Arterial: On top of a ruptured atherosclerotic lesion, active inflammation (think heart attack); platelet rich clot causes acute occlusions in coronary, carotid, vertebral, and peripheral arteries; white clot

Venous: Composed of red blood cells and fibrin; form because of Virchow's triad (abnormal blood flow, thrombophilia, endothelial dysfunction); endothelial layer is intact but has pro-coagulant properties->obstructive but not necessarily occlusive clot; red clot

Aspirin, Thienopyradine Compounds, Dipyramidole, GP-IIb/IIIa Receptor Antagonists

"Attack Them Damn Globs"

50x higher affinity for COX-1->permenant inactivation by platelets

Inhibiting COX blocks thromboxane A2->normally promotes platelet activation and aggregation

t1/2=15-20 minutes, dose=75-81mg/day

30% of asthma patients allergic

Enteric coated: GI protection? No evidence, lower bioavaiability, should chew it for quicker effect with chest pain

Used: Prevention, post MI

SE: Bleeding, Reye's in kids

Ticlopidine, Clipidogrel, Pasugrel

Inhibits ADP-induced platelet aggregation

Pro-drugs with different pathways of metabolism

Irreversible P2Y12 receptor inhibition on the platelet and blockage of adenylate cyclase

Ticlopidine: 1st gen, inhibits its own metabolism ("Tickles it")->greater t1/2 with more use, not protective until 2 weeks of use; Neutropenia, TTP, GI; 60% cleared unchanged in urine->dose adjust in renal insufficiency

Clipidogrel (plavix): Rapid oral absorption and metabolism; Given after or during MI; dosed 1x/day (since permenant inactivation of platelets); CYP2C19 inhibitor (must identify poor metabolizers); SE=bleeding, etc; Uses: MI, recent MI or stroke, PAD, percutaneous coronary intervention

CAPRIE trial: clopidogrel and aspirin have similar efficacy and hemorrhage

CURE and COMMIT trials: clopidogrel and aspirin worked better together and have additive effect

PRODIGY trial: Is dual therapy necessary for >6 months?

Pasugrel: More potent, more rapid onset, and less metabolic variation than Clopidogrel; TRITON-TIMI 38 trial: decreases non-fatal MI but increases serious bleeding so no effect on overall mortality; Use: ACS patients managed with PCI

Vasodilator (NOT selective for large vessels->decreased collateral blood flow in angina) and Anti-platelet

T1/2=10 hours, dosed 2x daily

Must be dosed with aspirin ("di=2 medications needed"): on it's own, no platelet activity; in combo, reduces stroke risk 20%

SE: Headache, hypotension, bronchospasm, MI, arrhythmia, nausea, dizziness, rash, parathesias

Block the final common pathway of platelet aggregation

Abciximab: human/murine monoclonal Ab, Requires high receptor occupancy; IV; Very short t1/2; Irreversible->slow restoration of normal platelet function (2 days); Platelet infusion corrects bleeding; SE: Bleeding, thrombocytopenia, allergies, AV nodal block

Tirofiban: Non-peptide tyrosine derivative; rapid binding->inhibits platelet aggregation in 5 minutes; t1/2=1.5hours; platelet infusion does NOT correct bleeding; Platelets normalize in 2-4 hours; SE: Bleeding, thrombocytopenia

Eptifibatide: Peptide from snake venom; reversible inhibition; same t1/2 and peak plasma levels as tirofiban; Renally cleared->bleeding in patients with renal insufficiency; platelets normalize quickly (1 hour); SE: Bleeding, thrombocytopenia, angina, bradycardia

"ATE: As you go from beginning to end of word, higher t1/2, more reversible, platelets normalize slower"

2 types: Indirect-mediated by plasma cofactors and usually bind ATIII; Direct-bind coagulation factors w/o cofactor

Target Thrombin

Unfractioned Heparin, LMWH, and Fondaparinux

For Factor IIa (thrombin) to be inhibited, heparin chains must be long; For Xa inhibition, a pentasaccharide bridge is all that's needed

Highly sulfated mucopolysaccharide of different sizes, activities, and pharmacokinetics

Binds ATIII to help quicken ATIII's inhibition of thrombin->The combo covalently binds thrombin (factor IIa) and Xa

IV bolus then weight-based infusion

Must monitor aPTT or anti-Xa levels

T1/2=7 minutes, rapidly reversible (can have surgery 4-6 hours after discontinuation)

Protamine sulfate: fish sperm, binds heparin molecule to reverse its anticoagulant effects; SE=hypotension, bradycardia, allergies

SE: HIT (all heparin products are contraindicated w/ previous HIT), bone loss, skin necrosis, alopecia, hypersensitivity, bleeding, inhibition of vascular smooth muscle proliferation, LFT elevation

Same thing as UH, but smaller so less effective at bridging ATIII to thrombin (can still inhibit Xa)

Inhibition of Xa>Inhibition of IIa (opposite in UH)

T1/2=3-6 hours

Weight-based dosed in subcutaneous injections

Minimal non-specific binding (unlike UH)->usually don't need to monitor, except in obesity or renal impairment we monitor anti-Xa

