Methods for treating bleeding disorders using a platelet subpopulation
View Patent ↗The present invention relates to a platelet subpopulation with high binding capacity to recombinant activated factor VII (rFVIIa), and its use for the treatment of bleeding disorders and for determining whether a subject is a candidate for treatment with rFVIIa.
1. A method of treating a bleeding disorder in a subject in need thereof, the method comprising
a) selecting a subject by (i) incubating a platelet population obtained from the subject with at least 5 nm of rFVIIa and (ii) detecting a subpopulation of platelets comprising at least 1% of the platelet population wherein said platelet subpopulation has at least a 4-fold higher binding capacity to rFVIIa, as compared to the binding capacity to rFVIIa of the other platelets in the platelet population and
b) administering a therapeutically effective amount of rFVIIa to a subject identified by step (ii).
2. The method of claim 1 , wherein the subpopulation of platelets comprises platelets having about a 6-fold higher binding capacity to rFVIIa, as compared to the binding capacity to rFVIIa of the other platelets in the platelet population.
3. The method of claim 1 , wherein the bleeding disorder is hemophilia A or hemophilia B.
4. The method of claim 1 , wherein the subject is a human.
5. The method of claim 1 , wherein the bleeding disorder is a non-hemophilia bleeding disorder and the subject does not have an unacceptable risk of thrombosis.
6. The method of claim 1 , wherein the subpopulation of platelets comprises at least 2% of the platelet population.
7. The method of claim 1 , wherein the subpopulation of platelets comprises at least 3% of the platelet population.
8. The method of claim 1 , wherein the bleeding disorder is congenital hemophilia A with inhibitors or acquired hemophilia A with inhibitory auto an bodies to FVIII.
9. The method of claim 1 , wherein the bleeding disorder is congenital hemophilia B with inhibitors or acquired hemophilia B with inhibitory auto antibodies to FIX.
10. The method of claim 1 , wherein the bleeding disorder is blood loss from trauma, FVII deficiency, FV deficiency, FX deficiency, FXI deficiency, FXIII deficiency, fibrinogen deficiency, prothrombin deficiency, dilutional coagulopathy, thrombocytopenia, blood loss from high-risk surgeries, intracerebral hemorrhage, von Willebrand disease or von Willebrand disease with inhibitors to von Willebrand factor.
11. The method of claim 1 , wherein the platelets in the subpopulation of platelets are activated.
12. The method of claim 1 , wherein the platelets in the subpopulation of platelets are non-activated.
13. The method of claim 1 , wherein the platelets in the subpopulation of platelets are coated.
14. A method of treating a bleeding disorder in a subject in need thereof, the method comprising
a) selecting a subject by (i) incubating a platelet population obtained from the subject with at least 5 nm of rFVIIa and (ii) determining that the subject lacks a subpopulation of platelets comprising at least 1% of the platelet population wherein said platelet subpopulation has at least a 4-fold higher binding capacity to rFVIIa, as compared to the binding capacity to rFVIIa of the other platelets in the platelet population, and
b) administering a therapeutically effective amount of an alternative therapy that does not comprise the administration of rFVIIa to a subject identified by step (ii).
15. The method of claim 14 , wherein (ii) comprises determining that the subject lacks a subpopulation of platelets comprising at least 1% of the platelet population wherein said platelet subpopulation has about a 6-fold higher binding capacity to rFVIIa, as compared to the binding capacity to rFVIIa of the other platelets in the platelet population.
16. The method of claim 14 , wherein the alternative therapy is Prothrombin Complex Concentrate, activated Prothrombin Complex Concentrate, recombinant Factor IX, recombinant Factor VIII, recombinant anti-hemophilic factor, desmopressin, Factor IX complex, cryoprecipitated anti-hemophilic factor (AHF), fresh frozen plasma (FFP), recombinant porcine FVIII, recombinant FV variants, recombinant FVIIIa variants, recombinant FXa variants, FXIII, prothrombin, fibrinogen, a mix of coagulation factors, antibodies mimicking FVIII, peptides mimicking FVIII, compounds mimicking FVIII, peptide inhibitors of TFPI, antibody inhibitors of TFPI, compounds inhibiting TFPI, or compounds inhibiting anti-coagulant proteins.
17. The method of claim 14 , wherein the bleeding disorder is hemophilia A or hemophilia B.
18. The method of claim 14 , wherein the subject is a human.
19. The method of claim 14 , wherein the bleeding disorder is a non-hemophilia bleeding disorder.
20. A method of treating a bleeding disorder in subject in need thereof, the method comprising
a) selecting a subject by (i) incubating a platelet population from a subject with at least 5 nm of rFVIIa and (ii) detecting a subpopulation of platelets comprising at least 1% of the platelet population wherein said platelet subpopulation has at least a 3.5 fold higher binding capacity to rFVIIa upon dual activation of the platelet population by two agonists, as compared to the binding capacity to rFVIIa of non-activated platelets obtained from subject, and
b) administering a therapeutically effective amount of rFVIIa to a subject identified by step (ii).
21. The method of claim 20 , wherein the bleeding disorder is hemophilia, blood loss from trauma, FVII deficiency, FV deficiency, FX deficiency, FXI deficiency, FXIII deficiency, fibrinogen deficiency, prothrombin deficiency, dilutional coagulopathy, thrombocytopenia, blood loss from high-risk surgeries, intracerebral hemorrhage, von Willebrand disease or von Willebrand disease with inhibitors to von Willebrand factor.
22. The method of claim 20 , wherein the subject is a human.
23. The method of claim 20 , wherein the subpopulation of platelets comprises at least 2% of the platelet population.
24. The method of claim 20 , wherein the subpopulation of platelets comprises at least 3% of the platelet population.
25. The method of claim 20 , wherein the bleeding disorder is congenital hemophilia A with inhibitors or acquired hemophilia A with inhibitory auto antibodies to FVIII.
26. The method of claim 20 , wherein the bleeding disorder is congenital hemophilia B with inhibitors or acquired hemophilia B with inhibitory auto antibodies to FIX.