L30 - Anticoagulant therapy Flashcards
Mechanism of platelet plug formation?
1) Damaged endothelial cells (wall defect) expose collagen for GP Ib on resting platelets to stick to through von Willebrand’s factor (vWF)
2) Activated platelets degranulate (ADP, TXA2, 5-HT)»_space; bind to receptors on platelets»_space; express GP IIb/IIIa (= receptor for fibrinogen)»_space; form fibrin
Which coagulation pathway initiates immediate clotting?
Extrinsic pathway
TF/Factor 7a complex form within seconds
List 3 major physiological responses to blood vessel damage?
• Vasoconstriction • Platelet plug formation • Coagulation
Compare the activators of intrinsic and extrinsic pathways
Intrinsic = response to damage to endothelial cells or phospholipids released by activated platelets
Extrinsic = “tissue factor” leaks into the blood
2 major factors of thrombosis?
- Endothelial injury, e.g.:
Hypertension
Hyperlipidemia, diabetes mellitus (oxidative stress)
Infection (inflammation of endothelium) - Abnormal/turbulent blood flow, e.g.:
Atherosclerotic plaques
Cardiac arrhythmias
Name the 3 classes of anticoagulants and their function?
Antiplatelet agents*: inhibit Platelet adhesion, activation and aggregation
Anticoagulants*: inhibit activation of coagulation cascade
Thrombolytic agents: Breakdown formation of thrombus
- = prevention only
Name 4 antiplatlet agents?
- Cyclooxygenase (COX) inhibitor (aspirin)
- ADP receptor antagonists (clopidogrel, prasugrel)
- Glycoprotein (GP) IIb/IIIa receptor inhibitors
- Dipyridamole
Indication for low dose aspirin?
primary prevention of myocardial infarction (heart attack), ischemic stroke
Indication for Clopidogrel, prasugrel?
cannot tolerate aspirin (e.g. stomachache)
Indication for aspirin + clopidogrel?
(synergistic): e.g. after coronary angioplasty, stenting = prevent thrombosis
MoA of aspirin?
1) Forms covalent bond to irreversibly inhibit cyclooxygenase-1 (COX-1: cannot turn arachidonic acid (from membrane phospholipids) into prostaglandin H2)
2) Block thromboxane A2 (TXA2) synthesis in platelet
3) Decrease platelet aggregation
ADR of aspirin and clopidogrel?
Aspirin Increase incidence of gastric irritation, bleeding
= avoid in patients with peptic ulcer
Both increase Risk of prolonged bleeding
MoA of ADP receptor antagonists?
block P2Y receptors (= ADP receptor) = inhibit ADP-mediated platelet aggregation (cannot activate GPllb/IIIa receptors)
MoA of Glycoprotein (GP) IIb/IIIa receptor inhibitors? Give 3 examples?
1) Abciximab = monoclonal antibody to glycoprotein IIb/IIIa receptors
2) Eptifibitide, tirofiban = reversible blockers of glycoprotein IIb/IIIa receptors
Block GP IIb/IIIa receptors = prevent binding of fibrinogen to platelets = decrease platelet aggregation
Indication for GP IIb/IIIa receptor inhibitors?
given IV during coronary angioplasty, stenting
MoA of Dipyridamole? (2)
Increase cAMP in plt = prevent aggregation
- Inhibits phosphodiesterase»_space; cannot break down cAMP»_space; Increase intracellular cAMP levels in platelet
» decrease Ca2+
» inhibit platelet aggregation - Inhibits cellular reuptake of adenosine into platelets»_space; increase extracellular [adenosine]»_space; more can stimulate adenosine (A2) receptor
» more adenylate cyclase converts ATP to cAMP
» Decrease Ca2+
» inhibit platelet activation, aggregation
Preparation of Dipyridamole?
Ineffective when used alone
usually given in combination with aspirin / warfarin
Name 4 types of anticoagulants?
Heparin
Direct thrombin inhibitors
Direct factor Xa inhibitors
Warfarin
List 3 parental and one oral direct thrombin inhibitor?
Oral: dabigatran ***
Parental:
Hirudin (from leech saliva) ***
Lepirudin (recombinant/synthetic form of hirudin)
Argatroban (small molecule)
MoA of direct thrombin inhibitor?
Inhibit thrombin = cannot catalyze Fibrinogen to fibrin = decrease fibrin formation
List 3 Direct factor Xa inhibitors?
Rivaroxaban, apixaban, endoxaban
All orally active
MoA of Warfarin?
