These drugs are chemical derivatives of 4 hydroxy-coumarin. They are well-absorbed in the gut and transported in plasma bound to albumin. The drugs are metabolized by the liver and excreted in a hydroxylated form in the urine.
Coumarins act in the liver by inhibiting the synthesis of four vitamin K-dependent coagulation proteins, factors II, VII, IX, and X. The synthesis of several other vitamin K-dependent proteins is also impaired, although the significance of this inhibition is uncertain. The major mechanism of action is inhibition of a specific post-translational event in protein synthesis: the “y-carboxylation of multiple glutamic acid residues near the aminoterminus of the polypeptide chains. The failure of 7-carboxylation of glutamic acid residues markedly interferes with the function of the proteins by preventing calcium binding- and proper alignment of the activated factors on a phospholipid surface. A number of analogous proteins are synthesized and released that are not only hypofiinctional but also can interfere with normal coagulation reactions. For this reason plasma from patients receiving coumarin cannot be compared directly with dilutions of normal plasma or to plasma from individuals who congenitally lack vitamin K-dependent coagulation factors.
Coumarins do not act immediately, because time is required for normal coagulation factors already present in the plasma to be cleared. This lag period varies according to the plasma survival times of the K-dependent factors, being shortest for factor VII and longest for factor II. Accordingly, the one-stage prothrombin time might appear adequately prolonged 24 hours after a large loading dose of a coumarin derivative because of the relatively short half-life of factor VII, but plasma levels of the other three factors would still be high. Moreover, protein C, a newly described vitamin K-dependent protein with anticoagulant and fibrinolytic effects, has a half-life comparable to that of factor VII. Therefore, by reducing effective protein C levels a large loading dose of a coumarin derivative might tip the hemostatic balance toward coagulation rather than anticoagulation in the first 24-48 hours of therapy. Animal studies support the need for a period of overlap of heparin and warfarin therapy. The introduction of warfarin on day 4-5 will usually keep the total duration of heparin therapy at no more than 7-10 days. A clinical trial comparing the longer course of heparin therapy with a shorter course of heparin therapy (3-5 days) and immediate initiation of warfarin is needed. When monitoring coumarin therapy, it is important to recognize that the heparin can be easily removed from blood samples before performing the prothrombin time. In North America the predominant coumarin derivative in clinical use is racemic sodium warfarin.
Monitoring Coumarin Therapy
Therapy is most commonly monitored with the one-stage prothrombin time described by Quick. The clotting time is measured after mixing citrated plasma with calcium and a well characterized tissue thromboplastin. The major sources of this lipoprotein are rabbit brain in North America, human brain in the United Kingdom and parts of Europe, and bovine brain in Scandinavia and other parts of Europe. Commercially available tissue thromboplastins vary in potency, and consequently prothrombin times performed with different thromboplastins are not always directly comparable, which has resulted in much confusion over the years as to the intensity of the anticoagulant effect required.
Ahother major difficulty with coumarin therapy is the number of factors that influence coumarin metabolism and action. A complete review of these factors is beyond the scope of this article, but generally they can be divided into those that interfere with albumin binding of warfarin and those that increase or decrease the clearance of warfarin. Other interactions can occur including changes in clotting factor concentrations, variable vitamin K absorption and the introduction of separate hemostatic defects (Table 4). Ideally a patient treated with warfarin should be receiving no other drugs, should use alcohol not at all or only moderately, and should consume a diet that contained a constant amount of vitamin K ordered via My Canadian Pharmacy.
Intensity of Coumarin Therapy
As with heparin, a minimum level of anticoagulation seems necessary to achieve an antithrombotic state. In the past the suggested therapeutic range for ariticoagulation (rabbit brain thromboplastin) was a prothrombin time prolongation between 1.5 and 2.5 times the baseline value (INR of 4-10). Evidence from a recent study indicates that an effective level of anticoagulation is reflected by a prothrombin time prolongation only 1.2-1.5 times the baseline value using rabbit brain thromboplastin. This level of anticoagulation is equivalent to two times prolongation of the prothrombin time using human brain thromboplastin (INR = 2, or an INR of 2.0 to 3.0 using rabbit brain thromboplastin). It must be emphasized again that the minimum level of effective anticoagulation varies with individual thromboplastins. Another larger clinical trial is needed to confirm the findings by Hull et al, who showed that less intensive anticoagulation with warfarin results in fewer bleeding complications yet protects adequately against recurrent venous thromboembolism. Meanwhile, it would be reasonable to define a therapeutic range using rabbit brain thromboplastin of 1.2-1.5 times the baseline value (INR of 2.0-3.0).
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Table 3—Guidelines for Antithrombotic Therapy With Heparin and Warfarin in Venous Thromboembolism
|Disease suspected||Obtain baseline APTT, PT, and platelet count and give heparin bolus (5-10,000 units) IV|
|Order diagnostic test, eg, ventilation-perfusion lung scan, pulmonary angiogram, contrast venogram|
|Disease confirmed||Give loading dose of heparin (5,000 units) and start constant IV infusion at approximately 1,000 units/h|
|Monitor APTT at 4—6 hours and thereafter until the APTT is stabilized between 1.5 and 2.0 times control value|
|Monitor platelet count while administering heparin|
|Start warfarin by day 2 or 3 by instituting the estimated daily maintenance dose (usually 4-10 mg)|
|After at least 7-10 days of heparin therapy and 4-5 days of joint therapy, stop heparin and check PT four hours later|
|Maintain PT off heparin at 1.2 to 1.5 times control or pretreatment value (using rabbit brain thromboplastin)|
|Full-dose anticoagulation for at least 3months in patients without continuing risk factors, longer in other patients|
Table 4—Some Coumarin Interactions
|Enhancers (Prolonged Prothrombin Time)||Suppressors (Decreased Prothrombin Time)|
|Hypermetabolic states||Hereditary resistance|
|Low vitamin K diet||High vitamin K diet|