Antithrombotic therapy in peripheral arterial occlusive disease.
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Arterial Occlusive Diseases↗
Biomedical subjects
W C Krupski
Publications and source records attributed to W C Krupski.
Abdominal aortic aneurysm: defining the dilemma.
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Aortic Aneurysm, Abdominal↗
Carotid artery disease in women.
Our understanding of cerebrovascular disease in women is hampered by a paucity of studies that include adequate numbers of female patients. Most studies are heavily biased toward men. Although women have fewer strokes than men and have a better long-term prognosis after strokes or TIAs, cerebrovascular disease still affects large numbers of women. Presently, there is little convincing evidence that standard medical therapy with aspirin for prevention of strokes in women is of benefit. Perhaps, inclusion of insufficient numbers of women in the aspirin trials for symptomatic carotid stenoses explains the apparent lack of therapeutic efficacy. Although ticlopidine does not appear particularly promising for prevention of stroke, other novel antiplatelet and antithrombotic agents are being developed and need to be tested in women. Carotid endarterectomy prevents strokes in women and men, but women enjoy a lesser benefit; this appears to be true both for symptomatic and asymptomatic carotid stenoses. Whereas restenosis is more common in women than men, most lesions remain asymptomatic. Surgery will probably remain the mainstay of treatment for cerebrovascular disease in women and men, but in this era of "gender correctness," the striking absence of reliable data exclusively applicable to women confirms the need for additional studies.
Carotid Artery Diseases↗
Regression of atherosclerosis.
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Animals↗
Lasting safe interruption of endarterectomy thrombosis by transiently infused antithrombin peptide D-Phe-Pro-ArgCH2Cl in baboons.
To evaluate the relative antithrombotic efficacy and hemostatic safety of antithrombin therapy for vascular thrombus formation at sites of mechanical vascular injury, we administered the potent and specific irreversible synthetic antithrombin D-PHE-PRO-ARG chloromethyl ketone (D-FPRCH2Cl) after performing carotid endarterectomies in baboons. The continuous intravenous infusion of D-FPRCH2Cl, 100 nmol/kg per minute for 1 hour, abolished acute carotid endarterectomy thrombosis for at least 48 hours. The plasma level of D-FPRCH2Cl during the infusion was maintained steady at 7.2 +/- 0.9 mumol/L, but decreased rapidly after discontinuing its infusion (T50 17 minutes). Platelet deposition, measured in real time using autologous 111In-platelet scintillation camera imaging, was 1.51 +/- 0.40 x 10(8) platelet/cm in the 14 treated animals 90 minutes postoperatively, compared with 11.7 +/- 1.16 x 10(8) platelet/cm in 14 heparin-treated controls (P < .002). The antithrombotic benefit was equivalent for treatment begun either 5 minutes before (nine animals) or 15 minutes after (five animals) reestablishing flow in the operated vessel, ie, 1.59 +/- 0.36 x 10(8) platelet/cm versus 1.35 +/- 0.51 x 10(8) platelet/min, respectively; P > .5. Endarterectomy thrombosis remained decreased for at least 48 hours postoperatively, as determined by the ratio between net 111In-platelet radioactivity at the endarterectomized site versus whole blood (ratio 0.82 +/- 0.25 in the treatment group v 3.03 +/- 0.51 in heparin controls at 90 minutes, P < .005; and 0.85 +/- 0.23 v 3.25 +/- 0.48 at 48 hours, P < .002). The marked reduction in endarterectomy thrombosis in treated animals at 48 hours was confirmed by scanning electron microscopy. Thrombin activity formed rapidly and became immediately bound to thrombus on thrombogenic segments in untreated control studies; treatment with D-FPRCH2Cl irreversibly inactivated the thrombus-bound thrombin. Hemostatic function, as measured by bleeding time (BT), activated partial thromboplastin time (APTT), and prothrombin time (PT) was impaired throughout the intravenous administration of D-FPRCH2Cl (BT > 30 minutes, APTT > 150 seconds, PT > 50 seconds); BT, APTT, and PT values were normal 30 minutes after discontinuing the infusions. As expected, blood loss into the surgical wound was substantial in nine animals receiving therapy initiated before restoring flow in the operated vessel (mean 95 mL, range 45 to 130 mL). By contrast, beginning D-FPRCH2Cl therapy in five animals 15 minutes after restoring arterial flow, a time when surgical hemostasis had been achieved, prevented excessive blood loss (mean 15 mL, range 10 to 35 mL; P < .01 compared with earlier treatment) without compromising the antithrombotic effects.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Chloromethyl Ketones↗
Interruption of vascular thrombosis by bolus anti-platelet glycoprotein IIb/IIIa monoclonal antibodies in baboons.
