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Biomedical subjects

M M Samama

Publications and source records attributed to M M Samama.

At least 19 recordsLinked to original sources
PubMed2000

Assessment of treatment strategy in high-risk surgical patients.

The risk of postoperative venous thromboembolism (VTE) is dependent on the type of surgical procedure and specific characteristics of the patient. Patients with intrinsic factors placing them at higher risk of VTE remain at high risk, even if the procedural risk is low. The identification of factors such as age, obesity, and malignant disease, has made it possible to make a preoperative assessment of risk and ensures that the most appropriate thromboprophylactic regimen is prescribed. Despite the widespread use of prophylaxis, the incidence of VTE is still significant. The investigation and development of new pharmacologic agents, such as hirudins and their recombinant derivatives, may lead to better protection for patients at high or very high risk of VTE.

Adult↗
PubMed2000

[Aspirin and hemostasis].

Aspirin is one hundred years old, though its use has clearly evolved during the last 25 years. Identifying its action mechanism has allowed us to better understand the antithrombotic impact. Prostaglandin H synthetase (PGHS) is a bifunctional enzyme with cyclooxygenase and peroxydase activities. There are two isoforms: constitutive PGHS-1 and inducible PGHS-2. Aspirin irreversive acetylates the platelet cyclooxygenase involved in the formation of thromboxane A2, a powerful proaggregating agent and vasoconstrictor. More than 95% of inhibition of this synthesis takes place in two to three days using very weak doses of aspirin, on the order of 30 to 50 mg per day. Under some circumstances, this inhibition requires higher dosages. Certain clinical and biological circumstances could lead to a resistance to aspirin, making a readjustment of doses and sometimes complementary explorations necessary. The ISIS 2 study showed in an apparently irrefutable way the entry of aspirin into the antithrombotics arsenal, with a significant risk reduction of vascular death and recurrence of infarctus. Numerous studies have confirmed this efficacy. Consensus studies are based on information showing total coherence between the dose necessary to acetylate the enzyme to inhibit thromboxane A2 platelet production and the clinical antithrombotic effect. Aspirin seems to have a secure place, and it begins the third millennium in relative peace with new extra-platelet potentialities outside the framework of hemostasis and thrombosis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Comparative pharmacokinetics of LMWHs.

A variety of pharmaceutical preparations of low-molecular-weight heparins (LMWHs) are available. They belong to the same family of compounds-ie, heparin derivatives with a narrow distribution of mean molecular weights (MWs). LMWHs have different methods of preparation, which result in variations in mean MW, distribution of MW, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The mean MW of these compounds ranges from 3,600 to 6,500 daltons. The ratio of anti-Xa (aXa) and anti-IIa (aIIa) activities of the different LMWHs ranges from 1.5 to >10. After subcutaneous (SC) injection of a prophylactic or therapeutic dose, the peak values for plasma aXa or aIIa activity may vary twofold to threefold because of differences in bioavailability, plasma clearance (Clplasma), and half-life (t1/2). The injection of equivalent amounts of product, based on aXa and aIIa international units (IU), may result in different areas under the curve for the respective activities. Although tinzaparin has a high aIIa specific activity per milligram (and consequently, a low aXa/aIIa ratio), SC injection of 40 mg of enoxaparin (4,000 aXa IU) results in a higher aXa peak value in patients with total hip replacement than 4,500 aXa IU of tinzaparin. Differences in aIIa and aXa peak activities are more striking when high doses of LMWHs are used. The activated partial thromboplastin time (aPTT) can be significantly prolonged, an effect that is related to aIIa and aXa activity. The volume of distribution of LMWHs is of the same order of magnitude as that of the plasma volume. The mean retention time of aXa activity varies from 5.2 (dalteparin) to approximately 7 h (enoxaparin, nadroparin). Bioavailability of prophylactic doses of LMWHs ranges from 86% (dalteparin) to 98% (enoxaparin, nadroparin). PK parameters appear to be minimally affected by a patient's age. The Clplasma is different for each LMWH: 16 mL/min enoxaparin, 21 mL/min nadroparin, 33 mL/min dalteparin, 19 mL/min reviparin, and 22 mL/min tinzaparin. Accumulation of product has been observed for almost all LMWHs in patients with renal insufficiency. LMWHs are effective and safe for treatment or prophylaxis of venous thromboembolism during pregnancy, because they do not cross the placenta. No data are available regarding the passage of LMWHs into the milk in lactating women. Although LMWHs are also effective in prevention and treatment of thromboembolic disease in children, optimal use of these agents in pediatric patients has not been determined. In summary, the PD and PK of LMWHs have been well documented and have demonstrated that LMWHs have a more predictable response, a greater bioavailability, and a longer aXa t1/2 than unfractionated heparin. However, their distribution of MW affects their physicochemical and biological properties, as well as PK characteristics. The concept of aXa/aIIa ratio (determined in vitro) does not account for the differing PK of aXa and aIIIa activity in circulating blood.

