12 Anti-Coagulants Flashcards
Thrombin (IIa) mediated transformation of fibrinogen (I) to fibrin (Ia) involves activation of what factor?
Factor XIII
Role of Thrombin in protein C pathway
Thrombin cleaves protein C to activated protein C (APC), which then cleaves factors Va and VIIIa to give inactive products.
Process is accelerated in the presence of protein S and platelets.
Protein C and S are vitamin K dependent.
Factor V Leiden Mutation
Most common genetic disorder that increases chance of developing abnormal blood clots–activated protein C (APC) resistance
Don’t degrade clots
Heparin
- highly negatively charged (sulfate and carboxylic acid residues)
Mech:
- heparin catalyzes inhibition of several coagulation factors (2a, 10a) by antithrombin as a suicide inhibitor
- heparin increases the rate of thrombin-antithrombin reaction 1000x because induces conformational change in antithrombin making reactive site more accessible to the coagulation factor (proteases)
- LMWH poorly catalyze inhibition of thrombin
Absorption and Metabolism:
- not absorbed orally bc large and negatively charged
- half-life dose dependent
- cleared by reticuloendothelial system and liver ***
- anticoagulant choice in pregnancy
Administration:
- venous thromboembolism (continuous IV)
- cardiopulmonary bypass (high dose indefinitely)
- prophylaxis to prevent venous thrombosis (low dose SQ)
AEs:
- Bleeding
- Heparin-induced thrombocytopenia
Contraindications:
- active bleeding
- recent surgery
- uncontrolled hypertension
Therapeutic/Clinical Indications:
- initial treatment/prevention of DVT or pulmonary embolism
- initial management of unstable angina or acute MI
- coronary angioplasty, stent replacement, cardiopulmonary bypass
- hemodialysis
- anticoagulant of choice during pregnancy
Enoxaparin and Dalteparin
Low Molecular Weight Heparin (Anti-coagulant)
Mech:
- still allows inhibition of factor Xa by antithrombin(like heparin)
- shortness of chains prevents thrombin inhibition by antithrombin
Kinetics:
- parenteral
- uniform absorption
- longer half-life than heparin (4-6 hours)
- renal clearance (impairment = bleeding)
AEs:
- lower risk of bleeding and thrombocytopenia
Contraindications:
- active bleeding
- recent surgery
- severe uncontrolled hypertension
- renal impairment **
Use:
- acute/prophylaxis of DVT
- acute unstable angina and MI
- hip replacement surgery
Lepirudin and Bivalirudin
Direct Thrombin Inhibitors
Mech:
- inactivates thrombin by binding its catalytic site and exosite I (substrate recognition)
Kinetics:
- IV
- renal excretion
AEs:
- bleeding/hemorrhage
- use cautiously with renal failure
Contraindications:
- active bleeding
- recent surgery
- severe uncontrolled hypertension
- renal disease
Use:
- alternative to heparin in patients who have had heparin-induced thrombocytopenia
Fondaparinux
Direct Factor Xa Inhibitor
Mech:
- causes antithrombin-mediated selective inhibition of factor Xa
Kinetics:
- SQ
- renal clearance
AEs:
- bleeding
- hemorrhage
Contraindications:
- active bleeding
- recent surgery
- severe uncontrolled hypertension
- renal impairment
Use:
- DVT prophylaxis (hip/knee/abdominal sx)
- acute pulmonary embolism
- acute DVT without PE
Protamine Sulfate
Heparin Antagonist
- LMW positively charged molecule from fish sperm
Mech:
- chemical antagonist
- high affinity for negatively charged molecules
- formation of an inactive complex with heparin
AEs:
- weak anticoagulant (high dose or used alone)
- anaphylactic reaction (fish sensitivity/insulin products)
- severe pulmonary hypertension
Use:
- heparin overdose with acute bleed that can’t be controlled by stopping heparain
- reverse heparin following cardiopulmonary bypass
Warfarin
Anticoagulant: Vitamin K antagonist
- fat soluble
- structural analog of vitamin K
- administered racemic (S-warfarin more active)
Mech:
