WARFARIN

Warfarin, also known as coumadin, is a form of anticoagulant medication which is administered to stop the formation of thromboses (blood clots) and embolisms. Warfarin is made from coumarin, a chemical evident in plants, and must be monitored closely by means of regular blood testing. It reduces the chances of blood coagulation by means of interference with the metabolism of vitamin K.

Mechanisms of action

Warfarin prevents the formation of blood clots by altering the metabolism of vitamin K. Warfarin effectively prohibits the synthesis of clotting factors, called II, VII, IX and X, which are dependent on vitamin K. Warfarin also interferes with regulatory factors protein S, C and Z. Warfarin can also affect proteins that are not actively involved in the clotting process, such as osteocalcin.

The clotting factors need carboxylation of glutamic acid residues to bind phospholipids to the clotting factors. The carboxylation process is related to the oxidation of vitamin K, which produces vitamin K epoxide. Vitamin K epoxide is then reprocessed to the condensed form of the vitamin by an enzyme called vitamin K epoxide reductase (VKOR). Warfarin prohibits the actions of VKOR, reducing the available stores of vitamin K and the production of clotting (coagulation) factors. The body’s store of previously created factors decreases over the course of several days and the effects of warfarin become apparent. Coagulation factors are still produced by the body, but their function is impaired as a consequence of undercarboxylation. The factors are collectively known as proteins induced by vitamin K absence (or antagonism), or PIVKAs.

Uses

Patients who have a high risk of thrombosis (clotting) and those that have already had a blood clot are usually prescribed warfarin. Warfarin can help to prevent the development of future clots and lower the chances of an embolism. Embolism occurs when part of a blood clot breaks off and blocks the blood supply to one of the major organs. Patients with the following conditions may be prescribed warfarin:

• Atrial fibrillation.
• DVT (deep vein (or venous) thrombosis).
• Artificial heart valves.
• Pulmonary embolism.

Determining dosage instructions for warfarin can be complex, since it is identified as interacting with certain medications and chemicals found in food products. Interactions can either inhibit or enhance the actions of warfarin. Many types of antibiotic, including macrolides and metronidazole, will generally exacerbate the result of warfarin by interfering with the metabolism of the drug, while different broad-spectrum antibiotics cause the warfarin results to slow down, as they decrease the amount of bacterial flora in the bowel that produce high levels of vitamin K. Foods that contain a high level of vitamin K can also reduce the effectiveness of warfarin. Medical disorders and conditions, such as hyperthyroidism (overactive thyroid gland) or hypothyroidism (underactive thyroid gland) can also affect the action of warfarin.

As an effect of the difficulty in deciding dosage, doctors carry out regular blood tests to find a dose that will be effective without causing unpleasant or dangerous side-effects. Initially blood testing (known as INR) may be carried out twice a week, but once the patient’s blood test results are stable and a therapeutic level has been achieved, tests will be carried out less frequently.

When starting a patient on a course of warfarin doctors will choose how strong the therapy must be. The target INR result will vary according to the individual, but it is usually between 2 and 3.

Side-effects

The most frequent unwanted outcome of warfarin is haemorrhaging (bleeding), and although the danger of excessive bleeding is low it is possible. However, the benefits of treatment far outweigh the risks and doctors will highlight the potential dangers before treatment begins. The danger of bleeding is higher if the INR is not within the desired range (this may be a result of inadvertent or intentional overdose or interactions with medication or food). Bleeding may occur in the gums and nose, and blood can be present in the urine and faeces. Some people may also experience haemoptysis (coughing up blood).

Warfarin necrosis is a rare complication of taking warfarin. It is most common in people who have recently started taking the drug and have a deficiency in protein C (an inherent anticoagulant that needs vitamin K dependent carboxylation to function). Warfarin decreases the levels of protein C to begin with and this occurs at a faster compared to coagulation factors, which means that it can be counterproductive and increase coagulation. Many patients are initially prescribed heparin to prevent this from happening. If the tendency to coagulate, increases this can result in a massive thrombosis, which is accompanied by necrosis of the skin and gangrene in the limbs.

Purple toe syndrome is another uncommon outcome of warfarin treatment and is most common during the initial stages of treatment (within the first 8 weeks). Purple toe syndrome is caused by tiny deposits of cholesterol becoming free and travelling within the blood vessels found in the feet, causing the toes to look blue or purple in colour. Purple toe syndrome can be painful and affects the big toe most commonly, but it can also affect the sole of the foot (the plantar surface). In most cases of purple toe syndrome, warfarin treatment will be stopped.