Anticlotting agents

• increase activity of antithrombinIII --> inactivate thrombin and Xa
• Water soluable therefore acts in seconds, given IV, shorter half life
• Used acutely (days)
• Follow PTT (intrinsic pathway)
• anticoagulate both vitro and vivo
• Protamine sulfate (+ charged binds -ly chg heparin) reverses heparin
• Used in pregnancy
• Bleeding, osteoporosis, Heparin-induced thrombocytopenia (HIT)- heparin binds to platelet factor IV, causing antibody production that binds to and activates platelets leading to their clearance and resulting in a thrombocytopenic hypercoagulable state

Newer low-molecular weight heparins (enoxaparin) act more on Xa. have better bioavailability and 2-4 times longer t_1/2. can be administered subcutaneously and w/out laboratory monitoring. Not easily reversible.

• Hirudin (leeches) derivatives
• directly inhibit thrombin
• alternative to heparin for anticoagulating patients w/ HIT

• lipid soluble therefore given orally, have high plasma binding, takes 2-5days to fully work (t_1/2 of normal clotting factors), have longer half life, crosses placenta
• doesn't inhibit coagulation in vitro
• interferes w/ normal synthesis and gamma-carboxylation of vit K- dependent clotting factors II, VII, IX and X and protein C and S.
• Metabolized by P-450 pathway
• PT monitor
• fresh frozen plasma (fast) and vitK (overtime) for reversal
• Toxicity: skin/tissue necrosis- due to dec in protein C production. given w/ heparin initially to prevent this SE.

• used in early MI, early ischemis stroke (best if used w/in first 3 hrs)
• tPA covert fibrin-bound plasminogen thus targeting clots; others are not clot specific
• inc PT, PTT and no change in platelet count
• Aminocaproic acid reverses the toxicity

• acetylates and irreversibly inhibits cyclooxygenase (both COX1 and COX2) to prevent conversion of arachidonic acid to thromboxane A2 (TXA2) <--responsible for platelet aggregation
• inc bleeding time, no effect on PTT or PT
• Toxicity: gastric ulceration, bleeding, hyperventilation, Reye's syndrome, tinnitus (CN VIII)

• inhibit platelet aggregation by irreversibly blocking ADP receptors. inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa expression
• Toxicity: neutropenia (ticlopidine)

• inhibit phosphodiesterase III enzyme that degrade cAMP (inhibit platelet aggregation, vasodilator)
• Toxicity: nausea, headache, facial flushing, hypotension, abdominal pain