- reduced Vitamin K (KH2) required to catalyze conversion of clotting factor precursors to carboxylic acid derivatives; KH2 oxidized to vitamin K epoxide (KO)
- KO reduced by vitamin K epoxide reductase (VKORC1) to KH2 to be used again
- S-warfarin binds VKORC1 and prevents KO reduction to KH2
- without carboxylated cofactors, results in incomplete coagulation factors molecules that are biologically inactive
- competitive inhibition at CYP2C9
Absorption and Metabolism:
- oral admin
- 99% bound to albumin
- CYP2C9 clearance
AEs:
- hemorrhage
- purple toe syndrome (rare)
- skin necrosis/gangrene (rare)
Contraindications:
- CYP2C9 polymorphisms
- variations in Vit K epoxide reductase complex protein 1 (VKORC1)
- Teratogenic
- Liver/Kidney disease or vit K deficiency = prolonged effect
Reversal of Warfarin:
- INR 2-3: discontinuation for minor bleeding
- INR >5: administration of vitamin K; delayed effectiveness bc new clotting factors must by synthesized)
- Immediate reversal: exogenous administration of active clotting factors via transfusion
Drug interactions:
- very common
- inc risk of bleeding
Clinical indications:
- long term tx of venous thromboembolic disease
- prophylaxis against thromboembolism in atrial fibrillation, prosthetic heart valves, dilated cardiomyopathy
Polymorphisms in what genes account for variability in warfarin response?
CYP2C9 (pharmacokinetics)
- decreased enzyme activity = higher drug concentrations
VKORC1 (pharmacodynamics)
- more prevalent than CYP2C9
Dabigatran
Anticoagulant
Prodrug metabolized to active dabigatran
Mech:
- interacts with thrombin active site
- specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin
- ability to inhibit fibrin-bound thrombin is advantageous because thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by antithrombin and can locally activate platelets to trigger coagulation and thrombus expansion
Kinetics:
- oral admin with short half-life 14-17 hours
- kidney clearance
AEs:
- bleeding (less than warfarin)
- no antidote! (short half-life/excretion)
- GI upset (more than warfarin)
Contraindications:
- renal/liver/valvular heart disease
Drug interactions:
- not metabolized by cytochrome P450 (few interactions)
- Substrate for P-glycoprotein (Pgp) efflux transporter in gut and kidneys
- inducers decrease plasma concentration of dabigatran
- inhibitors increase plasma concentrations of dabigatran
Use:
- prophylaxis (knee/hip sx)
- prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
Rivaroxaban
Anticoagulant: Direct Factor Xa inhibitor
Mech:
- selective direct-acting factor Xa inhibitor via S1 and S4 pockets
- inhibits both free Factor Xa: decreases the amplified generation of thrombin without affecting existing thrombin levels (ensures primary homeostasis)
- inhibits clot bound Factor Xa: prevents extension the thrombus by blocking further generation of thrombin
Kinetics:
- oral admin (rapid/long half-life 5-9 hours)
- dual elimination (1/3 renal, 2/3 CYP3A4)
- P-glycoprotein substrate
AE:
- bleeding (lower than other anticoagulants)
- drug interactions (CYP3A4/Pgp)
Use:
- reduce risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
- DVT prophylaxis (knee/hip sx
Are the new oral anticoagulants better than warfarin?
warfarin:
- narrow therapeutic index
- interacts with many drugs
- slow onset and long offset of action
- teratogenic
- genetic variations require dose adjustments
costs??? The estimated price of dabigatran (150 mg twice a day) is about $6.75 to $8.00 per day. Warfarin, in contrast, costs as little as $50/year.
Mechanism of action, monitoring therapeutic level, and reversal agent available for warfarin.
What causes the clinical expression of acute MI?
Obstruction of the coronary artery by a thrombus
Are heparin and oral anticoagulants effective in reducing the size of preformed fibrin clots?
They are ineffective
What dissolves intravascular clots?
Plasminogen converted to Plasmin digests fibrin
What activates plasminogen to plasmin?
