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Block 4 - Heamatology > Lecture 13 - Physiology Of Coagulation > Flashcards

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
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2
Q

Normal endothelium inhibits platelet adhesion

A
  • PGI2
  • EDFR (NO)
  • t-PA
  • ADPase
  • Thrombomodulin
  • Heparan sulfate
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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
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4
Q

Platelet activation

A
  • shape changes: pseudopodia
  • granule release
  • microparticles shed: signal, transfer microRNA
  • receptor activation
  • phospholipid exposure
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5
Q

1) Adhesion

A
  • platelet GPIb-V-IX binds matrix vWF at high shear

- reversible adhesion to exposed extracellular matrix

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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
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7
Q

2) Activation

A
  • adhesion triggers GPIIb-IIIa activation

- irreversible binding to matric ligands, shape change and platelet activation

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8
Q

Molecular glue: Fibrin

A
  • platelet integrins (including GPIIb-IIIa) bind fibrin irreversibly
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9
Q

3) Stabilisation

A
  • critical

- secreted ADP and thromoxane recruit new platelets to thrombus and stabilise growing thrombus

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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
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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
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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
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13
Q

Hemostatic plug

A
  • a plug of degranulated platelets, fibrin mesh plus leukocytes recruited via P-selectin and fibrinogen receptors, and entrapped RBC
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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
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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
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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
Q

Coagulation

A
  • serpins
  • scavenge free proteases
  • thrombomodulin/Protein C pathway
  • activation of fibrinolysis
26
Q

Endothelium regulation of coagulation

A
  • altered expression of surface
  • receptors/glycans
  • soluble mediators
  • microparticle formation
27
Q

Fibrin formation is followed by lysis

A
  • plasmin: breaks down cell cloth
28
Q

Neutrophil extracellular traps bind bacteria and platelets

A
  • 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
Q

Coagulation involves

A
  • 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

Block 4 - Heamatology (23 decks)

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