Selective Xa Inhibitor Research Articles

Factor Xa Inhibitors and Low Molecular Weight Heparins in Perioperative Surgical Thromboprophylaxis: A Network Meta-Analysis.

venous thromboembolism (VTE) prophylaxis is crucial for reducing the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). This network metaanalysis was carried out to determine the most effective intervention among selective Xa inhibitors and low molecular weight heparins (LMWHs) for perioperative surgical thromboprophylaxis in major abdominal, pelvic, lumbar spine, and lower limb surgeries. A systematic literature search was conducted for randomized controlled trials (RCTs) comparing selective factor Xa inhibitors, LMWHs, and placebo as thromboprophylaxis agents in major abdominal, pelvic, lumbar spine, and lower limb surgeries. A Bayesian network metaanalysis was performed to compare all interventions for the risk of developing DVT, VTE, major VTE, total bleeding, and major bleeding. The surface under the cumulative ranking curves was used to rank all interventions. Of 1788 retrieved references, 42 RCTs comparing 11 anticoagulants were included. As compared to enoxaparin, the risk of DVT was significantly reduced in patients treated with fondaparinux [RR: 0.53 (95% CrI: 0.31, 0.93)] and rivaroxaban [RR: 0.42 (95% CrI: 0.27, 0.64)]; VTE in patients treated with bemiparin [RR: 0.09 (95% CrI: 0, 0.7)], edoxaban [RR: 0.43 (95% CrI: 0.18, 0.96)], fondaparinux [RR: 0.55 (95% CrI: 0.34, 0.91)] and rivaroxaban [RR: 0.56 (95% CrI: 0.34, 0.85)]; major VTE in patients treated with rivaroxaban [RR: 0.26 (95% CrI: 0.11, 0.6)]. According to the surface under the cumulative ranking curves (SUCRA) value, fondaparinux and bemiparin increase the risk of serious bleeding more than other factor Xa inhibitors and LMWHs. Rivaroxaban, fondaparinux, edoxaban, and bemiparin are superior perioperative thromboprophylaxis agents than enoxaparin in major surgeries. Fondaparinux and bemiparin have shown the highest risk of major bleeding compared to other factor Xa inhibitors and LMWHs.

Efficacy and tolerance of selective and non-selective factor Xa inhibitors in the prevention of thrombosis in kidney disease in patients with systemic lupus erythematosus and antiphospholipid syndrome

The use of factor Xa inhibitors is justified in the therapy of thrombosis in antiphospholipid syndrome (APS) and active lupus nephritis (LN). To monitor the efficacy and safety of these drugs, plasma anti-Xa (aXa) activity is determined. Objective : to assess the aXa activity of selective and non-selective factor Xa inhibitors in patients with systemic lupus erythematosus (SLE) and APS depending on how they affect the kidneys. Patients and methods. Clinical and laboratory findings were prospectively analyzed in SLE and APS patients who long received low molecular weight heparins (LMWHs) and selective Xa inhibitors, such as fondaparinux and rivaroxaban. The investigation enrolled 70 patients (54 females and 16 males) aged 39 years (range, 31 to 43 years) with SLE (n=15 (21%)), primary APS (PAPS) (n=10 (14%)), and SLE + APS (n=45 (65%)). Results . Kidney disease was diagnosed in 33 (47%) of the 70 patients. LN was detected in 15 (25%) of the 60 patients: 10 and 5 patients with SLE and SLE + APS, respectively. APS nephropathy (APSN) was manifested by elevated creatinine and urea levels with normal urine sediment and no history of glomerulonephritis and was observed in 18 (33%) of the 55 patients: in 16 with SLE + APS and 2 with PAPS. The therapeutic aXa range of 0.1—1.5 IU/ml was found in 43 (61%) of the 70 patients, low and high aXa activities were seen in 14 (20%) and 13 (19%) patients, respectively. In patients with APSN, the creatinine clearance (CC) depended on aXa levels: the highest CC was noted in patients with aXa >1.5 IU/mL, the lowest CC was in those with aXa <0.9 IU/ mL (p=0.046). The levels of aXa above the therapeutic range were more common in patients taking fondaparinux (9 (31%) out of the 29 patients) than in those using nadroparin (2 (7%) out of the 29 patients) (odds ratio (OR) 1.92; 95% confidence interval (CI), 1.25—2.97; p=0.04). In the fondaparinux group, high aXa was more frequently observed in patients with high SLE activity (7 (47%) out of the 15 patients) than in those with moderate or mild SLE activity (none out of the 7 patients) (OR 1.88; 95% CI, 1.17—3.01; p=0.037) and was unassociated with LN. The highest aXa level with no signs of hemorrhage was 2.08 IU/mL. Conclusion. The level of aXa is a qualitative laboratory marker for the efficacy and safety of LMWHs and fondaparinux. In patients with APS, the enhanced aXa activity of LMWHs and fondaparinux was associated with elevated CC and was not accompanied by hemorrhage. Fondaparinux is an effective and safe anticoagulant for the treatment and prevention of thrombosis in SLE and APS. The therapeutic window for aXa should be extended in these patients.

