Edoxaban improves acute venous thromboembolism while preserving protein C and protein S levels.

BACKGROUND: It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically, to an initial hypercoagulable state. Edoxaban, a direct inhibitor of activated factor X is widely used for the treatment of acute venous thromboembolism (VTE). However, the effect of edoxaban on circulating coagulation factors, in patients with acute VTE, remains unknown. METHODS AND RESULTS: We enrolled 57 patients with acute VTE with/without pulmonary embolism treated with edoxaban (n=37) or warfarin (n=20) in a clinical setting. Before treatment and 2 weeks after treatment, we evaluated thrombotic burden using ultrasound or computed tomography angiography. We also evaluated thrombin generation, represented by prothrombin fragment F1+2; thrombus degradation, represented by D-dimer; and levels of anticoagulants, including protein C, protein S, and antithrombin III. Both edoxaban and warfarin treatment improved thrombotic burden and decreased prothrombin fragment F1+2, and D-dimer. Edoxaban treatment preserved protein C and protein S levels. In contrast, warfarin decreased protein C and protein S levels. Neither treatment affected antithrombin III. CONCLUSIONS: Edoxaban improves VTE while preserving protein C and protein S levels, thereby indicating that edoxaban improves thrombotic burden while maintaining levels of anticoagulants.

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction.

Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic ß-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in ß-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.

Evaluación de la anticoagulación con rivaroxaban, en pacientes con fibrilación auricular no valvular de reciente diagnóstico / Evaluation of oral anticoagulation with rivaroxaban, in patients with new onset non valvular atrial fibrillation

Background: Atrial fibrillation (AF) generates a hypercoagulable state with an increased thrombin generation and raised levels of thrombin-antithrombin complexes, which results in a high risk of stroke and thromboembolism. Aim: To evaluate the anticoagulant effect of rivaroxaban by anti-Xa factor activity and its correlation with thrombin-antithrombin complexes, thrombin generation and prothrombin time in patients newly diagnosed with non-valvular AF. Patients and Methods: Prospective study in patients with indication of anticoagulation. Demographic variables, cardiovascular risk factors, CHA2DS2-VASc and HAS-BLED scores were recorded. Blood samples were taken at baseline, at 3 and 24 hours after the administration of the drug and at 30 days. Rivaroxaban levels, anti-Xa activity, prothrombin time, thrombin generation and plasma levels of thrombin-antithrombin complexes were determined. Results: We studied 20 patients aged 76.3 ± 8.0 years (60% female) with a CHA2DS2-VASc score > 2 points. The anti-Xa factor activity correlated with rivaroxaban plasma levels at 3 hours (r = 0.61, p < 0.01), at 24 hours (r = 0.85, p < 0.01) and at 30 days (r = 0.99, p < 0.01), with prothrombin time at 3 hours (r = -0.86, p = 0.019) and at 30 days (r = -0.63, p = 0.02) and with a sustained decrease in thrombin generation at 30 days of follow-up (r = -0.74, p < 0.01). There was no correlation with thrombin-antithrombin complexes (r = -0.02, p = 0.83). Conclusions: Rivaroxaban consistently inhibited the mild pro-coagulant state found in newly diagnosed non-valvular AF patients through the first 24 hours and this effect was maintained at 30 days. Plasma levels of the drug correlated with anti-Xa factor activity, thrombin generation and prothrombin time

Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin.

Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin-antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clot weight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis, we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolution.

[Evaluation of oral anticoagulation with rivaroxaban, in patients with new onset non valvular atrial fibrillation]. / Evaluación de la anticoagulación con rivaroxaban, en pacientes con fibrilación auricular no valvular de reciente diagnóstico.

