Clotting Physiology Flashcards
How do vessel walls prevent platelet adhesion if it is intact?
Partly due to negative charge, but also to:
- Thrombomodulin and heparan sulphate
- Prostacyclin and NO synthesis - cause vasodilatation and inhibit platelet aggregation
- Plasminogen activator production
How does endothelial damage lead to platelet activation and adhesion?
Platelets come into contact with and adhere to collagen and subendothelial bound von Willebrand factor.
Which surface molecule binds to VWF?
GP1b
Which platelet surface molecules bind to collagen in damaged endothelium?
GPIa/IIa and GP VI
What happens after GPIb binds to VWF?
GPIIb/IIIa is exposed and binds to VWF as well.
What happens to platelets within seconds of binding to damaged vessel walls?
Change shape and release:
- Dense bodies - contain ADP, serotonin, calcium
- Alpha-granules - contain PDGF, platelet factor 4, β-thromboglobulin, fibrinogen, VWF, fibronectin, Thrombin
What does the release of platelet ADP cause?
Change in conformation of GIIb/IIIa receptor - now able to bind to fibrinogen
What are the four stages of platelet involvement in haemostasis?
- Adherence
- Activation
- Aggregation
- Coagulation
What causes the initiation of the process of platelet aggregation?
ADP release - binds to ADP receptor
What does the activation of surface ADP receptors cause?
Activation of arachadonic acid, which is converted to thromboxane A2 by COX enzyme. This leads to aggregation
How does thromboxane A2 promote platelet aggregation?
Acts on the platelet’s own thromboxane receptors on the platelet surface, and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation
What happens in platelet aggregation?
Fibrinogen can form a direct bridge between platelets and so binds platelets into activated aggregates (platelet aggregation) and further platelet release of ADP occurs. A self-perpetuating cycle of events is set up leading to formation of a platelet plug at the site of the injury.
How soon after platelet adherence does activaiton occur?
Seconds
How soon after platelet adherence does aggregation occur?
Minutes
Which receptors does fibrinogen bind to?
GPIIb/IIIa
How do platelets facilitate coagulation?
They invert their phospholipid membranes, allowing coagulation to start
What are the main functions of vWF?
Primary function is binding to other proteins - important in platelet adhesion to wound sites:
- Binds to collagen
- Binds to platelet GPIb
- Binds to other platelet receptors when they are activated
What are the two main pathways involved in the coagulation pathway?
- Intrinsic
- Extrinsic
What activates the extrinsic coagulation pathway?
Tissue damage exposes tissue factor (TF) which binds to factor VII.
How does the extrinsic pathway activate Factor X?
TF–FVIIa complex directly converts factor X to active factor Xa and some factor IX to factor IXa.
What causes activation of the intrinsic pathway?
Initiated when contact is made between blood and exposed negatively charged surfaces
Which clotting factors are involved in activation of the intrinsic pathway?
Factor XII. This then activates factor XI, which activates IX and subsequently factor X
What limits Factor X activation by the extrinsic pathway?
TFPI - In the presence of factor Xa, tissue factor pathway inhibitor (TFPI) inhibits further generation of factor Xa and factor IXa.
In the face of inhibited Factor X activation by the extrinsic pathway due to influence of TFPI, how does the coagulation pathway continue factor X activation?
Intrinsic Pathway - Factor IXa/VIIIa complex activation of Factor X
How does thrombin increase the activation of Factor X?
Activates Factor VIII, which dramatically increases activity of factor IXa (generated by TF-factor VIIa) so further activation of factor X can proceed.
What would happen Without the amplification and consolidating action of factor VIII/factor IX complex on Factor X activation?
Bleeding will ensue as generation of factor Xa is insufficient to sustain haemostasis.
What is the purpose of Factor X activation?
Conversion of Prothrombin to Thrombin
What are the main actions of thrombin?
- Converts fibrinogen to fibrin
- Activates factor XIII - stabilizes fibrin clot by cross-linking adjacent molecules.
- Activates factor V - dramatically increases conversion of prothrombin to thrombin
- Activates Factor VIII - dramatically increases Factor X activation
What is the primary action of Thrombin?
Hydrolyses the peptide bonds of fibrinogen, releasing fibrinopeptides A and B, and allowing polymerization between fibrinogen molecules to form fibrin. This then forms a Fibrin Plug
Which factor causes cross-linking of fibrin molecules to form a fibrin plug?
Factor XIII
What are natural anticoagulants (which inhibit steps in the coagulation pathway)?
- Antithrombin
- Tissue factor pathway inhibitor (TFPI)
- Activated protein C and Protein S
What are the main functions of TFPI?
Inhibition of activation of Factor VII and Factor X
What are the main functions of antithrombin?
Inhibits thrombin, Xa, and other proteases
What are the main functions of Activated proteins S and C?
Inactivates factor V and factor VIII
How are fibrin plugs broken down?
Fibrinolysis - a normal haemostatic response that helps to restore vessel patency after vascular damage. The principal component is the enzyme plasmin, which is generated from its inactive precursor plasminogen
What activates fibrinolysis?
Tissue plasminogen activator - released from endothelial cells. Some plasminogen activation may also be promoted by urokinase, produced in the kidneys
What is the action of plasmin?
Breaks down fibrinogen and fibrin into fragments X, Y, D and E, collectively known as fibrin (and fibrinogen) degradation products (FDPs)
What is D-dimer?
D-dimer is produced when cross-linked fibrin is degraded. Its presence in the plasma indicates that the coagulation mechanism has been activated.
What regulates fibrinolysis?
- PAI-1 and PAI-2
- Alpha2-antiplasmin
- Alpha2-macroglobulin
