19th May 2025

Warfarin

Indications

Warfarin is used for its anticoagulation properties for the prevention or treatment of thromboembolic disease. Those conditions in which it may be used include: 

• prosthetic heart valves 
• antiphospholipid syndrome
• atrial fibrillation (AF)
• venous thromboembolism including deep vein thrombosis and pulmonary embolism. 

Note that in the settings of AF and venous thromboembolic disease, direct oral anticoagulants (DOAC) are the preferred drug to achieve anticoagulation due to reduced bleeding risk (particularly relevant in older adults) and reduced need for international normalised ratio (INR) monitoring. There are some situations, however, when warfarin may be chosen, for example due to lower cost, liver or renal impairment, extremes of body weight, patient preference, and availability of and familiarity with reversal agents. 

Drug class and mechanism of action

Warfarin is a vitamin-K antagonist. It is a coumarin derivative which produces its anticoagulant effects by inhibiting the hepatic vitamin K epoxide reductase complex. Inhibition of this complex results in decreased levels of vitamin K in its reduced form, which normally acts as a cofactor for gamma-carboxylation of vitamin K-dependent clotting factors (II [prothrombin], VII, IX and X), and proteins C and S. These vitamin-K dependent clotting factors therefore cannot function to promote haemostasis, as they cannot bind calcium and phospholipid membranes.

Adverse effects

Bleeding

In reducing the risk of thrombosis, warfarin simultaneously increases the risk of bleeding. Whilst warfarin technically doesn’t itself cause bleeding, in the incidence of a damage to a blood vessel wall, haemostasis is impaired as a result of warfarin therapy, leading to increased likelihood of significant haemorrhage.  Factors which increase the risk of bleeding in patients treated with warfarin include supratherapeutic INR, older age, prior bleeding, and comorbidities such as pre-existing bleeding disorders, diabetes, hepatic pathology, renal pathology and malignancy. Bleeding risk can be mediated by careful selection of the most suitable anticoagulation therapy taking into account individual patient factors; close INR monitoring and careful dose adjustment as required; thorough counselling regarding adherence; and addressing modifiable risk factors such as hypertension, renal and hepatic disease, falls prevention, and limiting use of drugs increasing bleeding risk (such as antiplatelets and interacting medications). The treatment of supratherapeutic INR and/or bleeding in patients taking warfarin may be managed by the administration of vitamin K, prothrombin complex concentrate, and in some situations, tranexamic acid, dependent on the severity of bleeding and the INR value.

Skin necrosis

Skin necrosis may be seen and is most likely within the first few days following initiation of warfarin anticoagulation, particularly when larger doses are used. It occurs most commonly on the trunk, digits, penis, and breast tissue. The mechanism is believed to be due to a reduction in protein C levels. 

Cholesterol embolization

Cholesterol embolization is a rare complication of warfarin use. It occurs due to embolization of cholesterol crystals and presents as dark purple mottling of the soles of the feet and the lateral aspects of the toes. It has been referred to as ‘blue toe syndrome’. 

Vascular calcification

Studies have demonstrated that coronary, femoral and aortic artery calcification increases in a significant proportion of patients taking warfarin therapy, and that this increases duration of therapy increases. However, there is no evidence to suggest that there is an associated increased risk of related clinical events (myocardial infarction, stroke, or peripheral vascular disease). 

Teratogenicity

Warfarin has a dose-related teratogenic effect. It carries the highest risk during the 6th and 12th weeks of gestation. Most commonly, teratogenic effects manifest as abnormalities of cartilage and bone development, for example chondrodysplasia punctata (causing calcific stippling of cartilage and other soft tissues surrounding bony articulations) and hypoplasia of the limbs. The mechanism for these effects is unclear.