Warfarin

Acute kidney injury, possibly as a result of episodes of excessive anticoagulation and hematuria, may occur in patients with a history of kidney disease or in patients with altered glomerular integrity.

May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders.

May cause major or fatal bleeding. Perform regular INR monitoring in all treated patients. INR levels achieved with warfarin therapy may be affected by concomitant medication, dietary modifications and/or other factors (eg, smoking). Risk factors for bleeding include high intensity anticoagulation (INR >4), age (≥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 wound, history of PUD, indwelling catheters, menstruating and postpartum women, drug-drug interactions, long duration of therapy, or known genetic deficiency in CYP2C9 activity. Patient must be instructed to report bleeding, accidents, or falls as well as any new or discontinued medications, herbal or alternative products used, or significant changes in smoking or dietary habits. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation.

Fatal and serious calciphylaxis (calcium uremic arteriolopathy) has been reported in patients with and without end-stage renal disease. If calciphylaxis is diagnosed, discontinue therapy and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

Necrosis or gangrene of the skin and other tissue can occur (rarely, • Atheroemboli/cholesterol microemboli: Warfarin therapy may release atheromatous plaque emboli; symptoms depend on site of embolization, most commonly kidneys, pancreas, liver, and spleen. In some cases may lead to necrosis or death. “Purple toe” syndrome, due to cholesterol microembolization, has been rarely described with coumarin-type anticoagulants. Typically, this occurs after several weeks of therapy, and may present as a dark, purplish, mottled discoloration of the plantar and lateral surfaces. Other manifestations of cholesterol microembolization may include 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. Disease-related concerns:

Use with caution in patients with prolonged dietary insufficiencies (vitamin K deficiency).

Use with caution in patients with heparin-induced thrombocytopenia and DVT; limb ischemia, necrosis, and gangrene have occurred when warfarin was started or continued after heparin was stopped. Warfarin monotherapy is contraindicated in the initial treatment of active HIT; warfarin initially inhibits the synthesis of protein C, potentially accelerating the underlying active thrombotic process.

Reduced liver function, regardless of etiology, may impair synthesis of coagulation factors leading to increased warfarin sensitivity.

Use with caution in patients with acute infection or active TB or any disruption of normal GI flora; antibiotics and fever may alter response to warfarin.

Use with caution in patients with renal impairment. Patients with renal impairment are at increased risk for bleeding diathesis; frequent INR monitoring is recommended.

Use with caution in patients with thyroid disease; warfarin responsiveness may increase (Ageno 2012). Special populations:

The elderly may be more sensitive to anticoagulant therapy.

Presence of the CYP2C9*2 or *3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) gene may increase the risk of bleeding. The *2 allele is reported to occur with a frequency of 4% to 11% in African-Americans and Caucasians, respectively, while the *3 allele frequencies are 2% to 7% respectively. Other variant 2C9 alleles (eg, *5, *6, *9, and *11) are also associated with reduced metabolic activity and thus may increase risk of bleeding, but are much less common. Lower doses may be required in these patients; genetic testing may help determine appropriate dosing. Other warnings/precautions:

Surgical patients: When temporary interruption is necessary before surgery, discontinue for approximately 5 days before surgery; when there is adequate hemostasis, may reinstitute warfarin therapy ~12 to 24 hours after surgery (evening of or next morning). Decision to safely continue warfarin therapy through the procedure and whether or not bridging of anticoagulation is necessary is dependent upon risk of perioperative bleeding and risk of thromboembolism, respectively. If risk of thromboembolism is elevated, consider bridging warfarin therapy with an alternative anticoagulant (eg, unfractionated heparin, LMWH) (Guyatt 2012).

Use care in the selection of patients appropriate for this treatment; ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient; ability to comply with routine laboratory monitoring is essential.