PURPOSE: Because the platelet membrane receptor glycoprotein IIb/IIIa plays a central role in the recruitment of platelets into forming thrombus, therapeutic inhibition of this receptor complex may be particularly useful to prevent thrombosis after small vessel arterial manipulation. METHODS: The relative hemostatic safety and antithrombotic efficacy for thrombus formation at sites of endarterectomy and implanted prosthetic vascular graft of a murine monoclonal antibody (LJ-CP8) against platelet glycoprotein IIb/IIIa have been determined in baboons after bolus injections in doses (10 mg/kg) that block platelet receptor function for fibrinogen and other adhesive glycoproteins (absent platelet aggregation and bleeding times > 30 minutes without affecting circulating platelet counts). RESULTS: Thrombus formation was eliminated by LJ-CP8 at sites of surgical endarterectomy in fresh segments of homologous aorta incorporated into chronic exteriorized arteriovenous femoral shunts (accumulation of indium 111-labeled platelets fell from 4.40 +/- 0.89 x 10(9) platelets/cm in control animals [n = 6] to 0.23 +/- 0.01 x 10(9) platelets/cm in treated animals [n = 4]; p < 0.005). The formation of thrombus was also abolished by LJ-CP8 at sites of 1 cm prosthetic vascular grafts (4 mm inner diameter polytetrafluoroethylene grafts) interposed into common carotid arteries (deposition of indium 111-labeled platelets decreased from 2.57 +/- 0.43 x 10(9) platelets/cm [n = 5] to 0.16 +/- 0.06 x 10(9) platelets/cm, [n = 4]; p = 0.004). However, LJ-CP8 injections produced substantial bleeding in the surgical wound during the first few hours after operation. Thirty days after operation all four graft implants were patent in JJ-CP8-treated animals compared with two of five in control animals (p = 0.06). CONCLUSIONS: We conclude that profound inhibition of platelet glycoprotein IIb/IIIa receptor function by single bolus injection of LJ-CP8 monoclonal antibody transiently abolishes platelet hemostatic function, eliminates acute thrombus formation at sites of endarterectomy and prosthetic vascular graft implants, and may improve vascular patency.
Animals↗
Exteriorized chronic aorto-caval arteriovenous access shunts in the baboon (Papio cynocephalus).
A chronic arteriovenous (AV) blood access shunt has been developed in baboons. It is composed of silicone rubber tubing extensions bonded to vascular graft polytetrafluoroethylene (ePTFE) cuffs, for creating anastomoses with the distal aorta and inferior vena cava. Following surgical implantation, shunts remain patent for months (X = 9 +/- 2.5 months) and provides long-term ex vivo access to non-anticoagulated blood (Mean Blood Flow = 312 +/- 69 mL/min).
Animals↗
Primary aortoduodenal fistula caused by severe atherosclerosis, not by aneurysm.
Primary aortoduodenal fistula is an uncommon cause of massive upper gastrointestinal hemorrhage usually due to pressure erosion of an abdominal aortic aneurysm into the third portion of the duodenum. This report describes a case of a 59-year-old man who died of massive gastrointestinal hemorrhage due to a primary aortoduodenal fistula. This case is unique in that the fistula formed as a result of complex atherosclerotic disease of the abdominal aorta, with adventitial chronic inflammation and foreign body reaction against atheromatous plaque, and not from an aneurysm. We were unable to identify any other reports of aortoduodenal fistulas developing spontaneously in the absence of aneurysmal disease of the aorta.
