Antiplatelets, Anticoags, thrombolytics

prevents blood loss

What is the purpose of normal clotting?

platelet activation/aggregation, initiation of 2 clotting pathways

What is required for a clot to form?

Endothelial injury (uncontrolled hyperlipidemia, HTN), Abnormal blood flow/stasis (arrhythmias), genetic hypercoaguability

What are the 2 things that cause a thrombosis (AKA a clot that is not supposed to be there)?

gives a surface for the activation of clotting factors

What is the purpose of aggregating and activating platelets?

Factor X

Where do the intrinsic and extrinsic clotting pathways converge?

conversion of prothrombin to thrombin

What is the role of factor Xa

phospholipids, Ca2+, Factor V

What can act as a co-factor to accelerate thrombin activation?

Activate fibrin and XIIIa (allows additional cross-linking)

What is the role of thrombin?

antiplatelets, anticoags, thrombolytics

What are the different classifications of the anti-thrombotic drugs?

Blocks aggregation, no new clot (ACS and MI)

What are anti-platelet drugs used for?

ASA

Examples of antiplatelet drugs

prevent conversion of factor II, prevent formation of new clot/extensive (stroke, PE, DVT)

What are anticoags used for?

Heparin, Factor Xa inhibitors, DTIs (direct thrombin inhibitors)

Examples of direct acting anti-coags?

warfarin

Examples of indirect acting anti-coags?

lyse existing clots - only agent capable (MI, PE, stroke)

What is the role of thrombolytics?

bleeding time

What laboratory test measures the ability of platelets to initiate clotting and is increased by anti-platelet drugs

PTT/aPTT (activated partial thromoplastin time)

What laboratory test is a measure of the intrinsic pathway to form a thrombosis and is increases 1.5-2.5x normal with direct acting anticoags?

PT (prothrombin time - reported as INR)

What laboratory test is a measure of the extrinsic pathway to form a thrombosis and is increased by warfarin?

blocks the binding of ADP (prevents aggregation)

What is the mechanism of action of P2Y12 receptor antagonists?

Clopidogrel, ticlopidine, prasurgel, ticagrelor

Examples of P2Y12-R antagonist

Irreversibly binds COX-1 (no TXA2), inhibits platelet aggregation

What is the MOA for ASA?

No cross link between fibrinogen and platelets

What is the MOA for IIb/IIIa glycoprotein receptor antagonists?

abiciximab, eptifibatide, tirofiban

Examples of Ib/IIIa glycoprotein receptor antagonists?

prophylaxis to decrease MI, TIA, ischemic stroke, re-occlusion of coronaries, stent implantation

What are the indications of ASA?

No new TXA2 results in a persistent antithrombotic effect

What is the reasoning behind taking ASA everyday?

bleeding, tinnitus (hypersensitivity rxn)

ADRs of ASA

do not give NSAIDs before ASA

What are some rules of the road for NSAIDs and ASA?

clopidogrel

What can you combine with ASA because they act on different mechanisms?

active metabolites IRREVERSIBLY bind P2Y12-R

What is the MOA for clopidogrel and prasugrel?

treatment/prevention of ACS, MI, stroke, peripheral vascular disease, prevent reocclusion during/after PCI

When are we using oral ADP-R antagonists?

CYP2C19 dependent activation (affected by genetics and DDI w/ PPIs)

Why do some clinicians not like clopidogrel?

shorter t1/2, rapid and consistent effect, esterase metabolism, greater response

Why do some clinicians preferred prasugrel?

CYP3A4 (no grapefruit)

Describe the metabolism of Ticagrelor?

CYP independent

Describe the metabolism of cangrelor

cilostazol, dipyridamole, pentoxifylline

What are some examples of phosphodiesterase inhibitors?

inhibits PDE (increases cAMP which inhibits platelet aggregation and produces vasodilation)

What is the MOA for Cliostazol?

intermittent claudication

What are the indications for cliostazol?

Unknown (inhibits platelet aggregation tho)

What is the MOA for dipyridamole?

prevention of thromboembolism after valve replacement

Indications for dipyridamole

ATIII (anti-thrombin III)

What is a weak inhibitor of Xa, IIa, and fibrinogen?

increase interaction between ATIII and Xa/IIa (inhibits new clot formation/extension of current)

MOA for heparin

enoxaparin, Dalte-, tinza-

What are some examples of LMWH?

only works on Xa, Sc only, 3.5 hr t1/2, decrease binding to platelets, better bioavailability, predictable anticoag effect, used in pregnancy

LMWH facts

fondaparinux

What is another direct acting anticoag that is sc and only targets Xa?

IV/SC, t1/2 1-2 hrs, rapid effect, erratic, used in pregnancy

Heparin facts

protamine

Antidote for Heparin and LMWH

anticoag for IV catheters, hemodialysis, cardiopulmonary bypass

Indications for heparin

bleeding, thrombocytopenia (less with LMWH), skin necrosis

ADRs for LMWH and heparin

HIT (heparin induced thrombocytopenia)

What is a hypersensitivity reaction that occurs in 3% of patients with 4-14 days of heparin use that has a rapid onset?

Stop the heparin, try DTI/Xa inhibitor/warfarin

If a patient presents with HIT what’s the game plan?

II, VII, IX, X

What clotting factors are activated by the reduced form of vitamin K?

Blocks vitamin K reductase (no effect on platelet or circulating clotting factors)

What is the MOA for warfarin?

LMWH

Since warfarin takes its sweet time to work (300 hours) what can we use to bridge?

depends on the patient (keep the INR between 2-3)

What is the optimal dose for warfarin

highly protein bound, significant liver metabolism (DDIs)

What makes warfarin have such as highly variable dosing regimen?

CYP2C9

What metabolizes S-warfarin

1A2, 2C12, 3A4

What metabolizes R-warfarin

fluconazole, amio, bactrim, metronidazole, NSAIDs, ASA

What increases the effects of warfarin?

Carbamazepine, rifampin, phenytoin, vitamin K foods/supplements

What decreases the effects of warfarin?

VKORC1, CYP2C9

What are some genetic variants that affect the sensitivity and metabolism of warfarin?

bruising, bleeding, teratogenic

ADRs for warfarin

phytonadione, 4 factor prothrombin complex concentrate, fresh frozen plasma

Antidote for wafarin

thromboembolic disorders, atrial fib, valve replacement

Indications for warfarin

-xabans

What are the direct oral Xa inhibitors?

dabigatran

What are the direct thrombin inhibitors?

less DDI/food effects, better predictability, no monitoring, no effect of PT, as effective as warfarin

Why are DOACs and DTIs taking over the market?

increased GI bleed risk

ADRS for DTIs?

idarucizumab

Reversal agent for DTIs?

andexanet

Reversal agents for direct acting Xa inhibitors?

t-PA (tissue plasminogen activator)

What is an endogenous molecule that can cleave plasminogen to plasmin which degrades the fibrin net?

alteplase, reteplase, tenecteplase

What are some examples of recombinant forms of t-PA that are used for MI, stroke, and PE in the ER?

hemorrhage

Major toxicity of t-pa

A2-antiplasmin, Aminocaproic acid, transexamic acid, whole blood, pack RBCs, fresh frozen plasma

Antidote for t-pa