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Gwen - Haematology > Clotting Physiology > Flashcards

Clotting Physiology Flashcards

1
Q

How do vessel walls prevent platelet adhesion if it is intact?

A

Partly due to negative charge, but also to:

  • Thrombomodulin and heparan sulphate (prevent cells sticking to endothelium wall)
  • Prostacyclin and NO synthesis - cause vasodilatation and inhibit platelet aggregation (prevents cells sticking together)
  • Plasminogen activator production
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2
Q

What’s haemostasis?

A

Natural process that stops blood loss when an injury occurs.

  1. Vascular spasm (vasoconstriction) - blood vessles narrow to increase BP (caused by thromboxane A2 from activated platelets and injured epithelial cells)
  2. Platelet plug formation - involves the activation, aggregation and adherance of platelets into a plug that serves as a barrier against flow
  3. Coagulation - involves a complex cascade in a hwihc a fibrin mesh is cleaved from fibrinogen.
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3
Q

What are the four stages of platelet involvement in haemostasis?

A
  1. Adherence
  2. Activation
  3. Aggregation
  4. Coagulation
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4
Q

How does endothelial damage lead to platelet activation and adhesion?

A

Platelets come into contact with and adhere to collagen and subendothelial bound von Willebrand factor.

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5
Q

What does von willebrand do?

A

It is the factor responsible for causing platelet adherance and aggregation. Causes the platelets to change form with adhesive filaments (extensions) that adhere to the subendothelial collagen on the endothelial wall.

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6
Q

Which surface molecule binds to VWF?

A

GP1b

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7
Q

Which platelet surface molecules bind to collagen in damaged endothelium?

A

GPIa/IIa and GP VI

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8
Q

What happens after GPIb binds to VWF?

A

GPIIb/IIIa is exposed and binds to VWF as well.

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9
Q

What happens to platelets within seconds of binding to damaged vessel walls?

A

Platelets are now activated and change shape and release:

  • Dense bodies - contain ADP, serotonin, calcium
  • Alpha-granules - contain PDGF, platelet factor 4, β-thromboglobulin, fibrinogen, VWF, fibronectin, Thrombin
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10
Q

What does the released ADP and VWF do next?

A

Causes nearby platelets to adhere and activate, continuing to release more ADP and WVF

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11
Q

What does thromboxane do?

A

Activated other plateelts and maintains vasoconstriction

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12
Q

What do PDGF/VEGF do in activation?

A

Involved angiogenesis

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13
Q

What do the released coagulation factors do?

A

Involved in the coagulation cascade that converts fibrinogen to fibrin mesh after platelet plug formation.

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14
Q

What does the release of platelet ADP cause?

A

Change in conformation of GIIb/IIIa receptor - now able to bind to fibrinogen

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15
Q

What causes the initiation of the process of platelet aggregation?

A

ADP release - binds to ADP receptor

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16
Q

What does the activation of surface ADP receptors cause?

A

Activation of arachadonic acid, which is converted to thromboxane A2 by COX enzyme. This leads to aggregation

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17
Q

How does thromboxane A2 promote platelet aggregation?

A

Acts on the platelet’s own thromboxane receptors on the platelet surface, and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation

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18
Q

What happens in platelet aggregation?

A

Fibrinogen can form a direct bridge between platelets and so binds platelets into activated aggregates (platelet aggregation) and further platelet release of ADP occurs. A self-perpetuating cycle of events is set up leading to formation of a platelet plug at the site of the injury. Note that the pain product is thromboxane A2 which helps with the aggregation - COX is the necessary enzyme

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19
Q

How soon after platelet adherence does activaiton occur?

A

Seconds

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20
Q

How soon after platelet adherence does aggregation occur?

A

Minutes

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21
Q

Which receptors does fibrinogen bind to?

A

GPIIb/IIIa

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22
Q

How do platelets facilitate coagulation?

A

They invert their phospholipid membranes, allowing coagulation to start

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23
Q

What are the main functions of vWF?

A

Primary function is binding to other proteins - important in platelet adhesion to wound sites:

  • Binds to collagen
  • Binds to platelet GPIb
  • Binds to other platelet receptors when they are activated
24
Q

What are the two main pathways involved in the coagulation pathway?

A
  • Intrinsic
  • Extrinsic

Both produce factor X - the common pathway merges them.

25
Q

What activates the extrinsic coagulation pathway?

A

Tissue damage exposes tissue factor (TF) which binds to factor VII.

26
Q

How does the extrinsic pathway activate Factor X?

A

TF–FVIIa complex directly converts factor X to active factor Xa and some factor IX to factor IXa.

27
Q

What causes activation of the intrinsic pathway?

A

Initiated when contact is made between blood and exposed negatively charged surfaces

28
Q

Which clotting factors are involved in activation of the intrinsic pathway?

A

Factor XII. This then activates factor XI, which activates IX and subsequently factor X

29
Q

What limits Factor X activation by the extrinsic pathway?

