Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Passive transient transfer of peanut allergy by liver transplantation.

We report a case of transient symptomatic transferred IgE-mediated peanut allergy after elective blood-group compatible liver transplantation. We show that the allergy was transient and therefore passive, authorizing further uneventful peanut consumption. Skin tests with commercial peanut extract and native peanut were performed in the recipient. Circulating specific IgE against peanut and recombinant peanut allergens (rArah1, rArah2, rArah3) was measured in stored serum samples collected from the recipient between 6 months before and 8 months after liver transplantation. Specific IgE levels in the donor were measured at the time of multiorgan donation. In the recipient, diagnosis of IgE-mediated peanut anaphylaxis was based on the clinical history and detection of specific IgE against peanut and recombinant major peanut allergens (rArah1, rArah2 and rArah3). Skin tests were negative and specific IgE undetectable 6 months after the clinical reaction. Oral peanut challenge was negative excluding persistent peanut allergy. This case confirms that IgE-mediated peanut allergy can be transferred by liver transplantation and shows that it may be transient and therefore passively acquired.

Perioperative management of combined heart-liver transplantation in patients with cirrhosis, renal insufficiency, or pulmonary hypertension.

UNLABELLED: STATING THE MAIN PROBLEM: Only few reports have detailed perioperative management and outcome of combined heart and liver transplantation (CHLT), and none describe the long-term renal function. METHODS: Three patients presented clinical signs of cardiomyopathy with reduced ejection fraction and proven cirrhosis with evidence of portal hypertension. Two of them presented renal failure, and the other pulmonary hypertension. After cardiac transplantation and closure of the sternum, liver transplantation was performed using systematically venovenous double-limb (portal and caval) bypass. RESULTS: Mean cold ischemic time for heart and liver was 2 h 46 min and 12 h 47 min, respectively. Intraoperative hemodynamics remained grossly stable during surgery. Mean transfusions were 12 red blood cell packs. All three patients received anti-R-Il2 antibodies at post-operative day 1 and 4. Mean plasma creatinine concentration was 90 ± 8 µmol/L one yr post-CHLT, vs 160 ± 62 µmol/L pre-CHLT. All three patients are alive with functional grafts after a mean follow-up of 26 months (12-38). CONCLUSION: CHLT could be performed safely through two consecutive and independent usual procedures. Perioperative hemodynamic stability, minimal blood loss, and routine splanchnic decompression are probably major determinants of a favorable outcome and good long-term renal function.

Preoperative nutrition forseverely malnourished patients in digestive surgery: A retrospective study.

INTRODUCTION: Malnutrition increases postoperative morbidity and mortality. The objective of this study was to evaluate preoperative refeeding in malnourished patients at risk of refeeding syndrome (RS). METHODOLOGY: A retrospective study, conducted between June 2016 and January 2017, reported to the CNIL, compared two groups of malnourished patients: a group of refeeding patients (RP) and a group of non-refeeding patients (NRP). The inclusion criteria were weight loss of more than 10% or albuminemia less than 35g/L and RS risk factor. The primary endpoint was postoperative morbidity. The secondary endpoints were weight change and serum albumin over 6 months. RESULTS: Seventy-three patients (30 RP and 43 NRP) were included. At the time of initial management, median weight loss was 18% [1-71], while albuminemia was 26g/L [13-40] in the RP group and 32.5g/L [32-48] in the NRP group (P=0.01). The overall postoperative morbidity rate was 88% (83% RP versus 90% NRP, P=0.47), and there was no significant difference between the 2 groups. The rate of anastomotic complications was 4% for RP versus 26% for NRP (P=0.03) after exclusion of liver surgery. Medium-term weight loss tended to be greater in RP (P=0.7). Nutritional support was continued until the third postoperative month in 13% of RPs vs. no NRPs (P=0.0002). CONCLUSION: After preoperative renutrition, we did not observe a decrease in morbidity but rather a decrease in the rate of anastomotic complications in favor of the RP group. This study underscores the middle-term importance of nutritional management in view of preserving the benefits of preoperative renutrition.

