May cause hypersensitivity reactions, including anaphylaxis (use with caution in anaphylactic disorders). May cause major or fatal bleeding (risk factors include high-intensity anticoagulation (INR>4), ≥65 years, variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open wounds, history of peptic ulcer, indwelling catheters, menstruating and postpartum women, drug-drug interactions, long duration of therapy, or known genetic deficiency in CYP2C9 activity). Necrosis or gangrene of skin and other tissue can occur due to paradoxical local thrombosis (higher risk if protein C or S deficiency). Cholesterol microembolization may cause «purple toe» syndrome (a dark, purplish, mottled discoloration of plantar and lateral surfaces), rash, livedo reticularis, gangrene, abrupt and intense pain in lower extremities; abdominal, flank, or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, or other symptoms of vascular compromise. Use with caution in prolonged dietary insufficiencies (vitamin K deficiency). Use with caution in heparin-induced thrombocytopenia and deep venous thrombosis; limb ischemia, necrosis, and gangrene occurred when warfarin was started or continued after heparin was stopped. Warfarin monotherapy contraindicated in initial treatment of active heparin-induced thrombocytopenia. Warfarin initially inhibits synthesis of protein C, potentially accelerating underlying active thrombotic process. Reduced liver function may impair synthesis of coagulation factors leading to increased warfarin sensitivity. Use with caution in acute infection or active tuberculosis or any disruption of normal GI flora (antibiotics and fever may alter response to warfarin), in moderate-to-severe renal impairment, and in thyroid disease. The elderly may be more sensitive to anticoagulant therapy. Ovulating women may be at risk of developing ovarian hemorrhage at time of ovulation. Presence of CYP2C9*2 or CYP2C9*3 allele and/or polymorphism of vitamin K oxidoreductase (VKORC1) gene may increase risk of bleeding. Other variant CYP2C9 alleles (e.g. *5, *6, *9, and *11) also associated with reduced metabolic activity and thus may increase risk of bleeding, but are much less common.