D
DrAllan
Before you castigate your physician regarding Coumadin management, please be aware of the multiple factor involved.
I am a physician and test myself every three days. I have marked fluctuations in my INR. True, I choose to alter my drug dosage rather than try to maintain a rigid diet and exercise routine.
Let me address a statement I have seen on this site that it takes three days to see an effect from Coumadin. This is only partially true. The effect of Coumadin is within hours of taking the drug such that the liver produces less of the clotting factors affected by the drug. It actually takes three days to see a decrease in the levels of circulating prothrombin that are present at the exact moment that you put the pill into your mouth. It is this lag between change in production and the natural decrease in clotting factors already present that makes management difficult.
The above explanation only accounts for trying to manage the elevated INR. The reverse of trying to increase the INR is even more frustrating.
Thus, if you are trying to increase the INR, i.e. reduce the amount of active coagulating products in the blood, then the net effect is the amount of decrease in production coagulant factors combined with the natural decrease of these same factors. The time course as later explained is markedly different. Likewise if you are trying to decrease the INR if it is to high depends on increasing the natural production of clotting factors in excess of there removal by the body.
Now for another confusing factor. You must have a grasp of the concept of ?half life?. This is the time that it takes for one half of the material under study to be removed by the body. For various drugs and natural products such as clotting factors, there is a percentage of concentration below which they are not effective. This concentration varies for each of the clotting factors involved in the clotting mechanism. The half-life of each of the factors is different as is the half-life of both Coumadin and vitamin k. Consider that there are x clotting factors involved in the prothrombin cycle () and you begin to see the difficulty in predicting response.
Finally there are a multitude of other factors related to the functioning of the liver where these factors are made. Alcohol is preferentially handled by the liver at the expense of directing attention to making clotting factors. Exercise increase blood flow to the muscles at the expense of the liver and creates metabolic breakdown products that must be metabolized by the liver and divert the cells from making clotting factors. Other drugs also preferentially occupy liver cells.
There are probably multiple other factors that I have not touched upon here that affect your INR. Pleas don?t blame a conscientious MD from not keeping you balanced.
Just some other facts. Traditionally INR tests are usually drawn in the AM to allow lab testing and the ability to convey the info to the doctor so that you may be advised of any needed changes in dosage for that evening. If you took your Rx in the AM then it would be the next day before you would effect a change.
I have taken the opportunity to copy some info from the web. Truthfully, as many times as I have read it, I can?t keep the various steps straight in my mind. Needless to say, the clotting mechanism and attempts to carefully interfere with it are very complex.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Clotting.html
Initiating the Clotting Process
? Damaged cells display a surface protein called tissue factor (TF)
? Tissue factor binds to activated Factor 7.
? The TF-7 heterodimer is a protease with two substrates:
_ Factor 10 and
_ Factor 9
_ Let's follow Factor 10 first.
? Factor 10 binds and activates Factor 5. This heterodimer is called prothrombinase because it is a protease that converts prothrombin (also known as Factor II) to thrombin.
? Thrombin has several different activities. Two of them are:
_ proteolytic cleavage of fibrinogen (aka "Factor I") to form:
_ soluble molecules of fibrin and a collection of small
_ fibrinopeptides
_ activation of Factor 13 which forms covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork ? the clot.
(Thrombin and activated Factors 10 ("Xa") and 11 ("XIa") are serine proteases.
Amplifying the Clotting Process
The clotting process also has several positive feedback loops which quickly magnify a tiny initial event into what may well be a lifesaving plug to stop bleeding.
? The TF-7 complex (which started the process) also activates Factor 9.
_ Factor 9 binds to Factor 8, a protein that circulates in the blood stabilized by another protein, von Willebrand Factor (vWF).
_ This complex activates more Factor 10.
? As thrombin is generated, it activates more
_ Factor 5
_ Factor 8, and
_ Factor 11 (all shown above with green arrows).
? Factor 11 amplifies the production of activated Factor 9.
Thus what may have begun as a tiny, localized event rapidly expands into a cascade of activity.
Protein C
With its many clotting promoting activities, it is probably no accident that thrombin sits at the center of the control mechanism.
? Excess thrombin binds to cell-surface receptors called thrombomodulin.
? The resulting complex activates a plasma protein called Protein C and its cofactor Protein S.
? Together these inhibit further thrombin formation
_ directly ? by inactivating Factor 5 and
_ indirectly ? by inactivating Factor 8.
Some inherited disorders that predispose to spontaneous clots, especially in the leg veins:
? inherited deficiency of Protein C or Protein S;
? inherited mutation in the Factor 5 gene producing a protein that no longer responds to the inhibitory effect of Protein C.
Recombinant Protein C is now available to treat people threatened with inappropriate clotting, e.g., as a result of widespread infection (sepsis).
Vitamin K
Vitamin K is a cofactor needed for the synthesis (in the liver) of
? factors 2 (prothrombin), 7, 9, and 10
? proteins C and S
So a deficiency of Vitamin K predisposes to bleeding.
Conversely, blocking the action of vitamin K helps to prevent inappropriate clotting.
Warfarin (aka coumadin) is sometimes prescribed as a "blood thinner" because it is an effective vitamin K antagonist. (Warfarin is also used as a rat poison because it can cause lethal (internal) bleeding when eaten.)