Functional metabolic characteristics of intact pig livers during prolonged extracorporeal perfusion: potential for a unique biological liver-assist device.

BACKGROUND: The clinical development of liver-support devices based on perfusion of either pig hepatocytes cartridges or whole pig livers has been hampered by the ability to use sufficient liver cell mass to provide adequate metabolic support, limited perfusion times, and the potential for patient exposure to pig zoonotic diseases. METHODS: We designed an original system in which an isolated intact pig liver was perfused extracorporeally under physiological conditions in a closed loop circuit with allogeneic pig blood and constant monitoring of major physiological and functional parameters. The perfusion circuit further included an interface membrane to provide for separation of patient and liver perfusion circulation. RESULTS: Prolonged (6-21 hr) liver perfusion did not produce significant liver damage as reflected by modest rises in the levels of the serum transaminases, stability of main biochemical parameters (including potassium), and the maintenance of normal cellular morphology. Optimal liver function was documented as measured by lactate consumption, control of glycemia, and the results of clotting studies and functional assays. The perfused liver cleared 82% and 79% of peak bilirubin and ammonia concentrations with clearing kinetics identical throughout perfusion. Indocyanine green clearance was identical to that observed in the living donor before explant surgery. CONCLUSIONS: In conclusion, the extracorporeal pig liver perfusion apparatus described here allows optimal pig liver function for prolonged periods of time. The microporous membrane to provide separation of donor organ and recipient and the high level of functional activity suggest that this form of liver metabolic support may have important clinical applications.

[Incidence and prevention of coronary complications after general surgery]. / Incidences et préventions des complications coronaires après chirurgie générale.

The frequency, the nature and physiopathological mechanisms of cardiac complications of general surgical patients are well known. Acute myocardial infarction, the main complication, occurs in 3 to 5% of high risk cases. Though usually subendocardial and asymptomatic, it jeopardizes short and medium term survival of patients. It occurs in the first 48 hours after surgery in the majority of cases, the diagnosis being confirmed by increased serum troponine I levels. The circulatory, mechanical and inflammatory changes and hypercoagulability, which are present during the perioperative period, interact, disturbing the energetic equilibrium of the myocardium and causing episodes of myocardial ischaemia which, if prolonged, result in necrosis of the subendocardial myocardium. These effects must be taken into consideration if the operative risk of coronary patients is to be reduced. It is essential to monitor the haemodynamic parameters which affect myocardial energy consumption both during and after surgery. Particular attention must be paid in the postoperative period which is characterised by metabolic stress and sympathetic hyperreactivity which predispose to prolonged episodes of silent myocardial ischaemia. Betablockers, which effectively prevent per and postoperative ischaemia without causing jeopardy to the haemodynamic status and which reduce the cardiac risk of general surgery have a role to play in the prevention of acute myocardial infarction in the postoperative period when prescribed before surgery and continued by oral administration during the first 6 postoperative days. The alpha-2-agonists affect sympathetic reactivity during and after surgery and are very well tolerated haemodynamically. If the current on-going multicenter trials show that they prevent postoperative cardiovascular complications, they could be prescribed prophylactically in patients at risk.

[Risk factors for mortality in abdominal aortic surgery]. / Facteurs de risque de mortalité après chirurgie de l'aorte abdominale.

