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Coumadin and Factor Half-lives

I received a question recently about Coumadin (warfarin) therapy and coagulation factor half-lives. Coumadin reduces the normal carboxylation of the glutamic acid γ-carbon. There are 12–18 glutamic acid units near the amino terminus of the vitamin K-dependent factors II (prothrombin), VII, IX, and X. When vitamin K-catalyzed γ-carboxylation becomes suppressed, these coagulation factors are unable to bind Ca++ ions and consequently unable to bind platelet phosphatidyl serine, thus becoming ineffective. The same thing happens near the amino termini of control proteins C and S.

The half-lives of the vitamin K-dependent factors are factor II, 60 h; factor VII, 6 h; factor IX, 24 h; factor X, 48 h. For the control proteins, protein C’s half-life is 7 hours, the protein S half-life has not been defined.

When starting Coumadin therapy, the first coagulation factor to become detectably reduced is factor VII, owing to its short half-life. Consequently, the prothrombin time (PT) becomes prolonged and the international normalized ratio (INR) nears the therapeutic range of 2–3. However, since factors II, IX, and X remain active, the patient is not anticoagulated and the INR cannot be trusted. In fact, owing to the 60 h half-life of factor II, the INR does not reflect therapeutic efficacy until after 3–4 days. The early prolongation of the PT can be viewed as a false indication of anticoagulation.

Additionally, protein C becomes reduced at nearly the same rate as factor VII. Protein C is a control protein, so during early Coumadin therapy, the patient is actually prothrombotic. For this reason, physicians “cover” Coumadin startup with unfractionated or low molecular weight heparin.

It is for these reasons that the PT is repeated daily at the start of Coumadin therapy, and the patient is not regarded as safely anticoagulated until two consecutive INR results are in the therapeutic range and match within ± 10%.

Comments (1)
Anticoagulant Therapy
Dave McGlasson
Nov 21, 2014 5:18am

From Dave McGlasson: In some research that
From Dave McGlasson: In some research that we published in 2008 we advocated using the chromogenic factor X (FX) assay for monitoring subjects on Coumadin: McGlasson DL et al: Blood Coagul Fibrinolysis 2008, 19:513–7. We found that the FX level corresponded with the INR therapeutic range of 2–3 at 18-48% FX activity. We also saw that the INR result when it gets above 3.0 tends to “flatten out.” Consequently we saw individuals with an INR in the ranges of 6.0-12.8 with FX levels the same as subjects in the therapeutic range.

Subsequently in McGlasson DL. Unexpected levels of FVII when monitoring Coumadin patients with unstable INRs. Clin Hemost Review 2000;8-9, We saw many individuals in the therapeutic range with factor VII levels by both clottable and chromogenic methods to have have elevated levels of FVII. We monitored 19 subjects with an unstable INR over a two month period who had been on Coumadin for at least 8 weeks, with a minimum of 6 time points. We found the mean of FVII clottable assays to be 52.9% activity. The chromogenic FVII assay mean was 62.6%. On a group of 50 stable INR subjects with a mean INR of 3.57 the FVII mean was still 34.5% activity. Rosborough saw similar results of the “flattening effect” of the INR in subsequent studies. The INR is not the best method to assess the “true effect” of the coumadin medication in subjects outside the elevated therapeutic range of the INR.

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