Anticoagulation

Warfarin is a water soluble vitamin K antagonist initially developed as a rodenticide. It is the coumarin derivative most often prescribed in North America.

• • Interferes with vitamin K-dependent clotting factors: II (prothrombin), VII, IX, and X.

  • Synthesis of vitamin K-dependent anticoagulant proteins, protein C and S, is also reduced.

Mechanism of Action

• • Vitamin K–dependent clotting factors have glutamic acid residues at their N termini ends. A posttranslational modification resulting in addition of a carboxyl group to these N termini carbon, results in the formation of carboxyglutamic acid. This modification is essential for expression of the activity of these clotting factors because it permits calcium-dependent binding to negatively charged phospholipid surfaces. The carboxylation process is catalyzed by a vitamin K–dependent carboxylase.

  • By blocking vitamin K epoxide reductase, warfarin inhibits vitamin K–dependent -carboxylation of factors II, VII, IX, and X. Dietary vitamin K is reduced to vitamin K hydroquinone (vitamin KH2) by vitamin K reductase. Vitamin KH2 serves as a cofactor for a vitamin K–dependent carboxylase that catalyzes the -carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium and interacting with anionic phospholipid surfaces. During this process, vitamin KH2 is oxidized to vitamin K epoxide, which is then reduced to vitamin K by vitamin K epoxide reductase.

  • Warfarin inhibits vitamin K epoxide reductase (VKOR), thereby blocking the -carboxylation process. This results in the synthesis of vitamin K–dependent clotting proteins that are only partially -carboxylated. Warfarin acts as an anticoagulant because these partially -carboxylated proteins have reduced or absent biologic activity. The onset of action of warfarin is delayed until the newly synthesized clotting factors with reduced activity gradually replace their fully active counterparts.

  • The antithrombotic effect of warfarin depends on a reduction in the functional levels of factor X and prothrombin, clotting factors that have half-lives of 24 and 72 h, respectively. Because of the delay in achieving an antithrombotic effect, initial treatment with warfarin is supported by concomitant administration of a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux, in patients with established thrombosis or at high risk for thrombosis.

Pharmacology

• • Warfarin is a racemic mixture of R and S isomers. Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract. Levels of warfarin in the blood peak about 90 min after drug administration. Racemic warfarin has a plasma half-life of 36–42 h, and >97% of circulating warfarin is bound to albumin. It is only the small fraction of unbound warfarin that is biologically active.

  • Warfarin accumulates in the liver where the two isomers are metabolized via distinct pathways. Oxidative metabolism of the more active S-isomer is effected by CYP2C9. Two relatively common variants, CYP2C9*2 and CYP2C9*3, have reduced activity. Patients with these variants require lower maintenance dose of warfarin. Polymorphisms in VKORC1 can also influence the anticoagulant response to warfarin. These findings have prompted the recommendation that patients starting on warfarin should be tested for these polymorphisms and that this information should be incorporated into their warfarin dosing algorithms.

  • In addition to genetic factors, the anticoagulant effect of warfarin is influenced by diet, drugs, and various disease states. Fluctuations in dietary vitamin K intake affect the activity of warfarin. A wide variety of drugs can alter absorption, clearance, or metabolism of warfarin. Because of the variability in the anticoagulant response to warfarin, coagulation monitoring is essential to ensure that a therapeutic response is obtained.

Monitoring

• • Warfarin therapy is most often monitored using the prothrombin time, a test that is sensitive to reductions in the levels of prothrombin, factor VII, and factor X. The test is performed by adding thromboplastin, a reagent that contains tissue factor, phospholipid, and calcium, to citrated plasma and determining the time to clot formation. Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors. Thus, less sensitive thromboplastins will trigger the administration of higher doses of warfarin to achieve a target prothrombin time. This is problematic because higher doses of warfarin increase the risk of bleeding.

  • The INR was developed to circumvent many of the problems associated with the prothrombin time. To calculate the INR, the patient's prothrombin time is divided by the mean normal prothrombin time, and this ratio is then multiplied by the international sensitivity index (ISI), an index of the sensitivity of the thromboplastin used for prothrombin time determination to reductions in the levels of the vitamin K–dependent clotting factors. Highly sensitive thromboplastins have an ISI of 1.0. Most current thromboplastins have ISI values that range from 1.0–1.4.

  • Although the INR has helped to standardize anticoagulant practice, problems persist. The precision of INR determination varies depending on reagent-coagulometer combinations. This leads to variability in the INR results. Also complicating INR determination is unreliable reporting of the ISI by thromboplastin manufacturers. Furthermore, every laboratory must establish the mean normal prothrombin time with each new batch of thromboplastin reagent. To accomplish this, the prothrombin time must be measured in fresh plasma samples from at least 20 healthy volunteers using the same coagulometer that is used for patient samples.

  • For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0. An exception is patients with mechanical heart valves, where a target INR of 2.5–3.5 is recommended. Studies in atrial fibrillation demonstrate an increased risk of cardioembolic stroke when the INR falls to <1.7 and an increase in bleeding with INR values >4.5. These findings highlight the fact that vitamin K antagonists have a narrow therapeutic window. In support of this concept, a study in patients receiving long-term warfarin therapy for unprovoked venous thromboembolism demonstrated a higher rate of recurrent venous thromboembolism with a target INR of 1.5–1.9 compared with a target INR of 2.0–3.0.

Dosing

• • Warfarin is usually started at a dose of 5–10 mg. The dose is then titrated to achieve the desired target INR. Because of its delayed onset of action, patients with established thrombosis or those at high risk for thrombosis are given concomitant treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux. Initial prolongation of the INR reflects reduction in the functional levels of factor VII. Consequently, concomitant treatment with the parenteral anticoagulant should be continued until the INR has been therapeutic for at least two consecutive days. A minimum 5-day course of parenteral anticoagulation is recommended to ensure that the levels of prothrombin have been reduced into the therapeutic range with warfarin.

