L30 - Anticoagulant therapy

Question 1

Mechanism of platelet plug formation?

Answer 1

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)&raquo_space; bind to receptors on platelets&raquo_space; express GP IIb/IIIa (= receptor for fibrinogen)&raquo_space; form fibrin

Question 2

Which coagulation pathway initiates immediate clotting?

Answer 2

Extrinsic pathway

TF/Factor 7a complex form within seconds

Question 3

List 3 major physiological responses to blood vessel damage?

Answer 3

• Vasoconstriction • Platelet plug formation • Coagulation

Question 4

Compare the activators of intrinsic and extrinsic pathways

Answer 4

Intrinsic = response to damage to endothelial cells or phospholipids released by activated platelets

Extrinsic = “tissue factor” leaks into the blood

Question 5

2 major factors of thrombosis?

Answer 5

1. Endothelial injury, e.g.:
    Hypertension
    Hyperlipidemia, diabetes mellitus (oxidative stress)
    Infection (inflammation of endothelium)
2. Abnormal/turbulent blood flow, e.g.:
    Atherosclerotic plaques
    Cardiac arrhythmias

Question 6

Name the 3 classes of anticoagulants and their function?

Answer 6

Antiplatelet agents*: inhibit Platelet adhesion, activation and aggregation

Anticoagulants*: inhibit activation of coagulation cascade

Thrombolytic agents: Breakdown formation of thrombus

• = prevention only

Question 7

Name 4 antiplatlet agents?

Answer 7

1. Cyclooxygenase (COX) inhibitor (aspirin)
2. ADP receptor antagonists (clopidogrel, prasugrel)
3. Glycoprotein (GP) IIb/IIIa receptor inhibitors
4. Dipyridamole

Question 8

Indication for low dose aspirin?

Answer 8

primary prevention of myocardial infarction (heart attack), ischemic stroke

Question 9

Indication for Clopidogrel, prasugrel?

Answer 9

cannot tolerate aspirin (e.g. stomachache)

Question 10

Indication for aspirin + clopidogrel?

Answer 10

(synergistic): e.g. after coronary angioplasty, stenting = prevent thrombosis

Question 11

MoA of aspirin?

Answer 11

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

Question 12

ADR of aspirin and clopidogrel?

Answer 12

Aspirin Increase incidence of gastric irritation, bleeding
= avoid in patients with peptic ulcer

Both increase Risk of prolonged bleeding

Question 13

MoA of ADP receptor antagonists?

Answer 13

block P2Y receptors (= ADP receptor) = inhibit ADP-mediated platelet aggregation (cannot activate GPllb/IIIa receptors)

Question 14

MoA of Glycoprotein (GP) IIb/IIIa receptor inhibitors? Give 3 examples?

Answer 14

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

Question 15

Indication for GP IIb/IIIa receptor inhibitors?

Answer 15

given IV during coronary angioplasty, stenting

Question 16

MoA of Dipyridamole? (2)

Answer 16

Increase cAMP in plt = prevent aggregation

1. Inhibits phosphodiesterase&raquo_space; cannot break down cAMP&raquo_space; Increase intracellular cAMP levels in platelet
   » decrease Ca2+
   » inhibit platelet aggregation
2. Inhibits cellular reuptake of adenosine into platelets&raquo_space; increase extracellular [adenosine]&raquo_space; more can stimulate adenosine (A2) receptor
   » more adenylate cyclase converts ATP to cAMP
   » Decrease Ca2+
   » inhibit platelet activation, aggregation

Question 17

Preparation of Dipyridamole?

Answer 17

Ineffective when used alone

usually given in combination with aspirin / warfarin

Question 18

Name 4 types of anticoagulants?

Answer 18

Heparin

Direct thrombin inhibitors

Direct factor Xa inhibitors

Warfarin

Question 19

List 3 parental and one oral direct thrombin inhibitor?

Answer 19

Oral: dabigatran ***

Parental:
 Hirudin (from leech saliva) ***
 Lepirudin (recombinant/synthetic form of hirudin)
 Argatroban (small molecule)

Question 20

MoA of direct thrombin inhibitor?

Answer 20

Inhibit thrombin = cannot catalyze Fibrinogen to fibrin = decrease fibrin formation

Question 21

List 3 Direct factor Xa inhibitors?

Answer 21

 Rivaroxaban, apixaban, endoxaban

All orally active

Question 22

MoA of Warfarin?