BACKGROUND: Atrial fibrillation (AF) generates a hypercoagulable state with an increased thrombin generation and raised levels of thrombin-antithrombin complexes, which results in a high risk of stroke and thromboembolism. AIM: To evaluate the anticoagulant effect of rivaroxaban by anti-Xa factor activity and its correlation with thrombin-antithrombin complexes, thrombin generation and prothrombin time in patients newly diagnosed with non-valvular AF. PATIENTS AND METHODS: Prospective study in patients with indication of anticoagulation. Demographic variables, cardiovascular risk factors, CHA2DS2-VASc and HAS-BLED scores were recorded. Blood samples were taken at baseline, at 3 and 24 hours after the administration of the drug and at 30 days. Rivaroxaban levels, anti-Xa activity, prothrombin time, thrombin generation and plasma levels of thrombin-antithrombin complexes were determined. RESULTS: We studied 20 patients aged 76.3 ± 8.0 years (60% female) with a CHA2DS2-VASc score > 2 points. The anti-Xa factor activity correlated with rivaroxaban plasma levels at 3 hours (r = 0.61, p < 0.01), at 24 hours (r = 0.85, p < 0.01) and at 30 days (r = 0.99, p < 0.01), with prothrombin time at 3 hours (r = -0.86, p = 0.019) and at 30 days (r = -0.63, p = 0.02) and with a sustained decrease in thrombin generation at 30 days of follow-up (r = -0.74, p < 0.01). There was no correlation with thrombin-antithrombin complexes (r = -0.02, p = 0.83). CONCLUSIONS: Rivaroxaban consistently inhibited the mild pro-coagulant state found in newly diagnosed non-valvular AF patients through the first 24 hours and this effect was maintained at 30 days. Plasma levels of the drug correlated with anti-Xa factor activity, thrombin generation and prothrombin time.

Simultaneous use of argatroban and heparin during cardiopulmonary bypass.

Heparin is the routine anticoagulant for cardiopulmonary bypass, but complications due to heparin are often reported. This study assessed argatroban as an alternative to heparin. Normothermic cardiopulmonary bypass with hemodilution was performed for 2 h in 15 dogs (mean weight, 9.8 kg) randomly assigned to 3 groups of 5 each. The controls were given heparin 200 IU x kg(-1) before cardiopulmonary bypass; group A had argatroban infused continuously at a rate of 20 microg x kg(-1) x min(-1); group H/A had half doses of both heparin (100 IU x kg(-1)) and argatroban (10 microg x kg(-1) x min(-1)). Blood samples were collected at 5 time points during the experiment. Activated clotting time, hemoglobin level, platelet counts, and serum concentrations of fibrinogen, antithrombin III, and thrombin-antithrombin III complex were measured. The platelet count was reduced significantly, and the production of thrombin-antithrombin III complex was inhibited in group H/A. Activated clotting time remained <300 sec at all time points in group A, but it was maintained at approximately 400 sec in group H/A. Fibrinogen and antithrombin III levels were reduced to half in all groups after initiation of cardiopulmonary bypass. The simultaneous use of heparin and argatroban infusion might be useful for cardiopulmonary bypass with hemodilution.

Human protein C zymogen concentrate in patients with severe sepsis and multiple organ failure after adult cardiac surgery.

PURPOSE: To describe outcome and changes in clotting and inflammatory parameters in an uncontrolled case series of consecutive patients with severe sepsis who received protein C concentrate soon after cardiac surgery. METHODS: From January 2007 to January 2008 nine consecutive adult patients with severe sepsis or septic shock and two or more organ failure after cardiac surgery received protein C concentrate, 50 IU/kg as a bolus followed by continuous infusion of 3 IU/kg per hour for 72 h. RESULTS: The increase in protein C levels was accompanied by an early drop in interleukins and near-normalization of prothrombin time, activated partial thromboplastin time, antithrombin and thrombin-antithrombin complex levels (p < or = 0.03). No patient experienced drug-related side effects. Thirty-day mortality was 11% (1 patient) compared to the expected mortality of 68%. CONCLUSIONS: In this pilot, uncontrolled study of nine patients with sepsis-induced double organ failure following cardiac surgery, treatment with protein C concentrate was associated with significant improvement in clinical, inflammatory and clotting parameters, no bleeding and low 30-day mortality.

Non-anticoagulant heparins and inhibition of cancer.

