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Haem extra cards > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is haemostasis

A

the cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult

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2
Q

What is haemostasis for?

A

to prevent blood loss from intact and injured vessels, enable tissue repair

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3
Q

describe the balance of haemostats

A

Bleeding - NORMAL HAEMOSTASIS - Thrombosis

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4
Q

what causes bleeding

A

Increase in:
Fibrinolytic factors
Anticoagulant proteins

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5
Q

what causes thrombosis

A

Increase in:
Coagulant factors
Platelets

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6
Q

outline steps in Haemostatic plug formation

A

Vessel constriction
Formation of an unstable platelet plug (platelet adhesion + platelet aggregation)
Stabilisation of plug with fibrin (blood coagulation)
Dissolution of clot and vessel repair (fibrinolysis)

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7
Q

how is the platelet plus broken down

A

fibrinolytic system

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8
Q

how are blood vessels anticoagulant

A

endothelial cells create a barrier between the blood and the procoagulant subendothelial structures

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9
Q

What component found underneath the endothelium is involved in triggering the coagulation cascade?

A

Procoagulant subendothelial structures

e.g. collagen
Tissue factor is also expressed on the surface of the cell that underlie blood vessels but it is NOT normally expressed within the circulation itself

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10
Q

what components do endothelial cells produce that are important in haemostasis

A

Prostacyclin
Thrombomodulin
Von Willebrand Factor
Plasminogen Activator

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11
Q

what cell do platelets originate from

A

megakaryocytes - mature in BM

Megakaryocytes are formed from blood stem cells

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12
Q

What process during maturation of the megakaryocytes is important for the formation of platelets?

A

Granulation

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13
Q

describe basic ultrastructure of platelet

A

OT got a nucleus but it is still a pretty active cell

storage granules

glycoprotein/thrombin receptors

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14
Q

what storage granules does the platelet contain and why are these granules important

A

ADP granules
alpha granules

storage granules for proteins including Factor V and VWF

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15
Q

what happens during platelet activation to the platelet itself (shape)

A 
conversion from passive to interactive cell
cytoskeleton change (disc shapes to pseudopod)
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16
Q

give some roles of platelets

A 
Haem/thrombosis
Cancer
Inflammation
Immunity
Atherosclerosis
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17
Q

why does VWF not normally interact with platelets in circulation

A

circulates in globular formation, binding sites hidden

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18
Q

how does collagen end up being exposed to platelets

A

endothelium damaged

sub endothelium exposed

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19
Q

Platelets can bind to the collagen in TWO ways:

A

It can bind via vWF to collagen (via the GlpIb receptor)

It can bind directly to the collagen (via the gly6 / glya2b1 receptor)

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20
Q

how do VWF sites become exposed

A

shear forces of flowing blood cause unravelling

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21
Q

under what specific conditions can platelets bind directly to collagen

A

ONLY at low shear - venous

not arteries/capillaries

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22
Q

what 2 molecules can actually cause platelet activation

A

Collagen and

thrombin( during coagulation)

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23
Q

once the platelet is bound to collagen/VWF how is it activated

A

int.signalling causes

release the ADP from the storage granules

synthesise thromboxane

agents bind to rc on surface activate them

24
Q

What happens following the passive adhesion of platelets andengagement of receptors?

A

The receptors signal inside the cell to release ADP from the storage granules and to synthesise thromboxane
These bind to receptors on the surface of the platelets and activate them

Once activated, GlpIIb/IIIa receptors become available, which can bind to fibrinogen and allows the platelets to aggregate

25
Q

Which receptors on the platelets become available following activation of the platelets and what do they bind to?

A

glycoprotein 2b/3a receptors become available

bind to fibrinogen and helps the platelets clump together

AGGREGATION

26
Q

main tests to Monitor Platelets and their Function

A

Platelet count - MOST IMPORTANT
Bleeding time
Platelet aggregation

27
Q

normal range of platelets

A

Normal range: 150-400 x 109/L

28
Q

at what point does spontaneous bleeding common

A

below 40 x 109/L

between 40-100 no spontaneous but bleeding but bleeding with trauma

29
Q

what is spontaneous bleeding often caused by

A

autoimmune thrombocytopenia

This is where autoimmune antibodies remove the platelets from the circulation

30
Q

what are features of Auto-ITP

A

purpura, multiple bruises and ecchymoses

31
Q

as platelet count continues to drop what else becomes a concern

A

below 10 = severe

Leukaemia -

Leukaemic cells populate the bone marrow so it crowds out the megakaryocytes so the platelets aren’t produced in sufficient numbers = THROMBOCYTOPENIA