Aorta, Abdominal↗
Comparison of cardiac morbidity rates between aortic and infrainguinal operations: two-year follow-up. Study of Perioperative Ischemia Research Group.
PURPOSE: We have previously prospectively compared the differences in perioperative cardiac ischemic events in 140 patients undergoing major abdominal (n = 53) versus infrainguinal (n = 87) vascular operations. This study was designed to extend these observations by determining the 2-year cardiac prognosis of patients at high risk undergoing abdominal aortic versus infrainguinal vascular operations. METHODS: Data included historical, clinical, and laboratory data collected during the in-hospital period, and at 6 months, 1 year, and 2 years after surgery. This information was collected independently of the usual clinical care visits. Data were analyzed with Cox's proportional hazards model. RESULTS: There were 11 in-hospital deaths overall (five [9%] aortic; six [7%]) infrainguinal). 628 days (median 726 days). Fifteen patients (12%) had fatal myocardial infarctions, two (4%) of which occurred in patients who underwent aortic procedures and 13 (16%) of which occurred in patients who underwent infrainguinal operations. Nonfatal myocardial infarctions befell one (2%) patient undergoing aortic surgery and four (5%) patients undergoing infrainguinal surgery. One (2%) patient undergoing aortic surgery and three (4%) patients undergoing infrainguinal surgery were admitted to the hospital with unstable angina during the follow-up period. In all, adverse cardiac outcomes occurred in 20 of 81 (25%) patients who had infrainguinal procedures compared with four of 48 (8%) patients who had aortic operations (p = 0.04). Multivariate analysis showed that a history of diabetes (p = 0.001) and definite coronary artery disease (p = 0.01) are independently associated with adverse outcomes after both types of peripheral vascular operations. CONCLUSIONS: The incidence of long-term adverse cardiac outcomes in patients at high risk undergoing infrainguinal operations is substantially greater than in those undergoing aortic operations, mostly because of a greater prevalence of diabetes, and definite coronary artery disease in the former group.
Aged↗
Influence of aspirin in the management of asymptomatic carotid artery stenosis. VA Cooperative Study Group on Asymptomatic Carotid Stenosis.
PURPOSE: Aspirin therapy is recommended commonly for symptomatic extracranial carotid artery occlusive disease. However, its role in the management of asymptomatic carotid artery stenosis has not been reported previously. METHODS: In 11 clinical centers during the period 1983 to 1991, 444 adult male patients with significant asymptomatic carotid artery stenosis (> or = 50% arteriographically) were randomized to receive optimal medical management including aspirin plus carotid endarterectomy (n = 211) or optimal medical management alone (n = 233). At the conclusion of the study (mean follow-up time 47.9 months), at the time of a patient's death, or at occurrence of a neurologic end point, 16% of patients (n = 72) were not taking any aspirin, 51% (n = 226) had been converted to receiving enteric-coated aspirin, and only 33% (n = 146) were taking plain aspirin (27% at reduced dosage). Among patients from the medical group, 37 (16%) of 233 were not taking any aspirin and formed the basis for this retrospective analysis of the group for which no control population was available. RESULTS: Mortality rates in this group were not significantly different for patients not taking aspirin as compared with the rates for those taking aspirin, although patients not taking aspirin had a higher incidence of myocardial infarction (27%) as compared with patients taking aspirin (8%), p < 0.05. The incidence of ipsilateral neurologic events for patients not taking aspirin as compared with that for patients who were taking aspirin, respectively, was as follows: stroke, 13.5% and 8.7%, p > 0.05; stroke and transient ischemic attack, 37.8% and 17.3%, p < 0.05. No significant differences were observed in stroke severity scores for patients taking or not taking aspirin. CONCLUSION: These data suggest that patients with significant asymptomatic carotid artery stenosis who are intolerant of aspirin have a higher incidence of neurologic events than those patients able to tolerate the drug.
