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MEDICAL BIO > WEEK 5-7 - haemostasis > Flashcards

WEEK 5-7 - haemostasis Flashcards

1
Q

haemostasis

A

the stopping of bleeding

haem = blood
stasis = halt

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2
Q

haemostasis and the circulatory system

A

haemostasis prevents excessive blood loss upon damage

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3
Q

haemostasis
components

A

1) blood vessel vasoconstriction

2) platelets

3) coagulation

4) fibrinolysis

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4
Q

haemostasis components:
1) blood vessel vasoconstriction

A

Vasoconstriction – reduces flow, limits volume of blood, promotes platelet and coagulation factor activation

nervous reflex (happens within seconds)

release of serotonin and thromboxane A2 from activated platelets

fibrinopeptide’s released during coagulation

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5
Q

haemostasis components:
2) platelets

A

small cell with no nucleus
lifespan 10 days
150-400 million per ml of blood
we produce ~1.2 million every second

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6
Q

haemostasis components:
2) platelets
made by:

A

made by megakaryocytes in bone marrow

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7
Q

haemostasis components:
2) platelets
megakaryocyte development

A

Matures by endomitosis – DNA replicates without nuclear or cell division – enlargement of cytoplasm

myeloid stem cell –> megakaryocyte development –> platlets

megakaryocyte:
Keep replicating nucleus but don’t divide
Gearing up to produce lots of platelets (each meg 1000 platelets)

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8
Q

haemostasis components:
2) platelets
platelet production in vivo

A

Thrombopoietin from the liver and kidney increases meg number and maturation

Demonstrated in fluorescent microscopy imaging in mice

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9
Q

haemostasis components:
2) platelets
platelet structure

A

surface glycoproteins important for activation

open membrane (canalicular) system provides large surface to which coagulation proteins are absorbed

storage granules - discharged on activation
- Alpha -> large molecules
- Dense -> Ca2+, serotonin

rich in signalling and cytoskeletal proteins
- Can change shape –> key aspect of platelet function

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10
Q

haemostasis components:
2) platelets
platelets monitor…

A

blood vessel integrity

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11
Q

haemostasis components:
2) platelets
action

A

damage exposes the subendothelial layer
- site of vessel injury (collagen, laminin etc exposed)

platelets plug hole at site of injury
- formation of platelet clot or thrombus

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12
Q

haemostasis components:
2) platelets
what is the clot called

A

thrombus

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13
Q

haemostasis components:
2) platelets
morphology change

A

resting - circular
activated - has membrane protrusions (pseudopodia)

When a platelet adhere to a substrate
- Lamellipodia and filopodia

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14
Q

haemostasis components:
2) platelets
platelet tethering is mediated by the…

A

GPIb-VWF interaction which enables binding of GPVI to collagen.

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15
Q

haemostasis components:
2) platelets
what is essential for firm platelet adhesion

A

Cellular activation and inside-out upregulation of β1- and β3 integrin affinity is essential for firm platelet adhesion.

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16
Q

haemostasis components:
2) platelets
what mediates thrombus growth

A

Released ADP and TxA2 amplify integrin activation on adherent platelets and mediate thrombus growth by activating additional platelets.

the platelet to release ADP and thromboxane A2, which activates other platelets

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17
Q

haemostasis components:
2) platelets
what locally triggers thrombin generation and contributes to platelet activation

A

exposed tissue factor

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18
Q

haemostasis components:
2) platelets
what stabilises the growing thrombus

A

stabilised by signalling CLEC-2

whose ligand/counter receptor remains to be identified

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19
Q

haemostasis components:
2) platelets
STEP 1: tethering and rolling

A

via GPIb-vWF

GP receptor on platelet attacked to vWF on collagen
Catching and release so slows down slowly (binding characteristics)
- Rolls and slows down then comes to rest on site of damage

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20
Q

haemostasis components:
2) platelets
STEP 1: tethering and rolling
- evidence for important of GPIb-V-IX and von willebrand factor (vWF)