I am a physician and test myself every three days. I have marked fluctuations in my INR. True, I choose to alter my drug dosage rather than try to maintain a rigid diet and exercise routine.
Let me address a statement I have seen on this site that it takes three days to see an effect from Coumadin. This is only partially true. The effect of Coumadin is within hours of taking the drug such that the liver produces less of the clotting factors affected by the drug. It actually takes three days to see a decrease in the levels of circulating prothrombin that are present at the exact moment that you put the pill into your mouth. It is this lag between change in production and the natural decrease in clotting factors already present that makes management difficult.
The above explanation only accounts for trying to manage the elevated INR. The reverse of trying to increase the INR is even more frustrating.
Thus, if you are trying to increase the INR, i.e. reduce the amount of active coagulating products in the blood, then the net effect is the amount of decrease in production coagulant factors combined with the natural decrease of these same factors. The time course as later explained is markedly different. Likewise if you are trying to decrease the INR if it is to high depends on increasing the natural production of clotting factors in excess of there removal by the body.
Now for another confusing factor. You must have a grasp of the concept of ?half life?. This is the time that it takes for one half of the material under study to be removed by the body. For various drugs and natural products such as clotting factors, there is a percentage of concentration below which they are not effective. This concentration varies for each of the clotting factors involved in the clotting mechanism. The half-life of each of the factors is different as is the half-life of both Coumadin and vitamin k. Consider that there are x clotting factors involved in the prothrombin cycle () and you begin to see the difficulty in predicting response.
Finally there are a multitude of other factors related to the functioning of the liver where these factors are made. Alcohol is preferentially handled by the liver at the expense of directing attention to making clotting factors. Exercise increase blood flow to the muscles at the expense of the liver and creates metabolic breakdown products that must be metabolized by the liver and divert the cells from making clotting factors. Other drugs also preferentially occupy liver cells.
There are probably multiple other factors that I have not touched upon here that affect your INR. Pleas don?t blame a conscientious MD from not keeping you balanced.
Just some other facts. Traditionally INR tests are usually drawn in the AM to allow lab testing and the ability to convey the info to the doctor so that you may be advised of any needed changes in dosage for that evening. If you took your Rx in the AM then it would be the next day before you would effect a change.
I have taken the opportunity to copy some info from the web. Truthfully, as many times as I have read it, I can?t keep the various steps straight in my mind. Needless to say, the clotting mechanism and attempts to carefully interfere with it are very complex.
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Clotting.html
Initiating the Clotting Process
? Damaged cells display a surface protein called tissue factor (TF)
? Tissue factor binds to activated Factor 7.
? The TF-7 heterodimer is a protease with two substrates:
_ Factor 10 and
_ Factor 9
_ Let's follow Factor 10 first.
? Factor 10 binds and activates Factor 5. This heterodimer is called prothrombinase because it is a protease that converts prothrombin (also known as Factor II) to thrombin.
? Thrombin has several different activities. Two of them are:
_ proteolytic cleavage of fibrinogen (aka "Factor I") to form:
_ soluble molecules of fibrin and a collection of small
_ fibrinopeptides
_ activation of Factor 13 which forms covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork ? the clot.
(Thrombin and activated Factors 10 ("Xa") and 11 ("XIa") are serine proteases.
Amplifying the Clotting Process
The clotting process also has several positive feedback loops which quickly magnify a tiny initial event into what may well be a lifesaving plug to stop bleeding.
? The TF-7 complex (which started the process) also activates Factor 9.
_ Factor 9 binds to Factor 8, a protein that circulates in the blood stabilized by another protein, von Willebrand Factor (vWF).
_ This complex activates more Factor 10.
? As thrombin is generated, it activates more
_ Factor 5
_ Factor 8, and
_ Factor 11 (all shown above with green arrows).
? Factor 11 amplifies the production of activated Factor 9.
Thus what may have begun as a tiny, localized event rapidly expands into a cascade of activity.
Protein C
With its many clotting promoting activities, it is probably no accident that thrombin sits at the center of the control mechanism.
? Excess thrombin binds to cell-surface receptors called thrombomodulin.
? The resulting complex activates a plasma protein called Protein C and its cofactor Protein S.
? Together these inhibit further thrombin formation
_ directly ? by inactivating Factor 5 and
_ indirectly ? by inactivating Factor 8.
Some inherited disorders that predispose to spontaneous clots, especially in the leg veins:
? inherited deficiency of Protein C or Protein S;
? inherited mutation in the Factor 5 gene producing a protein that no longer responds to the inhibitory effect of Protein C.
Recombinant Protein C is now available to treat people threatened with inappropriate clotting, e.g., as a result of widespread infection (sepsis).
Vitamin K
Vitamin K is a cofactor needed for the synthesis (in the liver) of
? factors 2 (prothrombin), 7, 9, and 10
? proteins C and S
So a deficiency of Vitamin K predisposes to bleeding.
Conversely, blocking the action of vitamin K helps to prevent inappropriate clotting.
Warfarin (aka coumadin) is sometimes prescribed as a "blood thinner" because it is an effective vitamin K antagonist. (Warfarin is also used as a rat poison because it can cause lethal (internal) bleeding when eaten.)