OBJECTIVE: To analyse pre and peroperative variables for predicting mortality after abdominal aortic surgery. STUDY DESIGN: Prospective study. PATIENTS: We prospectively included 658 consecutive patients undergoing abdominal aortic surgery from January 1993 to July 1997. METHODS: Age, gender, hypertension, history of myocardial infarction or coronary revascularization, angina pectoris, diabetes, arrhythmia, cardiac insufficiency, serum creatinine > 150 mumol.L-1, beta-blockers therapy, calcium channel inhibitors, angiotensin converting enzyme inhibitors were preoperative analysed variable. Type of aortic disease (anuerysms versus aortic occlusion), duration of surgery, blood loss, type of laparotomy (medium versus lombotomy) were peroperative analysed variables. Haemoglobinemia was monitored during surgery and patients were transfused if haemoglobinaemia < 80 g.L-1. RESULTS: Thirty-three patients died after aortic surgery (5%). In multivariate analysis, angina pectoris (OR = 5.47, P < 0.001), chronic obstructive bronchopulmonary disease (OR = 2.27, P = 0.05) and duration of surgery (OR = 1.60, P < 0.001) were the independent predictive factors of mortality. Age, blood loss were predictive factors only in univariate analysis. CONCLUSION: Angina pectoris and COBP were the two independent preoperative factors of mortality. The duration of surgery was the only peroperative factor. Well monitored blood loss was not a predictive factor.

Does desflurane alter left ventricular function when used to control surgical stimulation during aortic surgery?

BACKGROUND: Although desflurane is commonly used to control surgically induced hypertension, its effects on left ventricular (LV) function have not been investigated in this clinical situation. The purpose of the present study was to evaluate the LV function response to desflurane, when used to control intraoperative hypertension. METHODS: In 50 patients, scheduled for vascular surgery, anesthesia was induced with sufentanil 0.5 microg/kg, midazolam 0.3 mg/kg and atracurium 0.5 mg/kg. After tracheal intubation, anesthesia was maintained with increments of drugs with controlled ventilation (N2O/O2=60/40%) until the start of surgery. A 5 Mhz transesophageal echocardiography (TEE) probe was inserted after intubation. Pulmonary artery catheter and TEE measurements were obtained after induction (to)(control value), at surgical incision (t1) if it was associated with an increase in systolic arterial pressure (SAP) greater than 140 mmHg (hypertension) and after control of hemodynamic parameters by administration of desflurane (return of systolic arterial pressure to within 20% of the control value) (t2) in a fresh gas flow of 31/ min. RESULTS: Sixteen patients developed hypertension at surgical incision. SAP was controlled by desflurane in all 16 patients. Afterload assessed by systemic vascular resistance index (SVRI), end-systolic wall-stress (ESWS) and left-ventricular stroke work index (LVSWI) increased with incision until the hypertension returned to post-induction values with mean end-tidal concentration of 5.1+/-0.7% desflurane. No change in heart rate, cardiac index, mean pulmonary arterial pressure, stroke volume, end-diastolic and end-systolic cross-sectional areas, fractional area change and left ventricular circumferential fiber shortening was noted when desflurane was added to restore blood pressure. CONCLUSION: This study demonstrates that in patients at risk for cardiac morbidity undergoing vascular surgery, desflurane is effective to control intraoperative hypertension without fear of major cardiac depressant effect.

Treating anesthesia-induced hypotension by angiotensin II in patients chronically treated with angiotensin-converting enzyme inhibitors.

UNLABELLED: Although angiotensin II bolus administration may be used to increase blood pressure in patients chronically treated with angiotensin-converting enzyme inhibitors (ACEI) who have severe hypotension on anesthetic induction, no data are available describing its time course and its effects on the left ventricular function. Fourteen patients chronically treated with ACEI for hypertension and scheduled for vascular surgery were prospectively studied. Patients with cardiac insufficiency were excluded. A transesophageal echocardiography probe was inserted to assess systolic left ventricular function. When hypotension was observed (systolic arterial pressure [SAP] <85 mm Hg), an I.V. bolus of 2.5 microg of angiotensin II (AII) was given, and hemodynamic variables were recorded each 30 s over 5.5 min. Results are expressed as mean +/- SEM. Sixty seconds after the AII bolus injection, the SAP increased from 78 +/- 3 to 152 +/- 6 mm Hg. SAP remained higher than control until the 5th min. This was associated with significant increases in end-diastolic area (from 15.1 +/- 0.6 to 19.3 +/- 1.0 cm2, P < or = 0.001), end-systolic area (from 6.6 +/- 0.4 to 10.7 +/- 0.7 cm2, P < or = 0.001), end-systolic wall stress (from 32 +/- 0.05 to 82 +/- 7 kdynes/cm2, P < or = 0.001). In addition, a decrease in fiber-shortening velocity (from 1.1 +/- 0.05 to 0.76 +/- 0.04 circ/s, P < or = 0.05) and in fractional area change (from 0.57 +/- 0.02 to 0.44 +/- 0.02, P < or = 0.05) was observed. Heart rate did not significantly change during the study. Increases in preload and afterload were observed. However, the administration of AII causes a transient impairment in left ventricular function. We conclude that AII, given as an I.V. bolus of 2.5 microg, is effective in restoring arterial blood pressure within 60 s in patients chronically treated with ACEI. IMPLICATIONS: Severe hypotension on anesthetic induction in patients chronically treated with angiotensin-converting enzyme inhibitors for hypertension could be treated with an I.V. bolus of 2.5 microg of angiotensin II.