A

GPIb-deficient humans have bernard-soulier bleed disorder (affects one per million)
–> platelets cannot catch to collagen

vWF-deficient humans have van Willebrand disease bleeding disorder (one per 100)
–> platelets aret tethering properly to sites of damage

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21
Q

haemostasis components:
2) platelets
the main mediator of membrane conformation

A

von willebrand factor

4% of blood

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22
Q

haemostasis components:
2) platelets
STEP 2: platelet activation and secretion

A

ADP T x A2
- secretion and positive feedback signalling

inside out integrin activation

TF (can also activate platelets) -> thrombin
- coagulation cascade

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23
Q

haemostasis components:
2) platelets
STEP 3: firm adhesion and thrombus growth

A

Platelets stick together by fibrinogen bridges

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24
Q
A
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25
haemostasis components: 2) platelets STEP 3: firm adhesion and thrombus growth evidence for importance of integrins
humans deficient fro the major platelet integrin alpha-llb-beta3 have Glanzmann's disease bleeding disorfer (one per 200,000)
26
haemostasis components: 2) platelets what would you see through microscope
Initial rolling of platelets eventually Forming large aggregates
27
haemostasis components: 2) platelets major platelet surface glycoproteins - GPIb-IX-V
- binds vWF - initial platelet rolling on von willebrand factor bound to collagen on damaged blood vessel wall
28
haemostasis components: 2) platelets major platelet surface glycoproteins GPVI/FcRy -
- powerful activation via tyrosine kinases and calcium signalling leading to integrin activation and granule secretion collagen
29
haemostasis components: 2) platelets major platelet surface glycoproteins integrins
firm adhesion and spreading fibrinogen collagen
30
haemostasis components: 2) platelets major platelet surface glycoproteins G protein coupled receptors
positive feedback activation thrombin ADP TXA2
31
haemostasis components: 2) platelets activated platelets fight...
infection and promote repair chemokines cytokines growth factors
32
haemostasis components: 2) platelets activated platelets promote...
coagulation phosphatidylserine flipped from inner leaflet to outer leaflet of plasma membrane (Not normally exposed to the environment) to create a negatively charged surface to recruit coagulation factors (that are +vely charged) can ultimately produced net
33
haemostasis components: 3) coagulation basics
vessel injury --> activation of circulating coagulation factors (mostly serine proteases + cofactors + calcium) on tissue factor, collagen and platelet surface --> dramatic amplification cascade --> thrombin generation --> converts soluble plasma fibrinogen into fibrin --> fibrin enmeshes the platelet aggregate, stabilising the clot
34
haemostasis components: 3) coagulation occurs on exposed...
collagen, platelet surface and tissue factor
35
haemostasis components: 3) coagulation one factor IX generates...
two hundred million fibrin
36
haemostasis components: 3) coagulation aims to ensure...
localised and limited production
37
haemostasis components: 3) coagulation what initiates coagulation
tissue factor When exposed to blood activated coagulation cascade
38
haemostasis components: 3) coagulation tissue factor
transmembrane protein - smooth muscles - fibroblasts - activated endothelial cells Tissue factor on cells not normally exposed to blood
39
haemostasis components: 3) coagulation thrombin has a dual role in
platelet activation and the coagulation cascade
40
haemostasis components: 3) coagulation initiation (or extrinsic) pathway
Small amount of thrombin activates factors V, VIII and XI, as well as platelets. Extrinsic because activated by external trauma. This extrinsic pathway does not generate enough thrombin insufficient to generate significant fibrin (for a sufficient a stable fibrin net)
41
haemostasis components: 3) coagulation initiation (or extrinsic) pathway: factor X
Factor x usually inactive Activated when is cleaved by TF VIIa
42
haemostasis components: 3) coagulation initiation (or extrinsic) pathway: activity of serine proteases
When cleaved exposes active site of factor x So can go on to cleave other targets example: activation of factor X by factor IX
43
haemostasis components: 3) coagulation intrinsic pathway
