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Biomedical subjects

M M Samama

Publications and source records attributed to M M Samama.

At least 37 records · Page 2Linked to original sources
PubMed2002

[Biological markers for acute phase hemostasis in coronary thrombosis].

Associated with rheological conditions, multiple factors regarding haemostasis and fibrinolysis contribute to the instability and rupture of atherosclerotic plaque. Various biological parameters are modified during the occurrence of a coronary thrombotic episode, but do these increasingly identified alterations constitute a cause or a direct consequence of this accident? With the increasing identification of markers more and more sensitive but of limited specificity, the relative abundance of studies in the literature contrasts with the paucity of effective assets for everyday clinical practice. In fact, the potential use of these indicators in the evaluation of the pathogenesis of vascular accident, their eventual prognostic value, their predictive nature in therapeutic strategy, and their relevance for patient classification and follow up remain to be established on a wider scale. There is growing interest in the detection of evidence of cellular cooperation or a vascular compartment lesion thanks to the development of new diagnostic tools such as flux cytometry or immunoenzymology. While advances in biology have allowed undeniable clarifications of the physiopathology of coronary accidents and in the management of thrombotic pathology, it must nevertheless be endeavoured to give a practical response to the numerous questions where doubt remains, and to pursue the search for markers or tests clinically relevant.

Acute-Phase Reaction↗
PubMed2001

The role of platelet factor 4 in platelet aggregation induced by the antibodies implicated in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a severe side effect of heparin treatment. Recent studies using immunological methods demonstrated that antibodies contained in plasma, or in purified total immunoglobulin (Ig)G from patients suffering HIT, recognize as target antigen the complex heparin/platelet factor (PF4). In the present study, the role of PF4 in in-vitro platelet aggregation induced by purified total IgG or platelet-poor plasma from patients suffering HIT was investigated. In order to demonstrate the functional role of PF4, an anti-PF4 antibody that specifically blocked PF4 was used. In an experimental system composed of washed platelet suspension, incubation of F(ab')2 fragments (0.125 microg/ml) of the polyclonal anti-PF4 antibody resulted in complete inhibition of platelet aggregation triggered by purified total IgG from patients suffering HIT and heparin. In platelet-rich plasma, a significantly higher concentration (4.25 microg/ml) of the anti-PF4 F(ab')2 was required to inhibit platelet aggregation induced by HIT-PPP and heparin. Intermediate concentrations of the anti-PF4 antibody partially inhibited platelet aggregation. In plasma milieu, the concentration of PF4 was about five-fold higher in comparison with that measured in the purified system. The intensity of platelet aggregation depended on the concentration of HIT-IgG. Platelet aggregation was abolished in the presence of high concentrations of heparin (superior or equal to 10 IU/ml). The present study shows that PF4 is essential for platelet aggregation triggered by the antibodies related to HIT in the presence of heparin. The concentration of PF4 that is available to bind with heparin or with the HIT-related antibodies is critical for platelet aggregation induced by HIT antibodies.

Antibodies↗
PubMed2001

The thrombophilic state in cancer patients.

Thrombosis and disseminated intravascular coagulation are common complications of cancer. Specific conditions associated with cancer such as stasis due to immobilization or blood flow obstruction, surgery, infections, endothelium damage due to chemotherapeutic agents and abnormalities of blood coagulation contribute to the hypercoagulable and thrombophilic state of cancer patients. This procoagulant state in cancer arises mostly from the capacity of tumor cells to express and release procoagulant activities (cancer procoagulant and tissue factor). Decreased levels of inhibitors of coagulation, impaired fibrinolysis, the presence of antiphospholipid antibodies and an acquired activated protein C resistance contribute to the hypercoagulable state. The activation of coagulation is also implicated in tumor proliferation through interactions of coagulation with inflammation and increased tissue factor pathway inhibitor. Laboratory diagnosis of the thrombophilic state include (1) elevation of clotting factors, fibrinogen/fibrin degradation products, hyperfibrinogenemia and thrombocytosis and (2) elevation of specific markers of activation of coagulation: fibrinopeptide A, fragment 1 + 2, thrombin-antithrombin complexes and D-dimers. However, none of the tests has any predictive value for the occurrence of thrombotic events in one individual patient. In patients with venous thromboembolism a noninvasive screening for occult cancer is able to detect a relatively high incidence of hidden cancer and the search for thrombophilia seems important in patients without known cancer.

