Half-Lives of Clotting Factor Proteins

One thing that makes warfarin anticoagulation so difficult to manage, both for doctors and people taking warfarin, is that the anticoagulant effect of warfarin (or of an increase in the dosage of warfarin, for example) takes effect more rapidly than the antithrombotic effect. One explanation for this is that prothrombin has a half life, in the blood, of 96 hours or something, like 5 days, but the other clotting factors have much shorter half-lives. So warfarin shuts down all clotting factor production rapidly, but the previously-made clotting factors are still circulating in the blood. Prothrombin is the last to decline, and there can be a dangerous period during which there's an anticoagulant effect of warfarin that's taken hold in the face of ongoing thrombogenicity (mediated by the activation of prothrombin with minimal levels of the other clotting factors). This type of thing can probably make the effects of things like riboflavin or CoQ10 on the vitamin K cycle difficult to assess, especially since the coagulation system is not well understood. Two people can have the same levels of clotting factors, but one person can have a much, much greater degree of activation of the coagulation cascade. The prothrombin time is also a very insensitive measure of the coagulation cascade and reflects the degree of prothrombin activity on a sort of "semi-logarithmic" scale (whereby a one-digit change in the INR requires prothrombin levels to change by 50 percent or something like that). The way it would work, though, if CoQ10 were affecting clotting factor production, would be that cessation of CoQ10 would not produce an immediate effect. It takes 2-3 weeks for the serum CoQ10 to return to normal in clinical trials, and then to clear the liver would take another week, probably, and then there's the 5-10 days for the prothrombin levels to decline, etc. Riboflavin is cleared much more rapidly (hours to a couple of days), but, again, there would still be the circulating clotting factors. It's just that researchers sometimes try to test these things in humans, and the designs of the studies don't really allow the issue to be evaluated. One article tested 100 mg of non-emulsified CoQ10 in patients with warfarin and used a change in the INR as the endpoint for analysis, I think. 100 mg of nonemulsified CoQ10 will take probably a month to reach steady-state levels in the liver, the bioavailability is so low as to produce very minimal effects on anything at that dose, and the INR is totally insensitive to changes in prothrombin activation. The coagulation cascade seems to work more locally and cause ongoing, low-level damage and neurodegneration, for example. There are some articles that show that thrombin receptor antagonists improve cognitive functioning dramatically, and the people don't have overt clots before the treatment. There's a low-level, ongoing impairment of tissue oxygenation or activation of phospholipases, producing mitochondrial toxicity, etc. It's ironic that the actions of thrombin basically produce mitochondrial dysfunction, and yet CoQ10 and riboflavin are assumed to be purely beneficial effect on mitochondrial functioning. Thrombin, produced by the activation/cleavage of prothrombin, has just very extreme and self-perpetuating effects and can be really damaging. It's an extremely potent activator of platelets, and it has direct neurotoxic effects, etc. There are a couple of crazy articles, out of 10,000 or however many showing wild, damaging effects from thrombin, based on in vitro data, showing protective effects of "small amounts" of thrombin. But, for the most part, it maintains the almost totally-unregulated, self-perpetuating quality of the coagulation cascade.