Abstract: Compositions and methods for regulating the blood coagulation pathway are disclosed. More particularly, the present disclosure relates to thrombin-thrombomodulin fusion proteins and their use as blood anticoagulants and for treating sepsis.

Abstract: Compositions and methods for regulating the blood coagulation pathway are disclosed. More particularly, the present disclosure relates to thrombin-thrombomodulin fusion proteins, vectors, host cells and methods for preparing the thrombin-thrombomodulin fusion proteins. The present disclosure further relates to methods for measuring protein C in plasma and kits for measuring protein C in plasma.

Abstract: Compositions and methods for regulating the blood coagulation pathway are disclosed. More particularly, the present disclosure relates to thrombin-thrombomodulin fusion proteins and their use as blood anticoagulants and for treating sepsis.

Abstract: Compositions and methods for regulating the blood coagulation pathway are disclosed. More particularly, the present disclosure relates to thrombin-thrombomodulin fusion proteins, vectors, host cells and methods for preparing the thrombin-thrombomodulin fusion proteins. The present disclosure further relates to methods for measuring protein C in plasma and kits for measuring protein C in plasma.

Abstract: A recombinant serine protease precursor that auto-activates in an aqueous buffer to form a mature active enzyme is disclosed. A contemplated precursor contains 1 to about 10 heterologous amino acid residues that function to enhance by at least ten-fold the room temperature rate of auto-lytic bond cleavage to form the active enzyme relative to the auto-lytic cleavage rate of the native enzyme precursor when each precursor is dispersed in an aqueous buffer at an optimal pH value for the proteolytic activity of the protease. Illustrative active enzymes include serine proteases such as thrombin and protein C. A method of preparing and using an enzyme precursor is also disclosed.

Abstract: One aspect of the invention contemplates a mutant E-WE thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence. Another aspect contemplates a thrombin precursor that contains the amino acid residue sequence Asp/Glu-Gly-Arg at positions 325, 326 and 327 based on the preprothrombin sequence. A third aspect contemplates a thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence as well as the amino acid residue sequence Asp/Glu Gly Arg at positions 325, 326 and 327 based on the preprothrombin sequence. Also contemplated is a composition that contains an effective amount of mutant thrombin dissolved or dispersed in a pharmaceutically acceptable carrier. A method is also disclosed for enhancing treating and preventing thrombosis in a mammal in need using that composition.

Abstract: A recombinant serine protease precursor that auto-activates in an aqueous buffer to form a mature active enzyme is disclosed. A contemplated precursor contains 1 to about 10 heterologous amino acid residues that function to enhance by at least ten-fold the room temperature rate of auto-lytic bond cleavage to form the active enzyme relative to the auto-lytic cleavage rate of the native enzyme precursor when each precursor is dispersed in an aqueous buffer at an optimal pH value for the proteolytic activity of the protease. Illustrative active enzymes include serine proteases such as thrombin and protein C. A method of preparing and using an enzyme precursor is also disclosed.

Abstract: One aspect of the invention contemplates a mutant E-WE thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence. Another aspect contemplates a thrombin precursor that contains the amino acid residue sequence Asp/Glu-Gly-Arg at positions 325, 326 and 327 based on the preprothrombin sequence. A third aspect contemplates a thrombin precursor that contains the SEQ ID NO:1 amino acid residue sequence as well as the amino acid residue sequence Asp/Glu Gly Arg at positions 325, 326 and 327 based on the preprothrombin sequence. Also contemplated is a composition that contains an effective amount of mutant thrombin dissolved or dispersed in a pharmaceutically acceptable carrier. A method is also disclosed for enhancing treating and preventing thrombosis in a mammal in need using that composition.

Abstract: The present invention provides methods for inhibiting the anticoagulation effect of a thrombin inhibitor in a patient in need thereof comprising administration of a therapeutically effective amount of a variant prothrombin or thrombin that is capable of binding the thrombin inhibitor and that has reduced procoagulant activity. Variant prothrombins or thrombins of use in the methods of the present invention include thrombin mutants W215A, W215A/E217A, or variants thereof in which the amino acids at positions 215 and/or 217 are alanine. Methods are also provided in which the thrombin mutants are administered with an additional active agent, particularly hemostatic agents such as activated factor VII or activated prothrombin complex concentrate. In one embodiment of the invention, the methods are useful in the treatment of patients in which a direct thrombin inhibitor has been administered, particularly argatroban.

Abstract: The present invention relates to novel antithrombotic variants of thrombin or fragments thereof that are capable of proteolytically activating protein C, but which are substantially free of fibrinogen cleavage activity. The present invention further relates to variant polypeptidess that may be cleaved to yield active thrombin variants. The present invention also relates to methods of inhibiting thrombus formation in an animal or human subject by delivering an antithrombotic variant thrombin of the present invention to the blood of the subject. The present invention relates also to methods that use the novel variant thrombins for determining the level of protein C activation in a blood sample, or the thrombogenic potential of a patient.

Abstract: The present invention relates to novel antithrombotic variants of thrombin or fragments thereof that are capable of proteolytically activating protein C, but which are substantially free of fibrinogen cleavage activity. The present invention further relates to variant polypeptidess that may be cleaved to yield active thrombin variants. The present invention also relates to methods of inhibiting thrombus formation in an animal or human subject by delivering an antithrombotic variant thrombin of the present invention to the blood of the subject. The present invention relates also to methods that use the novel variant thrombins for determining the level of protein C activation in a blood sample, or the thrombogenic potential of a patient.