  • Because warfarin has a narrow therapeutic window, frequent coagulation monitoring is essential to ensure that a therapeutic anticoagulant response is obtained. Even patients with stable warfarin dose requirements should have their INR determined every 2–3 weeks. More frequent monitoring is necessary when new medications are introduced because so many drugs enhance or reduce the anticoagulant effects of warfarin.

Side Effects

• • Like all anticoagulants, the major side effect of warfarin is bleeding. A rare complication is skin necrosis. Warfarin crosses the placenta and can cause fetal abnormalities. Consequently, warfarin should not be used during pregnancy.

  • Bleeding

    • At least half of the bleeding complications with warfarin occur when the INR exceeds the therapeutic range. Bleeding complications may be mild, such as epistaxis or hematuria, or more severe, such as retroperitoneal or gastrointestinal bleeding. Life-threatening intracranial bleeding can also occur.

    • To minimize the risk of bleeding, the INR should be maintained in the therapeutic range. In asymptomatic patients whose INR is between 3.5 and 4.5, warfarin should be withheld until the INR returns to the therapeutic range. If the INR is >4.5, a therapeutic INR can be achieved more rapidly by administration of low doses of sublingual vitamin K. A vitamin K dose of 1 mg is usually adequate for patients with an INR between 4.9 and 9, whereas 2–3 mg can be used for those with an INR > 9. Higher doses of vitamin K can be administered if more rapid reversal of the INR is required or if the INR is excessively high.

    • Patients with serious bleeding need more aggressive treatment. These patients should be given 10 mg of vitamin K by slow IV infusion. Additional vitamin K should be given until the INR is in the normal range. Treatment with vitamin K should be supplemented with fresh-frozen plasma as a source of the vitamin K–dependent clotting proteins. For life-threatening bleeds, or if patients cannot tolerate the volume load, recombinant factor VIIa or prothrombin complex concentrates can be used.

    • Warfarin-treated patients who experience bleeding when their INR is in the therapeutic range require investigation into the cause of the bleeding. Those with gastrointestinal bleeding often have underlying peptic ulcer disease or a tumor. Similarly, investigation of hematuria or uterine bleeding in patients with a therapeutic INR may unmask a tumor of the genitourinary tract.

  • Skin Necrosis

    • A rare complication of warfarin, skin necrosis usually is seen 2–5 days after initiation of therapy. Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the border of these lesions reveals thrombi in the microvasculature.

    • Warfarin-induced skin necrosis is seen in patients with congenital or acquired deficiencies of protein C or protein S. Initiation of warfarin therapy in these patients produces a precipitous fall in plasma levels of proteins C or S, thereby eliminating this important anticoagulant pathway before warfarin exerts an antithrombotic effect through lowering of the functional levels of factor X and prothrombin. The resultant procoagulant state triggers thrombosis. Why the thrombosis is localized to the microvasculature of fatty tissues is unclear.

    • Treatment involves discontinuation of warfarin and reversal with vitamin K, if needed. An alternative anticoagulant, such as heparin or LMWH, should be given in patients with thrombosis. Protein C concentrates or recombinant activated protein C can be given to protein C–deficient patients to accelerate healing of the skin lesions; fresh-frozen plasma may be of value for those with protein S deficiency. Occasionally, skin grafting is necessary when there is extensive skin loss.

    • Because of the potential for skin necrosis, patients with known protein C or protein S deficiency require overlapping treatment with a parenteral anticoagulant when initiating warfarin therapy. Warfarin should be started in low doses in these patients, and the parenteral anticoagulant should be continued until the INR is therapeutic for at least two to three consecutive days.

Pregnancy

• • Warfarin crosses the placenta and can cause fetal abnormalities or bleeding. The fetal abnormalities include a characteristic embryopathy, which consists of nasal hypoplasia and stippled epiphyses. The risk of embryopathy is highest if warfarin is given in the first trimester of pregnancy. Central nervous system abnormalities can also occur with exposure to coumarins at any time during pregnancy. Finally, maternal administration of warfarin produces an anticoagulant effect in the fetus that can cause bleeding. This is of particular concern at delivery when trauma to the head during passage through the birth canal can lead to intracranial bleeding. Because of these potential problems, warfarin is contraindicated in pregnancy, particularly in the first and third trimesters. Instead, heparin, LMWH, or fondaparinux can be given during pregnancy for prevention or treatment of thrombosis.

  • Warfarin does not pass into the breast milk. Consequently, warfarin can safely be given to nursing mothers.

Special Problems

• • Patients with a lupus anticoagulant or those who need urgent or elective surgery present special challenges. Although observational studies suggested that patients with thrombosis complicating the antiphospholipid antibody syndrome required higher intensity warfarin regimens to prevent recurrent thromboembolic events, two randomized trials showed that targeting an INR of 2.0–3.0 is as effective as higher intensity treatment and produces less bleeding. Monitoring warfarin therapy can be problematic in patients with antiphospholipid antibody syndrome if the lupus anticoagulant prolongs the baseline INR.

  • If patients receiving long-term warfarin treatment require an elective invasive procedure, warfarin can be stopped 5 days before the procedure to allow the INR to return to normal levels. Those at high risk for recurrent thrombosis can be bridged with once- or twice-daily SC injections of LMWH when the INR falls to <2.0. The last dose of LMWH should be given 12–24 h before the procedure, depending on whether LMWH is administered twice or once daily. After the procedure, treatment with warfarin can be restarted.