32
Q

what else can activate platelets

A

thrombin

33
Q

where are clotting factors synthesised

A

Liver

Endothelial cells

Megakaryocytes

34
Q

what are all the zymogens in the pathway

A

serine protease domain-containing proteins

once activated cleave substrate after specific arg/lys residue

35
Q

what is needed to trigger start of coagulation

A

TF bearing cells need to be exposed

36
Q

what does TF combine with to start the coagulation cascade

A

TF meets factor 7 (plasma proteins)
Switches enzyme on
forming TF-7a complex

37
Q

what is unique about TF

A

only procoagulant factor that does not require proteolytic activation

38
Q

where is TF normally located

A

not exposed to blood VSMC, fibroblasts

39
Q

where is TF expressed highly

A

certain organs: lungs, brain, heart, testis, uterus, placenta

40
Q

describe the domain structure of factor 7

A

Serine protease domain
2X Gla domain - binds to phospholipids
EGF domain - protein protein interaction

41
Q

what is unique about gla domains

A

binds to phospholipid surfaces (gives ability of coagulation proteins to bind to -ve charged phospholipids)

formation dependent on Vit k

42
Q

Which factors are affected by warfarin?

A

2, 7, 9, 10

43
Q

What is common to all of these factors and what is the significance of this common feature? (factors affected by warfarin)

A

They have a cluster of glutamic acid

The glutamic acid is recognised by an enzyme in the liver and undergoes post-translational modification in the presence of vitamin K to Gamma-carboxyglutamic acid

Once this extra carboxyl group is added, calcium can facilitate the binding of gamma carboxyglutamic acid to the activated platelet membrane phospholipid

44
Q

How does warfarin actually inhibit the post-translational modification of these factors?

A

Warfarin inhibits vitamin K epoxide reductase thus inhibiting the gamma carboxylation of factors 2, 7, 9 and 10

This means that it stops the ability of the clotting factors to bind to the surface of the platelets

ultimately reduces thrombin production

45
Q

What factors do megakaryocytes produce?

A

Factor V

Von Willebrand Factor

46
Q

what are the 2 jobs of the TF-7a complex

A

proteolyse FX - FXa

proteolyse F1X - F1Xa

47
Q

Tissue factor activates the clotting cascade in 2 ways but what is the difference in these 2 pathways

A

9 to 9a – slower but produces more thrombin

10 to 10a – faster (but inefficient)

48
Q

what do both factors 9a/10a do

A

convert prothrombin (2) to thrombin (2a)

49
Q

State two accelerating factors. What are they activated by?

A

Factor VIII - precursor for 9
Factor V
They are activated by trace amounts of thrombin

50
Q

besides further propagating coagulation what does thrombin do

A

catalyses cleavage of fibrinogen into fibrin

51
Q

what does TFPI do

A

TFPI binds and forms complex with 10a
this binds and inactivates TF-7a via a Kunitz domain

therefore no 10a production

52
Q

why can TFPI not stop coagulation alone

A

very low conc in blood

53
Q

Describe the function of the Protein C anticoagulant pathway.

A

Thrombin also has a role in anticoagulation

It binds to thrombomodulin on the surface of endothelial cells and by binding to thrombomodulin it activates protein C,

Protein C along with co-factor protein S INACTIVATES FACTOR Va and FACTOR VIIIa

54
Q

what factors regulate coagulation and where in the cascade do they act

A

TFPI regulates initiation off coagulation

Protein C/S regulates propagation phase of coagulation

Anti thrombin - prevents thrombin acting away from site of damage

55
Q

what does antithrombin do

A

Anti-thrombin has a reactive loop that irreversibly inhibits the active site on the clotting factors

So anti-thrombin acts as a scavenger in mopping up free serine proteases that escape damage site

56
Q

What two proteins assemble on the surface of a clot to allow fibrinolysis to take place? Where are these proteins made?

A

Plasminogen converted to plasmin by
Tissue Plasminogen Activator (tPA)

Plasminogen is a plasma protein
tPA is produced by endothelial cells

57
Q

State three laboratory tests for blood coagulation.

A

Activated Partial Thromboplastin Time (APTT)
Prothrombin Time (PT)
Thrombin Clotting Time (TCT)

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