[Prevention of thromboembolism in digestive and abdominal surgery. New heparins].
Explore the source record for details and available documents.
Digestive System Diseases↗
Biomedical subjects
M Samama
Publications and source records attributed to M Samama.
[The new heparins].
Low molecular weight heparins are increasingly prescribed in France. Prepared from standard heparin by depolymerisation, they show a markedly decreased anti IIa activity and a anti Xa/anti IIa ratio ranging from 2 to 4. Their mode of action in the coagulation system is still not well known and it is difficult to explain the mechanism of their antithrombotic effect, demonstrated in vivo. They seem to inhibit the first traces of thrombin and then counteract the priming and amplification of coagulation. Their fibrinolytic activity is also a disputed question, but seems to be lower than that of standard heparin. The pharmacological studies show a venous as well as arterial antithrombotic activity of a low molecular weight heparin on several animal models, a lower but not negligible bleeding risk as compared to unfractionated heparin. Furthermore heparin fragments have a weak interaction with platelets, which allow to foresee a greater efficacy of LMWH than standard heparin in arterial thrombosis. Some very rare cases of thrombocytopenia in patients treated with LMW heparins have been recently reported. The compared pharmacokinetics of heparins gave proof of a renal elimination of low molecular weight heparin and a bio availability of about 90% after subcutaneous injection. Many clinical studies allowed to define indications of heparin fragments in prophylactic treatment after surgery as well as in medical patients and in curative treatment in case of deep vein thrombosis. However, others studies must be carried out to define the real efficacy of such a treatment during pulmonary embolism, disseminated intravascular coagulation and myocardial infraction, or during thrombotic complications after vascular surgery.
Heparin, Low-Molecular-Weight↗
[Coagulation and bronchopulmonary cancers: from clinical aspects to biology].
Activation of coagulation and of the fibrinolytic system has been identified in small cell and non-small cell cancers respectively. For the clinician this poses the diagnostic problem of a thrombosis, which is most often venous with or without pulmonary emboli, complicating the evolution of an already diagnosed cancer. The inverse is that these features may reveal an underlying neoplasm and amongst the most common of these would be bronchopulmonary cancer. Numerous laboratory studies have shown the existence of a state of hyper-coagulability, with disseminated intra-vascular coagulation, which is more or less compensated and is the more marked, the more advanced the cancer is. One should not fail to recognise that this state of hyper-coagulability may be aggravated by certain cytotoxic drugs. At the level of the tumour itself, there seems to be interactions between the cancer cells and the coagulation and fibrinolytic system: these interactions are very different according to the histological type as to whether they are small cell or non-small cell bronchopulmonary cancers.
Anticoagulants↗
[Elements of choice of thrombolytic agents in myocardial infarction].
Five thrombolytic agents have been used in the acute phase of myocardial infarction: streptokinase, recombinant tissue plasminogen activator (rt-PA) and its acyl enzyme (APSAC), urokinase and pro-urokinase. Experience with the latter two agents is much more limited. The antigenicity, biological half-life, fibrino-specificity and cost are important parameters to be taken into account when choosing a therapeutic agent. The doses expressed in different units or in milligrams vary with the product used. Large scale clinical trials have not shown improved efficacy of new thrombolytic agents. The role of associated treatments, aspirin and/or heparin and their respective doses, the timing of their administration are also important elements in the evaluation of efficacy judged by the frequency of coronary recanalisation and early reocclusion. The haemorrhagic risk is difficult to assess and seems more related to heparin therapy than the prescription of aspirin. Mutants of rt-PA obtained by genetic engineering and other new thrombolytics are currently under evaluation to try and obtain new, more effective and safer thrombolytic agents.
Humans↗
[Erythrocyte aggregation and clinical course stages of venous insufficiency of the legs].
A double vicious circle at the venule and capillary level had already been pointed out by J. Dormandy and G. Nash as a pathophysiologic mechanism of rheological disorders associated with venous insufficiency of the lower limbs. Afterwards, such disorders were found by many authors when ex vivo analysis were performed on venous insufficient patients. However the time of their onset and their evolution in the course of the disease remain unknown. We studied red cell aggregation and plasma fibrinogen in 67 patients depending on the evolutive stage: 1st stage: isolated functional disorders, 2nd stage: trunk varicose vein linked to ostial incompetence, 3rd stage: trunk varicose vein linked to ostial incompetence with chronic trophic skin changes. The results showed that red cell aggregation and fibrinogen values are increased with the severity of the diseases. The rheological parameters increase when compared to controls from the first stage. Within the studied population, we avoided skewed results due to age and fibrinogen level by covariance analysis. Therefore recorded differences were practically linked with erythrocyte aggregability. Thus, red cell aggregation appears to be both an aggravating factor and a severity marker of the disease, proving the relevance of a rheological treatment in the lower limb insufficiency.
