Use of VWF stabilized FVIII preparations and of VWF preparations without FVIII for extravascular administration in the therapy and prophylactic treatment of bleeding disorders

1. A method for treating von Willebrand disease (VWD) and/or hemophilia A, comprising extravascularly administering a composition comprising purified von Willebrand factor (VWF) and factor VIII (FVIII), wherein the ratio of VWF antigen (VWF:Ag) to factor VIII-coagulant (FVIII:C) is larger than 5:1, wherein the VWF has a ratio of von Willebrand factor to ristocetin cofactor activity (VWF:RCoF) to von Willebrand factor antigen (VWF:Ag) which is equal to or less than 1:1.05, wherein the VWF is not chemically modified.

2. A method for treating von Willebrand disease (VWD) and/or hemophilia A, comprising extravascularly co-administering von Willebrand factor (VWF) and factor VIII (FVIII), wherein the ratio of VWF antigen (VWF:Ag) to factor VIII-coagulant (FVIII:C) is larger than 5:1, wherein the VWF has a ratio of von Willebrand factor to ristocetin cofactor activity (VWF:RCoF) to von Willebrand factor antigen (VWF:Ag) which is equal to or less than 1:1.05, wherein the VWF is not chemically modified, and wherein the extravascular co-administration:

a) prolongs the time period during which the FVIII activity in plasma is increased by at least 0.01 U/mL,

b) increases the maximal concentration of FVIII activity in plasma, or

c) increases the area under the data curve (AUDC) of FVIII activity as compared to the respective parameter when the FVIII is administered in the same concentration, dose, and in the same mode of extravascular administration but without VWF.

3. The method according to claim 2 , wherein the extravascular co-administration prolongs parameter a) by at least a factor of 3, increases parameter b) by at least a factor of 3, or increases parameter c) by at least a factor of 5 as compared to the respective parameter when the FVIII is administered in the same concentration, dose, and in the same mode of extravascular administration but without VWF.

4. A method for treating von Willebrand disease (VWD) and/or hemophilia A by generating fewer inhibitory antibodies against FVIII as compared to when the FVIII is administered in the same concentration, dose, and in the same mode of extravascular administration but without VWF comprising extravascularly co-administering von Willebrand factor (VWF) and factor VIII (FVIII), wherein the ratio of VWF antigen (VWF:Ag) to factor VIII-coagulant (FVIII:C) is larger than 5:1, wherein the VWF has a ratio of von Willebrand factor to ristocetin cofactor activity (VWF:RCoF) to von Willebrand factor antigen (VWF:Ag) which is equal to or less than 1:1.05, and wherein the VWF is not chemically modified.

5. The method according to claim 4 , wherein the extravascular co-administration generates at least 15% fewer inhibitory antibodies as compared to when the pharmaceutical composition of FVIII is administered in the same concentration, dose, and in the same mode of extravascular administration but without VWF, and wherein the titer of inhibitory antibodies is determined with the Bethesda assay.

6. A method for treating von Willebrand disease (VWD) and/or hemophilia A, comprising extravascularly administering von Willebrand factor (VWF), wherein the VWF has a ratio of von Willebrand factor ristocetin cofactor activity (VWF:RCoF) to von Willebrand factor antigen (VWF:Ag) which is equal to or less than 1:1.05, and wherein the VWF is not chemically modified.

7. The method according to claim 1 , wherein the von Willebrand factor is derived from human plasma or is produced recombinantly.

8. A method for treating von Willebrand disease (VWD) and/or hemophilia A, comprising extravascularly administering a composition comprising purified von Willebrand factor (VWF) and factor VIII (FVIII), wherein the ratio of VWF antigen (VWF:Ag) to factor VIII-coagulant (FVIII:C) is larger than 5:1, wherein the VWF has a ratio of von Willebrand factor to ristocetin cofactor activity (VWF:RCoF) to von Willebrand factor antigen (VWF:Ag) which is equal to or less than 1:1.05, wherein the VWF is not chemically modified, and wherein the von Willebrand factor is derived from human plasma or is produced recombinantly.