the conventional arterial line value with 95% confidence; and b) a randomly determined hematocrit obtained from the blood-conserving arterial line would lie between 1.97 and -1.85 of the hematocrit taken from the conventional arterial line value with 95% confidence. CONCLUSIONS: We concluded that a) blood samples obtained with the blood-conserving arterial line demonstrate no evidence of hemodilution or heparin contamination; b) the blood-conserving arterial line provides blood samples without the need for an initial volume of blood to be discarded; c) the blood-conserving arterial line provides a means for blood conservation in the intensive care setting.

A role for platelets and thrombin in the juvenile stroke of two siblings with defective thrombin-adsorbing capacity of fibrin(ogen).

Binding of iodine-125-labeled thrombin to fibrin clots from two siblings with juvenile stroke was 30% of normal, and abnormally high amounts of the radioligand (not adsorbed by fibrin) were found in the supernatant. In concordance with this finding, supernatants from the patients' fibrin clots caused abnormal enhancement of platelet aggregation, ATP secretion, and binding of 125I-fibrinogen to platelets exposed to subthreshold concentrations of ADP or epinephrine. Hirudin suppressed the enhancing effect of the patients' supernatants, and substitution of gamma-thrombin for alpha-thrombin led to normalization of platelet responses. Under some experimental conditions, degradation of the patients' fibrinogen by plasmin was impaired. However, the euglobulin lysis time, the rate of fibrin degradation by plasmin, and the lysis of the patients' plasma clots by human melanoma tissue-type plasminogen activator were normal. Patients' plasmas, as well as purified fibrinogen, showed a prolonged thrombin time (partially corrected by 10 mM CaCl2) and an impaired release of fibrinopeptide A in response to thrombin. However, the release in response to reptilase was normal, and the reptilase, ancrod, and thrombin coagulase times were within control (normal) values. In addition, the patients' fibrinogen showed normal polymerization of preformed fibrin monomers, normal sialic acid content, and normal binding to ADP or epinephrine-stimulated platelets. Our studies support the concept that thrombin and platelets play an important role in the occurrence of stroke in these patients and suggest a direction to be followed to identify the mechanism(s) contributing to thrombosis in subjects with abnormal fibrinopeptide release.

Eicosapentaenoic acid ethyl ester as an antithrombotic agent: comparison to an extract of fish oil.

Evidence suggesting that dietary omega-3 polyunsaturated fatty acids decrease the risk of thrombosis comes mainly from studies involving supplementation with large amounts (15-20 g/day) of fish oil extract. We investigated the inhibition of platelet function by a moderate amount (4 g/d) of ethyl eicosapentaenoate (E-EPA) compared to a concentrated fish oil extract (6 g/d) when given as a supplement to an ordinary diet. We also determined the effects of these supplements on platelet EPA incorporation, thromboxane synthesis, calcium mobilization and fibrinogen binding. After 4 weeks, both omega-3 supplements increased the amount of EPA in platelet phospholipids. The fish oil extract, which contained docosahexaenoic acid (DHA), had increased the amount of DHA also. The total increase in omega-3 fatty acids was similar for both supplements. E-EPA decreased serum cholesterol by 13% and triacylglycerols, 35%; increased the bleeding time by 57% and the threshold dose of collagen needed to induce platelet aggregation by 46%. Thromboxane synthesis in response to collagen was decreased 65% by E-EPA. Thus, the dietary supplement of pure E-EPA was more effective in limiting platelet reactivity than a concentrated fish oil extract providing an equivalent amount of omega-3 fatty acids. As an antithrombotic agent, E-EPA should allow for reasonable daily doses in long-term treatment of cardiovascular disease.

Prostacyclin synthesis by endothelial cells from human umbilical veins: effect of cumulative population doublings.

There is a wide range of reported values for prostacyclin (PGI2) synthesis by cultured endothelial cells from human umbilical veins (HUVE). Part of this variation may be due to differences in isolation and culture conditions, but part may be due to previously unstudied variation in the number of population doublings (PDs) which the cells have undergone in vitro. Attention is now shifting to arachidonic acid (AA) metabolism by cells from adult human vessels and these cells may require increased PDs to obtain confluent cultures for testing. Therefore, we have examined the effect of number of cell population doublings as well as number of subcultivations on PGI2 synthesis using HUVE as a model system. Primary and first subcultivation cultures inoculated at high density, so that PDs at confluence were less than 4, synthesized 10 times as much PGI2 as the same isolates inoculated at low density with PDs greater than 4. Isolates inoculated and subcultivated so that the PDs at confluence after the fourth subcultivation were less than 6, showed 50% less PGI2 synthesis between the primary and first subcultivation and between the first and second subcultivations. Isolates with less than 4 PDs after the fourth subcultivation were carried further to determine the effect of extensive subcultivation. Four of six isolates showed a sudden increase in PGI2 synthesis which occurred between subcultivations 5 and 12 (PDs 4-6). These results demonstrate that AA metabolism is markedly affected by growth in culture and serial subcultivation.

