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We have previously demonstrated that recombinant human soluble (rhs) thrombomodulin (TM) inhibits the endotoxin (ET)-induced increase in pulmonary vascular permeability by inhibiting leukocyte activation. In the present study, we examined whether rhs-TM could inhibit the ET-induced increase in pulmonary vascular permeability in rats by activating protein C. rhs-TM did not inhibit ET-induced increases in pulmonary vascular permeability when its protein C activation ability was selectively inhibited by a monoclonal antibody (MAb) against rhs-TM (MAb R5G12). Histological examination revealed that neutrophil infiltration in lung tissues after ET administration was significantly reduced by rhs-TM, but infiltration was not reduced by MAb R5G12-pretreated rhs-TM. ET-induced intravascular coagulation was prevented by rhs-TM and by MAb R5G12-pretreated rhs-TM. However, ET-induced coagulation was not prevented by rhs-TM that had been treated with MAb F2H5, which cannot bind thrombin or activate protein C. These observations strongly suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes through thrombin binding and the subsequent protein C activation and may prevent ET-induced intravascular coagulation through thrombin binding.

Summary.  Background: Anticoagulants are often given for extended periods of time to patients at high risk for venous thromboembolism, such as after orthopedic surgery. Daily subcutaneous (sc) injections can be inconvenient to the patient. A long‐acting anticoagulant requiring less frequent dosing could make treatment more acceptable. Thrombomodulin is a natural anticoagulant that activates protein C, which leads to inactivation of factor (F)Va and FVIIIa and decreased thrombin formation. Recombinant human thrombomodulin is a novel anticoagulant with a long half‐life in animal models. Methods and results: This phase I study examined pharmacokinetics, pharmacodynamics, and safety of recombinant human soluble thrombomodulin (ART‐123) after administration of doses between 0.02 and 0.06 mg kg−1 body weight intravenously (iv), and between 0.02 and 0.45 mg kg−1 sc in 55 healthy volunteers. The plasma half‐life was 2–3 days after sc injection of various single doses. Plasma ART‐123 levels estimated to be needed for prevention of thrombus formation in humans were maintained for at least 6 days after single sc injection of 0.30 and 0.45 mg kg−1 ART‐123. Antithrombotic activity with these doses was demonstrated by achieving prothrombinase inhibition of more than 80% for more than 6 days after administration. No major bleeding occurred. Pharmacodynamic modeling revealed that adequate antithrombotic ART‐123 levels can be achieved for 6 days with one dose of 0.45 mg kg−1 ART‐123, and for 12 days with 2 doses of 0.30 mg kg−1, given 5 days apart. Conclusions: Recombinant human soluble thrombomodulin (ART‐123) has a long half‐life after sc injection and is well tolerated, making it a suitable agent to be tested in clinical thromboprophylaxis trials.

This study demonstrated that intravenous infusion of recombinant human soluble thrombomodulin (rhs-TM) could inhibit disseminated intravascular coagulation (DIC) caused by 4 hr infusion of tissue factor (TF) in rats. Extended infusion of TF reduced fibrinogen and platelet counts and elevated serum FDP level. Pretreatment and coinfusion of rhs-TM could block changes of these DIC-parameters without prolongation of APTT. Heparin, which is a potent anti-DIC drug, could also inhibit these changes with extra prolongation of APTT and PT. Thus, these results suggest thrombomodulin prevent DIC less bleeding tendency than heparin.

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