Low-molecular-weight heparins (LMWH) appear to prolong survival of patients with cancer. Such a beneficial effect is thought to be associated with interruption of molecular mechanisms involving the heparan sulfate (HS) chains of cell surface and extracellular matrix proteoglycans (HSPGs), growth factors and their receptors, heparanase, and selectins. The beneficial effects of heparin species could also be associated with their ability to release tissue factor pathway inhibitor from endothelium. The utility of heparin and LMWH as anticancer drugs is limited due to their anticoagulant properties. Non-anticoagulant heparins can be obtained either by removing chains containing the antithrombin-binding sequence, or by inactivating critical functional groups or units of this sequence. The non-anticoagulant heparins most extensively studied are regioselectively desulfated heparins and 'glycol-split' heparins. Some modified heparins of both types are potent inhibitors of heparanase. A number of them also attenuate metastasis in experimental models. With cancer cells overexpressing selectins, heparin-mediated inhibition of tumor cells-platelets aggregation and tumor cell interaction with the vascular endothelium appears to be the prevalent mechanism of attenuation of early stages of metastasis. The structural requirements for inhibition of growth factors, heparanase, and selectins by heparin derivatives are somewhat different for the different activities. An N-acetylated, glycol-split heparin provides an example of application of a non-anticoagulant heparin that inhibits cancer in animal models without unwanted side effects. Delivery of this compound to mice bearing established myeloma tumors dramatically blocked tumor growth and progression.

The effect of supervised exercise and cilostazol on coagulation and fibrinolysis in intermittent claudication: a randomized controlled trial.

BACKGROUND: The prothrombotic, hypofibrinolytic state that develops in patients with intermittent claudication (IC) upon walking due to ischemia-reperfusion injury (IRI) of the leg muscles may contribute to the high incidence of life- and limb-threatening thrombotic events observed in this patient group. Treatments, such as angioplasty, that obtund the IRI also ameliorate the procoagulant diathesis. The effect on this diathesis of supervised exercise and cilostazol, both of which provide symptomatic benefit in IC, but without significantly obtunding IRI, is unknown. METHODS: Thirty-four patients (27 men and 7 women; median age, 67 years; range, 63-72 years) were randomized to receive best medical therapy (BMT) plus supervised exercise (n = 9), BMT plus cilostazol (n = 9), BMT plus supervised exercise plus cilostazol (n = 7), or BMT alone (n = 9) in a 2 x 2 factorial design. Thrombin-antithrombin complex and prothrombin fragments 1 and 2, both markers of thrombin generation; plasminogen activator inhibitor antigen and tissue plasminogen activator antigen, both markers of fibrinolysis; ankle-brachial pressure index (ABPI); and initial and absolute claudication distance (ACD) were measured at baseline and then 3 and 6 months after randomization. RESULTS: At 6 months, when compared with receiving BMT only, supervised exercise and cilostazol resulted in improvements in ABPI of 18% and 13% and in ACD of 40% and 64%, respectively. The effects on ABPI and ACD of combining supervised exercise and cilostazol were additive. Supervised exercise, cilostazol, and supervised exercise combined with cilostazol had no significant effect on any of the four hemostatic markers. CONCLUSIONS: Treatment of IC by supervised exercise or cilostazol results in significant improvements in ABPI and ACD but has no demonstrable effect on the prothrombotic diathesis. This suggests that supervised exercise and cilostazol, unlike angioplasty, are unlikely to have a long-term beneficial effect on the thrombotic risks faced by these patients.

Effects of a protease inhibitor, ulinastatin, on coagulation and fibrinolysis in abdominal surgery.

PURPOSE: Ulinastatin is well known to inhibit the activity of polymorphonuclear leukocyte elastase (PMNE). The PMNE concentration correlates with the activities of coagulation and fibrinolysis. The purpose of the present study was to investigate the effects of ulinastatin, a protease inhibitor, on coagulation and fibrinolysis in abdominal surgery. METHODS: Thirty patients, aged 40 to 70 years, with American Society of Anesthesiologists (ASA) physical status I or II, scheduled for major abdominal surgery, were enrolled. Anesthesia was induced with midazolam and thiopental, and was maintained with sevoflurane, nitrous oxide in oxygen, and an epidural block. An infusion of ulinastatin, 6000 units x kg(-1) in 30 min, was started 1 h after the start of surgery in the ulinastatin group (15 patients). In the control group (15 patients), no protease inhibitors were infused. White blood cell count; platelet count; prothrombin time; activated partial thromboplastin time; and plasma concentrations of PMNE, antithrombin (AT), fibrin/fibrinogen degradation product (FDP), fibrinogen, plasminogen, plasmin-(alpha2) plasmin inhibitor complex (PIC), and thrombin-antithrombin complex (TAT) were measured before, at the end of, and 12 h after surgery. RESULTS: TAT, PIC, and FDP after surgery were significantly lower in the ulinastatin group than in the control group. AT was decreased in the control group but not in the ulinastatin group, with significant differences between the two groups. CONCLUSION: Ulinastatin could inhibit coagulation and fibrinolysis in abdominal surgery.