The hemodynamic effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists.

UNLABELLED: The use of angiotensin II receptor subtype-1 antagonists (ARA), recently introduced as antihypertensive drugs, is becoming more prevalent. We studied the prevalence and severity of hypotension after the induction of general anesthesia in 12 patients treated with ARA until the morning of surgery. The hemodynamic response to induction was compared with that of patients treated with beta-adrenergic blockers (BB) and/or calcium channel blockers (CB) (BB/CB group, n = 45) and angiotensin-converting enzyme inhibitors (ACEI) (ACEI group, n = 27). A standardized anesthesia induction protocol was followed for all patients. Hypotension occurred significantly (p < or = 0.05) more often in ARA-treated patients (12 of 12) compared with BB/CB-treated patients (27 of 45) or with ACEI-treated patients (18 of 27). There was a significantly (P < or = 0.001) increased ephedrine requirement in the ARA group (21+/-3 mg) compared with the BB/CB group (10+/-6 mg) or the ACEI group (7+/-4 mg). Hypotension refractory to repeated ephedrine or phenylephrine administration occurred significantly (P < or = 0.05) more in the ARA group (4 of 12) compared with the BB/CB group (0 of 45) or the ACEI group (1 of 27), but it was treated successfully by using a vasopressin system agonist. Treatment with angiotensin II antagonism until the day of surgery is associated with severe hypotension after the induction of anesthesia, which, in some cases, can only be treated with an agonist of the vasopressin system. IMPLICATIONS: Hypotensive episodes occur more frequently after anesthetic induction in patients receiving Angiotensin II receptor subtype-1 antagonists under anesthesia than with other hypotensive drugs. They are less responsive to the vasopressors ephedrine and phenylephrine. The use of a vasopressin system agonist was effective in restoring blood pressure when hypotension was refractory to conventional therapy.

Transjugular intrahepatic portosystemic shunt worsens the hyperdynamic circulatory state of the cirrhotic patient: preliminary report of a prospective study.

The aim of this prospective nonrandomized study was to assess the immediate and short-term sequelae of transjugular intrahepatic portosystemic shunting on the circulatory hyperdynamic state of the cirrhotic patient. Twelve transjugular portosystemic shunting procedures were performed in 12 cirrhotic patients for sclerotherapy failure (10 cases) and/or intractable ascites (4 cases). Self-expandable stents 10 mm in diameter were used in all cases. Portal pressure measurement and right-heart catheterization were performed before and 30 min and 1 mo after the procedure. The portoatrial pressure gradient decreased from 15 +/- 3 to 7 +/- 3 mm Hg 30 min after surgery (p < 0.0001) to 8 +/- 3 mm Hg 1 mo after surgery (p < 0.001, in comparison with basal values). The cardiac index increased from 4.5 +/- 1.3 to 5.7 +/- 1.5 L/min.m2 30 min after surgery (p < 0.001) to 7.4 +/- 1.4 L/min.m2 1 mo after surgery (p < 0.001). Systemic vascular resistance decreased from 808 +/- 323 to 646 +/- 209 dyne.sec.cm-5 30 min after surgery (p < 0.01) to 467 +/- 101 dyne.sec.cm-5 1 mo after surgery (p < 0.05). This study demonstrates that transjugular portosystemic shunting rapidly and significantly worsens the hyperdynamic circulatory state of the cirrhotic patient. Although apparently noninvasive, this procedure should be considered with caution in cirrhotic patients with limited cardiac reserve.