A

TFPI - In the presence of factor Xa, tissue factor pathway inhibitor (TFPI) inhibits further generation of factor Xa and factor IXa.

30
Q

In the face of inhibited Factor X activation by the extrinsic pathway due to influence of TFPI, how does the coagulation pathway continue factor X activation?

A

Intrinsic Pathway - Factor IXa/VIIIa complex activation of Factor X

31
Q

How does thrombin increase the activation of Factor X?

A

Activates Factor VIII, which dramatically increases activity of factor IXa (generated by TF-factor VIIa) so further activation of factor X can proceed.

32
Q

What would happen Without the amplification and consolidating action of factor VIII/factor IX complex on Factor X activation?

A

Bleeding will ensue as generation of factor Xa is insufficient to sustain haemostasis.

33
Q

What is the purpose of Factor X activation?

A

Conversion of Prothrombin to Thrombin

34
Q

What are the main actions of thrombin?

A
  • Converts fibrinogen to fibrin
  • Activates factor XIII - stabilizes fibrin clot by cross-linking adjacent molecules.
  • Activates factor V - dramatically increases conversion of prothrombin to thrombin
  • Activates Factor VIII - dramatically increases Factor X activation
35
Q

What is the primary action of Thrombin?

A

Hydrolyses the peptide bonds of fibrinogen, releasing fibrinopeptides A and B, and allowing polymerization between fibrinogen molecules to form fibrin. This then forms a Fibrin Plug

36
Q

Which factor causes cross-linking of fibrin molecules to form a fibrin plug?

A

Factor XIII

37
Q

What are natural anticoagulants (which inhibit steps in the coagulation pathway)?

A
  • Antithrombin - degrades thrombin, Factor IXa, Factor Xa, Facor XI
  • Tissue factor pathway inhibitor (TFPI) - limits the action o ftissue factor and the factors ir produces. Switches off factor 7 and 10.
  • Activated protein C and Protein S - vit K dependant, degrade factor 5 and 8
38
Q

What are the main functions of TFPI?

A

Inhibition of activation of Factor VII and Factor X

39
Q

What are the main functions of antithrombin?

A

Inhibits thrombin, Xa, and other proteases

40
Q

What are the main functions of Activated proteins S and C?

A

Inactivates factor V and factor VIII

41
Q

What is the role of vitamin K?

A

Involved in the synthesis of many factors of the coagulation cascade. Vit K antagonized by warfarin.

Needs both calcium and vit K to form.

42
Q
A
43
Q

How are fibrin plugs broken down?

A

Fibrinolysis - a normal haemostatic response that helps to restore vessel patency after vascular damage. The principal component is the enzyme plasmin, which is generated from its inactive precursor plasminogen

44
Q

What activates fibrinolysis?

A

Tissue plasminogen activator - released from endothelial cells. Some plasminogen activation may also be promoted by urokinase, produced in the kidneys

45
Q

What is the action of plasmin?

A

Breaks down fibrinogen and fibrin into fragments X, Y, D and E, collectively known as fibrin (and fibrinogen) degradation products (FDPs)

46
Q

What is D-dimer?

A

D-dimer is produced when cross-linked fibrin is degraded. Its presence in the plasma indicates that the coagulation mechanism has been activated.

47
Q

What regulates fibrinolysis?

A
  • PAI-1 and PAI-2
  • Alpha2-antiplasmin
  • Alpha2-macroglobulin
48
Q

Mechanism of action of warfarin

A

Inhibit hepatic vitamin K. Conversion of γ-carboxylation of glutamate to coagulation factors II, VII, IX, and X depends on vit K so without it no coagulation cascade.

49
Q

Mechanism of action of NOACs

A

Selective inhibition of factor Xa (so cannot convert prothrombin to thrombin, so cannot convert fibrinogen to fibrin)

50
Q

Mechanism of action of aspirin

A

Irreversible inhibits the COX enzyme which reduces platelet aggregation

51
Q

Mechanism of action of clopidogren (/pasugrel, ticagrelor, ticlopidine)

A

Prevents platelet aggregation by binding to ADP receptors on surface of platelets (independent of COX pathway so works synergistically with aspirin)

52
Q

How do fibrinolytic drugs work?

A

Catalyse conversion of plasminogen to plasmin which acts to dissolve fibrinous clots

53
Q

Mechanism of action of heparins and donaparinux

A

Heparin - inactivates factor Xa and thrombin

Fondaprinux (a synthetic drug similar to heparin) inhibits antithrombin (and therefore factor Xa) and is anticoag of choice in many positals

54
Q

What test measures the intrinsic pathway?

A

aPTT

55
Q

What test measures the extrinsic pathway?

A

PT

56
Q

If there is a vitamin K deficiency what is seen on blood tests?

A

Increased APTT, increased PT, no change in bleeding time

Gwen - Haematology (33 decks)

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