Model system to study interaction of platelets with damaged arterial wall. II. Inhibition of smooth muscle cell proliferation by dipyridamole and AH-P719.

A new in vivo model for the initial events in atherogenesis was employed to investigate drugs which may inhibit intimal muscle cell proliferation following repeated limited endothelial cell injury. An artery forceps was placed over the central artery of the ear of an anesthetized rabbit for 30 min. The forceps were removed, blood flow resumed in the vessel, and platelets contacted the damaged vessel wall. When a vessel was injured two or more times the smooth muscle cells of the media migrated into the intima and proliferated there between 1 and 3 weeks after the last injury despite restoration of an apparently intact endothelium. The intima of control undamaged vessels sometimes contained a few individual smooth muscle cells while vessels injured two, four, or six times showed correspondingly increasing numbers of layers of intimal smooth muscle cells covering increasing amounts of the intima. Arteries from thrombocytopenic rabbits showed, at most, a single layer of smooth muscle cells covering a small area. In rabbits pretreated with dipyridamole (1.5 mg/kg) for 3 days before each injury, proliferation was also limited to a small area. Neither aspirin (8 mg/kg) nor ticlopidine (40 mg/kg, 5X over 3 days), which inhibit platelet aggregation ex vivo, nor the continuous presence of heparin (800 U/kg, bid), reported to inhibit smooth muscle cell growth in vitro and in vivo, prevented smooth muscle cell proliferation in response to two injuries. However, a potent inhibitor of platelet cyclic-adenosine monophosphate (cAMP) phosphodiesterase, AH-P719 (1.5 or 2.1 mg/kg), was able to inhibit intimal smooth muscle cell proliferation in doses that inhibited platelet aggregation ex vivo.

The carbon dioxide rate of rise in awake apneic humans.

Currently available estimates of the PaCO2 rate of rise in resting humans with resting lung volume were gathered during general anesthesia. The PaCO2 rate of rise during apnea in awake subjects was determined to acquire a value that may be more applicable to awake, ventilator-dependent, critically ill patients. Clinically, apnea occurs at functional residual capacity. With FiO2 = 1.0, 20 volunteers held their breaths at functional residual capacity for 0, 10, and 20 seconds, and then for as long as possible. They exhaled through an infrared CO2 analyzer after each interval to determine end-tidal pCO2. An estimate of the logarithmic PaCO2 rise during breath holding at functional residual capacity was 7 mmHg during the first 10 seconds (43 mmHg/minute), 2 mmHg during the next 10 seconds (13 mmHg/minute), and 6 mmHg/minute thereafter. In conclusion, PaCO2 increases more rapidly in awake apneic humans than earlier thought. The values reported herein probably are better for estimating duration of apnea in conscious, critically ill patients than are values obtained during general anesthesia.

Alloxan-induced hyperglycemia in rabbits and the response of platelets to aggregating agents in vitro and to exposed subendothelium in vivo.

Many patients with diabetes mellitus show increased platelet aggregation and prostaglandin synthesis in response to physiological agents such as ADP and collagen when their platelets are tested in platelet-rich plasma or washed platelet suspensions. However, the relationship between increased platelet aggregation in vitro and increased thrombosis in vivo is difficult to establish with certainty. We have developed an in vivo model system in rabbits which tests the response of platelets in circulating native blood to an arterial vessel wall with limited damage such as might occur in arteries of patients with diabetes mellitus. We have used this model system to investigate whether 5 to 9 weeks of alloxan-induced hyperglycemia increases platelet adhesion and aggregation on a damaged vessel wall in vivo as well as platelet aggregation in vitro. Our results show that rabbit platelet function is not affected by extreme hyperglycemia and suggest that alloxan-induced diabetes in the rabbit may not be a good model for human diabetes mellitus.

Metabolism of 1-alkyl-2-acyl-GPC in human platelets in response to stimulation by thrombin.