Aspirin↗
Adverse effects of aspirin in the treatment of asymptomatic carotid artery stenosis. The VA Cooperative Asymptomatic Carotid Artery Stenosis Study Group.
We prospectively analyzed adverse effects of aspirin in a multicentered cooperative study undertaken to determine the role of endarterectomy in the treatment of asymptomatic carotid artery stenosis. Persons with active peptic ulcer disease or known intolerance to aspirin were excluded from the study. Patients initially received 650 mg aspirin twice daily. After a 54-month recruitment period, 444 patients in 11 centers were followed up for as many as 8 years (mean 47.9 +/- 27.9 months). Patients intolerant to 650 mg aspirin twice daily could be switched to enteric-coated aspirin or "low-dose" aspirin (80 to 325 mg daily). At the conclusion of the study, we performed a cross-sectional analysis of aspirin usage and complications. Overall, there were 757 episodes reported wherein adjustments in study medications were made, including cessation and change in formulation or dosage. At the conclusion of the study, at the time of death, or at occurrence of a neurologic end point, 16% of patients were off medication entirely, 51% had been converted to enteric-coated aspirin, and only 33% were taking regular aspirin with 27% of those having been placed on a reduced dosage. Adverse reactions were ascertained from 4954 patient visit records. In all there were a total of 837 adverse reactions reported, or one in every 5.9 visits. The most frequently reported reaction was heartburn or stomach pain for which 372 episodes were reported in 184 (42%) patients. Nausea or vomiting occurred on 79 occasions in 58 patients, and bloody stools were reported 52 times in 41 patients. We conclude that high-dose aspirin therapy for asymptomatic carotid artery stenosis is poorly tolerated and that adverse reactions even to low-dose enteric-coated aspirin are common even in patients screened for aspirin intolerance.
Aged↗
Magnetic resonance angiography of the carotid artery combining two- and three-dimensional acquisitions.
To assess the agreement between magnetic resonance angiography and conventional angiography in the evaluation of carotid stenosis, 61 carotid arteries of 40 patients were studied by combined two- and three-dimensional magnetic resonance angiography and conventional angiography. Stenosis of the internal carotid artery was categorized as mild, moderate, severe, critical, or complete occlusion. In 42 arteries, the degree of stenosis according to magnetic resonance angiography correlated exactly to that found by conventional angiography. In the remaining 19 carotid arteries, the magnetic resonance angiographic measurement of stenosis differed from the conventional angiographic measurement by only one size category. The Spearman rank correlation coefficient was 0.95 (p < 0.001). This study showed that by combining information from two- and three-dimensional magnetic resonance angiographic studies and making use of the advantages of each method, magnetic resonance angiography was comparable to conventional angiography in determining carotid stenosis. Magnetic resonance angiography tended to demonstrate a higher level of stenosis when there was a discrepancy. These data demonstrate that magnetic resonance angiography is a steadily improving technology. Although additional studies need to be done, it seems clear that magnetic resonance angiography will be an imaging modality comparable in accuracy to conventional angiography.
Aged↗
Antihemostatic and antithrombotic effects of monoclonal antibodies against von Willebrand factor in nonhuman primates.