Age-related differences in heparin response.

INTRODUCTION: Major physiological differences in the coagulation system throughout childhood, compared to adults, are well documented. However, the impact of this on anticoagulant drugs is unknown. This study aimed to determine whether heparin therapeutic range determination is affected by the age of plasma donors and whether age-specific therapeutic ranges for heparin therapy may need to be considered in the clinical setting. MATERIALS AND METHODS: Plasma samples were obtained from healthy children and adults, and pooled into age-specific pools. These were spiked with different concentrations of heparin and APTT; Anti-Factor Xa and Anti-Factor IIa were measured using standard techniques. The experiments were repeated using three separate plasma pools, and results expressed as means with standard deviations. RESULTS AND CONCLUSIONS: The results show clear age-related differences in APTT for the same Anti-Factor Xa heparin concentration. The differences were more pronounced in younger children, with higher APTT for same Anti-Factor Xa. The Anti-Factor IIa activity of heparin for a given Anti-Factor Xa activity also differed between age-specific plasma pools. This study suggests that when using heparin in children, basic assumptions about the drug mechanism of action and implications for therapeutic ranges need to be considered.

[The comparison of simvastatin and atorvastatin effects on hemostatic parameters in patients with hyperlipidemia type II]. / Porównanie wplywu simwastatyny i atorwastatyny na wybrane parametry ukladu krzepniecia u chorych z hiperlipidemia typu II.

The studies results of statin influence on hemostasis are various. The aim of our study was to evaluate the effects of simvastatin and atorvastatin on hemostatic parameters, such as activity of factor X, antithrombin III, fibrinogen concentration and Lp(a). 72 patients (pts) aged 40-65 were involved in the study; 49 of them suffered from hyperlipidemia II (hlp II) with the initial concentration of total cholesterol (TC) >200 mg/dL, cholesterol LDL (LDL-C) >145 mg/dL, triglycerides (TG) <400 mg/dL. The control group consisted of 20 healthy persons. The pts with hlp II who underwent 4 weeks long lipid lowering diet were randomized into two groups: I--27 pts treated with simvastatin (20 mg/d), II--22 pts treated with atorvastatin (10 mg/d). The active statin therapy lasted 8 weeks. The activity of factor X and antithrombin III (AT III) was estimated by amidolytic methods, fibrinogen concentration (Fb) by the Clauss method, Lp(a)-immunoenzymatic method. The mean values of factor X activity and Fb serum concentration were higher in pts with hip II than in the control group, the AT III activity was lower. The Lp(a) concentration didn't differ between groups. Statin treatment was associated with significant reduction of factor X activity. Both simvastatin and atorvastatin markedly increased AT III (87%, 98%) in comparison to the initial values. No changes of Lp(a) concentration were observed during statin therapy. Atorvastatin therapy significantly increased the Fb concentration (12.3%). Simvastatin treatment didn't influence Fb concentration.

Effects of postmortem heparinization in canine lung transplantation with non-heart-beating donors.