Age Factors↗
PubMed2000

Pharmacologic modulation of thrombin generation associated with human clots by human purified antithrombin alone or in the presence of low molecular weight heparin or unfractionated heparin.

Procoagulant activities associated with human clots may contribute to thrombus extension. We investigate the inhibition of clot-associated factor Xa and thrombin activities by purified human antithrombin either alone or as combination with a low molecular weight heparin (enoxaparin) as compared with unfractionated heparin (UFH). The standard clots were prepared by recalcification of frozen platelet-poor human plasma. Clot-associated thrombin was measured on the clot after clot incubation in recalcified buffer or recalcified prothrombin solution. The enzymatic reaction was measured using a specific substrate for thrombin (CBS 3447). The thrombin concentration was determined both on the clots and in the reaction mixtures. In parallel, prothrombin fragment 1.2 and thrombin-antithrombin complexes (TAT) were measured using enzyme-linked immunosorbent assay methods. We demonstrated that in the presence of purified human prothrombin and antithrombin (AT), a partial inhibition of clot associated thrombin activity correlated with an increase of TAT complexes. However, antithrombin was unable to inhibit thrombin generation induced by the clot-associated factor Xa. Enoxaparin (low molecular weight heparin) and UFH did not enhance clot-bound thrombin inhibition induced by AT. We conclude that clot-bound thrombin is accessible to human antithrombin alone. AT is also able to inhibit thrombin generated by factor Xa-associated clot. However, neither a low molecular weight heparin or UFH enhanced the effect of AT alone.

Antithrombin III↗
PubMed1999

The heparin management test: a new device for monitoring anticoagulation during coronary intervention.

Whole blood coagulation analysers are widely used during percutaneous coronary interventions. The precise degree of anticoagulation in patients is important in this setting. The aim of this investigation was to compare the results obtained with ACT (Hemochron) and HMT, the Heparin Management Test (TAS) in patients undergoing percutaneous coronary interventions. Patients (n = 100) were enrolled prospectively. Each patient received 10,000 units of heparin. At the end of the procedure, the mean ACT was 284+/-31 seconds and the mean HMT was 292+/-33 seconds. The correlation between the two methods was highly significant (r = 0.64, p<0.001). The HMT correlates well with ACT values in patients undergoing percutaneous coronary interventions. Its use in the management of these patients should be considered.

Angina, Unstable↗
PubMed1999

[Where to look for progress in antithrombotic treatments?].

Thrombosis is the most frequent cause of venous and arterial vascular events. Anticoagulants and antiplatelet agents are able to prevent both types of thrombotic episodes. However, available agents have limitations which justify the search for new antithrombotic drugs or at least the clinical investigation of combined treatment with already available drugs. Progress in the knowledge of the mechanism of thrombosis guides the search for new antithrombotic agents. Novel strategies should take into account the intensity of the thrombogenic stimulus involved in the occurrence of the thrombotic episodes. Among antiplatelet agents, the logic combination of aspirin and ticlopidine or clopidogrel is already challenging the anti-GP IIb/IIIa orally active compounds. Among anticoagulant agents a long list of competitors for the replacement of oral anticoagulants and heparins is already available. They target factors Xa, IIa or VIIa. A promising alternative is to increase the thromboresistance of the vascular wall.

