Methods for Treating Bleeding Disorders

Abstract

A method of factor X1-dependent blood coagulation enhancement in a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated polysaccharide (NASP) to the subject. A method of factor X1-dependent blood coagulation enhancement in a subject in need of enhanced blood coagulation comprising: (i) selecting a subject that is not deficient for factor X1; and (ii) administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated polysaccharide (NASP) to the subject, wherein the NASP enhances blood coagulation in a factor X1-dependent manner. A method of identifying a non-anticoagulant sulfated polysaccharide (NASP) which is capable of enhancing blood coagulation in dependence on FXI, the method comprising: a) combining a blood or plasma sample comprising activation competent FXI with a composition comprising a sulfated polysaccharide and measuring the clotting or thrombin generation parameters of the blood or plasma sample; b) combining a corresponding blood or plasma sample deficient in activation competent FXI with a composition comprising the sulfated polysaccharide and measuring the clotting or thrombin generation parameters of the blood or plasma sample; and c) comparing the clotting or thrombin generation parameters of the blood or plasma samples as determined in steps (a) and (b) with each other, wherein a decrease in the clotting time of the blood sample or an increase in peak thrombin or decrease in peak time of the plasma sample comprising activation competent FXI compared to the clotting time of the blood sample or peak thrombin or peak time of the plasma sample deficient in activation competent FXI is indicative of a NASP which is capable of enhancing blood coagulation in dependence on FXI.

1 . A method of factor XI-dependent blood coagulation enhancement in a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated polysaccharide (NASP) to the subject, wherein the NASP enhances blood coagulation in a factor XI-dependent manner. 
     
     
         2 . The method of  claim 1 , wherein the NASP is selected from the group consisting of pentosan polysulfate (PPS), fucoidan, N-acetyl-heparin (NAH), N-acetyl-de-O-sulfated-heparin (NA-de-o-8H), de-N-sulfated-heparin (De-NSH), de-N-sulfatecl-acetylated-heparin (De-NSAH), periodate-oxidized heparin (POH), chemically sulfated laminarin (CSL), chemically sulfated alginic acid (CSAA), chemically sulfated pectin (CSP), dextran sulfate (DXS) and heparin-derived oligosaccharides (HDO). 
     
     
         3 . The method of  claim 2 , wherein the NASP is PPS. 
     
     
         4 . The method of  claim 2 , wherein the NASP is fucoidan. 
     
     
         5 . The method of  claim 2 , wherein the NASP enhances the activation of factor XI. 
     
     
         6 . The method of  claim 1 , wherein the NASP is administered at a dosage of about 0.01 mg/kg to about 200 mg/kg. 
     
     
         7 . The method of  claim 1 , wherein the subject has a bleeding disorder 25 selected from the group consisting of a congenital coagulation disorder caused by a blood factor deficiency, a chronic or acute bleeding disorder, and an acquired Coagulation disorder. 
     
     
         8 . The method of  claim 7 , wherein the blood factor deficiency is of one or more factors selected from the group consisting of factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, factor XIII, and von Willebrand factor. 
     
     
         9 . The method of  claim 1 , wherein the cause of the need for enhanced blood coagulation is prior administration of an anticoagulant or surgery or other invasive procedure. 
     
     
         10 . The method of  claim 1 , further comprising administering an agent selected from the group consisting of a procoagulant, an activator of the intrinsic coagulation pathway, an activator of the extrinsic coagulation pathway, and a second NASP. 
     
     
         11 . The method of  claim 10 , wherein the activator of the intrinsic coagulation pathway is selected from the group consisting of factor Xa, factor IXa, factor XIa, factor XIIa, and kallikrein. 
     
     
         12 . The method of  claim 11 , wherein the activator of the extrinsic coagulation pathway is selected from the group consisting of tissue factor, factor VIIa, thrombin, and factor Xa. 
     
     
         13 . The method of  claim 1 , further comprising administering one or more factors selected from the group consisting of factor XI, factor XII, prekallikrein, high molecular weight kininogen (HMWK), factor V, factor Va, factor VII, factor VIII, factor VIIIa, factor IX, factor X, factor XIII, factor II, factor VIIa, and von Willebrand factor. 
     
     
         14 . The method of  claim 9 , wherein the anticoagulant is selected from the group consisting of heparin, a coumarin derivative, such as warfarin or dicumarol, tissue factor pathway inhibitor (TFPI), antithrombin III, lupus anticoagulant, nematode anticoagulant peptide (NAPc2), factor VIIa inhibitors, active-site blocked factor VIIa (factor VIIai), factor IXa inhibitors, active-site blocked factor IXa (factor IXai), factor Xa inhibitors, including fondaparinux, idraparinux, DX-9065a, and razaxaban (DPC906), active-site blocked factor Xa (factor Xai), inhibitors of factors Va and VIIIa, including activated protein C (APC) and soluble thrombomodulin, thrombin inhibitors, including hirudin, bivalirudin, argatroban, and ximelagatran, and an antibody or antibody fragment that binds a clotting factor. 
     
     
         15 . The method of  claim 14 , wherein the anticoagulant is an antibody orantibody fragment that binds a clotting factor selected from the group consisting of Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XIII, Factor II, Factor XI, Factor XII, von Willebrand factor, prekallikrein, and high molecular weight kininogen (HMWK). 
     
     
         16 . The method of  claim 1  wherein the subject is deficient in factor XI, the method further comprising administering factor XI. 
     
     
         17 . The method of  claim 1  wherein the subject is deficient in factor VIII, the method further comprising administering factor VIII or a procoagulant bypassing agent. 
     
     
         18 . The method of  claim 17  wherein the patient has inhibitor antibodies against factor VIII. 
     
     
         19 . The method of  claim 1  wherein the subject is deficient in factor IX, the method further comprising administering factor IX. 
     
     
         20 . The method of  claim 19  wherein the patient has inhibitor antibodies against factor IX. 
     
     
         21 . The method of  claim 1  wherein the NASP is administered via a non-intravenous route. 
     
     
         22 . A method of factor Xi-dependent blood coagulation enhancement in a subject in need of enhanced blood coagulation comprising:
 (i) selecting a subject that is not deficient for factor XI; and   (ii) administering a therapeutically effective amount of a composition comprising a non-anticoagulant sulfated polysaccharide (NASP) to the subject,   
       wherein the NASP enhances blood coagulation in a factor Xi-dependent manner. 
     
     
         23 . (canceled)