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IMED2002 > Basics of haemostasis: How to clot, but not too much > Flashcards

Basics of haemostasis: How to clot, but not too much Flashcards

1
Q

What is primary haemostasis?

A

Primary clot formation which is the role of platelets

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2
Q

What is secondary haemostasis?

A

Formation of fibrin clot

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3
Q

What is blood homeostasis?

A

Stop significant blood loss at site of injury but switching off clotting so that blood doesn’t clot everywhere

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4
Q

What are the structures and systems involved in haemostasis?

A

Vascular endothelium

Platelets

Procoagulant and anticoagulant proteins

Fibrinolytic system

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5
Q

What 2 processes are in balance in a healthy person?

A

Clot formation and clot lysis

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6
Q

What are bleeding problems a result off?

A

Too much lysis too little clotting

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7
Q

What are clotting problems a result of?

A

Too much clotting too little lysis

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8
Q

What happens to blood vessels in response to injury?

A

Vasoconstriction

eg. pain receptors can cause reflex vasoconstriction

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9
Q

How does a blood clot form?

A

1- Initiation:
Following vascular injury there is reflex vasospasm of smooth muscle for a short time. Vascular endothelium stops producing NO and prostacyclin.

Injury exposes important subendothelial proteins like VWF and tissue factor.

2- Platelet adhesion and activation:

Circulating platelets bind to subendothelial matrix through platelet surface receptor (glycoprotein 1b/IX/V complex), via von-Willebrand factor.

Other interactions such as GP1a/IIa binding to collagen are important as well.

Platelets are activated by collagen, VWF, thrombin, and ADP.

Activated platelets change shape and release their granules. Activated platelets also express a new receptor which is a fibrinogen receptor allowing more agreggation of platelets.

ADP and TXA2 also recruit other platelets to help form platelet plug

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10
Q

How does intact endothelium prevent platelet adherence?

A

By producing NO and prostacyclin

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11
Q

What are the most important factors to platelet activation?

A

Platelets are activated by collagen, VWF, thrombin, and ADP

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12
Q

What happens to platelets when they are activated?

A

Activated platelets change shape and release their granules. Activated platelets also express a new receptor which is a fibrinogen receptor allowing more aggregation of platelets.

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13
Q

What do circulating platelets bind to?

A

Subendothelial matrix

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14
Q

How do circulating platelets bind to subendothelial matrix?

A

Though platelet surface receptor

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15
Q

What is the platelet surface receptor that binds to subendothelial matrix called?

A

Glycoprotein 1b/IX/V complex

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16
Q

How does von-Willebrand factor (VWF) help with platelet aggregation?

A

Important for binding and aggregation.

It combines with GPIb, GPIIb/IIIa and the collagen sunbendothelial microfibrils creating a link at many sites allowing the platelet to start spreading.

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17
Q

What receptor on the platelet binds directly to collagen?

A

GP1a/IIa

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18
Q

What do the granules of activated platelets contain?

A

ADP

Thromboxane 2

Fibrinogen

Von Willebrand Factor

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19
Q

What receptor do activated platelets express? What does it do?

A

Glycoprotein IIb/IIIa

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20
Q

What do ADP and TXA2 in granules do?

A

Recruit other platelets to help with platelet plug formation

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21
Q

What do ADP and TXA2 in granules do?

A

Recruit other platelets to help with platelet plug formation

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22
Q

What must happen before GPIIIa can be exposed to VWF?

A

GPIa must adhere to the collagen that the VWF is going to bind to

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23
Q

What must happen before GPIIb can be exposed to VWF?

A

GPIb must bind to VWF

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24
Q

What happens after GPIIb/IIIa binding to VWF?

A

Spreading of platelet

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25
Q

What are the 4 processes in platelet response?

A

Adhesion

Aggregation

Secretion

Pro-coagulant activity

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26
Q

What is the overall function of platelets?

A

Initial closure of vessel wall defect

Vasoactive substances result in platelet granule release (containing coagulation proteins and propagating messengers) which has a propagating effect activating clotting factors to bind to platelet surface and increase thrombin generation

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27
Q

What is purpura?

A

Autoimmune destruction of platelets

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28
Q

What happens during secondary haemostasis?

A

A fibrin clot is formed

29
Q

What are the key steps to forming a fibrin clot?

A

Tissue factor combines with favtor VIIa to form FVIIa-TF complex.

The complex activates the other proteins that produce thrombin on top of the platelet surface

Thrombin then converts fibrinogen to fibrin.

30
Q

What are the steps of coagulation?

A

Factor VIIa - TF complex activate small amounts of factor 9 to 9a and factor 10 to 10a

Factor 10a cleaves prothrombin to thrombin

Thrombin activates platelets which release further coagulation proteins.

Thrombin also activates proteins required to produce more thrombin

Thrombin is produced in large scale on the platelet surface.

At multiple locations there is positive feedback from thrombin (factor 11, factor 8, factor 5)

Factor 13 is not part of coagulation cascade and instead helps to cross-link fibrin

31
Q

Simplification of thrombin formation so far

A

F7a-TF activates F9+F10 activates thrombin (aka F2) which feeds forward to factor 11, 8, and 5 (positive feedback)

32
Q

What is another name for thrombin?

