Haemostasis and thrombosis Flashcards
What are the differences between haemostasis and thrombosis?
Haemostasis is physiological (blood coagulation to prevent excessive blood loss), whereas thrombosis is pathophysiological (blood coag within BV –> obstructs blood flow)
Summarise the steps of coagulation
3 steps:
- Initiation - small scale thrombin production on TF bearing cells
- Amplification - large scale thrombin production on platelet surface
- Propagation - thrombin mediated generation of fibrin strands
What happens in the first step of coagulation?
Initiation:
- Small scale thrombin production
- Tissue factor bearing cells activate factors X and V forming prothrombinase complex
- Prothrombinase complex activates factor II (prothrombin) –> IIa (thrombin)
- Antithrombin in blood inactivates factors IIa, Xa
How can step 1 of coagulation be targeted pharmacologically?
ANTI-COAGULANTS:
1. Factor IIa inhibitor - dabigatran
- Factor Xa inhibitor - rivaroxaban
- Increase activity of antithrombin - heparin, dalteparin (low MW heparin)
- Reduce levels of other factors - warfarin (vit K antagonist)
Explain the process of platelet activation
- Thrombin binds to protease-activated receptor (PAR) on platelet surface
- PAR activation –> rise in IC Ca2+
- Ca2+ rise –> platelet shape change + exocytosis of ADP from dense granules
- ADP activates P2Y12 receptors (paracrine/autocrine) –> platelet activation/aggregation
- COX
- PAR activation liberates arachidonic acid
- COX generates thromboxane A2 from AA - GPIIb/IIIa receptor
- TXA2 activation –> expression of GPIIb/IIIa integrin receptor on platelet surface
- GPIIb/IIIa involved in platelet aggregation
What major clinical conditions are antiplatelet drugs indicated for in?
Arterial thrombosis
- Acute coronary syndromes - STEMI and NSTEMI
- AF - prophylaxis of stroke
What major clinical conditions are anticoagulant drugs indicated for in?
DVT
PE
Thrombosis during surgery
AF - prophylaxis of stroke
What major clinical conditions are thrombolytics indicated for in?
Stroke - first line
ST-elevated MI
Only used within certain time period o/w ineffective and too dangerous (excessive bleeding)
What is haemostasis?
Essential physiological process - blood coagulation prevents excessive blood loss
What is thrombosis?
Pathophysiological process - blood coagulates within blood vessel –> obstructs blood flow
What step of coagulation do anticoagulants target?
Step 1 - initiation
What step of coagulation do antiplatelets target?
Step 2 - amplification
What step of coagulation do thrombolytics target?
Step 3 - propagation
Under pathological conditions, what can happen during the initiation step of coagulation?
Too much thrombin can be formed
How can step 2 of coagulation be targeted pharmacologically?
- Prevent platelet activation/aggregation - clopidogrel - P2Y12 receptor antagonist
- Inhibit TXA2 production - aspirin - irreversible COX-1 inhibitor
- Prevent platelet aggregation - abciximab
What happens in the second step of coagulation?
Amplification: platelet activation and aggregation:
- Thrombin (factor IIa) activates platelets
- Activated platelet changes shape, becomes sticky and attaches other platelets
What kind of drug is clopidogrel? How does it work?
Anti-platelet drug
P2Y12 (ADP) receptor antagonist
Prevents platelet activation and aggregation
What kind of drug is aspirin? How does it work?
Anti-platelet drug
Irreversible COX-1 inhibitor
Inhibits production of thromboxane A2
What kind of drug is abciximab? How does it work?
Anti-platelet
Prevents platelet aggregation
What kind of drug is dabigatran? How does it work?
Anti-coagulant Factor IIa (thrombin) inhibitor
What kind of drug is rivaroxaban? How does it work?
Anti-coagulant
Factor Xa inhibitor
What kind of drug is heparin? How does it work?
Anti-coagulant
Potentiates action of antithrombin
What kind of drug is dalteparin? How does it work?
Anti-coagulant Low MW heparin Potentiates action of antithrombin Activates portion of antithrombin concerned w/breakdown of factor Xa more than IIa Longer half life than heparin
What kind of drug is warfarin? How does it work?
Anti-coagulant
Vit K epoxide reductase antagonist
Vit K required in gamma-carboxylation of factors II, VII, IX, X
Stops production of clotting factors
What happens in the thirdstep of coagulation?
Propagation: generation of fibrin strands:
- Large scale thrombin production on platelet surface
- Thrombin (factor IIa) binds to fibrinogen and converts fibrin strands
- Net of fibrin traps all platelets within it
How can step 3 of coagulation be targeted pharmacologically?
Thrombolytics
Convert plasminogen to plasmin (anticoag factor) - breaks down preformed clots
ALTEPLASE - recombinant tissue type plasminogen activator (tPA)