Adult↗
Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin.
OBJECTIVE: To evaluate the efficacy and safety of two subcutaneous prophylactic regimens for postoperative deep vein thrombosis after total hip replacement. DESIGN: Prospective open randomised multicentre trial. SETTING: 28 European departments of orthopaedic surgery. INTERVENTION: All patients had bilateral phlebography 10 days after surgery. 31 patients receiving low molecular weight heparin and 29 receiving unfractionated heparin were excluded from the efficacy analysis for various reasons. PATIENTS: 349 patients undergoing total hip replacement between September 1988 and May 1989. 174 patients received subcutaneously a low molecular weight heparin (Fraxiparine) with anti-factor Xa activity of 41 IU/kg/day for three days, then 62 IU/kg/day from day 4 to day 10. 175 patients received subcutaneous unfractionated heparin at intervals of eight hours; doses were adjusted to maintain the activated thromboplastin time at two to five seconds above control values. MAIN OUTCOME MEASURE: Total incidence of deep vein thrombosis and incidence of proximal deep vein thrombosis on bilateral phlebography. RESULTS: The total incidence of deep vein thrombosis was 16% in patients receiving unfractionated heparin and 12.6% in patients receiving low molecular weight heparin (p = 0.45), and the incidence of thrombosis of the proximal veins was 13.1% and 2.9% respectively (p less than 0.001). Four patients receiving unfractionated heparin and one receiving low molecular weight heparin developed pulmonary embolism. The incidence of bleeding complications was low and comparable in the two groups. CONCLUSION: Low molecular weight heparin is at least as effective as unfractionated heparin in preventing deep vein thrombosis and is more effective at preventing thrombosis of the proximal veins in patients undergoing hip replacement. Low molecular weight heparin is not more likely to cause bleeding complications and is simpler to give than unfractionated heparin.
Blood Coagulation↗
Rapid aequorin loading into platelets in the presence of DMSO--characteristics of the responses (changes in light transmission and in calcium) to various agonists.
We have looked at different parameters which could modify platelet behaviour during and after aequorin loading in the presence of DMSO. There is a decreased platelet reactivity in response to ADP, PAF and A-23,187 which appears to be mainly due to the exposure to EGTA during washing and loading and the 1 ml volume of the test suspension. All the studied agonists (including PMA) which elicit aggregation are able to induce an intracellular Ca2+ change detected with the aequorin probe. By contrast, epinephrine alone induces neither aggregation nor Ca2+ rise, but potentiates the responses to ADP. Different consecutive phases in Ca2+ changes after stimulation with ADP, PMA and A-23,187 can be evidenced. In the presence of external Ca2+, the second component of the Ca2+ change evoked with ADP is dependent on aggregation and the subsequent TXA2 synthesis. When the external medium is Ca2+ depleted, the two Ca2+ peaks induced by ADP disappear whereas a Ca2+ rise persists (endogenous mobilization) with the other agonists, being independent of TXA2 and ADP release. Ca2+ mobilization parallels activation with A-23,187 but not with low concentrations of thrombin.
Aequorin↗
Importance of plasminogen activator inhibitor type 1 (PAI-1) for preventing single chain urokinase plasminogen activator (scu-PA) conversion into two chain urokinase plasminogen activator (tcu-PA) in plasma in vitro.
We have studied the effects of PAI-1 on the conversion of scu-PA into tcu-PA in vitro in plasma containing or not a 125I-fibrin clot by determining tcu-PA activity on S2444. Two preparations of PAI-1 have been used, a fraction of medium conditioned with the monkey Vero cells (Vero-Prep), the antiurokinase activity of which is inhibited at 83% by anti PAI-1 IgG, or purified human PAI-1 from HT 1080 fibrosarcoma cells. Scu-PA purified from human kidney cells has been treated with diisopropylfluorophosphate before use. In plasma, conversion of scu-PA into the tc form is accelerated by addition of anti PAI-1 IgG. In plasma containing a clot, generation of tcu-PA, is considerably delayed after addition of the Vero-Prep or human PAI-1. Clot lysis is also decreased but to a lesser extent than it would be expected from the level of tcu-PA activity. Addition of anti PAI-1 antibodies shortens the lag phase before tcu-PA appears and moderatly accelerates clot lysis. These results demonstrate the importance of PAI-1 for the stability of scu-PA in plasma in vitro by delaying its conversion into tcu-PA.
