Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans.

BACKGROUND: We conducted a double-blind, randomized, crossover study to assess the antithrombotic effects of the combination of aspirin (acetylsalicylic acid, ASA) and clopidogrel, with or without a loading dose, versus ASA alone in a model of arterial thrombosis in humans. METHODS AND RESULTS: Eighteen male volunteers received the following 3 regimens for 10 days separated by a 1-month period: (1) 325 mg ASA daily, (2) 325 mg ASA+75 mg clopidogrel daily, (3) 325 mg ASA daily+300-mg clopidogrel loading dose on day 1 and +75 mg clopidogrel per day on days 2 to 10. The antithrombotic effect was measured 1.5, 6, and 24 hours after drug intake on day 1 and 6 hours after drug intake on day 10. Arterial thrombus formation was induced ex vivo by exposing a collagen-coated coverslip in a parallel-plate perfusion chamber to native blood for 3 minutes at an arterial wall shear rate. Without a loading dose, clopidogrel+ASA developed an antithrombotic effect within 6 hours after the first intake. It was superior to that produced by ASA, but it was moderate (P

A new method for quantifying platelet deposition in flowing native blood in an ex vivo model of human thrombogenesis.

No quantitative, simple and non-radioactive method has been described for measuring the platelet content of experimental thrombi. The aim of the present study was to develop a simple method for quantifying platelets in thrombi formed on thrombogenic surfaces in flowing native human blood. To test the relevance of this new method, the effect of unfractionated heparin on arterial thrombus formation was investigated. Tissue factor (TF)- and collagen-coated coverslips were exposed to non-anticoagulated blood at an arterial wall shear rate (2,600 s(-1)) for 1 to 4 min. Platelet deposition was quantified by measuring the P-selectin (PS) and beta-thromboglobulin (betaTG) content of dissolved plasmin-digested thrombi using immunoenzymoassays; fibrin deposition was determined by measuring the D-dimer levels. These results were compared to those established by morphometrical analysis. Morphometric evaluation showed that fibrin deposition was maximum on TF by 1 min perfusion time. Platelets deposited subsequently and reached a maximum at 3 min. On collagen, platelets deposited directly on the collagen fibrils without detectable fibrin deposit. Platelet deposition increased from 1 to 4 min. Platelet deposition quantified by PS was correlated to the values obtained by morphometry (r = 0.72, r = 0.67, p <0.001, on TF and collagen, respectively). As compared to PS, betaTG measurements gave an underestimation of the size of the thrombus platelet number. Unfractionated heparin infused through a mixing device proximal to the perfusion chamber to obtain plasma concentrations of 0.5, 1 and 3 IU/ml, reduced fibrin deposition on TF-coated coverslips in a dose-dependent manner (77% reduction at 3 IU/ml, p <0.01), but had no significant effect on platelet deposition (33% at 3 IU/ml, p >0.05). In contrast, heparin had no effect on fibrin or platelet deposition on collagen-coated coverslips. Thus, a new quantitative and simple method for measuring platelet deposition in flowing blood has been developed and characterized. Utilizing this system, we have demonstrated that unfractionated heparin did not inhibit arterial thrombus formation either on procoagulant or on proaggregant surface.

Laparoscopic appendicectomy: case reports of vascular injury in 2 children.

The authors report 2 similar cases of serious vascular injury occurring during laparoscopic appendicectomy. These cases stress the potential risk of major accidents with laparoscopic surgery. There should be great care in the choice of indications and during the procedures.

[Percutaneous transluminal endarterectomy of femoro-popliteal atheromatous lesions. Technique. Indications. Results after 6 months]. / Athérectomie transluminale percutanée des lésions athéromateuses fémoro-poplitéees. Technique. Indications. Résultats à 6 mois.