OBJECTIVE: Microthrombus formation appears to be one of the major detrimental factors in lung transplantation from non-heart-beating donors. The purpose of this study was to evaluate the effects of postmortem heparinization by closed-chest cardiac massage in a canine model of left single-lung allotransplantation from non-heart-beating donors. METHODS: Left lung transplantation was performed in 18 weight-matched pairs of mongrel dogs. Donors were killed with an intravenous injection of potassium chloride and left at room temperature for 2 hours. The cadaveric donors were assigned randomly to one of the three groups. In group 1 (n = 6), no heparin was given as a control. In group 2 (n = 6), heparin sodium (1000 U/kg) was administered intravenously before cardiac arrest. In group 3 (n = 6), heparin sodium (1000 U/kg) was administered intravenously 10 minutes after death, then closed-chest cardiac massage was performed for 2 minutes. After 2 hours of cardiac arrest, donor lungs were flushed with low-potassium dextran-glucose solution and preserved for 60 minutes. After left lung transplantation, the right pulmonary artery was ligated, and recipient animals were followed up for 3 hours. Univariate and multivariate repeated analyses were used for statistics. RESULTS: Both groups 2 and 3 had significantly better gas exchange and lower pulmonary vascular resistance than group 1. Changes in thrombin-antithrombin III complex concentration during the warm ischemia indicated that postmortem heparinization suppressed clotting activation in the donor. CONCLUSIONS: Postmortem heparinization by cardiac massage is beneficial in lung transplantation from non-heart beating donors by preventing microthrombus formation.

Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin.

The abilities of three synthetic oligosaccharides to accelerate antithrombin inhibition of ten clotting or fibrinolytic proteinases were compared with those of unfractionated, fractionated high-affinity and low-molecular-weight heparins. The results show that the anticoagulant effects of the latter three heparins under conditions approximating physiologic are exerted almost exclusively by acceleration of the inactivation of thrombin, factor Xa and factor IXa to near diffusion-controlled rate constants of approximately 10(6) - 10(7) M(-1).s(-1). All other proteinases are inhibited with at least 20-fold lower rate constants. The anti-coagulant ability of the synthetic regular (fondaparinux) and high-affinity (idraparinux) pentasaccharides is due to a common mechanism, involving acceleration of only factor Xa inhibition to rate constants of approximately 10(6) M(-1).s(-1) . A synthetic hexadecasaccharide, containing both the pentasaccharide sequence and a proteinase binding site, exerts its anticoagulant effect by accelerating antithrombin inactivation of both thrombin and factor Xa to rate constants of approximately 10(6) - 10(7) M(-1).s(-1), although thrombin appears to be the more important target. In contrast, factor IXa inhibition is appreciably less stimulated. The conformational change of antithrombin induced both by the pentasaccharides and longer heparins contributes substantially, approximately 150-500-fold, to accelerating the inactivation of factors Xa, IXa and VIIa and moderately, approximately 50-fold, to that of factor XIIa and tissue plasminogen activator inhibition. The bridging effect due to binding of antithrombin and proteinase to the same, long heparin chain is dominating, approximately 1000-3000-fold, for thrombin inhibition and is appreciably smaller, although up to approximately 250-350-fold, for the inactivation of factors IXa and XIa. These results establish the proteinase targets of heparin derivatives currently used in or considered for thrombosis therapy and give new insights into the mechanism of heparin acceleration of antithrombin inhibition of proteinases.

A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next?

Heparin is a sulfated glycosaminoglycan isolated from animal organs that has been used clinically as an antithrombotic agent since the 1940s. In the early 1980s it was discovered that a unique pentasaccharide domain in some heparin chains activates antithrombin III (AT-III), a serine protease inhibitor that blocks thrombin and factor Xa in the coagulation cascade. Sanofi-Synthélabo and Organon developed a synthetic analogue of this pentasaccharide. The resulting antithrombotic drug arixtra, which went on the market in the USA and Europe in 2002, shows superior antithrombotic activity and brings about AT-III-mediated activity against factor Xa exclusively. Structure-based design has subsequently led to analogues with longer-lasting activity, such as idraparinux, as well as novel conjugates and long oligosaccharides with specific anti-Xa and antithrombin activities. The new drug candidates are more selective in their mode of action than heparin and less likely to induce thrombocytopenia.

Activation of coagulation occurs after electrical cardioversion in patients with chronic atrial fibrillation despite optimal anticoagulation with warfarin.

