HIS30 Anticoagulant Therapy Flashcards
Process of Haemostasis
3 major events occur when blood vessel damaged
1. Vasoconstriction (↓ bleeding, transient)
2. Platelet plug formation (platelet aggregation to injury site, stop bleeding temporarily)
3. Coagulation (after interaction between coagulation factors —> fibrin stick to platelet plug, make it stronger, takes longer time, and completed after vasoconstriction and platelet plug formation occur)
Process (Platelet activation + Fibrin formation):
Endothelial cells damaged
—> Collagen exposed + Coagulation cascade activated (formation of fibrin)
—> vWF released from endothelial cells bind to collagen + bind to GPIb protein of platelet
—> Platelet can attach to injury site and becomes activated
—> **release ADP, TXA2, 5-HT
—> bind to receptors on platelet
—> Platelet express GPIIb/IIIa protein
—> **Fibrinogen binds to GPIIb/IIIa protein and serves as bridge
—> Link platelets together to form platelet plug (platelet aggregation)
—> Platelet plug together with Fibrin (from coagulation cascade)
—> Blood clot
Collagen —> vWF —> Platelet —> plug —> Thrombin —> Coagulation —> Fibrin —> Platelet + Fibrin —> Clot
Intrinsic and Extrinsic pathway
Intrinsic pathway:
- more complex
- occurs more slowly in response to damage to endothelial cells / phospholipids released by activated platelets
- exposed collagen serves as Surface contact
Extrinsic pathway:
- few steps
- occur rapidly (within seconds) once Tissue factor (found in endothelium, smooth muscle cells, fibroblasts) leaks into blood
Fibrin
Fibrin undergo polymerisation
—> link together form meshwork
—> attach to platelet plug
—> strengthen structure of platelet plug
Pathogenesis of thrombosis
When endothelium is normal, haemostasis is regulated
- Haemostasis only restricted to local site of injury (no injury no platelet plug)
- Size of haemostatic plugs is restricted
Thrombosis:
Platelets activity + Coagulation reactions inappropriately regulated
—> Clot uncontrollably enlarge
2 major factors:
1. Endothelial injury (∵ HT, hyperlipidaemia (∵ ROS), DM (∵ ROS), infection etc.)
2. Abnormal blood flow (∵ Atherosclerotic plaque —> turbulent blood flow, Cardiac arrhythmia —> stagnant blood in atrium)
Thromboembolism:
Clot / Thrombus may be detached and occluded lumen of blood vessel in other organs (e.g. lungs, heart, brain / other organ, causing death / other disasters)
Prevention + Treatment of Thromboembolism
Platelet adhesion, activation, aggregation (Antiplatelet agents)
—> Activation of coagulation cascade (Anticoagulant: reduce coagulation factors)
—> Formation of fibrin
—> Formation of thrombus (Thrombolytic agents)
Antiplatelet: prevention of thrombus in **Artery (blood mainly contain platelet)
Anticoagulant: prevention of thrombus in **Vein (blood flow slower, coagulation cascade easily activated)
Antiplatelet agents
- COX inhibitor
- Aspirin - ADP receptor antagonists
- Clopidogrel
- Prasugrel - Glycoprotein IIb/IIIa receptor inhibitors
- Abciximab: monoclonal Ab to GPIIb/IIIa receptors
- Eptifibitide, Tirofiban: reversible blockers of GPIIb/IIIa receptors - Dipyridamole
- COX inhibitor (Aspirin)
Aspirin (irreversible COX inhibitor —> longer effect)
MOA:
- Inhibit COX —> ↓ TXA2 synthesis in platelet —> ↓ platelet aggregation
Therapeutic uses:
- Low dose (80mg) Aspirin: primary prevention of MI and stroke