Percutaneous atherectomy was performed in 25 patients with 30 symptomatic femoro-popliteal stenosis. INITIAL RESULTS: 23 patients were successfully treated with disappearance of claudication and a mean 0.35 increase in the ankle-arm-index. Two early thrombosis occurred. Angiographic analysis: residual stenosis lower than 30% in 25 lesions; no dissection or embolization; effective treatment of eccentered and calcified lesions; no significant dissection after additional angioplasty. RESULTS AT 6 MONTHS FOLLOW-UP: (17 patients, 19 lesions): stable improvement in 14 patients; 2 restenosis; 1 new disease. Atherectomy restores a large lumen with minimal wall trauma, thus perhaps decreasing the restenosis rate.

[Cerebral blood volume, endarterectomy and SPECT]. / Volume sanguin cérébral, endartérectomie et SPECT.

Cerebral blood flow and cerebral blood volume were measured and quantified using single photon emission computed tomography before and after unilateral endarterectomy in 3 patients with bilateral severe lesions of the internal carotid artery. These parameters were measured using an intravenous injection of 133 Xenon and 99m Technetium respectively. Before endarterectomy cerebral blood volume was high in all patients suggesting a focal vasodilatation in response to a reduced cerebral perfusion pressure. After endarterectomy a decrease of cerebral blood volume and an increase of cerebral blood flow were observed. These preliminary results confirm that the hemodynamic adaptative mechanisms secondary to carotid occlusion are reversible when the stenosis is removed and demonstrate that these changes can be accurately measured using single photon emission computed tomography. Positron emission tomography was previously considered to be the only method able to quantify cerebral blood volume in man. Single photon emission computed tomography can also be considered a reliable technique to measure both cerebral blood flow and cerebral blood volume. This technique can then be used to assess individual cerebral vascular adaptative states and to evaluate the influence of cerebral hemodynamic changes on stroke occurrence in large longitudinal studies.

[Management of visceral artery aneurysms. Retrospective study of 23 cases]. / Prise en charge des anévrismes des artères digestives. Etude rétrospective de 23 cas.

STUDY AIM: To evaluate symptoms and results of the treatment of aneurysms of digestive arteries. PATIENTS AND METHOD: Retrospective study of 23 patients (14 male and 9 female, mean age = 51 years) treated in two departments of academic hospital. We studied the aneurysms characteristics (location, number, size, etiology) the type of treatment, and occurrence of post-operative complications. RESULTS: The aneurysms involved the splenic artery in 13 patients (56%), the superior mesenteric artery in 5 patients (22%), the hepatic artery in 3 patients (13%), the gastroepiploic artery in 2 patients (9%). There were thirty-one aneurysms (24 true aneurysms and 7 pseudo-aneurysms) in 23 patients. Diagnosis was mainly done by the CT-scan. An aneurysm rupture occurred in 7 patients (30%). Treatment was surgery for 26 aneurysms (84%) or a radiological embolization in 3; abstention was decided for 2 aneurysms (6%). No death was observed. CONCLUSION: The bad prognosis after rupture, the lack of predictive factors of rupture combined with the good results of surgical treatment suggest to prefer a surgical treatment at first. Embolization could be reserved for the contra-indication of surgery and when aneurysms are poorly accessible to surgery.

Total laparoscopic aortic repair for occlusive and aneurysmal disease: first 95 cases.

OBJECTIVES: To analyze the outcome of our preliminary experience with total laparoscopic aortic repair in patients with occlusive or aneurysmal disease. MATERIAL AND METHODS: From September 2002 to April 2005, we performed 95 consecutive total laparoscopic aortic repair procedures including 72 for aortic occlusive disease (group A) and 23 for abdominal aortic aneurysm (group B). RESULTS: In group A, mean operating time was 216+/-50 min with a mean clamp time of 57+/-21 min and surgical conversion was required in two cases (2.7%). No postoperative death occurred but there were three postoperative complications necessitating re-intervention (retroperitoneal hematoma, embolic ischemia, and early prosthetic infection). Mean duration of hospitalization was 8 days (range, 5-42 days). All grafts were patent at 2 months. In group B, mean operating time was 251+/-57 min with a mean clamp time of 101+/-15 min and surgical conversion was required in seven cases (30%). There was one postoperative death (4.3%) due to pulmonary embolism and one non-fatal complication (retroperitoneal hematoma). Mean duration of hospitalization was 6.4 days (range, 4-12 days). All grafts were patent at 2 months. CONCLUSION: Total laparoscopic repair is feasible and safe for occlusive and aneurysmal aortic disease. Operators must acquire technical skills using simulators.

