This study confirms the synergistic antithrombotic effects of a combined ASA and clopidogrel therapy and shows the early benefit obtained with a loading dose of clopidogrel.

This study demonstrates that a low haematocrit is the main determining factor of the prolonged bleeding time often encountered in uraemic haemodialysed patients. Thirty-three patients submitted to regular haemodialysis and having a platelet count greater than 100 X 10(9)/l were investigated with the following tests: simplate bleeding time, blood cell count, platelet aggregation induced by ADP, collagen and sodium arachidonate, arachidonate induced MDA synthesis, tests for detection of an acquired storage pool disease, and factor VIII complex level. The results were compared to two other groups; one of uraemic patients not yet subjected to haemodialysis and another of healthy volunteers. The results were basically identical in the two groups of uraemic patients. The only consistent abnormality was a 30-35% reduction in the platelet MDA synthesis in comparison with control subjects. There was a negative correlation between the log bleeding time and the haematocrit (r = 0.78, P less than 0.01). Fourteen uraemic patients having a prolonged bleeding time were submitted to a red cell transfusion programme and were investigated a second time under identical conditions. There was no change in any of the platelet function tests or in the factor VIII complex level, but the bleeding time was normalized when the post-transfusion haematocrit was over 26% (nine patients). This study emphasizes the role of anaemia in the pathogenesis of the prolonged bleeding time in uraemia and suggests that red cell transfusion can be a long-term efficient therapeutic measure to stop bleeding in these patients.

Heparin catalyses the inhibition of two key enzymes of blood coagulation, namely Factor Xa and thrombin, by enhancing the antiproteinase activities of plasma antithrombin III and heparin cofactor II. In addition, heparin can directly inhibit the activation of Factor X and prothrombin. The contributions of each of these effects to the anticoagulant activity of heparin have not been delineated. We therefore performed experiments to assess how each of these effects of heparin contributes to its anticoagulant activity by comparing the effects of heparin, pentosan polysulphate and D-Phe-Pro-Arg-CH2Cl on the intrinsic pathway of coagulation. Unlike heparin, pentosan polysulphate catalyses only the inhibition of thrombin by plasma. D-Phe-Pro-Arg-CH2Cl is rapid enough an inhibitor of thrombin so that when added to plasma no complexes of thrombin with its inhibitors are formed, whether or not the plasma also contains heparin. Heparin (0.66 microgram/ml) and pentosan polysulphate (6.6 micrograms/ml) completely inhibited the intrinsic-pathway activation of 125I-prothrombin to 125I-prothrombin fragment 1 + 2 and 125I-thrombin. On the addition of thrombin, a good Factor V activator, to the plasma before each sulphated polysaccharide, the inhibition of prothrombin activation was demonstrable only in the presence of higher concentrations of the sulphated polysaccharide. D-Phe-Pro-Arg-CH2Cl also completely inhibited the intrinsic-pathway activation of prothrombin in normal plasma. The inhibitory effect of D-Phe-Pro-Arg-CH2Cl was reversed if thrombin was added to the plasma before D-Phe-Pro-Arg-CH2Cl. The inhibition of the activation of prothrombin by the three agents was also abolished with longer times with re-added Ca2+. Reversal of the inhibitory effects of heparin and pentosan polysulphate was associated with the accelerated formation of 125I-thrombin-antithrombin III and 125I-thrombin-heparin cofactor complexes respectively. These results suggest that the anticoagulant effects of heparin and pentosan polysulphate are mediated primarily by their ability to inhibit the thrombin-dependent activation of Factor V, thereby inhibiting the formation of prothrombinase complex, the physiological activator of prothrombin.

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SummaryThis study was performed to determine the accuracy of D-Dimer fibrin derivatives, thrombin-antithrombin III (TAT) complexes and prothrombin fragments 1 + 2 (F 1 + 2) determinations for the diagnosis of deep vein thrombosis (DVT). One hundred and sixteen consecutive patients referred to the angiology unit of our hospital for a clinically suspected DVT were investigated. They were submitted to mercury strain gauge plethysmography and to ultrasonic duplex scanning examination; in cases of inconclusive results or of proximal DVT (n = 35), an ascending phlebography was performed. After these investigations were completed, the diagnosis of DVT was confirmed in 34 and excluded in 82. One half of the patients were already under anticoagulant therapy at the time of investigation. The 3 biological markers were assayed using commercially available ELISA techniques and the D-Dimer was also assayed with a fast latex method. The normal distribution of these markers was established in 40 healthy blood donors. The most accurate assay for the diagnosis of DVT was the D-Dimer ELISA which had both a high sensitivity (94%) and a high negative predictive value (95%). The D-Dirner latex, TAT complexes and F 1 + 2 were far less sensitive and provided negative predictive values which ranged between 78 and 85%. In spite of positive and significant correlations between the levels of ihe 3 markers, their association did not improve their overall accuracy for detecting D\/L Therefore, with the exception of the D-Dimer ELISA, these markers were of little value for the diagnosis of DVT in this specific population.

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Objective To establish the plasma evolution of prothrombin fragments 1+2 (F1+2), thrombin–antithrombin III complexes (TAT), fibrin fragment D‐Dimers (DD), von Willebrand factor antigen (vWf), Type 1 plasminogen activator inhibitor antigen (PAI) and blood platelet count during normal pregnancy and to compare these values with those obtained in hypertensive or pre‐eclamptic pregnancies. Design Cross‐sectional study. Subjects Forty‐seven healthy pregnant women with gestational age ranging between 5 and 40 weeks, and fourteen women with gestational age ranging between 25 and 38 weeks presenting with either gestational hypertension (n= 4) or pre‐eclampsia (n= 10). Numbers of nulliparous women in the control, hypertension and pre‐eclampsia groups were 13/47 (28%), 1/4 (25%) and 9/10 (90%), respectively. Results All six markers increased with gestational age in normal pregnant women (P<0.01). Using the upper limit of 95% prediction interval obtained from regression curves as normality threshold, TAT showed the best sensitivity (71%vs <30% for F 1+2, DD, vWf, PAI and platelet count). Conclusion TAT appears to be an interesting marker for detecting haemostatic system alterations in pregnancies complicated by hypertension or pre‐eclampsia. A large prospective study to determine its clinical usefulness for such complicated pregnancies is currently in progress.

SummaryThis paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. The study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses <1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (Cmax) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (Cl) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major role in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9 mg, Cmax, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the “steady state” was obtained 2 to 3 days after the first injection at which the mean Cmax was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8000 anti-XaIU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 μg ⋅ ml-1 (2 and 2.5 anti-Xa IU ⋅ ml-1).