Management of warfarin (coumarin) overdose

doi:10.1016/S0268-960X(98)90020-0

Blood Reviews

Volume 12, Issue 2, June 1998, Pages 91-98

https://doi.org/10.1016/S0268-960X(98)90020-0 Get rights and content

Abstract

Treatment with coumarin oral anticoagulants, such as warfarin, is effective antithrombotic therapy, but patients treated with these drugs are at significant risk of bleeding. The risk of haemorrhage increases with increasing intensity of anticoagulation and overanticoagulation is common. Reversal can be achieved by stopping the coumarin drug or administration of vitamin K, fresh frozen plasma or coagulation factor concentrates. However, there are surprisingly few studies defining the optimum dose of these products and there are no randomized studies comparing the relative benefit and risk of coagulation factor concentrates versus fresh frozen plasma. Guidelines for the management of overdose are based on level III and IV evidence and are, therefore, only grade B recommendations at best. Further studies are required to determine the most effective use of products and the dose required for safe reversal of overanticoagulation.

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When these are suspected, a full blood count and coagulation screen are indicated. In warfarin and difenacoum poisoning, the prothrombin time and international normalized ratio are elevated, and may remain so for weeks with difenacoum.9 Air, water and food-borne poisoning should be considered when clustering of cases occurs.
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This property is coupled with a narrow therapeutic window therefore displacing of warfarin from human serum albumin (HSA) can result in the occurrence of unexpected bleedings. Because of the delicate balance of bound and unbound forms of warfarin in the human organism its molecular interactions is of very high importance [5,6]. Metabolism of warfarin is mainly driven by Cytochrome P450 (CYP450) enzymes (for example CYP2C9) [7].
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Patients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) > 4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥ 4.5. We assessed: the relationship between different prothrombin time systems for INRs > 4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing.
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Management of warfarin (coumarin) overdose

Abstract

J Biol Chem

Lancet

J Biol Chem

J Biol Chem

Lancet

Thromb Res

Studies on the hemorrhagic agent 3,3′-methylene-bis-(4-hydroxycoumarin). The effect on the prothrombin and coagulation time of dogs and humans

Am J Med Sci

Preparation from spoiled sweet clover [3,3′-methylene-bis (4-hydroxycoumarin)] which prolongs coagulation and prothrombin time of blood, preliminary reports of experimental and clinical studies

Oral Anticoagulants

Guidelines on oral anticoagulation: third edition

Brit J Haem

On behalf of the Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT)

Lancet

Optimal oral anticoagulant therapy in patients with mechanical heart valves

New Engl J Med

Bleeding complications in oral anticoagulant therapy

Arch Int Med

Laboratory monitoring of anticoagulants

Multicentre study of replacement of the international reference preparation for thromboplastin, rabbit, plain

Thromb Haemostas

Hemorrhagic complications of oral anticoagulant therapy

British National Formulary

Clinical pharmacokinetics of oral anticoagulants

Clin Pharmacokinet

Proteins induced by vitamin K absence (PIVKAs): effect of coumarins on circulating clotting factors

Role of gamma-carboxyglutamic acid: an unusual protein transition required for calcium-dependent binding of prothrombin to phospholipid

J Biol Chem

Structure and mechanism of activation of vitamin K antagonists

Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition

Biochemistry

Evidence that warfarin anticoagulant action involves two distinct reductase activities

J Biol Chem

Influence of food on the bioavailability of drugs

Clin Pharmacol Ther