Washed human platelets were incubated with radioactive 1-[3H]alkyl-2-hydroxyglycero-3-phosphocholine (lyso-PAF) at 37 degrees C. [3H]lyso-PAF was converted by platelets into [3H]alkylacyl-GPC which was incorporated. Incorporation of radioactivity was time dependent and reached a maximum of 57 percent in one h. This formation and incorporation of [3H]alkylacyl-GPC was inhibited (50%) by extracellular calcium (1.3 mM). Labeled platelets were treated for 5 min with either thrombin (2.5 U/ml) or saline solution. While there was no change in the saline control, thrombin induced a reduction in the content of [3H]alkylacyl-GPC, accompanied by an increase in [3H]lyso-PAF presumably by stimulation of phospholipase A2. There was no apparent increase in radioactivity comigrating with PAF. This was probably due to the overwhelming dilution of the radioactive alkylacyl-GPC by the endogenous nonradioactive compound (ratio-1/3200). These studies suggest that human platelets can take up lyso-PAF and acylate it to alkylacyl-GPC which is susceptible to phospholipase A2 activity.

Acetyltransferase activity in human platelet microsomes and washed platelets.

It has been demonstrated that human platelets form platelet-activating factor (PAF) when stimulated by thrombin, collagen and ionophore A-23187, but the mechanism of its formation has not been elucidated. In this study we demonstrated increased acetyltransferase activity (i.e., transfer of the acetyl moiety of [3H]acetyl-CoA to lyso-PAF (1-alkyl-sn-glycero-3-phosphocholine) to form PAF) occurring in human platelet microsomes made from platelets stimulated by thrombin or ionophore A-23187. This stimulation resulted in a 2-4-fold increase in acetyltransferase activity over unstimulated platelets. Acetyltransferase activity was also demonstrated by incubating [3H]acetate with whole platelets and stimulating with thrombin or ionophore A-23187. Radioactive PAF was detected when the platelets were stimulated. None was formed without stimulation. These findings indicate that acetyltransferase may play a role in the biosynthesis of PAF by human platelets.

Trial of repeated low-dose aspirin in diabetic angiopathy.

We compared the ability of aspirin to suppress platelet aggregation and thromboxane synthesis in ten normal subjects and ten patients with diabetic angiopathy and high rate of entry of new platelets into the circulation. When single doses of 100 to 1,000 mg aspirin were ingested daily for 1 month, there were time gaps between doses in which platelets from diabetics and normals aggregated and formed thromboxane ex vivo in response to the combination of arachidonic acid plus collagen. Similar gaps were also found for diabetics, but not for normals, following four daily doses (every six hours) of 25 or 100 mg. Our data show that dose schedules of aspirin which may suffice in normals are not effective in patients with diabetic angiopathy, presumably because these patients have a high rate of entry of new platelets into the circulation. We suggest that continual suppression of platelet thromboxane synthesis and aggregation by low-dose, "slow-release" preparations of aspirin would be an ideal long-term approach for the prevention of thrombosis in patients with a high rate of entry of new platelets into the circulation.

Increased fibrinogen binding to platelets from patients with familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a disease marked by a high incidence of thrombotic episodes and hypersensitivity of the patients' platelets to naturally occurring aggregating agents. Prostaglandin/thromboxane (PG/Tx) formation, adenosine 5'-diphosphate (ADP) secretion, and fibrinogen binding to platelets are all believed to be involved in the mechanisms of platelet aggregation. Therefore, we studied the interrelated roles of these processes in the platelets of nine FH patients and 10 controls. In response to ADP, collagen, or thrombin, FH platelets bound about twice as much 125I-fibrinogen as controls. This ratio did not change after suppression of PG/Tx formation by aspirin. With or without aspirin, FH platelets always aggregated in response to significantly lower concentrations of these agents than did platelets from normal controls. After stimulation with thrombin or collagen, the hyperaggregable platelets from FH patients were shown to bind significantly more fibrinogen than control platelets even when PG/Tx formation was suppressed (aspirin) and secreted ADP was scavenged (apyrase). To determine whether the increased fibrinogen binding observed in FH platelets is due to a qualitative or quantitative abnormality of the platelet receptor, we used a monoclonal antibody (B79.7) that is specific for the receptor. The amount of B79.7 that bound to platelets from control and FH subjects was similar. In addition (as in normal individuals), the antibody inhibited aggregation and fibrinogen binding of FH platelets.