[Axillary-subclavian venous thrombosis. Therapeutic management]. / Thromboses veineuses axillo-sous-clavières. Conduite thérapeutique.

24 cases of axillary-subclavian venous thrombosis were studied according to the etiology: "intrinsic" thrombosis secondary to alteration of the endothelium (7 cases), "extrinsic" thrombosis secondary to compression at the level of the thoracic outlet (4 cases), "combined" thrombosis following a complex treatment of breast cancer (3 cases). The frequency of these thromboses, undoubtedly underestimated, seems low as compared to that of venous thromboses of the lower extremities. The frequency of pulmonary emboli is 8%. The treatment is limited to anticoagulants in case of intrinsic or combined thrombosis. In the third type, decompressive surgery is necessary, especially if there are abnormalities of the cervico-dorsal junction or associated neurological or arterial disorders.

[Retroperitoneal tumors and surgery of the great vessels]. / Tumeurs de siège rétro-péritonéal et chirurgie des gros vaisseaux.

The great vessels have long been considered as the limiting point for exeresis of abdominal tumors. We report eleven retroperitoneal tumors which led to more or less extensive vascular involvement. There were two benign tumors (neurofibroma, angiolymphoid tumor), 6 primary malignant tumors (liposarcoma, schwannosarcoma, corticoadrenal carcinoma, leiomyosarcoma of the inferior vena cava, leiomyosarcoma of the aorta, hemangiopericytoma) and 3 secondary malignant tumors (melanosarcoma, papillary cystadenocarcinoma, malignant germ cell tumor). Vascular surgery included mobilisation of the aorta or vena cava or total replacement with a prosthesis. There were no major complications and organ resection was limited to that required by tumor invasion. Despite a macroscopically satisfactory resection slice in all cases, local recurrence of malignant tumors was the rule leading to short term mortality (mean survival 30 months for primary sarcomas and 35 days for secondary forms). The therapeutic decision after careful CT and MRI word-up requires a discussion between the radiology, surgery and oncology teams. When the great vessels are involved, advice from a vascular surgeon should be acquired.

Nosocomial infection surveillance in a vascular surgery unit.

An epidemiological nosocomial infection surveillance program was conducted in the Vascular Surgery Unit of Purpan University Hospital, Toulouse, France, involving 389 patients hospitalized between June 1 and November 30, 1988. The methodology and inclusion criteria used were those of the Centers for Disease Control of Atlanta. Twenty-six patients had 30 nosocomial infections according to these criteria, a prevalence of 6.7% and an incidence of 5.6%. These patients were hospitalized for 485 of a total of 4317 days; bed occupation due to infection was 11.23%. Of the 30 infections, the most common were 13 (43.5%) urinary tract infections and six (20%) operative wound infections. E. coli (8 isolates) and Staphylococcus aureus (7 isolates) were the most frequently encountered offending microorganisms. A case-control study showed that mean hospitalization time was increased by 11 days (p less than 0.001) in infected patients and that antibiotics were used four times as often in these patients (p less than 0.001). Urinary tract infection represented 50% of nosocomial infections in our study. The prevalence and incidence of wound infection was 20% and 8%, respectively. Nosocomial infection always occurred in patients already infected or who were debilitated. Nosocomial infections prolonged hospitalization by 57%.

Antithrombotic efficacy of the vitamin K antagonist fluindione in a human Ex vivo model of arterial thrombosis : effect of anticoagulation level and combination therapy with aspirin.