explosively generates thrombin Primed by small amounts of thrombin from extrinsic pathway Requires calcium occurs on platelet surface factor IX Sets up positive feedback loop - So can get enough thrombin and can ultimately get the fibrin network
44
haemostasis components: 3) coagulation physiological coagulation
no role for factor XI
45
haemostasis components: 3) coagulation contact pathway
No bleeding problems in individuals with contact factor deficiencies Supplementary role in factor IX activation? refers to contact between: - factor XII (protease) - kallikrein (protease) - high molecular weight kininogen (cofactor)
46
haemostasis components: 3) coagulation formation and stabilisation of fibrin
Fibrinogen hydrolysis releases fibrin monomers Fibrin monomers initially link loosely via hydrogen bonds factor XIII is a transglutaminase which covalently cross-links fibrin Thrombin also activates factor 13 Covalently cross links fibrin -> polymerisation and stable fibrin via action of factor 13
47
summary of haemostatic plug formation
initial platelet activation and aggregation temporarily controls bleeding this clot or 'haemostatic plug' is stabilised by a fibrin meshwork produced by the coagulation cascade AND FINAL STEPS: clot retraction is mediated by the major platelet integrin , alpha-IIB-beta3 which linkes firbin to the platelet actin cytoskeleton plug beings to auto digest by the process of fibrinolysis
48
summary of haemostatic plug formation clot retraction mediated by
the major platelet integrin , alpha-IIB-beta3 which linkes firbin to the platelet actin cytoskeleton
49
summary of haemostatic plug formation 4) fibrinolysis
plug beings to auto digest by the process of fibrinolysis Back to healthy blood vessels with no sign of damage
50
physiological limitation of coagulation
important to limit effect of thrombin to the site of injury Unchecked coagulation would lead to dangerous blocking of vessels
51
physiological limitation of coagulation tissue factor pathway inhibitor (TFPI)
inhibits initiation pathway tissue factor pathway inhibitor (TFPI) - endothelial cells, plasma, platelets TFPI forms complex with VIIa, TF, Xa TFPI expressed by endothelial cells
52
physiological limitation of coagulation protein C and protein S
inhibit intrinsic pathway protein C - serine protease - released by endothelial cells and platelets - activated by thrombin and enhanced protein S
53
physiological limitation of coagulation protein C and protein S - mechanism
Thrombin binds to thrombomodulin on Ecs This complex activates the serine protease protein C Activated protein C inhibits cofactors VIII and V Protein C action is enhanced by cofactor protein S, which binds protein C to the platelet surface Protein C also enhances fibrinolysis
54
physiological limitation of coagulation antithrombin inhibits...
thrombin and other serine proteases antithrombin (plasma) --> Negative regulator of thrombin --> Clotting regulated to site of damage Inhibits by interacting to form high weight complexes
55
inhibition of coagulation by blood flow
at the periphery of the damaged area dilutes and disperses activated factors activated factors destroyed by the liver
56
components of haemostasis 4) fibrinolysis
tissue plasminogen activator inhibitor (t-PA) released by activated endothelium and platelets - tPA binds fibrin Negative regulatory pathway
57
most common coagulation disorders
haemophilia A - factor VIII deficiency haemophilia B - factor IX deficiency von Willebrand disease - vWF deficiency
58
most common coagulation disorders haemophilia A
- factor VIII deficiency 30-100 cases per million X-linked bleeding tendency treatment with recombinant factor VIII Prolonged coagulation More unstable clots A third no family history Bleeding into joints Avoid contact sports Anti-VIII antibodies
59
most common coagulation disorders haemophilia B
- factor IX deficiency 6-20 cases per million X-linked bleeding tendency treatment with recombinant factor IX
60
most common coagulation disorders von Willebrand disease
- vWF deficiency Variable severity vWF is a carrier for factor VIII, protecting it from premature destruction 10,000 cases per million bleeding tendency treatment to increase vWF production, vWF, anti-fibrinolytics
61
most common coagulation disorders haemophilia A treatment
with recombinant factor VIII
62
most common coagulation disorders haemophilia B treatment
with recombinant factor IX
63
most common coagulation disorders von Willebrand disease treatment
treatment to increase vWF production, vWF, anti-fibrinolytics

MEDICAL BIO (17 decks)

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