Blood Coagulation Factor Inhibitors↗
PubMed2001

Low-molecular-weight heparins: weeks or months instead of days of treatment.

Low-molecular-weight heparins (LMWHs) have been used for more than a decade in the prophylaxis and treatment of venous thromboembolism and recently in coronary artery disease. During the past few years, the duration of treatment has been increased in several pathologic conditions. A number of clinical studies provided evidence that the duration of prophylaxis after hip replacement should be prolonged up to 35 days after surgery. Several clinical trials concluded that LMWHs provide an effective and safe alternative to oral anticoagulants in the secondary prevention of deep vein thrombosis. A recent trial showed that extended dalteparin treatment is useful for protection against further complications while patients are waiting for invasive procedures. Finally, LMWHs seem to be safe during pregnancy.

Anticoagulants↗
PubMed2001

[Advances and perspectives in the prevention of venous thromboembolic disease].

The prevention of thrombo-embolic disease, the 3rd commonest cause of death, has made very great progress since the advent of low molecular weight heparins (LMWH) because the large number of clinical studies and consensus meetings have progressively refined the recommendations relating to their use with a variable level of evidence (1 or 2 A, B, C, or C+). Post-operative TE accidents have a multifactorial origin, involving factors inherent to the patients, environmental ones, and those relating to the type of surgical intervention. Major orthopaedic surgery, total hip replacement (THR), and total knee replacement (TKR) have benefitted from a greater number of clinical studies. The debate remains open concerning the timing of the first pre- or post-operative injection, and about taking into account the use or not of a regional anaesthetic. The duration of prophylactic treatment after THR remains under discussion between 10-14 days and 30 days, at least systematically after operation, or only in patients at high risk? Aspirin is not indicated due to its reduced and significantly inferior efficacity compared to heparins. In general medicine, well-defined groups, myocardial infarction, cerebral vascular accidents with immobilisation merit a prophylactic treatment (1A). In the acute phase of severe cardiac, pulmonary or infectious diseases prophylaxis is justified even if this recommendation (1A) is not regularly observed.

Anesthesia, Conduction↗
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↗
PubMed2000

Heparin-induced thrombocytopenia: laboratory diagnosis and management.

Heparin-induced thrombocytopenia (HIT), a drug-induced immunohaematological adverse reaction, is a rare but potentially very severe condition. The main problem for this complex syndrome is its recognition and management, which should be as early as possible to avoid the development of life-threatening complications. Most studies have reported heterogeneous populations of patients with other diseases that potentially induce thrombocytopenia. There is no gold standard diagnostic criteria, and we have established a score with anamnestic criteria that allows us to evaluate the likelihood of HIT. In clinical practice, the diagnosis is based on the analysis of clinical features and laboratory tests. Platelet aggregation test (PAT) and an ELISA test (heparin platelet-induced antibodies) are generally performed by expert laboratories to confirm the occurrence of HIT. In our experience, both tests are concordant in the majority of patients. PAT seems to correlate better with the clinical features while ELISA appears more specific. Regarding their limits, both are complementary in the determination of HIT diagnosis coupled to the clinical score system. The treatment often requires a multidisciplinary approach. Danaparoid (Orgaran) or lepirudin (Refludan) are the two alternative treatments for HIT patients with marketing approval. To avoid further exposure to heparin, every HIT patient should carry a written document that confirms the immunoallergy.

Animals↗
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↗