Pathophysiology
Clinical meaning
Warfarin inhibits vitamin K epoxide reductase (VKORC1), preventing the recycling of vitamin K from its epoxide form back to its reduced (hydroquinone) form. This depletes the reduced vitamin K required by gamma-glutamyl carboxylase to carboxylate glutamic acid residues on factors II, VII, IX, and X and proteins C and S. Without carboxylation, these factors cannot bind calcium and phospholipid membranes, rendering them functionally inactive. Reversal strategies restore functional coagulation factor activity. Vitamin K (phytonadione) provides substrate for gamma-glutamyl carboxylase, enabling hepatic synthesis of functional factors over 12-24 hours. Four-factor prothrombin complex concentrate (4F-PCC, Kcentra) provides preformed factors II, VII, IX, and X plus proteins C and S, correcting INR within 15-30 minutes. Fresh frozen plasma (FFP) contains all coagulation factors but requires large volumes (10-15 mL/kg), carries risks of volume overload and transfusion reactions, and requires ABO typing and thawing time. The clinician selects reversal strategy based on INR level, presence and severity of bleeding, urgency of invasive procedures, and patient-specific factors (heart failure limiting volume tolerance, thrombotic risk). INR-based algorithms guide management: INR 4.5-10 without bleeding requires warfarin hold...