AU2002323670A1 - Method for treating coumarin-induced hemorrhage - Google Patents
Method for treating coumarin-induced hemorrhageInfo
- Publication number
- AU2002323670A1 AU2002323670A1 AU2002323670A AU2002323670A AU2002323670A1 AU 2002323670 A1 AU2002323670 A1 AU 2002323670A1 AU 2002323670 A AU2002323670 A AU 2002323670A AU 2002323670 A AU2002323670 A AU 2002323670A AU 2002323670 A1 AU2002323670 A1 AU 2002323670A1
- Authority
- AU
- Australia
- Prior art keywords
- factor
- coumarin
- plasma
- conjunction
- individual
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000032843 Hemorrhage Diseases 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 9
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims 10
- 229960000956 coumarin Drugs 0.000 title claims 5
- 235000001671 coumarin Nutrition 0.000 title claims 5
- 210000002381 plasma Anatomy 0.000 claims description 13
- 230000000740 bleeding effect Effects 0.000 claims description 8
- 229930003448 Vitamin K Natural products 0.000 claims description 5
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 5
- 235000019168 vitamin K Nutrition 0.000 claims description 5
- 239000011712 vitamin K Substances 0.000 claims description 5
- 229940046010 vitamin k Drugs 0.000 claims description 5
- 208000034158 bleeding Diseases 0.000 claims description 4
- 239000003959 coumarin anticoagulant Substances 0.000 claims description 4
- 229960001912 dicoumarol Drugs 0.000 claims description 4
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000003721 vitamin K derivatives Chemical class 0.000 claims description 4
- 239000004023 fresh frozen plasma Substances 0.000 claims description 3
- 229960005080 warfarin Drugs 0.000 claims description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 claims description 3
- 108010014173 Factor X Proteins 0.000 claims description 2
- 239000003146 anticoagulant agent Substances 0.000 claims description 2
- 229940127219 anticoagulant drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 3
- 239000000203 mixture Substances 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108010071289 Factor XIII Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 201000000839 Vitamin K Deficiency Bleeding Diseases 0.000 description 2
- 206010047634 Vitamin K deficiency Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000016794 vitamin K deficiency hemorrhagic disease Diseases 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 102100022641 Coagulation factor IX Human genes 0.000 description 1
- 102100023804 Coagulation factor VII Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 108010023321 Factor VII Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- HIZKPJUTKKJDGA-UHFFFAOYSA-N dicumarol Natural products O=C1OC2=CC=CC=C2C(=O)C1CC1C(=O)C2=CC=CC=C2OC1=O HIZKPJUTKKJDGA-UHFFFAOYSA-N 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012413 factor vii Drugs 0.000 description 1
- 229940012426 factor x Drugs 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002642 gamma-glutamyl group Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108010013113 glutamyl carboxylase Proteins 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- -1 vitamin K epoxides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
METHOD FOR TREATING COUMARIN-INDUCED HEMORRHAGE
BACKGROUND OF THE INVENTION
Vitamin K controls the formation of prothrombin, factor VII, factor IX, and factor X by acting as a substrate for the enzyme γ-glutamyl carboxylase. This enzyme catalyzes the addition of carbon dioxide to the γ-carbon of protein-bound glutamic acid in the gla regions of the coagulation factors.
Coumarin anticoagulants, which include warfarin and dicumarol (dicoumarol), prevent the reduction of vitamin K epoxides in the liver microsomes and induce a state of vitamin K deficiency. A side effect of such anticoagulants is hemorrhage. If hemorrhage does occur, there is a need for a substance to inhibit the coumarin anticoagulant-induced bleeding.
DESCRIPTION OF THE INVENTION
The present invention fills this need by administering factor Xffl to patients afflicted with bleeding due to a coumarin anticoagulant-induced vitamin K deficiency. Factor XE can be administered alone or in conjunction with cryoprecipitate or fresh frozen plasma, generally two units or plasma. Vitamin K can also be administered at an initial dose of 5 to lOmg, generally subcutaneously. The administration of factor XHI can be applied prophylactically or at the time of a bleeding episode.
