Reaction to Warfarin

[SH]

53 years old woman prescribed Warfarin for transient ischemic attack, after few weeks she developed fever of unknown origin, she was prescribed one injection of cortico steroids , temperature improved for few days and increased again .Dose of warfarin was increased to adjust the PT ,which became 25 seconds while PT of control was 12 seconds , she was advised to wait for 2 days to repeat PT , unfortunately , after 2 days she developed peticheal hemorrhages , bleeding gums and massive intracerebral hemorrhage and proved to have thrombocytopenia

What are the possibilities? Just warfarin overdose?? Could be this fever due to wafarin and when she continued on it was this severe reaction?? Were corticosteroids wrong to be given with warfarin?
She was on (Amitryptilline and Imipramine)
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[SH]

I forgot to mention that , Iam the doctor supervising her neurological problem (TIA) , I didn't realise that Warfarin can cause fever and I was trying not to be rushing to cahnge her warfarin dose before repeating the PT after 2 days, I appreciate answers

[SH]

Is thereany hope that I will receive any reply for my question and if not can I have any idea why or what are the factors which determine answering or not answering questions, Thanks a lot

[R. Zein, Pharm D]

Dear SH

warfarin remains a very interesting drug, especially with its mechanism of action , it may take up to 36 hours for a warfarin dose to exert its full effects (by blocking the clotting factors)

usually INR is used to target coumadin dosing, not the PT. Based on this patient (TIA) her INR goal will be 2-3. do we have any information about her INR LEVEL?
I think this is a key point because higher INR levels will indicate higher risk of bleeding.

in addition, the patient as you mentioned, was on Amitryptilline and Imipramine..these agents can interefer with cytochrome P450 enzymes, which are involved in the metabolism of warfarin. in general most if not all anti-depressants are inhibitors of cyt. P450 enzymes, including Amitryptilline and Imipramine. therefore, it is possible that these two drugs inhibited the metabolism of warfarin, and caused an increase in INR, and eventually bleeding.

steroids as well can increase the risk of bleeding on patients recieving warfarin therapy by increasing INR.

one should also take into consideration, the patient's dietary intake. herbal products, vitamin K and E containing food can all cause fluctuation in the INR, and therefore, affect coumadin therapy.

it will be very helpful to have INR levels on this lady? what was her first dose of coumadin, and what is her wt? how often were her labs monitored/

Thank you very much

[SH]

Dear Dr Reham:
Thanks a lot for your valuable reply.Unfotunately , I don't have enough data at the moment about INR at that time , but can the PT be only double the control and INR to be more than 3 times the control ?
This bleeding was about 3 months of trying adjusting the PT.

Do you have any comment about the fever of unknown etiology that appeared or the thrombocytopenia which was found at time of bleeding. I mean any correlation between these signs and warfarin?

Best regards,
SH

[R. Zein, Pharm D]

Dear SH

although both PT/INR are both used to monitor warfarin, it is the INR that we use to adjust warfarin dosing.

it is hard to predict the value of INR based on PT. The fact that PT is double the control does not necessarily means INR is too high, or too low or even normal.

warfarin can be associated with hematological changes including lower blood count, and the incidence of warfarin causing fever has been reported as a side effect in than 1 % of the cases. The fever of unknown origin could be due to something else..it is very hard for me to assess this one in particular as it could be due to so many other underlying causes.

thank you very much

[SH]

Dear Dr Riham :
Thank you very much
I would be very grateful if you can inform me , In this less than 1% of patients developing fever on Warfarin , what could be the consequences if patient continued on it , ie. can it lead to a serious reaction including severe thrombocytopenia if he didn't stop Warfarin on developing fever ? and does this aggrevate more by increasing dose of Warfarin?

Apart from some lowering in blood constituents, does it cause severe throbocytopenia in any condition?

Is INR calculated by dividing (PT of patient/ PT of control ) raised to the power of certain constant different from lab to lab (ranges between 1-1.4)?
What is the highest acceptable INR above which bleeding can be fatal?


