Bad News Platelets Antiplatelet Agents

1.3 – “Bad Ne News ws Platelet Platelets”: s”: Antiplatelet Agent Agentss Physiology • Primary Hemostasis can be thought of as occurring in three steps. o Adhesion: Damage to vascular endothelium exposes collagen, to which von Willebrand Factor (VWF) binds (The “von Wille Brand Field” is looking a bit beat up, rather like damaged vascular endothelium with exposed collagen). VWF provides a substrate for platelet adhesion, binding platelets via the GpIb receptor (Ib on the bat the players are handing off). VWF binding induces a conformational change in the platelet, activating (the batter is ready to play because he now has a bat). o Platelet activation (home plate activates the game) induces degranulation, releasing various compounds including ADP, 5HT, TXA2, & Ca2+ needed for the coagulation cascade. ▪ Adenosine diphosphate (ADP): Powerful inducer of aggregation. Binds to platelet P2Y12 receptor, inducing platelet expression of surface GpIIb/GpIIIa receptors (“aggregate da players!” sign, with “Play Youth Ball 2-12” for P2Y12). GpIIb/IIIa receptors bind either VWF or fibrinogen. • Platelet surface receptor Glycoprotein IIb/IIIa binds fibrin & stimulates aggregation (Fibrinogen fries; seats 2b & 3b spectators attacking fry man). GpIIb/IIIa is activated by adhering to VWF, upregulated TXA2 synthesis, or binding ADP & inducing a conformational change. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. ▪ 5-HT: Serotonin stimulates local platelet aggregation and vasoconstriction (helmet with smiley-face; yellow platelet players are all aggregating on the base to try to tag the runner). ▪ Thromboxane A2 stimulates local platelet aggregation and vasoconstriction(thromboxane A2: 2 batter boxes labeled A2 on either side of the home plate). • TXA2 is a synthesized from arachidonic acid (AA league baseball) by either constitutively active COX-1 or inflammation induced COX-2. (Coach Cox is the head coach, and so is always active, while the second coach napping in the pit is only active when needed. Coach Cox is twisting his hat in his teeth, tightening it like with vasoconstriction.) o Platelets aggregate; as they are activated, they recruit more platelets and coagulation factors. Fibrin activation (coagulation cascades are considered secondary hemostasis) and crosslinking stabilizes the platelet plug. Circulating fibrinogen binds GPIIb/IIIa receptors, crosslinking adjacent platelets & forming a plug. Drugs • Aspirin o Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game). o Indications: ▪ Reduces CV events & angina in patients with arterial disease (“greasy pipes”) ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat, recurring symbol for ischemic stroke, will no doubt be told off next by the ref) ▪ Used in MI (banjo with broken strings). Should be chewed or crushed for more immediate effect (ump chewing ASA while chewing out coach). ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat used by the home team to cheat looks remarkably like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Side effects: ▪ Pseudo allergy (referee has a red, inflamed face). Usually seen in patients with comorbidities, e.g. the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. reactions can be divided into four types: • Type 1 – NSAID-induced asthma and rhinosinusitis • Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria • Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals • Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals • ADP receptor inhibitors (ADPRIs) o Include clopidogrel, prasugrel, ticlopidine (thienopyridines) & ticagrelor (a cyclopentyltriazolopyrimidine; only reversible agent). Note that the most common of these have “-grel-” somewhere in their name (hence the hot dog grill man). o Inhibit platelet aggregation by irreversibly the ADP P2Y12 receptor, preventing induction of further platelet activation (hot dog man is grabbing the ball, preventing the platelet players clustered around first base from working). o Indications: ▪ Reduce CV events & angina in patients with arterial disease (“greasy pipes”, and the angina anvil under the second grill) ▪ Used in MI (banjo with broken strings) ▪ Used as a preventative measure for ischemic stroke (painter with a black stripe on his hat is standing directly under the hot dog man) ▪ Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis (the corked bat looks like a mesh stent). Dual antiplatelet Tx usually given for 12 mos. – 2 years post stent placement (“play youth ball 2-12 yo”) o Adverse effects: ▪ Ticlopidine can cause neutropenia, thrombocytopenia, & granulocytopenia, even fatal (Ty Cobb shirt guy is holding a neutrophil hourglass) ▪ All can cause TTP, ticlopidine most. For both these reasons, ticlopidine is not used much nowadays. • Must obtain platelet count & WBC with differential every few weeks while on therapy. • Glycoprotein IIb/IIIa inhibitors o Include abciximab, a monoclonal antibody (ABC sports with IgG microphones); eptifibatide & tirofiban – “-fib-“ because also prevent platelet interaction with fibrinogen (tied for -ti- in names). o Have many of the same indications as APDRIs. o Block binding of the GPIIb/IIIa receptors (blocking conglomeration of the spectators by feeding fries) o Adverse effects: ▪ Thrombocytopenia (broken plates). Platelet count should be monitored ▪ Increased bleeding time (see this in all of the drugs d/t obstruction of platelet function). Used to ID patients with severe hemostatic defects (ketchup clock) • Phosphodiesterase inhibitors (“Don’t Phoster Disinterest”) o Include dipyridamole (pyramidal tent), cilostazol (3rd baseman has lost the ball) o Inhibition of PDE →↑cAMP within the platelet (green tent), which leads to activation of protein kinase A, ultimately inhibiting platelet function. o Causes arterial vasodilation (dilated sleeves). Direct coronary vasodilation associated with coronary steal (stealing a heart shaped base). ▪ In patients with stenotic coronary arteries d/t atherosclerosis, arteries beyond are already maximally dilated to maintain perfusion. When give a direct vasodilator, exacerbate ischemia by dilating other vessels and diverting blood away from stenotic area (crown-shaped red design on hat) o Can be helpful when treating claudication (dirt clods hitting legs); first line treatment for peripheral artery disease. o Dipyridamole used for coronary stress testing.