BACKGROUND: Because the adhesive glycoprotein von Willebrand Factor (vWF) mediates initial platelet attachment at sites of vascular injury and may also contribute to shear-dependent platelet thrombus formation, we have determined in vivo the relative antithrombotic efficacy and hemostatic safety of infusing murine monoclonal antibodies against vWF. METHODS: In baboons with chronic arteriovenous shunts, thrombus formation was initiated by interposition of thrombogenic Dacron vascular grafts (VG) and endarterectomized baboon aortic segments (EAS). Thrombus formation on VG and EAS was assessed by use of real-time scintillation camera imaging of indium 111-labeled platelet deposition. In control and treated animals (anti-vWF antibody) platelet hemostatic competence was evaluated by means of serial measurements of platelet count, bleeding time, and ex vivo platelet aggregation in response to adenosine diphosphate and ristocetin. RESULTS: Although bolus antibody infusions did not affect circulating platelet counts, bleeding times were immediately prolonged to 28 +/- 4 minutes (vs 4.7 +/- 0.4 minutes before treatment, p = 0.01). Bleeding times normalized within 24 hours after antibody administration. Platelet aggregation in response to adenosine diphosphate was unchanged by antibody therapy, whereas ristocetin-induced platelet aggregation was abolished acutely and remained impaired for 24 hours. Platelet deposition on VG after 60 minutes of exposure to flowing blood was 2.95 +/- 0.74 x 10(9) platelets/cm in six control animals as compared to 1.86 +/- 0.16 x 10(9) platelets/cm in five treated animals (p = 0.04). Similarly, platelet deposition on EAS averaged 4.40 +/- 0.89 x 10(9) platelets/cm in control studies and was reduced significantly by antibody therapy (1.52 +/- 0.50 x 10(9) platelets/cm, p = 0.02). CONCLUSIONS: Despite profound interruption of platelet hemostatic functions, therapeutic targeting of vWF modestly inhibits platelet-dependent thrombosis.
Animals↗
Combined carotid endarterectomy and coronary artery revascularization: a sobering review.
The clinical outcome of 99 patients who underwent combined single-stage carotid thromboendarterectomy and coronary artery bypass grafts in three different hospitals over a 15-year period was analyzed. Coronary revascularization was elective in 16 patients, urgent in 46 and emergent in 37 patients. Asymptomatic carotid artery stenosis of greater than or equal to 80% was detected in 79% of patients. Sequential reconstruction of the carotid artery circulation followed by restoration of the coronary circulation was performed in all patients by two separate surgical teams. The population included 79 men and 20 women, with a mean age of 67 +/- 6 years, of whom 53% had a previous myocardial infarction, 59% had hypertension and 49% had a history of smoking. Three or more coronary arteries were revascularized in 90% of patients. The overall major neurological complication rate was 25%, with an 11% stroke rate ipsilateral to the operated carotid. Other major complications included respiratory failure (5%), multisystem failure (8%), and myocardial infarction (8%). The overall mortality was 12%. Ten of the 12 deaths were directly related to the cardiac operation, and 2 died as a result of stroke. We conclude that a combined carotid and coronary artery operation results in a high morbidity and mortality in institutions with excellent records for each operation when performed separately. Whenever possible, these high risk patients should be carefully assessed regarding the need for both procedures, since prophylactic carotid endarterectomy has not been shown to significantly reduce the neurologic risk of coronary bypass.
Aged↗
Comparison of cardiac morbidity between aortic and infrainguinal operations. Study of Perioperative Ischemia (SPI) Research Group.
We prospectively compared the differences in perioperative cardiac ischemic events in 140 patients undergoing major abdominal (n = 53) versus infrainguinal (n = 87) vascular operations. Preoperative dipyridamole thallium cardiac scintigraphy was performed in a subset of 38 of these patients, with treating physicians blinded to the test results. Myocardial ischemia was measured during operation with use of continuous 12-lead electrocardiography (ECG) and transesophageal echocardiography. Continuous two-lead ambulatory ECG (Holter monitoring) was performed before, during, and after operation for 4 days. Outcome events were cardiac death, nonfatal myocardial infarction, unstable angina, ventricular tachycardia, and congestive heart failure. Results of the study indicated that most demographic variables, such as age, hypertension, cigarette smoking, serum cholesterol, were comparable between patients having aortic or infrainguinal arterial operations. However, in the infrainguinal group more patients had diabetes, second vascular operations, angina pectoris, heart failure, dysrhythmias, and used digitalis. Abnormalities in preoperative Holter monitoring, ECGs, and thallium scan abnormalities were equivalent between groups. During operation, whereas Holter and ECG abnormalities were comparable, more patients undergoing aortic procedures suffered ischemia as determined by transesophageal echocardiography (26% vs 10%, p = 0.019). After operation there were 21 (24%) outcome events in patients having infrainguinal bypasses compared with 15 (28%) patients having aortic procedures (p = NS). Ischemia by Holter monitoring (n = 133) occurred after operation in 46 (57%) patients having infrainguinal operations compared with 16 (31%) patients having aortic reconstructions (p = 0.005). Because preoperative cardiac disease and adverse cardiac outcomes occurred with similar or even greater frequency in both groups of patients, we conclude that the risk for postoperative cardiac ischemic events in lower extremity vascular operations is at least as great as for aortic operations.