- Clopidogrel in combination with Aspirin (synergistic) (e.g. after coronary angioplasty and stenting)
SE:
- Prolonged bleeding risk
- Aspirin: ↑ incidence of gastric irritation, bleeding (avoid in peptic ulcer)
(↓ prostaglandin —> ↑ gastric acid, ↓ mucus, HCO3 secretion)
- ADP receptor antagonists
Clopidogrel, Prasugrel
MOA:
- Block P2Y receptors (i.e. ADP receptor) —> ↓ platelet expression of GPIIb/IIIa protein —> ↓ platelet aggregation
Therapeutic uses:
- Clopidogrel, Prasugrel: patients who cannot tolerate Aspirin
- Clopidogrel in combination with Aspirin (synergistic) (e.g. after coronary angioplasty and stenting)
SE:
- Prolonged bleeding risk
- Glycoprotein IIb/IIIa receptor inhibitors
Abciximab: monoclonal Ab to GPIIb/IIIa receptors
Eptifibitide, Tirofiban: reversible blockers of GPIIb/IIIa receptors
MOA:
- Blockade of GPIIb/IIIa receptors —> prevent binding of fibrinogen to platelet —> ↓ platelet aggregation
Administration:
- Parenteral (IV injection)
Therapeutic use:
- Use during coronary angioplasty, stenting
- Dipyridamole
PDE/Adenosine uptake inhibitor
MOA:
1. Inhibits Phosphodiesterase that break down cAMP
—> ↑ cellular cAMP levels in platelets (↑ cAMP —> ↓ Ca —> Inhibit activation, aggregation)
—> inhibit platelet aggregation
- Inhibits cellular reuptake of Adenosine into platelets
—> ↑ extracellular adenosine
—> ↑ stimulation of adenosine (A2) receptor
—> ↑ ATP
—> ↑ cAMP
Therapeutic use:
- Ineffective when used alone
- In combination with Aspirin / Warfarin
Anticoagulants: Heparin, LMW Heparin, Fondaparinux
- Heparin
- large sulfated polysaccharides (MW 15,000-20,000)
- “head” bind to Antithrombin via specific **Pentasaccharide sequence
- “tail” can bind Thrombin directly
- **Immediate effect
MOA:
- Bind to Antithrombin (change conformation of Antithrombin) (+ Thrombin)
—> ↑ Antithrombin affinity to Thrombin, Factor 10a (also 9a, 11a, 12a) (Facilitate interaction between Antithrombin and Thrombin)
—> Inhibition of Thrombin, Factor 10a (also 9a, 11a, 12a)
—> Affect ***Intrinsic pathway significantly
—> ↓ Coagulation
Therapeutic use:
- Immediate / Short-term anticoagulation
- Deep vein thrombosis, Pulmonary embolism prevention
- During / after angioplasty, stenting after MI
- ***Does not cross placenta (suitable in pregnancy)
Administration:
- IV / Deep SC
SE:
- Bleeding (bruising)
- Hypersensitivity
- **Heparin-induced thrombocytopenia (Thrombosis + Low platelet count)
—> development of Ab
—> bind to PF4 in platelet + Heparin
—> interaction between Ab, Heparin, Platelet —> **Immune complex
—> **Platelet activation, initiate blood clot formation (Thrombosis)
AND
—> **↑ Platelet removal by splenic macrophages (recognise immune complex)
End result:
—> Platelet count ↓
—> ***Thrombocytopenia
- Monitor platelet count before, during heparin therapy
- Direct thrombin inhibitor
Reversal of Heparin action (easily overdose):
- Stop drug
- ***Protamine sulfate —> combined with Heparin as a stable complex —> ↓ Heparin activity
- LMW heparin (Enoxaparin) (MW ~5,000)
- Retain same Pentasaccharide sequence as regular heparin - Fondaparinux
- Pentasaccharide sequence only
LMW heparin / Fondaparinux
MOA: ↑ Antithrombin binding to Factor Xa (***no “tail” —> NO effect on Antithrombin binding to Thrombin, only work on Factor Xa)
Comparisons between Heparin, LMW Heparin, Fondaparinux