Thrombin is a main mediator of arterial thrombus formation, and its inhibition is an important antithrombotic strategy. However, the place of vitamin K antagonists among the different therapeutic strategies for preventing arterial thrombus formation is still debated. We studied the antithrombotic efficacy of the vitamin K antagonist fluindione in a human ex vivo model of arterial thrombosis and determined whether aspirin enhances fluindione efficacy. Ten healthy male volunteers were randomly assigned to receive fluindione, alone or in combination with aspirin (325 mg/d). Fluindione was given at increasing doses to give a stable international normalized ratio (INR) between 1.5 and 2.0 and between 2.1 and 3.0. We induced arterial thrombus formation ex vivo by exposing collagen- or tissue factor (TF)-coated coverslips in a parallel-plate perfusion chamber to native blood for 3 minutes at an arterial wall shear rate of 2600 s(-1). Platelet and fibrin deposition were measured by immunoenzymatic methods. Fluindione inhibited thrombus formation on TF-coated coverslips in a dose-dependent manner by 50% and 80% at INR 1.5 to 2.0 and INR 2.1 to 3.0, respectively (P<0.05). Fluindione in combination with aspirin inhibited TF-induced thrombus formation in a comparable manner. Collagen-induced thrombus formation was not reduced in subjects treated by fluindione. It was reduced by 50% to 60% in those treated with fluindione plus aspirin, regardless of the level of anticoagulation (P<0.05). Thus, the effectiveness of fluindione for preventing arterial thrombosis is dependent on the nature of the thrombogenic trigger. Fluindione is very effective in preventing TF- but not collagen-triggered thrombus formation. Aspirin enhances the antithrombotic effectiveness of fluindione, because combined treatment interrupts both TF- and collagen-induced thrombus formation.

Comparison of the antithrombotic effect of PEG-hirudin and heparin in a human ex vivo model of arterial thrombosis.

Polyethylene glycol (PEG)-hirudin is a derivative of hirudin with a long plasma half-life. We have compared the efficacy of PEG-hirudin with unfractionated heparin (UH) in preventing arterial thrombosis. Arterial thrombus formation was induced ex vivo in 12 healthy human volunteers by exposing a tissue factor-coated coverslip positioned in a parallel-plate perfusion chamber to flowing nonanticoagulated human blood drawn directly from an antecubital vein at an arterial wall shear rate of 2600 s-1 for 3.5 minutes. PEG-hirudin, UH, or saline (as control) were administered ex vivo through a heparin-coated mixing device positioned proximal to the perfusion chamber. Platelet and fibrin deposition was quantified by immunoenzymatic measure of the P-selectin and D-dimer content of dissolved plasmin-digested thrombi, respectively. UH was administered to a plasma concentration of 0.35 IU/mL. This concentration prolonged the activated partial thromboplastin time from 32+/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent platelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 microg/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 seconds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 microg/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required to significantly prevent fibrin deposition (0.5 microg/mL) corresponded to a much shorter prolongation of activated partial thromboplastin time (48+/-2 seconds) than that needed for UH (79+/-4 seconds). Thus, our results are compatible with the view that thrombin is greatly involved in recruitment of platelets in evolving thrombi, and that PEG-hirudin is an effective agent for preventing arterial thrombosis in a human ex vivo experimental model.

Nonfractionated heparin fails to inhibit arterial thrombosis in a human ex vivo thrombosis model.

The effect of nonfractionated heparin on the formation and composition of arterial thrombus is unclear. The purpose of this study in a human ex vivo model was to analyze fibrinoplatelet thrombi and test the inhibitory effect of nonfractionated heparin on arterial thrombus formation. Experiments were carried out in Sakariassen perfusion chambers. Strips coated with either tissue factor (TF) or collagen were exposed to human blood collected from healthy volunteers at an arterial shear stress rate of 2600 s-1 for 1 to 4 min. Platelet deposition was determined using immunoenzymatic techniques to quantify P-selectine, a platelet membrane receptor, in thrombi. Fibrin deposition was determined by quantifying fibrin degradation products released after application of plasmin (D-dimers). Heparin was injected into the blood flow through a blender port system located between the venous puncture site and perfusion chamber. The results of the study showed that in a human ex vivo model, formation of arterial thrombus on two thrombogenic surfaces (tissue factor and collagen) is not inhibited by nonfractionated heparin.

The thrombomodulin/protein C/protein S anticoagulant pathway modulates the thrombogenic properties of the normal resting and stimulated endothelium.