Aged↗
Perioperative myocardial ischemia in patients undergoing noncardiac surgery--I: Incidence and severity during the 4 day perioperative period. The Study of Perioperative Ischemia (SPI) Research Group.
To determine the incidence and characteristics of perioperative myocardial ischemia, the electrocardiographic (ECG) changes consistent with ischemia during the 4 day perioperative period were documented and characterized in 100 patients with or at risk for coronary artery disease undergoing noncardiac surgery. Using continuous two channel ECG monitoring (leads CC5 and CM5), the frequency and severity of ECG ischemic episodes defined by ST segment depression greater than or equal to 1 mm or elevation greater than or equal to 2 mm during the preoperative (up to 2 days), intraoperative and early postoperative (first 2 days) periods were compared. Preoperatively, 28 patients (28%) exhibited 105 episodes of ischemia; intraoperatively, 27 patients exhibited 39 episodes and postoperatively, 42 patients exhibited 187 episodes. There was no difference between the pre- and intraoperative episode characteristics. However, postoperative ischemic episodes were the most severe. The mean ST change was 1.5, 2 and 2.6 mm for pre-, intra- and postoperative episodes, respectively (p less than 0.0001 postoperative versus pre- or intraoperative); duration of ischemic episodes was 69, 45 and 207 min, respectively (p less than 0.005 postoperative versus preoperative, p less than 0.001 versus intraoperative) and area under the ST curve was 88, 74 and 383 mm.min (p less than 0.009 postoperative versus preoperative, p less than 0.005 versus intraoperative). Ninety-four percent of all postoperative ischemic episodes were silent; 80% of all episodes occurred without acute change (+/- 20% of control) in heart rate and 77% of intraoperative episodes occurred without acute change in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Simultaneous resection of renal carcinoma and abdominal aortic aneurysm.
A 62-year-old man with a 6.5 cm abdominal aortic aneurysm and coexistent left renal cell carcinoma was treated by simultaneous radical left nephrectomy and abdominal aortic aneurysm repair. Care was taken to avoid potential infection of the bypass graft by inadvertent contamination with urine. Pathologic examination of the left kidney revealed a renal cell carcinoma, clear cell type, with no evidence of invasion into the renal vein or lymph node metastases. The patient had an uncomplicated recovery and is well and free of disease four years after operation. In cases of equivalently life threatening surgical diseases, simultaneous resection is warranted.
Aorta, Abdominal↗
The peripheral vascular consequences of smoking.
Cigarette smoking is associated with an increased risk and extent of advanced atherosclerotic vascular disease in peripheral as well as coronary arteries. The likelihood of claudication, amputation, stroke, abdominal aortic aneurysm, and failure of vascular reconstruction is higher in smokers than nonsmokers. Smoking exerts its deleterious effects through many interactive mechanisms. Nicotine and carbon monoxide produce acute cardiovascular consequences, including altered myocardial performance, tachycardia, hypertension, and vasoconstriction. Smoking injures blood vessel walls by damaging endothelial cells, thus increasing permeability to lipids and other blood components. Among metabolic and biochemical changes induced by smoking are elevated plasma, free fatty acids, elevated vasopressin, and a thrombogenic balance of prostacyclin and thromboxane A2. Chronic smoking is associated with a tendency for increased serum cholesterol, reduced high density lipoprotein, and other lipid effects that contribute to atherosclerosis. In addition to rheologic and hematologic changes from increased erythrocytes, leukocytes, and fibrinogen, smokers have alterations in platelet aggregation and survival that produce thrombosis. Considering the ubiquitous repercussions of this menace, vascular surgeons should play an active role in motivating their patients to quit smoking.
Cardiovascular Diseases↗