Thrombosis

Question 1

What is haemostasis and its main phenomena?

Answer 1

Arrest of blood loss from damaged vessels, during injury, platelets aggregate, become stabilised by fibrin.

Question 2

What is thrombosis?

Answer 2

Formation of occlusive thrombi leading to myocardial infarction, ischaemic stroke.

Question 3

What is the first step of haemostasis?

Answer 3

Exposure of platelets to collagen, von Willebrand factor and thrombin in extracellular matrix leads to platelet adhesion and activates the release of mediators.

Question 4

What does the release of mediators cause?

Answer 4

Thromboxane A2 (mediator) which is released when platelets are activated, causes vasoconstriction of the damaged blood vessel.

Question 5

What is the role of ADP in platelet aggregation?

Answer 5

ADP causes a conformation change in GPIIb/IIIa which causes adjacent platelets to bind more avidly through fibrinogen crosslinking.

Question 6

What are the steps involved in the clotting pathway (initiation)?

Answer 6

Tissue factor which is not present in patent blood vessels come into contact with FVII and becomes activated. This activates FX to FXa which cleaves FII (prothrombin) to produce FIIa (thrombin). Thrombin cleaves fibrinogen to fibrin which crosslink to produce an insoluble mesh.

Question 7

What are the steps involved in the clotting pathway (amplification and propagation)?

Answer 7

Initiated by thrombin, FV interacts with FXa to produce larger amounts of thrombin. This takes place on activated platelets.

Question 8

What are some characteristics of an arterial thrombus?

Answer 8

• usually associated with atherosclerosis
• form at site of vascular injury/ disturbed blood flow
• large platelet component
• pro-phylaxis with anti-platelet drugs
• most causes of MI and 80% of strokes

Question 9

What are some characteristics of a venous thrombus?

Answer 9

• associated with stasis of blood or vascular injury following surgery/trauma
• platelet component, large fibrin component, RBC component
• prophylaxis with anti-coagulants
• 3rd leading cause of cardiovascular associated death

Question 10

What is the main role of anti-platelet drugs?

Answer 10

Limit growth of, decrease risk of, arterial thrombosis act by inhibiting platelet aggregation.

Question 11

How does aspirin act as an anti-platelet drug?

Answer 11

It irreversibly inhibits cylooxygenase (COX-1) in cells which is required for the production of thromboxane A2, a potent platelet agonist, vasoconstrictor and mitogen. Low dose aspirin does not affect vascular biosynthesis of PGI2 as the endothelium can still synthesis COX-2.

Question 12

How do PIIY12 receptors antagonists act as an anti-platelet drug?

Answer 12

Activation of platelets via PIIY12 receptor is necessary for full platelet aggregation and irreversible clot formation. These antagonists inhibit this.

Question 13

How do GPIIb-IIIa antagonists act as an anti-platelet drug?

Answer 13

Involved in fibrinogen cross-linking of platelets, they block immediate restenosis following coronary angioplasty.

Question 14

When are anti-platelet drugs used and what are the advantages of them?

Answer 14

Used for secondary prevention, have some benefit for primary prevention; block restenosis following angioplasty. There are multiple platelet activation pathways which means that there is incomplete efficacy even though pharmacological inhibition is complete.

Question 15

What is sub-optimal with current therapy?

Answer 15

Aspirin: 100% TXA2 inhibition however only 25% reduction in all cardiovascular outcomes as secondary prevention; aspirin resistance within 5-65% of patients.
Clopidogrel: 7-18% reduction in cardiovascular outcomes; patient to patient variability e.g. stomach ulcers, neutropenia etc.
Risk of major haemorrhage.

Question 16

What is the purpose of anticoagulants and fibrinolytic therapy?

Answer 16

Inhibit coagulation cascade, prevent propagation of blood clot but do not dissolve clot. Thrombolytics used for rapid removal of the thrombus in coronary artery.

Question 17

What is the mechanism of Heparin?

Answer 17

Inhibits serine-protease factors XIIa, XIa, Xa, IXa and thrombin, directly and via the potentiation of the plasma serine-protease inhibitor anti-thrombin III.

Question 18

What is the mechanism of vitamin K antagonists?

Answer 18

Warfarin inhibits vitamin dependent epoxide reductase activity which modifies FVII, FIX, and prothrombin during synthesis in liver.

Question 19

How do FXa inhibitors affect the production of thrombin?

Answer 19

FXa is required for the formation of thrombin by acting on prothrombin.

Question 20

How do thrombin inhibitors act as anti-coagulants?

Answer 20

They (FIIa inhibitors, direct thrombin inhibitors) block active site of thrombin, inhibit both clot bound and free thrombin.

Question 21

What are the advantages to taking DOAC vs other anticoagulants?

Answer 21

Anticoagulants like Warfarin require monthly blood tests, dietary considerations, and possibility of uncontrolled bleeding; DOACs require less monitoring and may reduce the risk of brain bleed when taken for stroke prevention.

Question 22

What do fibrinolytics (clot busters) do?

Answer 22

Activate plasminogen which produces plasmin, causing the clot to break into soluble fragments.

Question 23

What type of drug should be used in different scenarios?

Answer 23

Anti-coagulants: venous thrombosis/embolism and sometimes in arterial thrombosis
Anti-platelet drugs: used to reduce risk of thrombosis both short-term and long-term
Thrombolytics: used for rapid removal of the thrombus in coronary/cerebral artery thrombosis