Thanks a lot for your cooperatin as this case is of great importance in my practice

[R. Zein, Pharm D]

Dear SH.
thank you very much for your responses. i am enjoying this discussion and it is in deed a learning opportunity for me.

when i mentioned that warfarin can cause fever in up to 1 % of cases, i was trying to check all the possible side effects of warfarin that has been reported in pharmacology references, and 1 % was documented (as a rare side effect). i havent found an article about warfarin and fever, dosing, etc. There is no data about warfarin causing fever and how it was managed.

However, it is possible that the fever was not due to warfarin, and fever has been shown to increase the responsiveness to warfarin, that is bleeding. it has been shown that hypermetabolic states produced by fever increase warfarin responsiveness probably by increasing the catabolism of vitamin K– dependent coagulation factors.

we have heard more about heparin induced thrombocytopenia not warfarin induced thrompocyopenia. Was your patient on heparin, or aspirin? or any other medications beside the anti-depressants?

you are right about calculating INR based on PT, but the accuracy of PT is system dependent. INR can be calculated using INR = (patient PT/mean normal PT)ISI

ISI or International Sensitivity Index can vary from place to place, therefore calculating the INR using the working prothrombin is only valid when the ISI of the thromboplastin is known. This is why in my institution, we usually order both when patients are on coumadin, but adjust the dose based on INR not the PT.

i don't know what is the highest acceptable INR range, but i can share with you what i have seen in my practice. I had patients that present with INRS up to 20 without bleeding, and i had patients that present with INRS of 6 or lower and bleeding . it is really patient-dependent. So depending on the patient if their INR is 4-6 and they arent bleeding we usually hold warfarin for few days. In cases where the patient has risks of bleeding or they are bleeding we usually stop the coumadin of course and give vitamin K.

The key i think it to keep the INR at targeted goal : 2-3 for most indications and 2.5-3.5 for patients with mechanical prosthetic heart valves.

I am sorry that i could not be of any help regarding the warfarin, fever, and thrombocytopenia. i did a lot of research in pubmed but nothing came out. That is why it is very possible that whatever happened to the patient had a different underlying cause or maybe this is a newly discovered aspect of warfarin that you came across with this patient.

Regardless, i hope that your patient feels better, and thank you very much for this discussion.

[SH]

Dear Dr Riham:
Thank you very much for your great effort and time
Iam very grateful for your cooperation and more than valuable discussion.

I would like to clarify that patient was feverish for about one month during which her PT was not high enough as for adequate anticoagulation (so I doubt that bleeding was due to catabolic state induced by fever) and then mild increase in dose of Warfarin was added after which the PT became about 25 sec after which ,that's why I was wandering if this mild increase in dose can induce such a dramatic change, and as I mentioned before I preferred not to be rushing in decreasing dose again and decided to repeat test after 2 days but ...it was too late

I really can't remember if she was still on Aspirin or not when she started Warfarin? But she was on Aspirin in earlier periods for some years and didn't suffer any bleeding

As regarding Heparin she used it only for short period until Warfarin started working and this was stopped some weeks before even the fever

I don't know if it is of any value to mention this , but unfortunately the patient died just few hours after the intracerebral bleeding .But it is a big question mark what happened exactly??

Again thanks a lot ,
SH

[R. Zein, Pharm D]

Dear SH
I am sorry about your patient. But having all the information, it is unlikely that fever was caused by warfarin. Although she recieved heparin for while until the warfarin was added to the regimen, frequent monitoring of the platelet count will help determine if the patient had HIT.

Although heparin was stopped , patients can have delayed heparin induced thrombocytopenia. I am not sure if her platelets started to drop while on heparin or after stopping the heparin for several weeks. But one could have ruled out this possibility by measuring the heparin antibody. if positive, this indicates HIT, if not, most likely it is caused by something else.

the reason i asked if she was on aspirin, is just due to the additive effect. when each aspirin or warfarin are given alone, they may never cause bleeding, but sometimes when given together there is a higher chance of bleeding that is all.

any ways, i wish you all the best, and i thank you for your time and discussion. it was a pleasure discussing the case with you. I am sorry about the belated response, but i was gone for a year, and that is why i did not see your case until few days a go.

have a great day