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%.