Renal impairment->life threatening retroperitoneal bleeding possible

Only partially reversed w/ protamine sulfate

Less likely to cause bone loss or HIT

Synthetic analog of high affinity pentasaccharide

Long t1/2 (17 hours)

Greater anti-Xa, no anti-thombin

Daily doses

Minimal non-specific binding->monitoring normally not necessary

Protamine sulfate is ineffective, factor VIIa may reverse

Renal failure->bleeding (like LMWH)

Does NOT cause HIT, so safe for patients w/ HIT history

Hirudin: 1st one, no longer used

Bivalent/Hirudin-derived: Bind active site or fibrinogen-binding exosite 1 of thrombin; Bivarudin and Lepirudin; IV; short t1/2 of 20-60 minutes

Univalent/Small molecule inhibitors: Bind active site of thrombin only; Argatroban and Dabigotran

Bivalirudin: Enzymatically eliminated->safe in patients with hepatic/renal disease

Lepirudin: Inhibits free and clot-bound thrombin; renally cleared; associated with antibody formation and anaphylaxis

Argatroban: Binds free or fibrin-bound thrombin, Hepatically cleared (be careful in liver dysfunction); IV, short t1/2

Dabigatran: Oral; longest t1/2 (12 hours); pro drug-converted to active metabolite in a non-CYP450 mechanism; renally cleared; normally no monitoring necessary, sometimes monitor thrombin time or aPTT; approved for patients in non-valvular afib

Inhibit Vit K dependent factors: II, VII, IX, X (which need to be carboxylated to be activated)

Could also inhibit protein C and S->pro-thrombotic, but this is unusual (possibly in cancer)

Warfarin:

Oral

Absorbed in GI tract and hepatically metabolized by CYP450

Must monitor w/ PT/INR because the drugs metabolism can change in different states

Drug interactions-increase or decrease metabolism, esp antibiotics : decreases rate of Vit K synthesis and absorption in gut flora

t1/2=24-36 hours

Similar to rat poison (antidote=factors and Vit K)

Start at low dose, monitor INR every 2-3 days

Bridging: Once INR is in therapeutic range, we overlap therapies for 4 days to make sure therapeutic levels are actually reached

Anticoagulant and Antithrombotic:

Anticoagulant: Binds factor VII->can't enter coagulation cascade

Antithrombotic: Inhibits Xa and IIa

SE: Bleeding (give Vit K), thrombotic complications (gangrene, necrosis)

Fibrinolytic system catalyzes conversion of plasminogen to plasmin to dissolve fibrin clots

Tissue Plasminogen activator (tPA): relesed from endothelial cells in response to stasis, converts plasminogen to plasmin; Plasminogen activator inhibitor 1 and 2 regulate->because of this and it's rapid clearance, tPA only has a minimal effect on circulating plasminogen

Fibrin bound plasminogen CAN be bound by tPA->clot removed

Fibrinolytics: work similar to fibrin-bound plasminogen; non-specifically dissolve pathogenic and helpful clots

Used for: STEMI (NOT NSTEMI), pumonary embolism with hemodynamic compromise, thrombosed IV access, catheter directed thrombolysis (ex: for a DVT)

Streptokinase, Alteplase/tPA, Urokinase, Reteplase, Tenecteplase ("end in ase")

1st gen, Not fibrin specific

Forms a complex with plasminogen to induce a conformational change to plasmin

Patients with previous strep infections->may have pre-formed antibodies->anaphylaxis

2nd gen, Produced from tPA by recombination technology

Fibrin specific

More effective than streptokinase, but more expensive

2nd gen drug that's barely used because it's not fibrin specific but it's expensive

Some utility for thrombotic catheter occlusions, severe PE

3rd gen, mutant of Alteplase with increased efficacy, similar cost and risk profile

Renally cleared, others are hepatically cleared (Renal)

3rd gen, new, recombination of alteplase with similar efficacy

The most fibrin specific

Administered in a rapid, 5 second push

ASSENT-II trial: similar rates of stroke and ICH, decreased non-CNS bleeds

A hypercoagulable state (3-5x risk of thromboembolic complications)

Why? Higher levels of factors VII->X, lower protein S, increased resistance to Protein C, placental inhibitors of fibrinolysis, venous stasis, progesterone-induced vasodilation, compression of IVC, increased hormones

Pros and Cons of drugs during pregnancy:

UH: Doesn't cross placenta, no teratogenic effects, reversed with protamine (good); could cause HIT, osteoporosis, must be administered by continuous IV (bad)

LMWH: Similar to UH, partially reversed with protamine; check Xa to assure correct dosing since there's increased renal clearance in pregnancy; lower HIT and osteoporosis than UH, more convenient (subcutaneous injections) (good), more expensive (bad)

Fondaparinux: long t1/2 and doesn't cross placenta (good), not reversible with protamine (bad); use in pregnant women who are HIT+

Dipyramidole: Deemed safe, but effects unclear

Thienopyradines: High-risk patients only, effects unclear

Aspirin: Inhibits prostaglandin synthesis->may prematurely close ducturs arteriosus, may cause prolongation of labor or bleeding (bad); may delay premature labor risk (good); use: in specific situations when arterial clotting is a risk

Wararin: Women with very high risk of thrombosis; Known teratogenic effects (6-10%); risk of fetal bleeding later in pregnancy; safe for breastfeeding