Anticoagulants: Warfarin
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Anticoagulants: Warfarin
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Anticoagulant drugs p. 418
warfarin as p. 441
Bleeding
warfarin p. 441
Extrinsic pathway p. 204
warfarin and p. 441
Fresh frozen plasma p. 434
warfarin reversal p. 724
for warfarin toxicity p. 247
Heparin p. 440
warfarin vs p. 441
Hypercoagulability p. 690
warfarin adverse effect p. 441
Necrosis p. 205
warfarin p. 441
Prothrombin
warfarin effect on p. 441
Spontaneous abortion
warfarin p. 632
Stroke p. 525
warfarin for p. 441
Teratogens p. 632
warfarin as p. 441
Vitamin K
warfarin reversal p. 724
for warfarin toxicity p. 247, 441
Warfarin p. 441
adverse effects of p. 433
coagulation cascade p. 418
cytochrome P-444 and p. 251
for DVT p. 691
griseofulvin and p. 198
heparin vs p. 441
PT measurement p. 431
reversal of p. 724
teratogenicity p. 632
therapeutic index of p. 233
toxicity treatment p. 247, 434
vitamin K antagonist p. 69
Transcript
Anticoagulant medications are used to prevent blood clots from forming. These medications work by interfering with the normal function of plasma proteins called coagulation factors, which take part in secondary hemostasis. But let’s focus specifically on the anticoagulant warfarin, which works by preventing the synthesis of coagulation factors II, VII, IX and X, and anticoagulation proteins C and S. Now, to understand the regulation of clot formation we first need to talk briefly about hemostasis-- in which hemo refers to the blood, and stasis means to halt or stop. Hemostasis is divided into two phases: primary and secondary hemostasis.
Primary hemostasis involves the formation of a platelet plug around the site of an injured blood vessel, and secondary hemostasis reinforces the platelet plug with the creation of a protein mesh called fibrin. To get to fibrin, a set of coagulation factors each of which or enzymes need to be activated. These enzymes are activated via a process called proteolysis- which is where a portion of the protein is clipped off. In total, there are twelve coagulation factors numbered factors I-XII, but there’s no factor VI. Most of these factors are produced by liver cells, and it turns out that producing coagulation factors II, VII, IX, and X requires an enzyme that uses vitamin K.
Now, when vitamin K is absorbed from the digestive tract and travels to the liver, it’s in its dietary form and it’s called vitamin K quinone. An enzyme, called quinone reductase, takes electrons from NADPH, and donates them to vitamin K quinone, converting it into the reduced form which is called vitamin K hydroquinone. Then, vitamin K hydroquinone acts as a cofactor by donating its electrons to an enzyme called gamma glutamyl carboxylase, which converts the non-functional forms of coagulation factors II, VII, IX, and X into their functional forms. Gamma glutamyl carboxylase adds a carboxyl group, which is a chemical group made up of one carbon, and two oxygens, onto the end of glutamic acid residues on the proteins.
After the carboxylation step, vitamin K is in an oxidized form, where it can accept electrons, and it’s called vitamin K epoxide. Vitamin K epoxide gets converted back into vitamin K quinone by another enzyme called vitamin K epoxide reductase, or VKOR, which donates electrons to vitamin K epoxide using a thiol group. In this fashion, a single molecule of vitamin K can be reused many times. As it turns out, the drug warfarin, which was first used as a rat poison, blocks the function of this enzyme which blocks vitamin K from getting recycled and as a result factors II, VII, IX, and X don’t get activated.
Sources
- "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
- "Rang and Dale's Pharmacology" Elsevier (2019)
- "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
- "Overview of hemostasis" J.C. Aster, H. Bunn (Eds.), Pathophysiology of Blood Disorders, 2e. McGraw-Hill. (2016)
- "Nomograms" D. Nicoll, C. Mark Lu, S.J. McPhee (2017)
- "Ischemic Stroke: Risk Stratification, Warfarin Teatment and Outcome Measure" J Atr Fibrillation (2015)
- "Critical Issues and Recent Advances in Anticoagulant Therapy: A Review" Neurology India (2019)