Oops - missed dose

[pellicle]

Hi

Some studies suggest that rapid fluctuations are more dangerous than being out of range. On the other hand, it may depend upon *how* out of range one is. Your thoughts?

keeping in mind its the simulation not actual measurements: both returned to desired INR quickly, there was very little difference between the two responces (particularly with the 3 period moving average). My thoughts are that there is little difference between the results for either strategy. If anything there was a steeper slope on the INR curve (perhaps less desirable) with the follow up with next dose is ~ x1.5 dose than the do nothing and resume approach

if you were out of range and missed a dose, then well ... that would be different (and a different scenario

 

[pem]

Thanks pellicle. I understand that, in terms of INR, there was very little difference between the two responses, but I wonder if INR provides is by itself completely predictive of outcome. In other words, perhaps there are effects concerning the fluctuation of coumadin levels that are not reflected in the INR measurement. One point of interest on this is that in a Swedish study of literally millions of people on anticoagulation therapy (for all sorts of reasons, not just valve-related), they found that when major INR swings were related to medically induced (e.g., over or under dose of coumadin), there were adverse effects, but when INR swings occurred naturally (which they do apparently for everyone), there were no such effects. So it seems there is something physiological at play here that might not be evident in INR measurements by themselves. Thoughts?

Best,
pem

 

[pellicle]

Hi

I understand that, in terms of INR, there was very little difference between the two responses
...
One point of interest on this is that in a Swedish study of literally millions of people on anticoagulation
... there were no such effects. So it seems there is something physiological at play here that might not be evident in INR measurements by themselves. Thoughts?

my thoughts:
It is indeed an intriguing idea. My time in Biochem and that area of science makes me significantly aware that we can not really visualize these systems. Much of what we "know" is based on inference and assumptions. Mostly that inference and assumption is supported and borne out by application of 'effects' to that process and it behaves as we expect. Much can be learned quickly by visualising things, and we have no proper visualization of this system (we can't pull the back off the clock and see how the gears are actually turning).

This is however from a VERY limited and narrow perspective.

My analogy is that it is rather like a mechanical watch or clock. We observe reactions to things but we can only see the hands and the face. We are just uncertain about the actuality of the mechanisms involved.

Now my reading of the warfarin interaction with the thrombosis reactions is that we have some lack of knowledge in exactly what is going on at each and every stage. I have not studied this biochemistry myself in great detail *(yet) but let me quote something from wikipedia: (apologies if it would appear I am attempting to teach grandma to suck eggs here)

Warfarin ... decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K1 to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII.

so its clear that warfarin works to essentially limit the amount of K1 in the system by killing off its effective recycling. This is important as it does not actually kill off Vit K ... as it goes on to say:

Despite being labeled a vitamin K antagonist, warfarin does not antagonize the action of vitamin K1, but rather antagonizes vitamin K1 recycling, depleting active vitamin K1.[3]

however we are (as I understood it) not entirely certain of the role that is played by other parts of the metabolism here. So given we know roughly that warfarin is metabolised by the body (into what I am unclear and by what mechanism I am also unclear) we know that warfarin has a half life in the body (something like 2 days I understood), I do not know how well vitamin K is metabolised, what its half life is, how effective the recycling is and (importantly) if there is another mechanism for its recycling (which is perhaps more convoluted and inefficient).

It seems possible that some other sequence of chemical cascade could be present which effects the thrombin reaction but somehow does not register similarly in the methods of measuring INR.

I am not familiar enough with thrombogenesis, the reactions of Vit K1 and Vit K2 in this metabolism and their metabolism interference by warfarin.

so in a nutshell ... seems possible, more research needed.

 

[pem]

so in a nutshell ... seems possible, more research needed.

Indeed

Thanks for a thoughtful technical analysis. I think there are different mechanisms at play, as you suggest, regarding the action of various agents on thrombolitic processes. For example, heparin acts in a different way, I think. In my own oversimplified way of thinking about this, there is a kind of pipelined process for clotting, and different agents affect that process at different stages with different potential consequences. It seems quite complex, and I'll bet that even though we (the royal scientific "we") have a handle on a lot of it, there are bits we don't understand or appreciate fully. So when I see results like those published in the Swedish study that say "hey, if you make your INR swing using medicine, that can cause problems, but if it happens on its own, no big deal" it makes me wonder why and how the answer to the "why" question might be used to improve clinical outcomes.

Thanks for engaging on this!
pem

 

[pellicle]

Hi

. So when I see results like those published in the Swedish study that say "hey, if you make your INR swing using medicine, that can cause problems, but if it happens on its own, no big deal" it makes me wonder why and how the answer to the "why" question might be used to improve clinical outcomes.

Although it is but one person, the member here Protimenow had as I recall a TIA which I recall was related to his INR. It might be interesting if he would be willing to share some details on that to see if it fits your conjecture of :

Natural INR swings are less dangerous than drug related ones

 

[Freddie]

Hi

Although it is but one person, the member here Protimenow had as I recall a TIA which I recall was related to his INR. It might be interesting if he would be willing to share some details on that to see if it fits your conjecture of :

Natural INR swings are less dangerous than drug related ones

FWIW, a TIA can happen even if your INR is in range. A TIA can happen at any time, to anyone with or without being on Warfarin.

Now, back to the original question.......the missed dosage? Can one assume that the dosage was corrected?

 

[pellicle]

FWIW, a TIA can happen even if your INR is in range.

I guess ... but is it made more likely by it not being?

 

[Bina]

I guess ... but is it made more likely by it not being?

I believe so, and am very careful to keep my INR above 2.2

 

[pellicle]

My line above was meant to be rhetorical.

Meaning that in reply to :

FWIW, a TIA can happen even if your INR is in range. A TIA can happen at any time, to anyone with or without being on Warfarin.

I addeded:

I guess ... but is it made more likely by it not being?

to suggest that while it can happen to anyone and it can happen at any time that being in range was likely to reduce it. As I was discussing the results of the research Pem brought up I agreed with Freddie but wanted to get back to the context of the discussion I was having with Pem. Naturally others are welcome do join that discussion.