Endogenous factors:
- t-PA
Exogenous (Drug):
- alteplase (recombinant t-PA)
Tissue-type plasminogen activator (t-PA)
Endogenous activator synthesized by vascular endothelial cells and released at local sites
Mech:
- t-PA activates fibrin-bound plasminogen to fibrin-bound plasmin and initiates clot resolution
- during early stage, little t-PA released due to plasminogen activator inhibitors (PAI-1 and PAI2)
- when PAI production decreases and t-PA production increases, results in breakdown of clot
- free plasmin inactivated by alpha2-antiplasmin (protects fibrin and other clotting factors like 8 and 5)
- unwanted fibrin thrombi removed, while fibrin in wounds persists to maintain hemostasis
AE:
- hemorrhage (dissolve pathologic thrombi and fibrin sites of vascular injury)
Alteplase
Thrombolytic Agent: Exogenous Tissue plasminogen activator (t-PA)
Mech:
- binds and activates fibrin-bound plasminogen 100x more rapidly than free plasminogen
- efficient degradation of clot fibrin due to high affinity
Kinetics:
- IV
- short half-life (1-4 mins)
- rapid hepatic clearance
AEs:
Hemorrhage:
- lysis of fibrin at sites of vascular injury
- systemic lytic state from systemic formation of plasmin (fibrinogenolysis and destruction of clotting factors 5 & 8)
- more bleeding in combination with aspirin or heparin
- risk of bleeding dependent on dose/duration of therapy
Contraindications:
- active (GI) bleeding
- recent surgery
- Cerebrovascular accident (CVA)
- hemorrhagic disorder
- hypersensitivity
- severe uncontrolled hypertension
- pregnancy or postpartum period
Indications for use:
- Acute MI (STEMI)
- Acute ischemic stroke
- Acute pulmonary embolism/DVT
Aminocaproic Acid
Potent inhibitor of Fibrinolyisis (Procoagulant)
- competitive inhibitor of plasmin(ogen) to fibrin
- should reverse states that are associated with excessive fibrinolysis
- concentration in urine can be 100x than in plasma
Use: treating urinary tract bleeding
What provides the initial hemostatic plug at sites of vascular injury and participate in pathologic thromboses that lead to MI, stoke, and peripheral vascular thromboses?
Platlets
What factors allow platelets to adhere to subendothelium of damaged blood vessels?
GPIa/IIa and GPIb are platelet integrins that bind to collagen and vWF causing adherence to subendothelium of damaged blood vessel
Result of PAR1/PAR4 or P2Y1/P2Y12 receptor stimulation?
Activates fibrinogen-binding protein GPIIb/IIIa (integrin) and COX-1 to promote platelet aggregation and cross-linking
What is the result of fibrinogen binding?
Cross-linking of adjacent platelets
What PG is synthesized by endothelial cells to inhibit platelet activation?
PGI2
Low-Dose Aspirin
Anti-platlet
Mech:
- irreversible inhibition of platelet COX 1 and 2
- blocks TXA2 formation in platelet
- preserves PGI2 in vascular endothelium
Kinetics:
- rapidly absorbed in upper GI
- effects in 1 hour
- half-life = 20 mins but effect on COX is permanent bc anucleate and cannot synthesize new enzyme
- may take 10 days for new platelet population
AEs:
- bleeding and GI irritation
- dose-related (saturation)
Use:
- acute/ prophylaxis of MI
- acute/ prophylaxis phase of ischemic stroke
- unstable angina
- preeclampsia prophylaxis
Dipyridamole
Anti-platelet
Mech:
- PDE inhibition
- increases cAMP which inhibits platelet aggregation
AE:
- Headache
- GI upset
Use:
- prevention of thromboemboli in patients with prosthetic heart valves (given in combination with warfarin)
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Anti-platelet
Mech:
- inhibit ADP-induced platelet aggregation by binding P2Y12 receptor on platelet surface
- if stimulate ADP receptor = platelet aggregation
- if block ADP receptor = block platelet aggregation
- all irreversible antagonists (except ticagrelor)
Kinetics:
- oral admin
- Clopidogrel and Ticlopidine are prodrug metabolized to active compound by CYP2C19
- Prasugrel is prodrug that is inactivated then converted via CYP3A4 to active metabolite (two-step process)
- increased potency due to more efficient generation of active metabolite
- more predictable/consistent levels of platelet inhibition
AEs:
- Bleeding
- dyspnea (ticagrelor)
- severe neutropenia (ticlopidine) –used much less
