Lecture 13 - Physiology Of Coagulation Flashcards
1
Q
3 agents that play a role in response to blood vessel injury
A
- Platelets: adhere
- blood vessels: constrict
- clotting factors: generate fibrin
2
Q
Normal endothelium inhibits platelet adhesion
A
- PGI2
- EDFR (NO)
- t-PA
- ADPase
- Thrombomodulin
- Heparan sulfate
3
Q
Platelets
A
- adhere and spread
- rapid activation -> release of granule contents
- dense granules: Ca, ADP5HT
- alpha granules, cytokines, clotting fctors
- platelets also provide a surface for clotting factors
4
Q
Platelet activation
A
- shape changes: pseudopodia
- granule release
- microparticles shed: signal, transfer microRNA
- receptor activation
- phospholipid exposure
5
Q
1) Adhesion
A
- platelet GPIb-V-IX binds matrix vWF at high shear
- reversible adhesion to exposed extracellular matrix
6
Q
Molecular velcro: vWF
A
- reversible binding/tethering, under high shear brings platelets into contact with damaged vessel walls
- 2 roles: platelet adhesion and carrier protein for factor 8 mediates platelet adhesion
- endothelial cells: weibel-Palade bodies
7
Q
2) Activation
A
- adhesion triggers GPIIb-IIIa activation
- irreversible binding to matric ligands, shape change and platelet activation
8
Q
Molecular glue: Fibrin
A
- platelet integrins (including GPIIb-IIIa) bind fibrin irreversibly
9
Q
3) Stabilisation
A
- critical
- secreted ADP and thromoxane recruit new platelets to thrombus and stabilise growing thrombus
10
Q
Strategies for antiplatelet therapy I
A
- block amplification pathways - thromboxane synthesis (aspirin) or ADP (clopidogrel)
- reduce responses to a wide range of stimuli
- incomplete platelet inhibition
- wide safety margin
- suitable for ongoing prophylaxis
- eg: aspirin, ADP receptor antagonist
11
Q
Strategies for antiplatelet therapy II
A
- block major receptor for platelet-platelet binding
- prevent aggregation responses to a wide range of stimuli
- complete platelet inhibition
- narrow safety margin
- suitable for shortterm prophylaxis
12
Q
Aggregation
A
- activated GPIIb-IIIa mediates aggregation via fibrinogen, vWF
- release of granule contents - all local, microparticles recruits additional platelets and triggers coagulation
- resting platelets do not adhere to healthy endothelium
- activated platelets and endothelium initiate coagulation
- microparticles - submicron membrane vesicles, selevtive expression of proteins, mediate coagulation, inflammation, signalling and modulation
13
Q
Hemostatic plug
A
- a plug of degranulated platelets, fibrin mesh plus leukocytes recruited via P-selectin and fibrinogen receptors, and entrapped RBC
14
Q
Coagulation pathway
A
- cascade hypothesis
- coagulation proteins circulate in inactive forms zymogens
- sequential activation to serine protases
- reactions require a phospholipid surface (platelets
15
Q
Fibrin formation by thrombin
A
- fibrinogen monomer + thrombin -? Fibrin monomer
- multiple fibrin monomers come together to form a fibrin polymer
- factor 13 cross links the polymers
16
Q
Extrinsic pathway
A
- Cell damage/matrix exposure
- tissue factor + VII -> X. X+ V -> II to Thrombin
- thrombin conversts fibrinogen into fibrin
- assay is prothrombin time (PT) or INR
17
Q
Intrinsic pathway
A
- HMWK + PKK
- XII -> XI -> IX. IX + 8 -> X
- X + V -> 2 to thrombin
- thrombin converst fibrinogen to fibrin
- assay: activated partial thromboplastin time (APTT)
18
Q
Initiation
A
- tissue factors exposed on damaged cell membranes or microparticles
- circulating F7a binds TF - activated FX
- trace amounts of thrombin generated at site of injury
- excess thrombin cleared by serpins
19
Q
Activation
A
- thrombin activates upstream clotting factors especially XI and IX
- thrombin activates platelets at site of injury
- platelets express negatively charged phospholipid supporting factor assembly
20
Q
Amplification
A
- factor complexes form on platelet surface
- increased efficiency of FXa and thrombin generation
- thrombin burst stabilises fibrin clot
- this step is defective in hemophilias and can be bypassed by rFVIIa
21
Q
Procoagulant membranes expose PS:
A
Anionic phospholipids are essential for assembly of factor complexes and thrombin generation
22
Q
Vit K dependent factors
A
- 2,7,9,10, protein C and S
- Gla-rich tail domains anchor factors to membrane
23
Q
Thrombin
A
- activates platelet aggregation
- activates endothelium and leukocytes
- activates cofactors VIII and V in clotting cascade
- enhances activation of XI and IX
- converts fibrinogen to fibrin
- activates XIII to crosslink fibrin
- triggers antithrombotic pathway via Protein C
24
Q
Platelet role in regulation of coagulation
A
- shedding of adhesion receptors
- irreversible or apoptotic changes
- rapid clearance of activated platelets
- microparticle formation
25
Coagulation
- serpins
- scavenge free proteases
- thrombomodulin/Protein C pathway
- activation of fibrinolysis
26
Endothelium regulation of coagulation
- altered expression of surface
- receptors/glycans
- soluble mediators
- microparticle formation
27
Fibrin formation is followed by lysis
- plasmin: breaks down cell cloth
28
Neutrophil extracellular traps bind bacteria and platelets
- highly conserved cellular defence mechanism - NETosis defers from apoptosis
- NET are abundant in experimental venous thrombi in baboons and mice, associated with fibrin and vWF
29
Coagulation involves
- localized activation of platelets and factors at the site of injury
- exposure of subendothelial matrix or tissue factor act as triggers
- activated membranes provides surface for clotting factor complexes
- explosive amplification for rapid hemostasis via platelet granule release and the cascade of clotting enzymes
- built in control of coagulation by simultaneous triggering of antithrombin and fibrinolytic pathways
