The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway). Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII). The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X. Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin. Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 4–5 days when starting therapy.
The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).
The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins.
The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.
The four Vitamin K dependent clotting factors are synthesized in the liver.
The details of stopping warfarin and introducing heparin are listed on this slide. Full dose heparin should be discontinued approximately 4 hours preoperatively to allow the APTT to fall to normal during the invasive procedure. Thereafter, heparin can be restarted when considered safe to do so depending on the procedure. Adjusted dose subcutaneous heparin or low dose subcutaneous heparin should be discontinued approximately 12 hours pre-procedure.
This shows a dosage adjustment algorithm which has been used successfully in an anticoagulation clinic.
This slide lists the various drugs that have been reported to interact with and potentate warfarin The strength of the evidence is shown in the left hand column with level I being strongest and level IV the weakest based on the study design of the report.
This slide lists the various drugs and foods that have been reported to interact with and inhibit warfarin. The strength of the evidence is shown in the left hand column.
This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin.