Antithrombotics

Question 1

What is thrombosis

Answer 1

formation of a clot that can cause myocardial infarction (due to thrombosis in the coronary artery), or ischaemia stroke (embolic)

Question 2

Coagulation mechanism that causes clot formation

Answer 2

Intrinsic (blood exposed to foreign surface) and extrinsic (tissue is damaged) pathways

extrinsic pathway releases thromboplastin, intrinsic releases clotting factors. They activate X, to convert prothrombin to thrombin, which converts fibrinogen to fibrin.

The platelets undergo adhesion and aggregation reactions. They bind (via Von willebrand’s factor) to the surface of the damage/disease, and release ADP and thromboxane, which promotes other platelets to aggregate. The release of ADP leads to expression of gp-IIb/IIIa, which binds to fibrinogen, which mediates the cross linking of platelets.

Question 3

Disorders of clotting and bleeding

Answer 3

Thrombosis

Venous clots (e.g., DVT)

Atrial fibrillation, which poses risk of a transient ischaemic attack + stroke

Question 4

Endogenous compounds that increase or decrease coagulation

Answer 4

PGI2 (increases cAMP) and NO (increases cGMP) prevent platelet aggregation

Thromboxane increases platelet aggregation by decreasing cAMP

Question 5

Aspirin antithrombotic mechanism

Answer 5

Low dose (75mg) used. used to prevent MI in people who have already had one. Also reduces stroke risk.

Irreversible inhibitor of COX. In endothelial cells, COX produces PGI2 and thromboxane, and contains a nucleus, which leads to the production of new COX, whereas in the non-nucleated platelets (which only produce thromboxane), they cannot produce new COX. This leads to a larger decrease in thromboxane, shifting the homeostasis to prevent clotting.

Question 6

ADP receptor antagonism antithrombotic

Answer 6

Clopidogrel, prasugrel (irreversible), and ticagrelor (reversible allosteric). Abciximab monoclonal antibody against GP IIb/IIIa.

All inhibit the GP IIb/IIIa expression that mediates fibrinogen binding.

Question 7

Fibrinolysis drugs and uses

Answer 7

Alteplase stimulates the conversion of plasminogen to plasmin, which dissolves the fibrinogen clots. Also degrades some clotting factors.

Licensed for ischaemic stroke (thromboembolic) and myocardial infarction

Question 8

Heparins anticoagulants mechanisms

Answer 8

e.g., enoxaparin (unfractionated), Heparin

which activates antithrombin III. This inactivates some of the clotting factors and thrombin. Does this by inhibiting serine proteases.

Has immediate effect. Used for DVT, which poses large risk for pulmonary embolism.

Question 9

Direct oral anticoagulants mechanisms

Answer 9

Dabigatran - thrombin inhibitors.
Apixiban and rivaroxaban inhibit activated factor X

Prevent the formation of thrombin from prothrombin, or inhibit the actions of thrombin (dabigatran), to prevent clotting.

few drug interactions, less bleeding, does not require monitoring.

Question 10

Warfarin mechanism, INR and uses

Answer 10

Blocks vitamin K reductase, which is necessary for vitamin K to act as a cofactor.

Vit K necessary in the production of prothrombin and factors VII, IX, and X. It produces these factors by mediating post-translational modifications.

Narrow therapeutic window and many DDIs: potential potentiation, or degradation by enzyme inducers.

Used for DVT, replaced heart valves, atrial fibrillation, etc…

It increases the international normalised ratio (INR) which measures the time for coagulation to occur following addition of thromboplastin. Used to measure the extent that it is working to inhibit coagulation.