We investigated the role of the thrombomodulin (TM/protein C/protein S anticoagulant pathway in modulating the thrombogenic properties of the endothelium. Endothelial cells (ECs) were placed in parallel-plate flow chambers and exposed to nonanticoagulated human blood at a venous wall shear rate (50 s-1). Fibrin deposition on resting ECs treated with a control IgG1 was negligible. In contrast, a significant amount of fibrin deposited when TM expression was specifically suppressed by > 95% by preincubating ECs with an anti-TM IgG1. Similarly, fibrin deposited on interleukin 1-stimulated ECs, but the fibrin deposition was further increased threefold with anti-TM IgG1. Comparable results were found when ECs were perfused at 650 s-1. When TM surface activity was enhanced by 150% by treating ECs with active phorbol ester (4-phorbol 12-myristate 13-acetate; PMA), the deposition of fibrin was 30% lower than on ECs not pretreated with PMA. Finally, fibrin deposition on stimulated ECs was significantly higher in 11 untreated patients with well-characterized deficiencies of protein C or S or heterozygous factor V Leiden mutation than in 11 healthy individuals, and it was significantly correlated to basal plasma levels of thrombin-antithrombin complexes. Thus, this study underlines the central role of the TM/protein C/protein S pathway in modulating the thrombogenic status of resting and stimulated ECs and indicates that basal coagulation system markers may be helpful in monitoring patients presenting a disorder of this anticoagulant pathway.

A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans.

No randomized study comparing the effect of combined ticlopidine and aspirin therapy versus each drug alone in reducing poststenting thrombotic complications has been performed. To compare these three antiplatelet regimens versus placebo, we conducted a double-blind randomized study using an ex vivo model of thrombosis. Sixteen healthy male volunteers were assigned to receive for 8 days the following four regimens separated by a 1-month period: aspirin 325 mg/d, ticlopidine 500 mg/d, aspirin 325 mg/d + ticlopidine 500 mg/d, and placebo. At the end of each treatment period, native nonanticoagulated blood was drawn directly from an antecubital vein over collagen- or tissue factor (TF)-coated coverslips positioned in a parallel-plate perfusion chamber at an arterial wall shear rate (2, 600 s-1 ) for 3 minutes. Thrombus, which formed on collagen in volunteers treated by placebo, were rich in platelets and poor in fibrin. As compared with placebo, aspirin and ticlopidine alone reduced platelet thrombus formation by only 29% and 15%, respectively (P > .2). In contrast, platelet thrombus formation was blocked by more than 90% in volunteers treated by aspirin + ticlopidine (P < .01 v placebo or each treatment alone). Furthermore, the effect of the drug combination therapy was significantly larger than the sum of the two active treatments (P < .05). Thrombus, which formed on TF-coated coverslips in volunteers treated by placebo, were rich in fibrin and platelets. Neither of the three antiplatelet treatments significantly inhibited fibrin deposition and platelet thrombus formation on this surface (P > .2). Thus, the present study shows that combined aspirin and ticlopidine therapy dramatically potentiates the antithrombotic effect of each drug alone, but that the antithrombotic effect of the combined treatment depends on the nature of the thrombogenic surface.

[Percutaneous transluminal atherectomy of the femoropopliteal arteries. Technic, indications, results after 6 months]. / Athérectomie transluminale percutanée des artères fémoro-poplitées. Technique, indications, résultats à six mois.

Percutaneous atherectomy was performed in 25 patients with 30 symptomatic femoro-popliteal stenoses. Twenty-three patients were successfully treated with resolution of claudication and a mean 0.35 increase in the ankle-arm-index. Two early thromboses occurred. Residual stenosis was less-than 30% in 25 lesions, with no dissection, and no embolization. Atherectomy seems to be an effective treatment for eccentric and calcified lesions. At 6 months follow-up (17 patients, 19 lesions) clinical and Doppler improvement remained stable in 14 patients; 2 restenosis and 1 new disease occurred. Atherectomy restores a large lumen with minimal wall trauma, thereby possibly decreasing the restenosis rate.