Factor Xm, also known as fibrin-stabilizing factor, circulates in the plasma at a concentration of 20 μg ml. The protein exists in plasma as a tetramer comprised of two
A subunits and two B subunits. Each subunit has a molecular weight of 83,000 Da, and the complete protein has a molecular weight of approximately 330,000 Da. Factor XHI
catalyzes the cross-linkage between the γ-glutamyl and ε-lysyl groups of different fibrin strands. The catalytic activity of factor Xm resides in the A subunits. The B subunits act as carriers for the A subunits in plasma factor XHI. Recombinant factor XHI can be produced according to the process described in European Patent No. 0 268 772 Bl. The level of factor Xm in the plasma can be increased by administering a factor XHI concentrate, derived from human placenta or plasma, called FffiROGAMMTN® (Aventis Corp.) or by administration of recombinant factor XHI. When recombinant factor Xm is used, only the 'A2'homodimer is generally administered without the 'B2' subunit. Administration of factor Xm to a subject is generally done intravenously. When administering therapeutic proteins by injection, the administration may be by continuous infusion or by single or multiple boluses. A pharmaceutical composition comprising factor Xm can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the therapeutic proteins are combined in a mixture with a pharmaceutically acceptable carrier. A composition is said to be a "pharmaceutically acceptable carrier" if its administration can be tolerated by a recipient patient. A suitable pharmaceutical composition of factor XHI will contain ImM EDTA, lOmM Glycine, 2% sucrose in water. An alternative formulation will be a factor XHI composition containing 20 mM histidine, 3% wt/volume sucrose, 2 mM glycine and .01% wt/vol. polysorbate, pH 8.
Other suitable carriers are well known to those in the art. See, for example, Gennaro (ed.), Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company 1995).
The levels of factor XHI in an individual can be determined by assays well known in the art such as the BERICHROM® F Xm assay (Dade Behring Marburgh GmbH, Marburg, Germany). The normal adult has an average of about 45 ml of plasma per kg of body weight. Each liter of blood has 1000 units (U) of factor Xffl. The amount of factor XDl administered should be enough to bring an individual's level of factor XHI in the plasma to at least 100% of normal plasma or preferably 1-5% above normal. A dose of .45 U/kg would raise the level of factor Xm by about 1% compared
to normal. One unit of factor XE is about 10 μg of recombinant factor XHI, which contains only the dimerized A subunit. Thus, to raise the level of factor XHI by 1%, one would administer about 4.5 μg of the A2 subunit per kilogram weight of the individual. So to raise the level 30% of normal, one would administer 13.5 U/kg. For a 75 kg individual this would be about 1,012.5 U. Some patients may have consumptive coagulopathies that involve factor XIII losses. In such cases, a higher dosing {e.g., 1- 2U/kg-%) or multiple dosing of factor Xm {e.g., l-2U/kg-%-day) may be required.
Claims (10)
1. A method for stopping coumarin anticoagulant-induced bleeding or hemorrhage in an individual comprising administering to said individual a therapeutically effective amount of factor XDl.
2. The method of claim 1 wherein the anticoagulant is warfarin or dicoumarol.
3. The method of claim 1 wherein the factor Xm is administered in conjunction with vitamin K.
4. The method of claim 1 wherein cryoprecipitate or fresh frozen plasma is administered in conjunction with the factor Xm.
5. The method of claim 1 wherein the factor XHI is recombinant human factor Xm.
6. The use of factor Xffl for the production of a medicament for the treatment of coumarin-induced bleeding or hemorrhaging in an individual.
7. The use of factor XDl in conjunction with vitamin K for the production of a medicament for the treatment of coumarin-induced bleeding or hemorrhaging.
8. The use of factor Xm in conjunction with a plasma-derived cryoprecipitate or fresh frozen plasma for the production of a medicament for the treatment of coumarin-induced bleeding or hemorrhaging
9. The use of factor Xm as recited in claims 6, 7 or 8 wherein the coumarin-induced bleeding is caused by warfarin or dicoumarol.
10. The use of factor Xm as recited in claims 6, 7, 8, or 9 wherein the factor X is recombinant factor XE.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/322,231 | 2001-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2002323670A1 true AU2002323670A1 (en) | 2003-03-24 |
Family
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