BACKGROUND: There is evidence for the activation of the coagulation system and a hypercoagulable state following cardioversion. The aim of the study was to determine whether electrical cardioversion in patients with chronic atrial fibrillation induced a prothrombotic state despite optimal anticoagulation. We studied the effects of electrical cardioversion on plasma levels of fibrinogen, antithrombin III, protein C and D-dimers. METHODS: We studied 24 patients with chronic atrial fibrillation who were on optimal anticoagulation and were referred for electrical cardioversion. Samples of venous blood were taken 2 h pre and post cardioversion and 1 month later. RESULTS: Plasma median concentrations of fibrinogen decreased significantly from 3.8 g/l (interquartile range 3.1-4.2 g/l) before cardioversion to 3.5 g/l (interquartile range 2.9-3.9 g/l) 2 h after cardioversion levels (P=0.004). The fibrinogen levels at 1 month post cardioversion (3.45 g/l, interquartile range 3.1-3.9 g/l) were also significantly lower than baseline (P=0.02). Plasma median levels of antithrombin III fell from 93.5 U/dl (interquartile range 89.3-97.0 U/dl) pre cardioversion to 89.5 U/dl (interquartile range 83.0-93.0 U/dl) 2 h after cardioversion (P=0.001) and returned to normal by 1 month (94.0 U/dl; interquartile range 89.3-98.5 U/dl; P=0.0001). There were no significant changes in plasma median D-dimer or protein C levels at any time. CONCLUSIONS: We have demonstrated a significant fall in the plasma fibrinogen and antithrombin III levels in patients with chronic atrial fibrillation early after electrical cardioversion, indicating thrombin generation. This study suggests that there are haemostatic changes of thrombogenesis induced by cardioversion despite optimal anticoagulation with warfarin.

[From heparin to synthetic antithrombotic oligosaccharides]. / De l'héparine aux oligosaccharides antithrombotiques de synthèse.

In the early eighties, following breakthroughs in oligosaccharide chemistry, we achieved the total chemical synthesis of pentasaccharides related to the antithrombin-binding domain in heparin. Selective inhibitors of coagulation factor Xa, thus obtained, represent a new class of efficient antithrombotic drugs. In a further step, we have designed and synthesised oligosaccharides (pentadeca--to eicosasaccharides), comprising an antithrombin binding domain prolonged by a thrombin binding domain. These compounds inhibit both factor Xa and thrombin, in the presence of antithrombin, while they are devoid of undesirable non-specific interactions, particularly with platelet factor 4 (PF4). The efficacy of these new synthetic antithrombotics, with a unique biological profile, will be evaluated in clinical trials.

Significant differential effects of hormone therapy or tibolone on markers of cardiovascular disease in postmenopausal women: a randomized, double-blind, placebo-controlled, crossover study.

OBJECTIVE: The objective was to compare the effects of tibolone and hormone therapy (HT) on lipid profile, vasodilation, and factors associated with inflammation and hemostasis. METHODS AND RESULTS: Fifty-three women received micronized progesterone (MP, 100 mg) with conjugated equine estrogen (CEE, 0.625 mg) or tibolone (2.5 mg) daily for 2 months, with a 2-month washout period. Compared with HT, tibolone significantly reduced total cholesterol (P<0.001), triglyceride (P<0.001), and HDL cholesterol (P<0.001) levels as well as triglyceride/HDL cholesterol ratios (P<0.001) but not LDL cholesterol levels. Tibolone significantly improved flow-mediated brachial artery dilator response to hyperemia from baseline values (P<0.001) by a magnitude similar to that found with HT (P=0.628). Compared with tibolone, which showed no changes, HT significantly increased high-sensitivity C-reactive protein (hsCRP, P=0.030) and reduced antithrombin III (P<0.001). HT and tibolone significantly increased prothrombin fragment 1+2 (F1+2) from baseline values (P<0.001 and P=0.004, respectively). The effects of HT and tibolone on hsCRP, antithrombin III, and F1+2 were significantly different. HT and tibolone significantly reduced plasma levels of plasminogen activator inhibitor type 1 antigen from baseline levels (P=0.006 and P=0.005, respectively) to a similar degree (P=0.988). CONCLUSIONS: Tibolone significantly improved flow-mediated brachial artery dilator response by a magnitude similar to that found with CEE+MP; however, tibolone did not significantly change hsCRP and antithrombin III, and tibolone increased F1+2 less than did CEE+MP.