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VKA Monitoring in Hepatic Insufficiency

Here is a challenging case from Hrvoje Melinšćak sent 5-30-24:

Dear George, In hepatic insufficiency there is often a prolonged basal protime, how to ensure therapeutic values of warfarin when the INR is already elevated? This is of particular concern in those with mechanical cardiac valves. Serum warfarin levels (spectrophotometry) are cumbersome and take days to weeks to return. Is there any experience with other assays, such as the chromogenic X assay? LMWH is not an option for the often accompanying renal insufficiency. How to accurately anticoagulate such a patient with a VKA? Any advice would be greatly appreciated!

My 5-31-24 preliminary response. Hello, Hrvoje Melinšćak, and thank you for your email. I’ve forwarded your question to four experts for help, all of whom responded. As you know, the PT will not be valid as liver disease results in reduced II, VII, IX, and X levels. Likewise, the chromogenic X assay is unreliable both because the X level is reduced in liver disease and because bilirubin, if present, interferes in chromogenic assays. One of my colleagues suggests that heparin anticoagulation is the favored choice in hepatic disease. May I suggest that you contact Dr. Pall Onundardotter, whose Fiix assay is described in my 1-6-2022 post, The Fiix-PT Assay; Improves on the PTINR?

Further response from Hrvoje Melinšćak on 5-31-24: The patient has a mechanical valve, hepatic insufficiency (cirrhosis), thrombocytopenia, and renal dysfunction, thus warfarin would be preferable. It is challenging for the comorbidities and the mechanical valve.  Unfractionated heparin has been employed; however, a transition to something more portable shall be necessary.  The Fiix does isolate FX and FII correcting for other deficiencies and may be superior regarding VKA monitoring; however, I would anticipate his low ambient FX would persist.  Moreover, we do not have the Fiix assay at our institution.

My comment on 6-1-24: I have no elegant solution that bypasses the limitations of hepatic insufficiency, renal dysfunction, and thrombocytopenia. Dr. Ali Sadeghi-Khomami, Precision BioLogic Research Director, mentions the time-honored PIVKA-II immunoassay, which measures the des-carboxy FII (prothrombin) produced in warfarin therapy, but acknowledges that the results could be compromised by renal insufficiency. I also speculate whether you can contrive to employ a mathematical ratio and proportion comparing the baseline PT to the therapeutic PT, but of course, I find no documentary support for the notion. We are looking for help!

6-3-24 follow-up: Dean Willett, Precision BioLogic Inc., recommended Tripodi A, Chantarangkul V, Primignani M, et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007;46:520-7. doi: 10.1002/hep.21732. PMID: 17659574. Click here for a PubMed link to the abstract and additional references.

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