Differential inhibitory effect of fondaparinux on the procoagulant potential of intact monocytes and monocyte-derived microparticles

Monocytes and monocyte-derived microparticles (MMPs) play a major role in acute coronary syndrome (ASC). Activated monocytes (ac-M) and MMPs support thrombin generation via tissue factor (TF). The aim of this study was to evaluate the inhibitory effect of fondaparinux, a selective Xa inhibitor, on thrombin generation supported by activated monocytes and MMPs. Monocytes were purified by elutriation. They were activated by LPS, allowing to obtain both ac-M and MMPs. Thrombin generation was performed using Fluoroscan(®) in these two cell models, in comparison with a cell-free model (TF 5 pM final). Two concentrations of ac-M (0.2 × 10⁶ and 1 × 10⁶/well) and four concentrations of MMPs (40,000; 80,000; 120,000 and 160,000/well) were tested. TGT was evaluated for increasing fondaparinux concentrations (0, 0.1, 0.4, 0.7 and 1.2 μg/ml). Without fondaparinux, 0.2 × 10⁶ ac-M and 160,000 MMPs induced comparable results. Fondaparinux inhibited thrombin generation in the three models. Inhibition was fondaparinux concentration dependent. Rate index was the most sensitive parameter, compared to lag-time, peak and endogenous thrombin potential. The rate index IC(50) were 0.69 ± 0.03 μg/ml for ac-M, 0.20 ± 0.03 μg/ml for MMPs, and 0.22 ± 0.02 μg/ml for cell-free model. Fondaparinux exerted an inhibitory effect at all concentrations, including the lowest (0.1 μg/ml). The extend of inhibition was similar between MMPs and cell-free models, and stronger than ac-M model. We assume that the efficacy of fondaparinux 2.5 mg once daily in ACS patients may be in part attributed to its inhibitory effect on MMPs.

Dual Inhibition of Blood Coagulation Factors Xa and Iia Synergize To Reduce Thrombus Weight and Thrombin Generation in a Rabbit Arteriovenous Shunt Model of Thrombosis.

Several compounds currently in development for the treatment of thrombotic disorders demonstrate high levels of specificity for single targets of the blood coagulation cascade such as factor Xa and thrombin. However, development of a single molecule dual inhibitor against factor Xa and thrombin may expand the efficacy to safety ratio of treatment options for arterial and venous thrombosis. The objective of this study was to determine if simultaneous administration of PD 0313052, a selective Xa inhibitor and argatroban, a direct thrombin inhibitor, would lead to a synergistic antithrombotic effect in a rabbit AV shunt model of thrombosis. Intravenous administration of PD 0313052 alone at doses of 0.1, 0.3, and 1.0 mg/kg/min resulted in thrombus weight (TW) reductions of 11±3, 25±10 and 67±7 % compared to the vehicle group. Argatroban at 1, 3 and 10 mg/kg/min reduced TW 16±13, 47±10 and 75±6 %. When PD 0313052 was administered at 0.1 mg/kg/min in combination with argatroban at 1, 3 or 10 mg/kg/min TW was reduced 50±7, 60±7 and 82±9 %. Likewise, argatroban at 1 mg/kg/min combined with 0.1, 0.3 or 1mg/kg/min of PD 0313052 resulted in TW reductions of 56±9, 60±9 and 84±5 %, respectively. At the lowest combined doses of PD 0313052 and argatroban there was no change in bleeding time relative to the additive fold-increases from each drug alone. The EC50 of intravenously administered PD 0313052 and argatroban was 67±23 and 178±58 ng/ml, respectively. When the drugs were combined the EC50 was reduced to 12±6 ng/ml with the PD 0313052/argatroban combination and to 83±29 ng/ml with the argatroban/PD 0313052 combination. A synergistic effect was also observed in an ex vivo assay of thrombin generation (TG). Predicted additive inhibition of TG based on the individual effects of each compound was −9±7, 9±2 and 29±7 % compared to 10±5, 32±5 and 55±3 % with the 313052/argatroban combination. The predicted effects of the argatroban/PD 0313052 combination was −9±7, 1±7 and 16±9 % compared to the actual inhibition of 5±3, 14±5 and 31±7 %. These results demonstrate a significant synergistic antithrombotic effect by combining low doses of a factor Xa and a thrombin inhibitor and support the hypothesis that development of a single molecule inhibitor against different hemostatic targets may offer greater efficacy in the prevention and treatment of venous and arterial thrombosis.