• intrinsic pathway: inside the cut, endothelial injury, slow pathway, aPTT; alter using heparin
• extrinsic pathway: outside the cut in the plasma, vitamin K - liver dependent, fast pathway, PT --> INR; alter using warfarin
• common pathway

• oral anticoagulant
• synthetic derivative of natural substance (coumarin)
• decreases blood coagulation by inhibiting vitamin K epoxide reductase
• vitamin K carboxylates factor II (prothrombin), VII, IX, and X and protein C and S
• delayed effect
• CNS

INR

warfarin

Quick test

normal: 12-15 seconds PT, 0.8-1.2 INR

warfarin activity determined partially by genertic factors

1. VKORC1 (pharmacodynamics, therapeutic effect) Asian Americans sensitive (little reductase), African Americans resistant (lot of reductase)

2. CYP2C9 (pharmacokinetics, metabolism) inhibitors include amiodarone, fluoxetine, zafirlukast

• warfarin is high protein binding, can be displaced by other high protein binding drugs, raising the INR
• increased vitamin K foods decreases INR
• antibiotics kill gut bacteria that produce vitamin K, which increases INR
• can self test INR

delayed onset = one week (until depletion of preformed coag F)

use heparin to bridge

antagonize with vit K [delayed effect] and

necrosis due to coagulation in periphery upon initiation of treatment

highly likely due to insufficient levels of protein C, or protein C with too short half life

osteoporosis

purple toe syndrome (cholesterol embolism, late in treatment)

do not use if pregnant

• sc/iv
• endogenous acidic substance (polysaccharide) complexed w/histamine
• pentasaccharide domain activates ATIII (most important endogenous anticoagulant) which inhibits factor X
• 18u oligosaccharide inhibits factor II
• PF IV is endogenous heparin antagonist
• immediate onset
• OK during pregnancy
• antagonize with protamine if needed

PTT

high MW heparin (dual mode of action)

low mW heparins are "clean" ATIII activators --> FX inhibitors

monitor using FX activity

• HIT (heparin induced thrombocytopenia): consumption of platelets
• osteroporosis
• ADR protamine: vasodilation and lower bp

low: longer half life, less admin; more predictable response (only 1); outpatient use

but

no reliable antagonism (protamine does not work as well); more expensive

medical leeches: hirudo medicinalis

hirudin: substance secreted by leeches, inactivates thrombin

first parenteral anticoagulation

brought back to prevent HIT

-rudin

stop HIT

lepi- (65 AA)

desi- (same except 2 N-ter AA)

bivali- (20 AA)

orally active: novastan (3AA),

• 80-100 surface receptors: for thrombin, TXA2, PAF, ADP, adrenaline, 5HT --> platelet activation
• all lead to activation of GP-IIb/IIIA, which binds fibrinogen
• cAMP, cGMP, PGI2, adenosin, NO/EDRF --> decrease aggregation (less receptors)

irreversible inhibitor by acetylation of COX

unselective COX inhibitor

platelets cannot synthesize COX

platelet COX more inhibited than endothelial COX

lose cardioprotective effect if add NSAID

• ADP inhibitors
• -grel
• used when ASA is contraindicated
• clopidogrel is prodrug, only oral admin, esterases, 15% active metabolite
• ASA can be po or iv
• ADP receptor = purinergic (P2RY12) receptor

GP-IIb/IIIa inhibitors

abciximab: Fab

adenosine reuptake inhibitor

adenosine is a PDE-inhibitor??

plasminogen activators

plasmin eats fibrin

rTPA has low antigenicity and high specificty but a short half life and high price, activates only plasminogen bound to fibrin, so is clot specific