- Bioavailability (SC)
- t 1/2
- Reversibility
- Heparin-induced thrombocytopenia
- Monitoring
Heparin
- 30% (too big to pass through vessel wall to enter blood)
- 0.5-1.5 hr (short, **dependent on dose)
- Protamine (100%)
- 1-5%
- **Required (1. bind to other molecules e.g. ***plasma protein —> individual variation in response to same dose 2. t1/2 dependent on dose —> elimination rate ↓ as dose ↑ —> patient easily overdose)
LMW Heparin
- 90% (smaller molecule)
- 3-6 hrs (longer)
- Protamine (<60-75%)
- 0.1-1% (smaller molecule, not induce immune response easily)
- Not required (effect easily predicted)
Fondaparinux
- 100% (smaller molecule)
- 17-21 hrs (longer)
- NOT reversible
- Case report (smaller molecule, not induce immune response easily)
- Not required (effect easily predicted)
Anticoagulants: Direct thrombin inhibitors, Direct Factor Xa inhibitors
Direct Thrombin inhibitors:
- Oral: Dabigatran
- Parenteral: Hirudin (from leech saliva), Lepirudin (recombinant form of Hirudin), Argatroban (small molecule)
Direct Factor Xa inhibitors:
- Rivaroxaban, Apixaban, Edoxaban
- Oral use
Monitoring NOT required for Direct thrombin inhibitors, Direct Factor Xa inhibitors
Anticoagulants: Warfarin
Vit K needed to convert non-functional precursors to functional clotting factors (including Prothrombin, Factor 7, 9, 10)
Vitamin K quinol (Hydroquinone) is oxidised —> Vitamin K epoxide
- in the oxidation process Vitamin K quinol activate clotting factors by adding γ-carboxyl group to glutamic acid residues
—> Gla domain on Coagulation factors
—> interact with Phosphatidyl serine (Phospholipid) on Platelet via Ca
MOA:
- Warfarin: Vit K epoxide reductase inhibitor
—> ↓ reduced vit K / quinol (prevent resumption of activity)
—> ↓ synthesis of clotting factors in ***Extrinsic pathway
—> ↓ clotting
Therapeutic use:
- Venous thrombosis, Pulmonary embolism prevention (short - long term)
- Clot formation on prosthetic heart valves prevention (long term)
- Reduction of thrombosis with AF (long term)
Pharmacokinetics:
- Orally active
- **48-72 hours to achieve full effect due to long t1/2 of clotting factors
- **Heavily protein bound (displaced by other drugs —> ↑ blood concentration)
- ***Metabolised by CYP450 (enzyme inducers/inhibitors)
- Affected by diet
SE:
- Bleeding
- ***Cross placenta (not given during pregnancy: use Heparin instead)
- Interaction with many drugs (heavily protein bound, metabolised by CYP450)
Reversal of warfarin:
- Stop drug
- ***Vit K
Monitoring required
Monitoring of Heparin effect
ONLY for Heparin (LMW heparin / Fondaparinux NO monitoring required)
**aPTT (activated partial thromboplastin time)
—> evaluate **Intrinsic pathway
—> ***Thrombin, Factor 10a (also 9a, 11a, 12a)
Thromboplastin:
- combination of both Phospholipids + Tissue factor
Kaolin (as surface activator) + Ca + Phospholipid (but do not add Tissue factor —> “partial” thromboplastin)
—> Intrinsic pathway 要有Contact surface (Phospholipid) 但唔使Tissue factor
—> activate ***Intrinsic pathway when added to plasma
—> clotting time detected by machine
Heparin binds to Antithrombin
—> Antithrombin/Heparin complex binds Thrombin and Factor Xa (and IX, XI, XII) (affect intrinsic pathway significantly)
—> ↑ clotting time
aPTT useful for monitoring Heparin effect (target: 1.5-2.5x longer than normal)