Treatment of aortic arch dissection using the elephant trunk technique.

The elephant trunk technique was developed to facilitate multiple-stage treatment of extensive aneurysm of the thoracic aorta. However, little information is available concerning its usefulness for aortic dissection. From April 1992 to July 1998, we used the elephant trunk technique for treatment of aortic arch dissection in 22 patients (including 19 men) with a mean age of 58.5 years (range 21 to 85 years). Twelve patients presented with type A dissection (acute in 3 and chronic in 9), 3 with type B acute dissection, and 7 with "non A/non B" dissections with retrograde extension to the aortic arch or entry site located in the aortic arch without involvement of the ascending aorta. All patients had aneurysms of the descending (n = 7) or thoracoabdominal (n = 15) aorta. Procedures were performed under hypothermic circulatory arrest at between 15 degrees and 20 degrees C. Antegrade cerebral perfusion was used in three cases. The procedure was associated with aortic valve replacement and/or coronary bypass in 6 cases and bypass of one or more supraaortic vessels in 13. In two patients the distal end of the elephant trunk was attached with an endovascular prosthesis during the same procedure. The ensuing results in these patients indicate that the elephant trunk technique can be highly effective for treatment of complex aortic arch dissection.

Treatment of intraoperative refractory hypotension with terlipressin in patients chronically treated with an antagonist of the renin-angiotensin system.

UNLABELLED: The goal of the present study was to determine whether terlipressin, an agonist of the vasopressin system, could counteract perioperative hypotension refractory to common vasopressor therapy and to analyze its circulatory effects. We enrolled 51 consecutive vascular surgical patients chronically treated with angiotensin-converting enzyme inhibitors or antagonists of the receptor of angiotensin II, who received a standardized opioid-propofol anesthetic. Of these 51 patients, 32 had at least one episode of hypotension, which responded to epinephrine or phenylephrine. In 10 other patients, systolic arterial pressure (SAP) did not remain above 100 mm Hg for 1 min, despite three bolus doses of ephedrine or phenylephrine. In these patients, we injected a bolus of 1 mg of terlipressin, repeated twice if necessary. Hemodynamic and echocardiographic variables were recorded every 30 s over 6 min. In eight patients, arterial pressure was restored with one injection of terlipressin; in two other patients, three injections were necessary. One minute after the last injection of terlipressin, the SAP increased from 88+/-3 to 100+/-4 mm Hg and reached 117+/-5 mm Hg (P = 0.001) 3 min after the injection and remained stable around this value. This increase in SAP was associated with significant changes in left ventricular end-diastolic area (17.9+/-2 vs 20.2+/-2.2 cm2; P = 0.003), end-systolic area (8.1+/-1.3 vs 9.6+/-1.5 cm2; P = 0.004), end-systolic wall stress (45+/-8 vs 66+/-12; P = 0.001), and heart rate (60+/-4 vs 55+/-3 bpm; P = 0.001). Fractional area change and velocity of fiber shortening did not change significantly. No additional injection of vasopressor was required during the perioperative period. No change in ST segment was observed after the injection. IMPLICATIONS: Terlipressin is effective to rapidly correct refractory hypotension in patients chronically treated with antagonists of the renin-angiotensin system without impairing left ventricular function.

Intraoperative blood loss in pediatric liver transplantation: analysis of preoperative risk factors.

