Lecture 10: Physiological coagulation Flashcards
Secondary Hemostasis?
A sequence of enzymatic reactions that is initiated and culminated in the formation of fibrin strands
A Fibrin mesh (also called a clot) is forms and entraops the plug
activated thrombin (= factor IIa) converts fibrinogen to fibrin
Important factors in enzymatic cleavage?
Most coagulation factors are activated through the enxymatic cleavage by another protease.
These often need cofctors that line up the molecules making the pathway more efficient. (without them often the reaction would not occur at anywhere near the required rate)
Blood coagulation Pathway?
- Tissue Factor is exposed at vessel wall
- Activated factor VII binds
- Factor X binds
- Factor II is activated and IIa is what causes fibrinogen -> fibrin
- Factors V, VIII and XI are activated
- XI and it’s co-factor VIII activate lots of X
- Xa and cofactor Va then activate lots more II –> IIa
- Fibrinogen cross links to Fibrin
What is Tissue factor?
A transmembrane protein expressed on subendothelial tissue (eg. smooth muscle, fibroblasts) and is NOT expressed on the endothelium or cellular blood components.
Part 1: Initiation complex?
Some previously activated factor VII (VIIa) in the blood binds to the TF and drags in and activates some factor X and IX
This small amount of Xa can convert some prothrombin to thrombin and gets the whole thing started
Complex 2: on the platelets surface
VIIIa and IXa are used to activate X to Xa - (IXa is the protease)
VIIIa Speeds up the reaction to a physiological rate
(NB: you need calcium to control the configuration of the protein and also phospholipid to make sure they line up properly on the membrane)
There is an amplification loop where thrombin activates XI to XIa that in turn activates more IXa as the TF complex eventually shuts down so we need another way of getting activated IX
Complex 3: On the platelet surface?
Xa binds with Va to convert prothrombin II to Thrombin IIa
Huge BURST of thrombin formed - much more than extrinsic Xase
(calcium and phospholipid are also needed here)
Another amplification loop occurs where thrombin activates more VIII, V, etc so cascade continues at site of injury.
Inhibitors of the clotting cascade?
TFPI - Tissue Factor Pathway Inhibitor blocks the activation of factor VII so it doesn’t get outta hand
Protein C and its cofactor Protein S shut off factor VIII and V (are K dependent and activated by thrombin via thrombomodulin
Antithrombin directly inhibits IXa Xa and Thrombin (requires natural heparin like compounds)
Vitamin K dependent Proteins? Why is it important?
II, VII, IX and X as well as Protein C and Protein S
All of these have relatively similar protein structures
- Is a fat soluable vitamin that is given to children at birth to prevent haemorrhagic disease of the newborn
- Carboxylates glutamate residues in the GLA domains of Vitamin K dependent proteins
- Abscence of the carboxylation results in failure to bind to membranes and lack of activity
- Cyclical process within the liver
- (Proteins will be made but will not bind to membrane and so will not be able to perform their jobs - results in bleeding)
Contact activation?
Is dependent on factor XII but deficiency is not associated with bleeding - is important in the lab (APPT)
Can activate factor XI but does not happen in normal physiological clotting pathways (Is a complecated pathway involved with inflammation)
Fibrinogen to Fibrin? Breakdown?
Thrombin cleaves off bits that allows links to form
Fibrinolysis is the bodys way of keeping coagulation from becoming excessive. Plasminogen is converted to plasmin by TPA(tissue plasminogen activator). Plasmin breaks down the fibrin bonds forming D-dimers that are able to be measured as reflect the amount of clotting that is occurring in the body.
