We investigated the protective effects of DX-9065a, an orally active, newly synthesized, and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation (DIC) in rats. Experimental DIC was induced by a 4 hour sustained infusion of thromboplastin at a dose of 2.5 mg/kg. The rats were orally administered DX-9065a at 10, 30,100 mg/kg 30 minutes before thromboplastin injection. In this DIC model, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin(ogen) degradation products, fibrinogen level, thrombin-antithrombin III complex level, prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administered at 100 mg/kg without thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggested that the new oral anti-Xa drug, DX-9065a, has a protective effect against thromboplastin-induced DIC model with little risk of bleeding.

Introduction: Careful monitoring of the hypercoagulable state is required during pregnancy. However, coagulation and fibrinolysis markers are not fully utilized because there are no reference values reflective of coagulation and fibrinolysis dynamics during pregnancy, which differ from the nonpregnant state. Methods: Changes in antithrombin (AT), fibrinogen (Fbg), prothrombin fragment 1+2 (F₁₊₂), thrombin–antithrombin complex (TAT), soluble fibrin (SF), D-dimer (DD), and protein S (PS) were investigated in healthy pregnant women, and reference ranges in the early, mid, late, and end stages of pregnancy were established. Results: The AT was essentially constant throughout pregnancy. The Fbg, F₁₊₂, TAT, and DD increased significantly as pregnancy progressed. In contrast, SF did not show a significant increase throughout the entire pregnancy period. Total PS antigen and total PS activity showed a corresponding decrease from early gestation. When test data in 3 cases in which deep vein thrombosis or intrauterine fetal death occurred during pregnancy were compared to the established reference ranges, all of the cases had multiple markers with values that exceeded the reference ranges. Conclusion: Establishing reference ranges for each week could potentially make it possible to evaluate abnormalities of the coagulation and fibrinolysis systems during pregnancy. Of note, SF might be a useful marker that reflects thrombus formation during pregnancy. Larger-scale studies will be required to establish reference ranges for every gestational week.

Summary: Tissue factor pathway inhibitor (TFPI) is present in a free-form and in lipoprotein-associated forms in plasma. In this study, the plasma concentrations of total TFPI (tTFPI) and free-form TFPI (fTFPI) were measured in 25 patients with Graves’ disease and 25 age-matched healthy subjects, and the relationship between thyroid state and plasma TFPI was examined. Plasma concentrations (median) of tTFPI and fTFPI in Graves’ patients who were hyperthyroid were significantly increased compared with Graves’patients who were euthyroid (152 ng/ml versus 124 ng/ml, p <0.01 and 41.3 ng/ml versus 20.2 ng/ml, p <0.0001, respectively), and control subjects (152 ng/ml versus 96 ng/ml, p <0.0001 and 41.3 ng/ml versus 18.7 ng/ml, p <0.0001, respectively). There was no significant difference in plasma fTFPI concentrations between the euthyroid group and the control group. Plasma fTFPI concentrations correlated closely with thyroid hormone (T3) levels in the patients (r = 0.559, p <0.005). Serial measurement of individual patients revealed that plasma concentrations of fTFPI and tTFPI were significantly decreased, reaching normal control values upon attainment of euthyroidism. In conclusion, the close correlation between plasma fTFPI and serum thyroid hormone levels suggests that thyroid hormones might influence the synthesis or metabolism of TFPI on the surface of endothelial cells in patients with Graves’ disease. This is the first report concerning high concentrations of plasma fTFPI in patients with hyperthyroidism.