Anticoagulants↗
PubMed1999

A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.

BACKGROUND: The efficacy and safety of thromboprophylaxis in patients with acute medical illnesses who may be at risk for venous thromboembolism have not been determined in adequately designed trials. METHODS: In a double-blind study, we randomly assigned 1102 hospitalized patients older than 40 years to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days. Most patients were not in an intensive care unit. The primary outcome was venous thromboembolism between days 1 and 14, defined as deep-vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6 and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of follow-up was three months. RESULTS: The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant. CONCLUSIONS: Prophylactic treatment with 40 mg of enoxaparin subcutaneously per day safely and effectively reduces the risk of venous thromboembolism in patients with acute medical illnesses.

Acute Disease↗
PubMed1999

Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving a low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery.

Studies in experimental animal models and in patients receiving low molecular weight heparin (LMWH) to prevent thromboembolic events after surgery have not demonstrated a clear relationship between anti-Xa and anti-IIa activities in plasma and either bleeding or prevention of thrombosis. The relationship between these clinical outcomes and ex vivo anti-Xa and anti-IIa activities, activated partial thromboplastin time (APTT) and D-dimers were evaluated in 440 patients undergoing total hip replacement and given prophylaxis once daily with a LMWH (tinzaparin or enoxaparin) in a multicentre double-blind randomized study. 221 patients received 4500 anti-Xa IU of tinzaparin; 219 patients received 40 mg (4000 anti-Xa IU) of enoxaparin. Both regimens were administered subcutaneously once daily. Blood samples for anti-IIa, anti-Xa, D-dimers levels and APTT were taken at baseline, on day 1, day 5 and on the day of discharge (days 8-14) and clinical assessments were performed dafly until day 14. All patients had bilateral venography between days 8 and 14. All coagulation tests were performed in central laboratories. A significant correlation was observed between anti-IIa activity and anti-Xa activity and the dose of each LMWH injected. The anti-Xa activity was significantly higher with enoxaparin and the anti-IIa activity was significantly higher with tinzaparin. No clear relationship between these two activities and the clinical outcomes was observed. This was also true with regards to APTT. Before and after surgery, D-dimers were significantly higher in patients with deep vein thrombosis (DVT) than in those without DVT but had no predictive value. Interestingly, a significant post-operative increase of D-dimers persisted in both groups of patients during the whole observation period, possibly suggesting that a longer duration of prophylactic treatment may be appropriate.

Anticoagulants↗
PubMed1999

Laboratory diagnosis of the thrombophilic state in cancer patients.

Perturbations of coagulation in cancer patients have been described for a long time. In up to 90% of cancer patients "routine" blood tests are abnormal leading to a hypercoagulable state in these patients. Among these tests are an increase in clotting factors, fibrinogen, fibrinogen/fibrin degradation products, and thrombocytosis. Markers of the activation of coagulation have been developed, and levels of FPA, F1+2, TAT, and D-Dimer have been found higher in cancer patients. More specific procoagulant activities in cancer (CP and TF) have also been described and can be measured but none of them have any predictive value for the occurrence of venous thromboembolism in these patients. Consistent with this hypercoagulable state in cancer is the finding that most cancer patients have reduced plasma levels of inhibitors of coagulation. These complex abnormalities are clinically expressed as thrombosis, low-grade or fulminant DIC which can be assessed by different laboratory tests, and as hemorrhage when the fibrinolysis system is impaired. However, no studies have shown to date a relationship between these abnormalities of the coagulation tests and the clinical expression in any single individual. Because these patients are at high risk for thrombosis in special conditions such as surgery or during chemotherapy, prophylaxis with various forms of heparin are recommended.

Blood Coagulation↗
PubMed1999

Management of pregnancy in women with thrombophilia.

