Warfarin is a coumarin derivative
It acts by inhibiting vitamin K synthesis and thereby limiting the coagulation factors that are dependent on vitamin K for their production.
These include factors II, VII, IX, X and proteins C and S.
How does loading of Warfarin work?
The loading dose causes factor VII concentration to decrease considerably within 24 h
However, prothrombin has a longer half-life and only decreases to 50% of normal after 3 days.
Therefore, a patient is fully anticoagulated only after this period.
A normal loading dose is 10 mg daily for 2 days followed by 5 mg per day titrated to effect.
How does interaction with other drugs causing increase/decrease clinical latency of Warfarin?
Warfarin is 99% protein bound (predominantly to albumin), which means it is easily displaced by other highly protein-bound drugs, leading to an increased anticoagulant effect.
It is almost entirely metabolized in the liver, which exposes it to further drug interactions.
Increased anticoagulant effect Inhibition of anticoagulant effect
Decreased vitamin K absorption Hepatic microsomal augmentation
• Laxatives • Phenobarbital
• Cholestyramine • Phenytoin
• Broad-spectrum antibiotics • Carbamazepine
Enhanced synthesis of clotting factors
Decreased protein binding • Oral contraceptives
• Gliclazide, tolbutamide
Hepatic microsomal inhibition
• Tricyclic antidepressants
• Alcoholic binges
Alteration of hepatic receptor sites for warfarin
What is the measure of Warfarin effect?
The anticoagulant effects can best be measured using the prothrombin time (PT), a measure of the extrinsic coagulation pathway.
International Normalized Ratio (INR) is normally used. It is a ratio of the patient's PT over the control for the normal population, with correction for the sensitivity of the thromboplastin used.
What are the issues that may arise with stopping Warfarin therapy peri-operatively?
There is a requirement of several days for the anticoagulant effect to resolve after warfarin or other vitamin K antagonist therapy is discontinued, potentially delaying more urgent surgery.
Rebound hypercoagulability may occur following the abrupt cessation of anticoagulation.
Several days may be required after warfarin therapy is resumed to reestablish a therapeutic and adequate level of anticoagulation.
What are the guidelines available for stopping Warfarin peri-operatively?
Timing of interruption and reversal
Reversing the anticoagulant activity of warfarin and other vitamin K antagonists depends upon the amount of time available before the surgical or invasive procedure, the elimination half-life of the vitamin K antagonist (ie, 36 to 42 hours for warfarin); as well as the estimated bleeding and thrombotic risk.
Fully elective surgery — In patients with an INR between 2.0 and 3.0 who are undergoing elective surgery that requires temporary cessation of anticoagulation, warfarin should be withheld for approximately five days to allow the INR to be normal (INR <1.3) or near normal (INR 1.3 to 1.4) before surgery.
Semi-urgent surgery — If more rapid reversal of warfarin anticoagulation is required (eg, over one to two days), warfarin should be withheld and a small dose of vitamin K administered, either intravenously (eg, 1.0 to 2.5 mg) or orally (eg, 2.5 to 5.0 mg).
Urgent surgery — If urgent reversal of warfarin anticoagulation is required (eg, less than one day), warfarin should be withheld and a higher dose (eg, 2.5 to 5.0 mg) of intravenous vitamin K administered. If more immediate correction is required (eg, minutes to hours), this can be achieved via the use of those prothrombin complex concentrates (PCCs) that contain adequate amounts of factor VII (eg, 4-factor PCC) or fresh frozen plasma, in addition to vitamin K.
Timing of warfarin resumption - Warfarin therapy should be restarted 12 to 24 hours after surgery, typically the evening after surgery, provided that surgical hemostasis has been achieved. If warfarin is resumed alone, without heparin bridging, a full anticoagulant effect will take four to six days to occur, thereby allowing a more gradual re-anticoagulation, which may be appealing in patients undergoing surgery associated with substantial expected blood loss.
What are the newer anticoagulant therapy that have been used for patients with thromboembolic risks (arterial/venous)?
Direct thrombin inhibitors (eg, dabigatran)
Dabigatran — Dabigatran is an oral direct thrombin inhibitor that is currently approved for use as stroke prevention in atrial fibrillation and, in some countries, for DVT prevention after hip and knee replacement surgery. It has a time to peak anticoagulant activity of two to three hours after ingestion and an elimination half-life of 12 to 14 hours in patients with normal renal function and approximately 28 hours in those with severe renal impairment.
Factor Xa inhibitors (eg, rivaroxaban, apixaban)
Rivaroxaban and apixaban — Rivaroxaban and apixaban are oral direct factor Xa inhibitors. As with dabigatran, they have a rapid onset of action (peak activity after two to three hours) and a similar elimination half-life of 9 to 12 hours, but, unlike dabigatran, are less dependent on renal clearance (eg, 25 to 33 percent instead of 80 percent)
What are the guidelines available in terms of stopping these newer anticoagulant agents?
In general, the rapid offset and onset of anticoagulation activity with these three agents, particularly in patients with normal or mildly-impaired renal function, obviates the need for bridging anticoagulation with heparin or LMW heparin (studies are ongoing to assess the efficacy and safety of interruption of the direct thrombin inhibitor and factor Xa inhibitor anticoagulants without the need for heparin or LMW heparin bridging).
Bridging may be considered for selected patient groups, which include:
pre-operative bridging with heparin in patients with impaired renal function who should stop dabigatran four to five days before surgery
post-operative bridging with low-dose heparin or LMW heparin in patients who have had major surgery and/or cannot take medications by mouth.
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