Animals↗
[Severe thrombocytopenia with pulmonary embolism and consumption coagulopathy during treatment with tedelparin].
Explore the source record for details and available documents.
Disseminated Intravascular Coagulation↗
Lupus anticoagulant associated with primary malignant lymphoplasmacytic lymphoma of the spleen: a report of four patients.
Primary lymphoma of the spleen is characterized by predominant splenomegaly. Lymphoplasmacytic malignant lymphoma of the spleen, of low malignancy in the Kiel classification, low and intermediate grade in the National Cancer Institute Working Formulation (NCIWF), is rare. It is often associated with a monoclonal immunoglobulin M (IgM). Four patients presenting with primary splenic lymphoma of plasmacytic type associated with a high level of monoclonal IgM and a lupus anticoagulant (LA) are described. This association has not previously been reported. In contrast with the usual heterogeneity of LA, this LA is relatively homogeneous with an important prolongation of the prothrombin time (greater than 18 sec for a control of 12), more prolonged partial thromboplastin time (PTT) of the mixture patient + control plasma than PTT of the patient plasma. Despite the important coagulation abnormalities, none of these four patients has presented any hemorrhagic or thrombotic complications, even during major surgery such as splenectomy. The lupus-like anticoagulant effect ran parallel with the monoclonal IgM. Survival, after splenectomy and chemotherapy, appears to be favourable: three patients are alive with survivals of greater than or equal to 7 years. The follow-up is as yet too short for the last patient.
Adult↗
[Safety of donors, quality of products, how much to reduce the quantity of citrate].
We examined 1,053 blood samples from 48 donors, for the effect of gradual reduction of citrate. We observed that: 1--Platelet count does not show any significant variation between 1/8 to 1/18 ratio. 2--In 13.3% of the cases, platelet clumping starts at 1/18 ratio. 3--There was no significant variation of the thrombin plasma level between 1/8 to 1/16 ratio (by measuring thrombin/ATIII complex). Our results show clearly that we can reduce the citrate ratio to 1/14 without expecting any adverse effect. Therefore we designated 1/14 as the security ratio. Parallel to this we also found that the average level +/- SD of ionized calcium is 100 +/- 10 muMol at 1/14 ratio.
Adult↗
Tumor necrosis factor stimulates urokinase-type plasminogen activator and inhibitor type 1 production in A549 lung carcinoma cells: treatment of monolayer and tridimensional cultures.
Explore the source record for details and available documents.
Cell Migration Inhibition↗
Pharmacokinetics and biodistribution of technetium 99m labelled standard heparin and a low molecular weight heparin (enoxaparin) after intravenous injection in normal volunteers.
For a better understanding of low molecular weight heparin pharmacokinetics, 99m technetium labelled heparin and enoxaparin were injected intravenously to four normal volunteers, after approval by the Ethics Committee and preliminary animals studies. In vitro and in vivo, the labelled products proved to be stable and identical to the non-labelled drugs. Radioactivity curves in blood, organs and urines were similar for both products. Anti Xa plasma half-life was 3 times longer for enoxaparin than for heparin. Anti IIa plasma half-lives were similar. However, radioactivity persisted much longer than biological activities for both products. After chromatography, most of the radioactivity was bound to AT III, where an anti Xa activity peak was also detected. The anti Xa activity peak seen after adding AT III to plasma was much higher with heparin than with enoxaparin. In urine, biological activities, measured with AT III supplementation, were higher with enoxaparin than with heparin. These results suggest that phenomena other than biodistribution are responsible for the differences in pharmacokinetics observed between these two products. The two most likely explanations are differences in metabolism and/or a release of an endogenous factor.
Adult↗
[Low molecular weight heparins in everyday practice].
Standard nonfractioned heparin has been used for fifty years in the treatment of thromboembolic accidents, and for fifteen years, since Kakkar's works, in the prevention of thromboembolic complications in a surgical and medical context [5]. The antithrombotic efficacy of nonfractioned heparin (NFH) is accompanied by hemorrhagic complications occurring in about 10% of the patients receiving a "curative" treatment at hypocoagulating doses and in about 5% of the patients receiving the low-dose "preventive" treatment. The interest raised by low molecular weight heparins (LMWH), prepared as early as 1970, was based on a concept that is currently called into question: their anti-Xa activity, accounting for the antithrombotic activity, is high, while the anti-IIa (antithrombin) activity, producing the hemorrhagic risks, is lower. The pharmacokinetic properties, including longer-lasting action and better bioavailability with subcutaneous delivery relative to standard heparin, have greatly facilitated their use in the clinical field by allowing the reduction of the daily number of injections. Extensive clinical trials have confirmed that the antithrombotic efficacy of the LMWH is at least equal, if not superior, to that of nonfractioned heparin, though without reducing the frequency of hemorrhagic complications in the prevention of postoperative phlebitis. A limited number of randomized clinical trials suggests that the LMWH might also be as effective as NFH, as expected at doses about 3 times as high as those used for prophylaxis.
Heparin, Low-Molecular-Weight↗
[Heparin in the treatment and secondary prevention of myocardial infarction. A critical review of the main trials].
The aim of this article is to assess the therapeutic value of standard heparin in the acute phase and secondary prevention of myocardial infarction. Only clinical trials with an adequate methodology have been analysed. In patients having undergone thrombolytic therapy associated with aspirin, heparin slightly reduces the mortality but only during the period of its administration. In a metaanalysis of approximately twenty clinical trials of patients not receiving thrombolytic or aspirin therapy, heparin was associated with a significant reduction of deep vein thrombosis, pulmonary embolism, recurrent myocardial infarction and cerebrovascular accidents. In the context of secondary prevention of myocardial infarction, the administration of a moderate dose of subcutaneous heparin resulted in a beneficial effect on morbidity and mortality in one published trial. The use of low molecular weight heparins for the prevention of coronary thrombosis merits attention because of the pharmacological and pharmacokinetic properties of these products.
Cerebrovascular Disorders↗
[Erythrocyte aggregation in vascular disease. Influence++ of hypertension].
In vascular diseases, when the vasomotor reserve is exhausted, microcirculation is strongly dependent on blood fluidity. For patients with vascular disorders, it was therefore decided to evaluate red blood cells (RBC) aggregation and disaggregation (SEFAM erythro-aggregometer) which are important factors determining blood viscosity in low flow areas. Our results show that, in essential hypertension (EH), RBC aggregation is significantly increased (+15%), and disaggregation is decreased (-20%). The highest frequency of troubles was found in EH. This observation led to exclusion of EH subjects in all the other studied pathological groups. When EH is excluded from a group of 70 patients with cerebrovascular disorders (CVD), we did not observe significant changes in RBC aggregation. However, in essential and post-thrombotic venous insufficiency there remains a significant increase in RBC aggregation (+10%) and a decrease in disaggregation (-13%). In diabetes, disaggregation is more disabled than for controls (-16%). In all these pathologies presence of EH magnifies the abnormalities, or makes them appear like in CVD. This study underlines the critical importance of taking the influence of hypertension into consideration when evaluating RBC aggregation in vascular pathology. The increase in RBC aggregability and in the shear resistance of the aggregates, when present in vascular pathology, is likely to add a burden to the circulatory system already hindered by a deficient vasomotor regulation system.
Adult↗
Specific anti-Xa activity of LMWH (Kabi 2165, CY 216, PK 10169) against the first international standard of LMWH: a collaborative study.
Explore the source record for details and available documents.
Factor Xa Inhibitors↗
Does increased platelet aggregation have a prognostic value in the deterioration of background diabetic retinopathy? The Damad Study Group.
Many case-control studies have suggested that increased platelet aggregation (PA) could be involved in the pathogenesis of diabetic microangiopathy. However, longitudinal data are needed to support this hypothesis. We consider here such an approach in the placebo group (93 diabetic patients) of a controlled clinical trial on the effect of PA inhibitors in the treatment of diabetic retinopathy (Damad program). We have measured spontaneous PA and PA induced by ADP, collagen and arachidonic acid before treatment and yearly during a 3-year period. The assessment of retinopathy was based on the changes in the number of microaneurysms present in the macular field as seen on fluorescein angiograms during follow-up. PA was estimated by maximal decrease in optical density. The lowest ADP concentration still able to induce irreversible aggregation was also determined. No significant correlations between any baseline PA measurements and end point criterion were found (all correlation coefficients lower than 0.20). No significant changes in mean PA were observed during follow-up. Within-subject variation of PA was markedly large accounting for 61% to 98% of the total variance of various measurements. Allowances for the main characteristics of diabetes made no substantial difference to the results. These negative findings can be partly attributed to the lack of reliability of PA tests. In our study, we conclude that PA tests are not useful measures for the prediction of evolution of background diabetic retinopathy.
Adenosine Diphosphate↗