Answer 22

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&raquo_space; cannot link with phosphatidylserine on platelet membrane
3) Decrease synthesis of clotting factors = reduce clotting

Question 23

Indication of warfarin?

Answer 23

Prevent:

• Thrombosis with AFib
• Venous thrombosis and Pulmonary embolism
• Heart valve causing clot

Question 24

Warfarin is orally active and can achieve maximum effect immediately after taking. T or F?

Answer 24

Partially false:

• Orally active = OK
• Maximum effect Takes 48-72 hours (2-3 days) due to long half-time of clotting factors

Question 25

C/O and ADR of warfarin?

Answer 25

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)

Question 26

How to reverse effects of Warfarin?

Answer 26

 Stop using drug  Give vitamin K

Question 27

MoA of Heparin?

Answer 27

1) bind to antithrombin via a specific pentasaccharide sequence 2) Cause Conformational change in antithrombin >> Increase binding affinity for thrombin and factor 10a >> limit coagulation cascade 3) Inhibit thrombin and factor 9a, 10a, 11a, 12a = decrease coagulation **affect intrinsic pathway the most = prolonged aPTT**

Question 28

Indications for heparin?

Answer 28

Immediate / short-term anticoagulation (Warfarin is longer term)  Prevent deep vein thrombosis, pulmonary thromboembolism  During and after angioplasty and stenting  After myocardial infarction

Question 29

Admin of heparin?

Answer 29

IV (or deep subcutaneous)

Question 30

Which anticoagulant can be safely used in pregnant women?

Answer 30

Heparin does not cross placenta  suitable for use in pregnancy

Question 31

ADR of heparin?

Answer 31

1. Bleeding (easy bruising, epistaxis, gum bleeding), Haemophilia 2. Hypersensitivity (allergic to heparin) 3. Heparin-induced thrombocytopenia

Question 32

Explain the MoA of Heparin-induced thrombocytopenia?

Answer 32

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

Question 33

Reversal of heparin action?

Answer 33

1) Stop using drug 2) Protamine sulfate: combines with heparin as a stable complex = decrease anticoagulant activity of heparin 3) Direct thrombin inhibitor

Question 34

Name 2 other variants of heparin and their structure? PK compared to regular heparin?

Answer 34

1. Low-molecular-weight heparin, e.g. enoxaparin: same pentasaccharide sequence as regular heparin 2. Fondaparinux: pentasaccharide sequence only Both have much higher bioavailability and longer t1/2

Question 35

MoA of Fondaparinux?

Answer 35

 Increases antithrombin binding to factor Xa  No effect on antithrombin binding to thrombin

Question 36

Which heparin variants are reversible?

Answer 36

Heparin and Low molecular weight heparin only by Protamine sulphate Not Fondaparinux

Question 37

Which heparin variant needs monitoring?

Answer 37

Heparin only Highly variable response, elimination, plasma conc

Question 38

What coagulation test is used to monitor heparin?

Answer 38

aPTT (activated partial thromboplastin time) = intrinsic and common pathway >> Heparin binds to antithrombin >> antithrombin/heparin complex binds thrombin and factor Xa (and IX, XI and XII) to increase clotting time

Question 39

What's mixed together in aPTT test?

Answer 39

Kaolin (surface activator) Ca Phospholipid (partial thromboplastin) Citrated plasma

Question 40

What coagulation test is used to monitor warfarin?

Answer 40

PT = Evaluates extrinsic pathway Warfarin decrease synthesis of clotting factors (prothrombin, factors VII, IX and X) = increase clotting time Target INR value = 2-3

Question 41

What's mixed together in PT test?

Answer 41

Thromplastin (Phospholipid + tissue factor) + Ca + citrated plasma

Question 42

List 4 thrombolytic drugs?

Answer 42

 Alteplase (recombinant tissue type plasminogen activator (tPA))  Streptokinase (from bacteria)  Anistreplase (streptokinase plasminogen complex)  Urokinase (endogenous protease obtained from human fetal kidney cells)

Question 43

MoA of thrombolytic drugs?

Answer 43

activate the formation of plasmin from plasminogen (precursor) >> break down fibrin >> lyse thrombi and remove blood clot

Question 44

Indication of thrombolytic drugs?

Answer 44

(for emergency use):  Pulmonary emboli  Deep venous thrombosis  Acute myocardial infarction

Question 45

ADR and Reversal of thrombolytic drugs?

Answer 45

ADR = bleeding Tranexamic acid: binds to plasminogen, plasmin = inhibits plasminogen activation Fresh plasma Coagulation factors