1) inhibits vitamin K epoxide reductase (exam)
2) less reduced vitamin K available to convert non-functional precursors to functional clotting factors by γ- carboxylation of Gla domain on prothrombin, factor 7,9,10»_space; cannot link with phosphatidylserine on platelet membrane
3) Decrease synthesis of clotting factors = reduce clotting
Indication of warfarin?
Prevent:
- Thrombosis with AFib
- Venous thrombosis and Pulmonary embolism
- Heart valve causing clot
Warfarin is orally active and can achieve maximum effect immediately after taking. T or F?
Partially false:
- Orally active = OK
- Maximum effect Takes 48-72 hours (2-3 days) due to long half-time of clotting factors
C/O and ADR of warfarin?
1) Bleeding (bruises, epistaxis, gum bleeding)
2) Interaction with significant number of drugs (displace protein bound and CYP450 metabolized drugs)
3) Cross placenta (should not be used during pregnancy = use heparin instead)
How to reverse effects of Warfarin?
Stop using drug Give vitamin K
MoA of Heparin?
1) bind to antithrombin via a specific pentasaccharide sequence
2) Cause Conformational change in antithrombin»_space; Increase binding affinity for thrombin and factor 10a»_space; limit coagulation cascade
3) Inhibit thrombin and factor 9a, 10a, 11a, 12a = decrease coagulation affect intrinsic pathway the most = prolonged aPTT
Indications for heparin?
Immediate / short-term anticoagulation (Warfarin is longer term)
Prevent deep vein thrombosis, pulmonary thromboembolism
During and after angioplasty and stenting
After myocardial infarction
Admin of heparin?
IV (or deep subcutaneous)
Which anticoagulant can be safely used in pregnant women?
Heparin
does not cross placenta suitable for use in pregnancy
ADR of heparin?
- Bleeding (easy bruising, epistaxis, gum bleeding), Haemophilia
- Hypersensitivity (allergic to heparin)
- Heparin-induced thrombocytopenia
Explain the MoA of Heparin-induced thrombocytopenia?
1) Develops IgG antibody against PF4 on heparin
2) heparin + IgG + PF4 complex interacts with platelets
3) i) Platelet release procoagulants = thrombosis
ii) Splenic macrophages remove platelet
Reversal of heparin action?
1) Stop using drug
2) Protamine sulfate: combines with heparin as a stable complex = decrease
anticoagulant activity of heparin
3) Direct thrombin inhibitor
Name 2 other variants of heparin and their structure? PK compared to regular heparin?
- Low-molecular-weight heparin, e.g. enoxaparin: same pentasaccharide sequence as regular heparin
- Fondaparinux: pentasaccharide sequence only
Both have much higher bioavailability and longer t1/2
MoA of Fondaparinux?
Increases antithrombin binding to factor Xa
No effect on antithrombin binding to thrombin
Which heparin variants are reversible?
Heparin and Low molecular weight heparin only by Protamine sulphate
Not Fondaparinux
Which heparin variant needs monitoring?
Heparin only
Highly variable response, elimination, plasma conc
What coagulation test is used to monitor heparin?
aPTT (activated partial thromboplastin time) = intrinsic and common pathway
> > Heparin binds to antithrombin»_space; antithrombin/heparin complex binds thrombin and factor Xa (and IX, XI and XII) to increase clotting time
What’s mixed together in aPTT test?
Kaolin (surface activator)
Ca
Phospholipid (partial thromboplastin)
Citrated plasma
What coagulation test is used to monitor warfarin?
PT = Evaluates extrinsic pathway
Warfarin decrease synthesis of clotting factors (prothrombin, factors VII, IX and X) = increase clotting time
Target INR value = 2-3
What’s mixed together in PT test?
Thromplastin (Phospholipid + tissue factor) + Ca + citrated plasma
List 4 thrombolytic drugs?
Alteplase (recombinant tissue type plasminogen activator (tPA))
Streptokinase (from bacteria)
Anistreplase (streptokinase plasminogen complex)
Urokinase (endogenous protease obtained from human fetal kidney cells)
MoA of thrombolytic drugs?
activate the formation of plasmin from plasminogen (precursor)»_space; break down fibrin»_space; lyse thrombi and remove blood clot
Indication of thrombolytic drugs?
(for emergency use):
Pulmonary emboli
Deep venous thrombosis
Acute myocardial infarction
ADR and Reversal of thrombolytic drugs?
ADR = bleeding
Tranexamic acid: binds to plasminogen, plasmin = inhibits plasminogen activation
Fresh plasma
Coagulation factors
