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Biomedical subjects

M M Samama

Publications and source records attributed to M M Samama.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1998

Comparison of activated clotting times to heparin management test for adequacy of heparin anticoagulation in percutaneous transluminal coronary angioplasty.

The aim of this study was to compare the activated clotting time (ACT) obtained with the Hemochron device and the Heparin Management Test (HMT) on a new automated whole-blood coagulometer, the Thrombolytic Assessment System, in patients undergoing angioplasty. Fifty patients undergoing balloon angioplasty were prospectively enrolled. The mean ACT after a 10,000 unit bolus of heparin was 283 +/- 39 sec at the end of the procedure. The mean HMT after 10,000 units of heparin was 286 +/- 31 sec at the end of the procedure in the same patients. The correlation between the two methods was significant (r = 0.6; P < 0.01). The HMT appears to correlate well with standard values obtained with the Hemochron ACT monitor in patients undergoing percutaneous transluminal coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1998

Comparative time course of thrombolysis induced by intravenous boluses and infusion of staphylokinase and tissue plasminogen activator in a rabbit arterial thrombosis model.

Staphylokinase (SAK), a protein with known profibrinolytic properties, has recently given encouraging results in acute myocardial infarction and in peripheral arterial occlusion. The aims of this study were to compare SAK with alteplase (recombinant tissue plasminogen activator rt-PA) in a rabbit arterial thrombosis model, in terms of femoral blood flow kinetics during and after thrombolysis, and to examine the biological effects of systemic fibrinolysis in vivo. We compared two modes of intravenous rt-PA administration, two modes of intravenous SAK administration and three different SAK dose regimens in a rabbit model of femoral artery thrombosis. The main finding was that the infusion of SAK following a single bolus administration gave statistically higher blood flow values than the infusion of the same dose of rt-PA following a single bolus administration (P < 0.05). In this experimental model, we also confirmed that SAK is a fibrin-specific and plasminogen-saving fibrinolytic agent at doses below 0.5 mg/kg. However, at higher doses (1.0 and 1.5 mg/kg), which are above usual therapeutic doses, SAK significantly reduced fibrinogen levels in a dose- and time-dependent manner (P < 0.05). These results indicate that SAK compares favorably with rt-PA in an rabbit arterial thrombosis model, yielding higher blood flow values. Moderate-dose SAK seems to be a fibrin-specific plasminogen activator, but in our model very high doses were associated with a decrease of fibrinogen.

Animals↗
PubMed1998

Comparative effects of synthetic pentasaccharide, low-molecular-weight heparin, unfractionated heparin and recombinant hirudin on the generation of factor VIIa and prothrombin activation after coagulation of human plasma.

We studied the effect of synthetic pentasaccharide, a low-molecular-weight heparin (enoxaparin), unfractionated heparin and recombinant hirudin on the generation of factor VIIa (FVIIa) and prothrombin activation after in-vitro clotting of human platelet-poor plasma. FVIIa was measured with a new clotting assay that uses recombinant tissue factor truncated to interact only with FVIIa. Residual prothrombin was measured using the conventional clotting assay. FVIIa and residual FII were measured in the liquid - called pseudo-serum (psi-serum) - obtained 1 h after clotting of normal platelet-poor plasma. A kinetic study of the generation of FVIIa was also performed. Coagulation was initiated by triggering the extrinsic, the intrinsic and both associated clotting pathways. Levels of FVIIa in the psi-sera (55+/-15, 258+/-18, and 164+/-18 ng/ml, in the extrinsic, intrinsic and intrinsic + thromboplastin psi-serum respectively; values are means+/-SEM) were significantly increased compared with those in the platelet-poor plasma (3 ng/ml). Pentasaccharide, low-molecular-weight heparin and unfractionated heparin inhibited the generation of factor VIIa or its activity, or both, in a dose-dependent manner in all the experimental systems (60-90% inhibition). A kinetic study revealed that the inhibition of the generation of FVIIa by pentasaccharide and heparins starts 1 min after triggering either the extrinsic or the intrinsic clotting pathway. The downregulation of FVIIa by heparins was effected mainly by their anti-Xa activity, but also by their inhibitory effect on the generation of prothrombinase. Pentasaccharide, enoxaparin and unfractionated heparin significantly inhibited prothrombin activation in both extrinsic and intrinsic experimental system. Hirudin had no inhibitory effect either on the generation of FVIIa or on prothrombin activation in any experimental system.

Blood Coagulation↗
PubMed1998

[Staphylokinase and its mutants: a new generation of thrombolytic agents].

Staphylokinase which is extracted from Staphylococci has been known for more than 40 years as a profibrinolytic compound. It has been obtained more recently by genetic engineering. Staphylokinase activates plasminogen into plasmin. It is a promising new thrombolytic agent for the treatment of acute myocardial infarction and thromboembolic disease in general. It is a fibrin specific thrombolytic agent which does not decrease plasma fibrinogen level in treated patients. However it is antigenic and the group of Louvain has made much effort to reduce its antigenicity without decreasing its thrombolytic activity. Mutants with a reduced antigenic activity have been recently obtained. These new thrombolytic agents could be superior to currently used drugs. Staphylokinase mutants could have a better benefit/cost ratio than other thrombolytic agents.

Amino Acid Sequence↗
PubMed1998

Monitoring heparin therapy using activated partial thromboplastin time--results of a multicenter trial establishing the therapeutic range for SILIMAT, a reagent with high sensitivity to heparin.

APTT is widely used for laboratory monitoring of treatment with unfractionated heparin (UFH). However, since its sensitivity to heparin varies significantly from one reagent to another, the therapeutic range had to be defined for each brand of APTT reagent. As an example, SILIMAT (bio-Mérieux) is a new APTT reagent containing rabbit brain phospholipids and micronized silica as an activator. Since its high sensitivity to heparin has been previously reported, a multicenter trial was carried out in an attempt to define the therapeutic range of APTT performed using this new reagent. For that purpose, 170 blood samples drawn for routine coagulation testing from 170 different patients treated with UFH were analyzed. A single batch of two different APTT reagents were used on KC10 coagulometers: SILIMAT and Automated APTT (Organon-Teknika) whereas the anti-Xa activity was evaluated by a chromogenic substrate-based assay. The same methodology was used in all the centers. In order to obtain a plasma anti-Xa activity within the therapeutic range i.e. between 0.30 and 0.70 IU/ml, the APTT ratios were found between 1.90 and 5.40 for SILIMAT, which corresponded to clotting times of the patients plasma between 63 and 178 s. The APTT ratios were significantly lower when evaluated using Automated APTT (between 1.70 and 4.10), with clotting times between 53 and 127 s. In addition, a good correlation was found between the Anti-Xa activity and APTT for both reagents (r > 0.65). However, it is not possible to make recommendations regarding the therapeutic ranges without restrictions. Although about 70% of the patients with an anti-Xa activity between 0.30 and 0.70 IU/ml had an APTT in the above defined ranges, the degree of concordance between the two assays is not absolute. Actually more than 30% of the patients had discordant anti-Xa activity and APTT and more than a quarter of the patients included in the above defined therapeutic range for APTT had an anti-Xa activity outside the 0.30-0.70 IU/ml range, whatever the reagent used. In conclusion, to define the therapeutic ranges of APTT using the recommended method is practicable but some critical points could be raised, suggesting that a better method is awaited in order to improve the standardization.

Adolescent↗