Secondary Haemostasis and fibrinolysis- amanda Flashcards
What is blood coagulation
Clotting- transformation of blood from a liquid into a solid state
Formation of clot on top of a platelet plug strengthens plug and reinforces the seal over a break in the vessel
- biological amplification system
What are the 3 essential pathways of coagulation ?
- extrinsic pathway
- intrinsic pathway
- common pathway
How many plasma clotting factors participate in the clotting cascade?
12
Examples of clotting factors:
Fibrinogen, prothrombin, tissue factor, calcium, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, factor XIII
Clotting factor thrombin….
-aka FIIa
-protease that cleaves soluble fibrinogen into insoluble fibrin
-generated by cleavage of another protease FXa
-FXa is activated by FIXa
Thrombin(contd)….
-thrombin activates 2 co-factors- FVa and FVIII
- requires Ca2+
-forms 2 complexes: tenase complex to rapidly generate FXa, prothrombinase complex to rapidly generate active thrombin
-process requires charged surfaces provided by activated platelets who express charged phospholipids on their cell wall membrane
How can thrombin normally be absent from the plasma to prevent blood always being coagulated, yet be readily available to trigger fibrin formation when a vessel is injured?
Prothrombin
What is the role of thrombin?
-converts fibrinogen into fibrin
-activates XIII to stabilise the fibrin meshwork
-acts in a positive feedback fashion to facilitate its own formation
-enhance activation of platelets
What is the importance of fibrin?
-ultimate step in clot formation: fibrinogen to fibrin
-conversion catalysed by thrombin enzyme at site of vessel injury
- fibrin adheres to damaged vessel forming loose meshwork, clot
- fibrin strands strengthened by chemical linkages
What is cross-linking in fibrin catalysed by?
Clotting factor XIII
What does sufficient activation of thrombin result in?
FXIIIa activation - fibrin crosslinking
Describe the extrinsic pathway of clot formation.
-traumatised tissue releases complex of several tissue factor or tissue thromboplastin from exposed subendothelium
- tissue factor is a receptor for protease FVIIa
- FVIIa binds much better to TF in presence of Ca2+ and negatively charged surfaces
-once activated FVIIa activates FXa and the common pathway is initiated
Why is the the extrinsic pathway called extrinsic?
Because you have to ADD tissue factor to get the blood to clot
Why are inflammatory conditions also linked to thrombosis ?
Tissue factor may also be expressed by endothelium in inflammatory conditions
Describe the process of the intrinsic pathway.
-blood trauma causes activation of factor XII and the release of platelet phospholipids (contains platelet factor 3)
-connective tissue under endothelium comprises collagen which results in FXII activation
-activated factor XII (XIIa) enzymatically activates FXI (XIa) which needs kininogen and is accelerated by prekallikrein
-without the requirement of cofactors or platelets FXIIa activates FXIa
-FXIa activates FIXa which initiates common pathway
What is protein C?
Vitamin K-dependent glycoprotein that is synthesised in the liver
Circulates in an inactive form
Activated by thrombin-thrombomodulin comple on endothelial cells
What does activated protein C do?
Degrades activated clotting factors Va and VIIIa
How does thrombomodulin reduce blood coagulation?
Converts thrombin to an anticoagulant enzyme from a procoagulant enzyme
What is Protein S?
Vitamin K-dependent anticoagulant protein.
Central role in regulation of coagulation
Why is there a need for inhibitors ?
Unchecked blood coagulation would lead to dangerous occlusion of blood vessels if the following were not in place: plasma inhibitors
Why is there need for plasma inhibitors?
-important that thrombin is limited to site of injury
-direct inactivation of thrombin via circulating inhibitors
-most potent is antithrombin III (ATIII)
-others include heparin cofactor II, a2 antiplasmin, a2-antitrypsin, thrombomodulin and tissue factor pathway inhibitor (TFPI)
What does TFPI stand for?
Tissue factor pathway inhibitor
- primary regulator of TF-VIIa activity during Haemostasis
What does TFPI prevent?
Prevents participation of TF in coagulation process by forming a stable quaternary complex, TF-VIIa-Xa-TFPI
What does anti-thrombin III do?
Forms a complex with activated FVIIa
What does thrombomodulin do?
Expressed on the surface of endothelial cells and a cofactor for thrombin changing it enzymic properties from procoagulant to anticoagulant
What does Protein C do?
Activated by the thrombin-thrombomodulin complex on endothelial cells
- activated protein C degrades the activated clotting factors Va and VIIIa
What do both TFPI and ATIII require prior to activation themselves?
Formation of the TF-FVIIa complex and presence of FXa
Give an overview of fibrinolysis.
- final effector molecule of coagulation is thrombin that activates fibrinogen to form fibrin
-final effector molecule of fibrinolysis is plasmin that cleaves fibrin
-fibrinolysis is a normal haemostatic response to vascular injury
What is fibrinolysis cascade?
Plasminogen -> plasmin -> fibrin degradation products
What is plasminogen?
Beta-globulin pro-enzyme produced in the liver and found in blood and tissue fluid
Plasminogen and fibrinolysis..
Plasminogen converted to plasmin upon enzymic activation e.g., tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA)
What is tPA?
Tissue plasminogen activator
- a serine proteas produced by endothelial cells that binds to fibrin
- localise plasmin generation to area of clot only
What are the activities of plasmin?
- digesting fibrin
- fibrinogen
- FV and VIII
- cleavage of peptide bonds in fibrin and fibrinogen produces a variety of split degradation products
Inactivation of plasmin .
-tissue plasminogen activator (tPA) is inactivated by plasminogen activator inhibitor-1 (PAI-1,2 & 3)
- platelets, endothelial cells, and vascular smooth muscle contain PAI-1
- circulating plasmin is inactivated by potent inhibitor a2-antiplasmin and a2-macroglobulin
- this prevents widespread destruction of fibrinogen and other coagulation factor proteins
What are 3 stages of Haemostasis?
- Primary Haemostasis
- Secondary Haemostasis
- Fibrinolysis