A

Factor II

33
Q

What does factor 13 do?

A

Not part of coagulation cascade and instead helps to cross-link fibrin

34
Q

What is thrombin important for?

A

Activation of coagulation factors

Activation of platelets

Activation of anticoagulant factors

Determining the balance of fibrinolysis

35
Q

What is fibrinolysis?

A

Process by which clot is removed

36
Q

What does tissue plasminogen activator do?

A

activates plasminogen and converts it to plasmin

37
Q

What does plasmin do?

A

Enzymatically attacks fibrin molecule producing fibrin degradation products that are cleared from circulation by macrophages

38
Q

What is produced after degradation by plasmin?

A

FDPs which form D-dimers (due to factor 13 cross-linkages)

39
Q

Summary of haemostasis after disruption of vascular endothelium:

A

Platelets bind to subendothelium collagen to initiate primary closure of the defect in vessel wall

Tissue Factor in subendothelium combines with factor 7 (FVII) in blood to form the FVII-aTF complex which activates other clotting proteins leading to thrombin production.

Large scale production of thrombin takes place on platelet surface which converts fibrinogen to fibrin and then fibrinolysis is activated to localise clot to site of injury.

40
Q

What is the purpose of thrombin?

A

To convert fibrinogen to fibrin

To activate factor 13 to form cross linkages

41
Q

What pathways can trigger coagulation?

A

Intrinsic and Extrinsic

42
Q

Where does the coagulation cascade happen?

A

On platelet surface (PL of platelet surface)

43
Q

What does the coagulation cascade bring?

A

10, 8, 9, calcium, and phospholipid.

44
Q

How is coagulation tested in the lab?

A

factor 12 is activated to test intrinsic pathway and is called APTT

Tissue factor is activated to test extrinsic pathway this test is called PT.

45
Q

What is the APTT test?

A

Activated Partial Thromboplastin Time which uses Kallikroin to start the intrinsic pathway.

46
Q

Where do the extrinsic and intrinsic pathway of coagulation meet?

A

At factor 10 activation and factor 2 activation

47
Q

How are PT and APTT tests conducted?

A

Citrate added to blood to remove calcium.

Blood is centrifuged to create platelet poor plasma and 3 hings are added:

Activator
Platelet substitute
and calcium (time to clot formation is measured when variables are known)

48
Q

What must be considered with screening tests?

A

Clinical history;

Personal bleeding history

Drugs

Family history

49
Q

What are the limitation of screening tests?

A

They are in vitro which isn’t always reliable.

50
Q

What are some important lab screening tests?

A

Platelet count

Prothrombin time (PT)

Activated partial thromboplastin time (APTT)

51
Q

What are the contents of plasma?

A

Water

Albumin

Clotting proteins

Antibodies

Salts

Vitamins

Urea

Hormones

52
Q

What is Prothrombin Time?

A

Measures time for clot to form after addition of Tissue Factor, phospholipid and calcium to decalcified, platelet poor plasma. It’s a good test for abnormalities in factors VII, X, V, II, and fibrinogen

53
Q

What is the reference range for prothrombin time?

A

13 - 15 seconds

54
Q

Which coagulation pathway does prothrombin time measure?

A

Extrinsic pathway

55
Q

How does a factor deficiency affect PT?

A

Prolongs time exponentially at lower factor.concentrations

A change often must be more than 30% before it is noticeable.

56
Q

What is PT used for?

A

Monitoring Vitamin K (and other stuff that we will learn later)

57
Q

What is the International Normalised Ratio?

A

Ratio between PT of a test compared to a normal sample. This is corrected for the sensitivity of tissue factor used.

58
Q

Why was the INR ratio developed?

A

To monitor patients on oral anticoagulants (warfarin)

59
Q

What is warfarin?

A

An anticoagulant

60
Q

What is in an APTT test?

A

Platelet poor plasma

Phospholipids

Contact activator (Kaolin)

Calcium

61
Q

What does APTT measure?

A

Intrinsic and common pathways

62
Q

What is the reference range of time for Activated Partial Thromboplastin TIme?

A

27 - 35s

63
Q

What must deficient factor be to be detected?

A

<40% before the APTT is prolonged

64
Q

What are the types of defects that fibrinogen can present?

A

Quantitative or qualitative defects

65
Q

What is the reference range of fibrinogen in blood?

A

2 - 4g/L

66
Q

How is the Clauss assay on fibrinogen conducted?

A

Clot diluted plasma with very high concentration of thrombin.

Use diluted plasma to remove effects of inhibitory substances such as warfarin

High thrombin concentration so clotting time independent of thrombin concentration for wide range of fibrinogen levels

67
Q

What do immunological assays measure?

A

Concentration of fibrinogen not activity

68
Q

What else is fibrinogen called?

A

fibrin

69
Q

What do fibrin tests reveal?

A

Whether the cause of a problem is too little fibrinogen or not very functinal fibrinogen

IMED2002 (29 decks)

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