- activation of clopidogrel by CYP2C19 potentially inhibited by proton pump inhibitors (omeprazole) to treat peptic ulcer resulting in less active metabolite and inc risk of CV events
Use:
- clopidogrel: unstable angina or NSTEMI with aspirin; STEMI; recent MI, stroke, peripheral arterial disease
- prasugrel: reduce rate of thrombotic CV events
- ticagrelor: secondary prevention of thrombotic events with aspirin
Abciximab
Anti-platelet
Glycoprotein IIb/IIIa receptor blocker
Mech:
- Fab fragment
- binds GP IIb/IIIa receptors to prevent fibrinogen binding and cross-linking of platelets
- noncompetitive inhibition due to steric hindrance from conformational change
Kinetics:
- IV
- quick onset
- due to slow clearance, functional half-life up to 7 days
AEs:
- bleeding
- thrombocytopenia
- hypotension
- bradycardia
Use:
- prevent platelet aggregation and thrombosis in patients undergoing percutaneous coronary interventions
- administed with aspirin and heparin (or LMWH)
- prevents vessel restenosis, reinfarction, and death
Eptifibatide
Anti-platelet
Glycoprotein IIb/IIIa receptor blocker
Mech:
- prevent fibrinogen cross-linking of platelets
- competitive, reversible inhibitor of GP IIb/IIIa
Kinetics:
- IV
- quick onset and offset
- effects reversible and platelet aggregation response returns to normal within 4-8 hours after discontinuing drug
- renal clearance
AEs:
- bleeding
- thrombocytopenia
- hypotension
- bradycardia
- caution in renal dysfunction!
Use:
- unstable angina and MI in combination with LMWH
- prevent coronary thrombosis in persons with unstable angina or NSTEMI
- prevent thrombosis in persons having coronary angioplasty or stent placement for STEMI
What is a protease responsible for converting fibrinogen to fibrin?
Thrombin
Which of the following is NOT correlated with Factor Xa?
- point of convergence between extrinsic and intrinsic pathways
- is the activated form of Factor X
- inhibition of factor VII to VIIa
- hydrolyzes and activates prothrombin to thrombin
- inhibition of factor VII to VIIa
What is primarily responsible for degradation of fibrin clot?
Plasmin
What is the process that prevents blood loss from damaged blood vessels?
Hemostasis
- vasoconstriction
- adhesion and activation of platelets (plug)
- formation of fibrin
What is the pathological formation of a “hemostatic” plug within the vasculature in the absence of bleeding?
Thrombosis
- injury to blood vessel wall ~atherosclerosis, plaque rupture
- altered blood flow ~veins of leg after sitting for long time
- abnormal coagulability of blood ~pregnancy, certain drugs, inheritable disease
What is a venous thrombosis? Where do they most often occur and what can they cause?
- associated with RBCs enmeshed in fibrin
- most venous thrombi occur in the superficial or deep veins of the leg
Deep venous thrombosis (DVT) in the larger leg veins are most serious because such thrombi often mobilize to the lungs and cause pulmonary infarction
What is an arterial thrombosis? Where do they most often occur and what can they cause?
- composed of platelets with little fibrin or red cells
- occurs after erosion or rupture of an atherosclerotic plaque
Platelet-mediated thrombi can cause ischemic injuries especially in tissues with a terminal vascular bed
Cardiac ischemia and stroke are most severe manifestations of atherothrombosis
What thrombosis is associated with RBC enmeshed in fibrin? What thrombosis is platelet-mediated?
Venous – RBCs enmeshed in fibrin creating mobile thrombi that cause pulmonary infarction
Arterial – platelet-mediated causing ischemic injuries
Name the drug that lyses a fibrin clot:
- heparin
- warfarin
- t-PA
- heparin and t-PA
- heparin, warfarin, t-PA
t-PA
Why can’t heparin be administered orally?
- it is large
- it is negatively charged
- too much magnesium
- A and B
- all of the above
- it is large
- it is negatively charged
Does warfarin or heparin have a longer half-life?
Warfarin
The major reason that warfarin is not used in emergency situations is:
- low bioavailability due to oral administration
- needs to be metabolized by cytochrome P450 to active metabolite
- inhibits only extrinsic clotting factors
- no effect on active clotting factors
- no effect on active clotting factors
