Warfarin

Summary

Warfarin, also known by its trade name Coumadin, is an anticoagulant that inhibits the activation of vitamin K, decreasing the levels of vitamin K-dependent clotting factors in blood. These include prothrombotic factors like Factor II, VII, IX, and X, as well as the thrombolytic factors Protein C and S. The overall effect of warfarin administration is anticoagulation, which manifests on laboratory testing as an increase in prothrombin time (PT) and international normalized ratio (INR). Clinically, warfarin is used as a long-term anticoagulant in patients with atrial fibrillation and deep venous thrombosis. Of note, warfarin is metabolized by the CYP450 system in the liver, and may undergo interactions with other drugs that induce or inhibit CYP450 enzymes. Notable side effects of warfarin use include bleeding and teratogenicity if taken during pregnancy. Crucially, skin necrosis is a rare side effect seen in the first few days of warfarin use due to early depletion of protein C. Skin necrosis may be avoided by short-term concomitant heparin in the first days of warfarin administration, known as a “heparin bridge”.  Reversal of warfarin involves replenishing vitamin K-dependent factors by administering fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC).

Key Points

• Warfarin
  • Also known by its trade name: Coumadin
  • Mechanism
    • Decreases synthesis of Vitamin-K dependent clotting factors
      • Includes Factors II, VII, IX, X, Protein C, Protein S
      • Warfarin inhibits vitamin K epoxide reductase, an enzyme required for synthesis of certain clotting factors in the liver
      • Slow rate of onset since drug functions by inhibiting synthesis (contrast vs. Heparin)
  • Clinical Use
    • Anticoagulation (long-term)
      • Atrial fibrillation
        • Clots formed by blood pooling in fibrillating atria can lead to stroke and other vascular events
      • Venous thromboembolism (e.g. DVT, PE) prophylaxis
  • Laboratory Findings
    • Increased PT and INR
      • Prothrombin time (PT) is a measure of the extrinsic coagulation cascade, used to monitor for therapeutic effect of warfarin
      • International Normalized Ratio (INR) is a normalized ratio derived from PT; calculated by dividing patient’s PT by an international population average
      • Therapeutic range is typically INR between 2-3
  • Adverse Effects
    • Skin necrosis
      • Warfarin inhibits synthesis of anticoagulant factors proteins C and S, which have shorter half-lives than other clotting factors → transient hypercoagulable state
      • Clot formation in vessels supplying skin leads to skin necrosis, usually seen in first days after administration
      • Heparin may be used as a “bridge” to avoid pro-thrombotic complications during initial administration of warfarin
    • Teratogenic
      • Crosses the placenta and can cause birth defects (skeletal abnormalities, nasal hypoplasia) and fetal hemorrhage
    • Bleeding
      • Obvious side effect seen in all anticoagulant drugs
      • Common with drug interactions involving CYP450 enzymes, when dosage is poorly monitored
    • Metabolized by CYP enzymes
      • Important: Many questions about CYP450 enzymes are asked in context of warfarin
      • P450 inducers (e.g. rifampin, phenobarbital, and phenytoin): decrease warfarin levels
      • P450 inhibitors (e.g. cimetidine, amiodarone, and TMP-SMX): increase warfarin levels
    • Other drugs that increase warfarin’s effects
      • Broad-spectrum antibiotics
        • Kill bacteria in the gut that produce Vitamin K, decreasing absorption/body stores
      • Sulfa drugs
        • Displace warfarin bound to albumin, raising free warfarin levels in the bloodstream
    • Other drugs that decrease warfarin’s effects
      • Dietary vitamin K
        • e.g. leafy greens like spinach and kale
      • Cholestyramine
        • Decreases GI absorption of warfarin
  •  Reversal
    • Rapid: Fresh-frozen plasma (FPP) or Prothrombin concentrate (PCC)
      • Restores depleted factors
    • Slow: Supplemental Vit K
      • Requires new hepatic synthesis of coagulation factors to function