The relative contribution of 14 preoperative risk factors to a high intraoperative blood loss was studied in 95 consecutive first pediatric orthotopic liver transplantations (OLT). Patients were distributed in two groups according to red blood cell (RBC) requirements. Wide interindividual RBC requirements were observed (median, 79 mL/kg; range, 4-586). The upper quartile of the population was defined as the high blood loss group and required 123 mL/kg or more (median, 161). On univariate analysis, the high blood loss group had a significantly higher proportion of patients with portal vein hypoplasia, intraabdominal malformations, signs of severe liver failure (encephalopathy, ascites, prolonged prothrombin time), and requiring inpatient support. Age, previous abdominal surgery, and platelet count had no prognostic value. All variables used in the univariate analysis were included in a stepwise logistic regression analysis. Only presence of portal vein hypoplasia, inpatient support, and use of a reduced-size liver graft were independently associated with a high blood loss. Adjusted odds ratios were 40.4 (95% confidence interval; 5.9-278), 5.4 (1.6-17.9), and 3.8 (0.9-15.2), respectively, highlighting the importance of portal vein hypoplasia as a risk factor for high blood loss.

Hemostatic changes in patients receiving hydroxyethyl starch: the influence of ABO blood group.

Hydroxyethyl starches (HES) interfere with coagulation because of their molecular structure and the amount infused during surgery. Coagulation defects include platelet dysfunction and a decrease of the VIII/von Willebrand factor complex (VIII/vWF). We examined the effects of 6% HES 200/0.6 on hemostasis by using an in vitro platelet function analyzer, the usual coagulation tests, the VIII/vWF complex assessment, and TEG analysis in patients undergoing abdominal surgery. The influence of the blood group was investigated. HES infusion induced primary hemostasis alterations, assessed by a prolonged platelet function analyzer closure time in the presence of epinephrine and adenosine diphosphate, which was not correlated with the platelet count. The decrease in VIII/vWF complex was proportional to the volume of infused HES (20 and 30 mL/kg) and was more pronounced in patients of the O blood group. The preoperative hypercoagulability status assessed by TEG analysis was reversed 24 h after HES infusion. In conclusion, 6% HES 200/0.6 induced immediate hemostasis alterations. Patients of the O blood group were likely to develop a von Willebrand-like syndrome after HES infusion. We conclude that intraoperative use of 6% HES 200/0.6 should be restricted in patients of the O blood group undergoing surgical procedures with high risk for bleeding.

Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome.

BACKGROUND: Nitric oxide inhibits platelet adhesion and aggregation in vitro. The aim of this prospective study was to assess the platelet antiaggregating activity of nitric oxide administered to patients with acute respiratory distress syndrome (ARDS) at increasing concentrations. METHODS: In six critically ill patients (mean age 37 +/- 16 yr) with ARDS (lung injury severity score > or = 2.2), the lungs were mechanically ventilated with inhaled nitric oxide (1, 3, 10, 30, and 100 ppm) randomly administered. Patients with cardiac dysrhythmias, septic shock, an underlying hemostasis disorder (constitutive or acquired), a platelet count less than 100 Giga/l, or a decreased platelet aggregation and those treated with antiplatelet or anticoagulant agents were excluded. Platelet aggregation was measured without nitric oxide and at each nitric oxide concentration in platelet-rich plasma issued from radial artery. Ivy bleeding time using a horizontal incision was simultaneously performed. RESULTS: After nitric oxide, a non-dose-dependent but statistically significant decrease in ex vivo platelet aggregation induced by three aggregating agents was observed: adenosine diphosphate = -56 +/- 18%, collagen = -37 +/- 18%, and ristocetin = -45 +/- 18% (P < 0.05). In each individual, Ivy bleeding time remained within normal values measured in healthy volunteers, and variations after nitric oxide did not correlate with changes in platelet aggregation. Simultaneously, arterial oxygenation improved significantly and pulmonary artery pressure decreased significantly. CONCLUSIONS: In patients with ARDS and without preexisting coagulation disorders, the beneficial effects of inhaled nitric oxide on arterial oxygenation and pulmonary circulation are associated with a significant inhibition of platelet aggregation. This antithrombotic effect is not associated with a significant prolongation of the bleeding time.