Hereditary thrombophilia increases the risk of thrombosis during pregnancy and postpartum. The recommendations resulting from the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy were published in Chest in late 1998. However, levels of evidence on this subject were low (C2). Furthermore, since publication of this ACCP consensus, new studies have demonstrated the safety of low-molecular-weight heparins (LMWHs) in pregnant women. In addition, it is now clear that all thrombophilias are not associated with the same level of thrombotic risk: factor V Leiden mutation and factor II 20210A variant are associated with a lower risk than antithrombin deficiency. Consequently, the ACCP recommendations have been reconsidered in the light of a more widespread use of LMWH and taking into account the differences in the level of risk of the different thrombophilias. A prophylaxis of thrombosis in pregnant women with thrombophilia is proposed based on published data and our personal experience. Although laboratory monitoring is usually not required during treatments with LMWH, it seems to be needed in pregnant women who receive long-term treatments.

Anticoagulants↗
PubMed1999

Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent--a pilot study in the setting of coronary angioplasty.

AIM OF THE STUDY: To assess the antithrombotic properties of SR90107/ORG31540. a sulfated pentasaccharide, which enhances specifically antithrombin III mediated inactivation of factor-Xa, in a clinical setting known to promote arterial thrombosis, i.e. coronary angioplasty. METHODS AND RESULTS: Percutaneous transluminal coronary angioplasty (PTCA) was carried out with conventional balloons with a single 5 min intravenous infusion of 12 mg pentasaccharide, and 500 mg intravenous aspirin. Heparin was not allowed before, during PTCA, and within 24 h after PTCA. The primary end point was the rate of abrupt vessel closure during and within 24 h after the procedure. The sample size was set at 60 evaluable patients, in order to be able to conclude with a good level of confidence (>95%) that the abrupt vessel closure rate was less than 10%, if less than 3 abrupt vessel closures were observed. Seventy-one patients were included in the study, of whom 10 needed elective stenting, and were not considered as evaluable for efficacy. Two out of the 61 remaining evaluable patients experienced acute vessel closure during the study period [3.28%, 95% confidence interval (0.4%; 11.4%)]. No major bleeding occurred. The drug plasma concentrations reached 1.91+/-0.39 mg/], 10 min after pentasaccharide injection, and decreased on average to 1. 18+/-0.27 mg/l at 2 h, and to 0.36+/-0.11 mg/l at 23 h after administration of pentasaccharide. Activated clotting time (ACT) and activated partial thromboplastin (aPTT) time remained within normal range. Thrombin-antithrombin complex levels fell from 22+/-17.1 to 4.5+/-3.4 microg/ml, prothrombin fragment 1+2 levels decreased from 2.15+/-1.01 to 1.73+/-0.87, and activated factor VII levels decreased from 43.4+/-16.8 mU/ml to 18.9+/-7.3 mU/ml respectively from baseline to 2 h following injection of the tested drug. CONCLUSIONS: Administration of pentasaccharide led to the inhibition of thrombin generation without modification of aPTT and ACT. The rate of abrupt vessel closure was within range of rates reported in historical series. Thus we conclude that the anti-thrombotic activity of pentasaccharide, as shown in this pilot trial in the setting of coronary angioplasty, deserves further investigation.

Adolescent↗
PubMed1999

[How to provide practical treatment for ambulatory patients with deep venous thrombosis].

Much interest has been focused on low molecular weight heparins (LMWH), light weight fragments of standard heparin, for the management of deep vein thrombosis (DVT) without pulmonary embolism (PE). LMWHs offer several advantages: predictable anticoagulant activity, better bioavailability, longer half-life, better patient and caretaker comfort, safety and efficacy at least comparable to continuous intravenous heparin. Ambulatory treatment is quite attractive and a large number of patients with DVT are now being managed as outpatients. There are however certain precautions which must be taken to avoid unsatisfactory anticoagulation and subsequent consequences which have nevertheless been shown to be exceptional in well-designed and well-conducted trials excluding patients with high risk for hemorrhage and based on attentive medical control. The purpose of this review is to propose clear and simple protocols for everyday practice aimed at a global diagnostic and therapeutic management of venous thromboembolism. The review of the literature draws attention to the need for confirmation of the clinical suspicion of DVT, practical application of the anticoagulant treatment, and the importance of the etiology search in order to avoid missing a congenital or acquired state of thrombophilia or an occult cancer revealed by DVT. Half of all cases of thrombosis are caused by these two etiologies. In addition, with the development of noninvasive methods for diagnosing DVT, the efficacy of clear therapeutic regimens and the simplification of coagulation tests warrant outpatient management in many cases of DVT in compliance with certain rules of good clinical practice: confirmation of the diagnosis and regular treatment controls. An essential element is the close collaboration between the patient, the physician, the nursing staff, the laboratory and the pharmacist.

