Clotting Flashcards
Draw a diagram of haemostasis
What are the two phases of haemostasis
Primary
Secondary
Primary haemostasis involves?
Formation of a primary platelet plug via adherence, activation and aggregation
- Adherence as with exposure of subendothelium platelrtys adhere to vWF and collagen
- Activation due to binding and local thrombin production
- Degranulation and conformatinal changes
- Binds soluble fibrinogen GP2B3a
Vasoconstriction
What are the 3 phases of a primary paltelet plug being formed
Adhesion, activation –> aggregation
How does platelet adhesion occur? What phase of haemostasis does this represent?
Primary haemostasis
- Adherence as with exposure of subendothelium platelrtys adhere to vWF and collagen
- Activation due to binding and local thrombin production
- Degranulation and conformatinal changes
- Binds soluble fibrinogen GP2B3a
Secondary haemostasis involves?
Deposition of insoluble fibrin from the coagulation cascade forming a mesh strengthening and stabilising the clot
This occurs via 3 phases
- Initiation
- Amplification
- Propogation
What are the 3 phases of secondary haemostasis
deposition of insoluble fibrin generated from the coagulation cascade forming a mesh strengthening and stabilising the clot
* Initiation phase - tissue factor exposed on subendothelial surfaces bonding with factor VIIa activating IX and X –> small amounts of thrombin –> activation of plt, V and VIII
* Amplification - amplification occurs with plt degranulation and activated surfaces with cofactor availability propogating the coagulation cascade reaction as both tissue factor-factor VIIa complex and XIa activate IX –> IXa - VIIIa (tenase) generates more Xa
* Propogation - Tenase generates large amounts of Xa –> interact with Va forming prothrombinase converting prothrombin to thrombin
◦ Thrombin propogates the reaction further while also converting fibrinogen to fibrin which polymerises to form a stable clot
What is included in the intiaition phase of secondary haemostasis
deposition of insoluble fibrin generated from the coagulation cascade forming a mesh strengthening and stabilising the clot
* Initiation phase - tissue factor exposed on subendothelial surfaces bonding with factor VIIa activating IX and X –> small amounts of thrombin –> activation of plt, V and VIII
* Amplification - amplification occurs with plt degranulation and activated surfaces with cofactor availability propogating the coagulation cascade reaction as both tissue factor-factor VIIa complex and XIa activate IX –> IXa - VIIIa (tenase) generates more Xa
* Propogation - Tenase generates large amounts of Xa –> interact with Va forming prothrombinase converting prothrombin to thrombin
◦ Thrombin propogates the reaction further while also converting fibrinogen to fibrin which polymerises to form a stable clot
What is included in the amplification phase of secondary haemostasis?
deposition of insoluble fibrin generated from the coagulation cascade forming a mesh strengthening and stabilising the clot
* Initiation phase - tissue factor exposed on subendothelial surfaces bonding with factor VIIa activating IX and X –> small amounts of thrombin –> activation of plt, V and VIII
* Amplification - amplification occurs with plt degranulation and activated surfaces with cofactor availability propogating the coagulation cascade reaction as both tissue factor-factor VIIa complex and XIa activate IX –> IXa - VIIIa (tenase) generates more Xa
* Propogation - Tenase generates large amounts of Xa –> interact with Va forming prothrombinase converting prothrombin to thrombin
◦ Thrombin propogates the reaction further while also converting fibrinogen to fibrin which polymerises to form a stable clot
What is included in the propogation phase of secondary haemostasis
deposition of insoluble fibrin generated from the coagulation cascade forming a mesh strengthening and stabilising the clot
* Initiation phase - tissue factor exposed on subendothelial surfaces bonding with factor VIIa activating IX and X –> small amounts of thrombin –> activation of plt, V and VIII
* Amplification - amplification occurs with plt degranulation and activated surfaces with cofactor availability propogating the coagulation cascade reaction as both tissue factor-factor VIIa complex and XIa activate IX –> IXa - VIIIa (tenase) generates more Xa
* Propogation - Tenase generates large amounts of Xa –> interact with Va forming prothrombinase converting prothrombin to thrombin
◦ Thrombin propogates the reaction further while also converting fibrinogen to fibrin which polymerises to form a stable clot
What are the 5 naturally occuring anticoagulants
Thrombomodulin
Portein C and S
Heparin sulfate
Antithrombin 3
What is thrombomodulin? What does it do? Where do you find it
- Thrombomodulin- cofactor for thrombin converting it from a procoagulant to an anticoagulant by activating protein C
◦ Glycoprotein present on endothelial cells
What are protein C and S? What is their production dpendent on? Whata re they regulated by? What are they activated by? What do they act on?
- Protein C and S - factor Va and VIIIa regulated, vitamin K dependent serine proteases
◦ Protein C favours destroying V and VIII
◦ Protein S enhances C by binding C to platelet surfac
protein C activated by thrombomodulin bound to thrombin
What does protein C do>
- Protein C and S - factor Va and VIIIa regulated, vitamin K dependent serine proteases
◦ Protein C favours destroying V and VIII
◦ Protein S enhances C by binding C to platelet surfac
protein C activated by thrombomodulin bound to thrombin
What does protein S do
- Protein C and S - factor Va and VIIIa regulated, vitamin K dependent serine proteases
◦ Protein C favours destroying V and VIII
◦ Protein S enhances C by binding C to platelet surfac
protein C activated by thrombomodulin bound to thrombin
What is heparin sulfate?
- Heparin sulfate - stimulates the activation of antithrombin which inactivates thrombin and factor Xa
Antithrombin 3 acts on?
- Antithrombin 3 - serine protease inhibitors inhibiting activated thrombin and activated factor X
What is vWF? How does it bind to platelets?
◦ VWF - large multimeric protein secreted by endothelial cells is present in an immobilised state in sub endothelial matrix and soluble form in plasma (does not bind), damage exposes it
‣ Adherence via glycoprotein receptor GP 1b/IX complex binds to VWF attached to collagen
What factors can activate a platelet?
‣ ADP
‣ Serotonin
‣ VWF
‣ Thrombin - protease activated receptors (PAR) initiate cell signalling pathways result in platelet granule secretion and remodellling of platelet cytoskeleton
What factors does the endothelium have to avoid clotting in the first place when healthy?
◦ Prevents exposure to collagen, tissue factor, VWF
◦ Glycocalyx layer contains mucopolysacchardies repealing PLT and coagulation factors
◦ Thrombomodulin activates protein C
◦ Heparin sulphate activating antithrombin 3 is secreted
◦ Vasodilators -NO, PGI2 enhance blood flow
◦ Tissue factor pathway inhibitor enhances protein C effect
How does platelet adhesion occur to the subendothelial matrix
Exposure to collagen in subendothelium of damaged vessels leading to ADHESION as platelets bind to vWF attached to collagen via glycoprotein receptor GP 1b/IX
When a platelet is activated what occurs?
Degranulation
Change in cellular surface proteins
- GP2B/3a
- Phsophatidylserine exposure for clotting cascade
Confirmational change
Aggregation promoting factors such as thromboxane A2 production
In the initiation phase of secondary haemostasis what ist he limiting step
‣ rate of reaction limited by lack of cofactors, and lack of cofactor bearing surfaces
◦ Thrombin activation causes local activation of platelets, and activates available cofactors V and VIII
What is Tenase composed fo
Factor 9 and factor 8complex
