Lecture 7 - Coagulation Flashcards
What are the 3 key things that need to occur for haemostasis to be achieved?
- Vessel constriction
- Platers- Activation, formation of platelet plug
- Coagulation - cascade activated ->formation of fibrin mesh
Normal endothelium has a central role in regulating haemostasis, what does it inhibit?
Normal endothelium inhibits platelet activation and coagulation
What occurs when endothelium becomes either injured, or activated?
And what occurs in the absence of endothelium?
Promotes platelet adhesion
When endothelium is absent platelets become activated, and coagulation is activated
What do the receptors found on the surface of platelets detect?
vWF and collagen
What does platelet activation result in?
Shape change (disk to sphere with pseudopods)
Secretion of granules
Synthesis of thromboxane A2
Activation of aggregation receptor (GP llb & lla)
What do platelets provide which is essential for coagulation?
Platelets provide phospholipid needed for coagulation
Briefly describe blood coagulation
It is an enzyme casade where proenzymes are sequentially activated to enzymes (using essential cofactors)
The cascade results in a tough fibrin meshwork which traps red cells, leucocytes and platelets and is enmeshed in damaged tissues
Describe the intrinsic pathway
It is called the intrinsic pathway because all of the factors are present in blood
Factor Xll becomes activated on foreign surfaces (e.g. glass tubes)
Factor Xll activates FXl (inactive proenzyme cleaved to become active)
Factor lX then becomes an active enzyme, this then works with FVlll (a cofactor) to activate FX
Factor X then actives prothrombin to thrombin, which is needed to cleave peptides off fibrinogen to make fibrin
How does the extrinsic pathway begin?
It’s called the extrinsic pathway since tissue fator is extrinsic to blood
Tissue factor activates factor Vll to Vlla
Tissue factor is found on injured tissue cells, or on macrophages and monocytes which are exposed to endotoxin
When FX becomes activated to Xa, and Prothrombin (ll) to thrombin (lla), what else becomes activated?
Factors Va, Vllla and Xla, and more platelets become activated
Briefly descirbe the extrinsic pathway up until the activation of thrombin
Tissue factor activates Factor Vll, an this activates Factor X, Leading to the activation of prothrombin to thrombin
Once Factor Xla has been activated, describe how it leads to a stable fibrin cross-linked meshwork
FXla activates lX to lXa
lXa with its cofactor Vllla activates X, which then activates ll to lla
Thrombin burst occurs, and at the same time factor Xlll is activated to become FXllla
The thrombin cleaves fibrinogen into fibrin monomers, which then polymerise to become a fibrin polymer to form a stable fibrin cross-linked mesh work
The FXllla causes a cross linking process with the fibrin
Where are coagulation factors found? and what holds them there?
Ca2+ binds the coagulation proteins to the platelet surface
The assembly of coagulation enzyme complexes occurs on activated platelet phospholipid surfaces
What are the two co-factors of the coagulation cascade?
FVa & FVllla are catalysts - they enhance enzyme activity
What are the sources of coagulation factors?
Liver
Endothelium and megakaryocytes - vWF
Four coagulation factors (enzymes) must bind Ca2+ and attach to activated platelet surfaces to achieve full functional activity, which factors are these?
And what happens when they bind Ca2+?
Factors ll, Vll, lX, X
And proteins C & S
Binding of Ca2+ alters the shape of the enzyme, exposing a phospholipid binding domain
Why is Vitamin K needed?
Vitamin K is needed to convert six inactive coagulation factors into functional proteins
When Vitamin K binding proteins are synthesised in the liver, they must first undergo gamma carboxylation (a PTM) to allow them to bind Ca2+ to bind to platelet surfaces
Vitamin K allows the coagulation proteins to undergo post-translational modification to allow them to bind Ca2+
Factors ll, Vll, lX, X and proteins C & S
What is the mechanism for warfarin?
Warfarin interferes with the cycling of Vit K.
Epoxide reductase is needed for converting the Vit K epoxide form back to the Vit K reduced form
And it is warfarin which inhibits the epoxide reductase enzyme
therefore warfarin prevents the epoxide form of Vit K from returning back into the reduced form of Vit K
How does polymerisation of fibrin monomers occur to form a cross linked fibrin mesh?
Polymerisation involves:
- Fibrinopeptide release by thrombin
- Enzyme-independant polymerisation
- Cross-linking by factor Xllla
How does fibrin support haemostasis?
Fibrin provides structual strength for the haemostatic plug and anchors the plug to adjacent tissues
What is the main inhibitor for blood coagulation?
Antithrombin, which inhibits factors Xla, lXa, Xa, lla - which stops fibrin production
And Protein Ca (with cofactor Protein S) enzymatically degrades FVa & FVllla
Thrombomodulin on the surface of endotheloum also binds thrombin, and when this binds Protein C is activated to Protein Ca (aPC), and then aPC inhibits Vllla and Va, this stops coagulation
Briefly describe fibrinolysis
Fibrinolysis involves the breakdown of fibrin
Plasminogen binds to fibrin is activated by either tPA or urokinase to become the serine protease plasmin.
Plasmin can then break down fibrin into large degredation products, and then into small degredation products
Apart of the small degredation products are D-dimers, and these can be measured to indicate how much fibrin breakdown has been occurring
If large amounts of t-PA are present, what happens?
While a clot is forming the t-PA will also bind to fibrin and activate plasminogen, and fibrinolysis will occur
How does endothelium clear excess fibrin in vessels?
Normal venous endothelium is able to release large amounts of t-PA and clear excess fibrin in these vessels (e.g. if a fibrin plug formed and extended down a vessel onto normal endothelium)