Ambulatory Care↗
PubMed1999

[New thrombolytic agents in myocardial infarction].

Myocardial infarction is the result of thrombotic coronary artery occlusion. Although present-day thrombolytics have major value by increasing the frequency of reopening of arteries responsible for myocardial infarction, by preserving myocardial function and, thereby, significantly reduce mortality. Nevertheless, they are subject to the following limitations: 1) excellent arterial partency is only obtained in 50% of cases: 2) reocclusion occurs in 5 to 10% of cases; 3) severe complications such as cerebral haemorrhage are observed in about 0.5% of cases. Therefore, the search to improve thrombolytic agents is intense. This article reports the recent advances in concept and production of new thrombolytic agents. The most recent results concern the production of mutants of T-PA (tissue plasmogen activator). Of these mutants, the reteplase (r-PA) has already received authorization for its commercialisation. Other t-PA mutants under development (phase 3) include TNK-t-PA and lanoteplase. Over the last few years, there has been renewed interest in staphylokinase. The results of the initial clinical trials with this agent have also been reported. Paradoxically, the mode of action of thrombolytic agents has an inherent pro-thrombotic effect. This explains some of the interest for anti-thrombotic agents as an adjuvant treatment of thrombolysis. The initial results of the association of thrombolytics with new glycoprotein IIb/IIIa platelet inhibitors and anti-thrombin agents are reported.

Coronary Disease↗
PubMed1999

Prevention of deep vein thrombosis after hip replacement--comparison between two low-molecular heparins, tinzaparin and enoxaparin.

Consecutive patients undergoing total hip replacement in 43 centres were randomly assigned to receive blindly either enoxaparin (40 mg) or tinzaparin (4,500 anti-Factor IU Xa), as once daily subcutaneous injections. The first injection was administered 12 h preoperatively. Efficacy was assessed by bilateral venography performed 12-14 days postoperatively. Efficacy and safety were blindly and centrally adjudicated. Among the 499 patients included, 440 had a venogram. The total incidence of DVTs was 44 (20.1%) of the 219 patients of the enoxaparin group and 48 (21.7%) of the 221 patients of the tinzaparin group. The upper limit of the 80% confidence interval of the difference between the two treatment groups was less than 5.0%. Therefore according to the protocol's specifications equivalence was shown. Proximal DVTs occurred in 10.5% of the enoxaparin group (23 patients) and in 9.5% (21 patients) of the tinzaparin group. No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died. The LMWH tinzaparin appears clinically to be as effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis after total hip replacement, at the doses used and under the conditions of this study.

Adult↗
PubMed1999

Applying risk assessment models in general surgery: effective risk stratification.

The risk of venous thromboembolism (VTE) in general surgery patients varies from 10-50% depending on the type of surgery and underlying patient risk factors. Despite the availability of effective antithrombotic therapies, thromboprophylaxis is substantially underused in the general surgical field. The development of risk assessment models (RAMs) that can accurately and prospectively categorize patients according to their thromboembolic risk level may lead to improved use of thromboprophylaxis. Several evidence-based RAMs are now available that include general surgery in their range of clinical categories, allowing patients to be stratified rapidly for thromboembolic risk. Therapeutic recommendations are included in some cases. Tailoring anticoagulant therapy according to risk of VTE should maximize the clinical benefit and cost-effectiveness of prophylaxis, and minimize the risk of bleeding complications. Further studies are required to validate novel RAMs in clinical practice, and to extend their scope to include patient groups with particular needs, such as those undergoing neurosurgical procedures.

Humans↗