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MEDICAL BIO > WEEK 5-7 - haemostasis > Flashcards

WEEK 5-7 - haemostasis Flashcards

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USMLE® Step 1 flashcards Biology 101 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
Q

haemostasis components:
2) platelets
STEP 3: firm adhesion and thrombus growth
evidence for importance of integrins

A

humans deficient fro the major platelet integrin alpha-llb-beta3 have Glanzmann’s disease bleeding disorfer (one per 200,000)

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26
Q

haemostasis components:
2) platelets
what would you see through microscope

A

Initial rolling of platelets eventually Forming large aggregates

27
Q

haemostasis components:
2) platelets
major platelet surface glycoproteins
- GPIb-IX-V

A
  • binds vWF
  • initial platelet rolling on von willebrand factor bound to collagen on damaged blood vessel wall
28
Q

haemostasis components:
2) platelets
major platelet surface glycoproteins
GPVI/FcRy -

A
  • powerful activation via tyrosine kinases and calcium signalling leading to integrin activation and granule secretion

collagen

29
Q

haemostasis components:
2) platelets
major platelet surface glycoproteins
integrins

A

firm adhesion and spreading

fibrinogen
collagen

30
Q

haemostasis components:
2) platelets
major platelet surface glycoproteins
G protein coupled receptors

A

positive feedback activation

thrombin
ADP
TXA2

31
Q

haemostasis components:
2) platelets
activated platelets fight…

A

infection and promote repair

chemokines
cytokines
growth factors

32
Q

haemostasis components:
2) platelets
activated platelets promote…

A

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
Q

haemostasis components:
3) coagulation
basics

A

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
Q

haemostasis components:
3) coagulation
occurs on exposed…

A

collagen, platelet surface and tissue factor

35
Q

haemostasis components:
3) coagulation
one factor IX generates…

A

two hundred million fibrin

36
Q

haemostasis components:
3) coagulation
aims to ensure…

A

localised and limited production

37
Q

haemostasis components:
3) coagulation
what initiates coagulation

A

tissue factor

When exposed to blood activated coagulation cascade

38
Q

haemostasis components:
3) coagulation
tissue factor

A

transmembrane protein
- smooth muscles
- fibroblasts
- activated endothelial cells

Tissue factor on cells not normally exposed to blood

39
Q

haemostasis components:
3) coagulation
thrombin has a dual role in

A

platelet activation and the coagulation cascade

40
Q

haemostasis components:
3) coagulation
initiation (or extrinsic) pathway

A

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
Q

haemostasis components:
3) coagulation
initiation (or extrinsic) pathway:
factor X

A

Factor x usually inactive

Activated when is cleaved by TF VIIa

42
Q

haemostasis components:
3) coagulation
initiation (or extrinsic) pathway:
activity of serine proteases

A

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
Q

haemostasis components:
3) coagulation
intrinsic pathway

A

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
Q

haemostasis components:
3) coagulation
physiological coagulation

A

no role for factor XI

45
Q

haemostasis components:
3) coagulation
contact pathway

A

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
Q

haemostasis components:
3) coagulation
formation and stabilisation of fibrin

A

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
Q

summary of haemostatic plug formation

A

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
Q

summary of haemostatic plug formation
clot retraction mediated by

A

the major platelet integrin , alpha-IIB-beta3 which linkes firbin to the platelet actin cytoskeleton

49
Q

summary of haemostatic plug formation
4) fibrinolysis

A

plug beings to auto digest by the process of fibrinolysis

Back to healthy blood vessels with no sign of damage

50
Q

physiological limitation of coagulation

A

important to limit effect of thrombin to the site of injury

Unchecked coagulation would lead to dangerous blocking of vessels

51
Q

physiological limitation of coagulation
tissue factor pathway inhibitor (TFPI)

A

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
Q

physiological limitation of coagulation
protein C and protein S

A

inhibit intrinsic pathway

protein C
- serine protease
- released by endothelial cells and platelets
- activated by thrombin and enhanced protein S

53
Q

physiological limitation of coagulation
protein C and protein S
- mechanism

A

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
Q

physiological limitation of coagulation
antithrombin inhibits…

A

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
Q

inhibition of coagulation by blood flow

A

at the periphery of the damaged area

dilutes and disperses activated factors

activated factors destroyed by the liver

56
Q

components of haemostasis
4) fibrinolysis

A

tissue plasminogen activator inhibitor (t-PA)
released by activated endothelium and platelets
- tPA binds fibrin

Negative regulatory pathway

57
Q

most common coagulation disorders

A

haemophilia A - factor VIII deficiency

haemophilia B - factor IX deficiency

von Willebrand disease - vWF deficiency

58
Q

most common coagulation disorders
haemophilia A

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
Q

most common coagulation disorders
haemophilia B

A
  • factor IX deficiency

6-20 cases per million
X-linked
bleeding tendency
treatment with recombinant factor IX

60
Q

most common coagulation disorders
von Willebrand disease

A
  • 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
Q

most common coagulation disorders
haemophilia A
treatment

A

with recombinant factor VIII

62
Q

most common coagulation disorders
haemophilia B
treatment

A

with recombinant factor IX

63
Q

most common coagulation disorders
von Willebrand disease
treatment

A

treatment to increase vWF production, vWF, anti-fibrinolytics

MEDICAL BIO (16 decks)

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