L23- Blood clotting cascade Flashcards
haemostasis
Stopping the flow of blood- is the human body’s response to blood vessel injury and bleeding.
Hemostasis includes three steps that occur in a rapid sequence:
(1) Vasoconstriction, a brief and intense contraction of blood vessels;
(2) Formation of a platelet plug; and
(3) Blood clotting or coagulation, which reinforces the platelet plug with fibrin mesh that acts as a glue to hold the clot
the clotting cascade has three parts
intrinsic
extrinsic
common pathway
intrinsic pathway is stimulated when
endothelial lining is damaged- promote binding of factor XII
- more important for amplification of cascade
extrinsic pathway is stimulated when
due to trauma- release of tissue factor III
-faster to produce fator X
both the intrinsic and extrinsic pathways lead to the
common pathway
outline the intrinsic cascade
Slower- more stages
- Damaged endothelial lining of blood cells promotes binding of factor XII (Hageman factor)
- Factor XII binds to sub endothelial surface
- Kallikrein cleaves (activates) XII à XIIa
- XIIa cleaves XIà XIa
- XIa cleaves IX à IXa
- IXa binds VIII and cleaves X à Xa
- Xa enters the common pathway
outline the extrinsic cascade
- Trauma activates factor VII à VIIA
- Tissue Factor binds VIIa and activates Xà Xa
- Xa enters the common pathway
outline common pathway
- Factor X cleaves prothrombin to thrombin
- Thrombin cleave fibrinogen to fibrin
- Cross-linking of fibin causes mesh clot
the clotting cascade allows
formation of a clot from activation of a very small amount of intita factor –> quick and precise
prothrombin
Prothrombin is a plasma protein produced by the liver. Clotting is caused by a series of clotting factors which activate each other, including the conversion of prothrombin to thrombin.
the protease (thrombin) part of prothrombin is contained in the
C-terminal domain of the protein (SERINE PROTEASE)
two kringle domains in prothrombin help keep
prothrombin in the inactive form
gla domains target it to
the appropriate site for it action
- addition of COOh groups to glutamate resides (In GLA) form carboxy glutamate
- allows itneraction with sites of damage and brings together clotting factor
what cleaves prothrombin to form thrombin
Xa- stimulated by Va
thrombin function
to cleave fibrinogen to fibrin
fibrin
an insoluble protein formed from fibrinogen during the clotting of blood. It forms a fibrous mesh that impedes the flow of blood.
structure of fibrinogen
- 340kDa protein
- 2 sets of tripeptides, a, b, g, joined at N-termini by disulphide bonds
- N-terminal regions of alpha and B chains are highly negatively charged and prevent aggregation of fibrinogen
formation of fibrin clot
1) Thrombin cleaves fibrinopeptides A and B from the central globular domains of fibrinogen
2) Globular domains at the C-terminal ends of the B and Y chains interact with exposed sequences at the N termini of the cleaved b and a chains to form a fibrin mesh/ clot
3) The newly formed clot is stabilised by the formation of amide bonds between the side chains of lysine and glutamine residues in different monomers.
4) This cross-linking reaction is catalysed by transglutaminase, which is activated by protransglutaminase by thrombin
classic haemophilia is a defect in
factor VIII
factor VIII
VIII (antihaemophilic factor) is not a protease, but markedly stimulates the activity of factor IXa, a serine protease
activity of VIII is markely increased by
limited proteolysis by thrombin and factor Xa
