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CVR > Haemostasis/ Clotting cascade > Flashcards

Haemostasis/ Clotting cascade Flashcards

1
Q

What is haemostasis?

A

Arrest of blood loss from damaged vessels

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2
Q

Haemostasis at rest?

A

Platelets circulate singly and are non-adhesive

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3
Q

Haemostasis during vessel wall injury?

A

Platelets aggregate, become stabilised by fibrin and arrest bleeding from severed vessels (clotting)

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4
Q

What is thrombosis?

A

Formation of occlusive thrombi leading to MI, ischaemic stroke.

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5
Q

What 2 factors do platelets release and the effect on these on endothelial and smooth muscle cells?

A

NO and TXA2

NO is released from platelets and endothelial cells which inhibit platelet activation.

TXA2 activates/ causes smooth muscle constriction

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6
Q

What do factor does endothelial cells release to inhibit platelet activation?

A

PGI2, prostacyclin

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7
Q

What is the first stage of haemostasis?

A

Primary haemostasis:
Formation/ aggregation of a platelet plug
Local vasoconstriction

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8
Q

Adhesion stage of primary haemostasis

A

Damage of blood vessel wall exposes platelets to vWF and collagen in extracellular matrix and adheres/ binds to them

Platelets express adhesion molecules e.g. GP1b which binds to vWF

Also express GPVI and integrin alpha2beta1 which binds to collagen

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9
Q

Activation stage of primary haemostasis

A

Binding of platelets to collagen and vWF activates platelets causing them to change shape

Platelets release mediators stored in their granules- 5-HT causing vasoconstriction

Synthesis of TXA2 from COX metabolism also causes vasoconstriction + additional platelets to adhere to damaged area and increase size of plug

Further activation of platelets adjacent to the ones being activated

ADP is released causing the receptor change if GPIIb/IIia

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10
Q

Aggregation stage of primary haemostasis

A

GPIIb/IIIa receptors cross link with fibrinogen acting as a bridge and making the clot more stable

Adjacent platelets stick to each other as a result

Formation of ‘soft platelet plug’

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11
Q

Stages of secondary haemostasis

A

Initiation/ extrinsic pathway

Amplification/ intrinsic pathway (& propagation)

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12
Q

Intiation/ extrinsic pathway

What activates the extrinsic pathway?

Example of a tissue factor bearing cell?

A

Extrinsic- activated by substances (TF) extrinsic to the blood which only occurs through vascular injury

Purpose is to create a thrombin burst.

Monocyte/ fibroblast examples of tissue factor bearing cells

(Following damage to the blood vessel, FVII leaves the circulation and comes into contact with TF expressed on tissue-factor bearing cells)

TF combines with FVII —> TF:FVIIa

Activates FX—> FXa

FXa complexes with FV—> FXa:FVa

Activates thrombin FII—> prothrombin FIIa

Prothrombin activates fibrinogen FI — fibrin FIa

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13
Q

Amplification/ intrinsic pathway

A

(activated by factors intrinsic to the blood)

Activated by thrombin and takes place on activated platelets

Thrombin activates :
FV – platelets release FV from alpha granules so FVa are expressed on the surface

FVIII– thrombin cleaves FVIII and vWF which allows FVIIIa to be expressed on the surface

FXI

FXIII

So overall, more thrombin is produced giving us acute control over the body’s ability so stop blood loss quickly

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14
Q

Propagation stage of the amplification pathway

A

FIX can be released from tissue factor bearing cells also to form FIXa (Caused by the FXIa)

Remember FXIa is activated by thrombin/ FIIa

FIXa forms a complex with FVIIIa to form a tenase complex
FIXa:FVIIIa

FIXa:FVIIIa converts FX —> FXa
Forms complex FXa:FVa

This produces more thrombin FIIa which converts more fibrinogen FI to fibrin FIa

Fibrin cross links together to form an insoluble clot

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15
Q

What ions/lipid do some of these steps require?

A

Ca2+ and phospholipids

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16
Q

What are arterial thrombi?

A
  • associated with atherosclerosis
  • form at site of vascular injury
  • contain a large platelet component
  • called ‘white clots’
  • pro-phylaxis with ANTI-PLATELET drugs
  • biggest cause of MI and 80% of strokes
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17
Q

What are venous thrombi?

A
  • associated with stasis of blood or vascular injury following surgery. trauma
  • contains a large fibrin component + platelet component
  • called ‘red clots’
  • prophylaxis with ANTI-COAGULANT drugs e.g. heparin, warfarin, factor X inhibitors (DOAC’s)
  • 3rd cause of CVR death
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18
Q

How might the body try to mitigate against the vulnerable plaque?

A

By forming a fibrous cap with a lipid rich core over it..

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19
Q

How might cap disruption occur?

A

Due to an inflammatory event

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20
Q

Fulcrum in thrombosis?

A

Treatment is a balancing act between trying to treat the clot formation and avoiding the risk of a haemorrhage.

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21
Q

How do antiplatelet drugs work?

A

Limit the growth of or decrease the risk of arterial thrombosis

Act by inhibiting platelet aggregation

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22
Q

Name some antiplatelet drugs

A
  • aspirin
  • P2Y12 receptor antagonists
    clopidogrel
    prasugrel
    ticagrelor
    cangrelor
  • GPIIb- IIIa anatagonists
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23
Q

What does TXA2 do?

A

Potent platelet agonist

Vasoconstrictor

Mitogen

Product of COX-1

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24
Q

How does aspirin work?

A

Low dose aspirin causes irreversible inhibition of COX-1

All other NSAIDS are reversible so are not cardioprotective

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25
Q

Why doesn’t low dose aspirin affect the biosynthesis of PGI2?

A

As the endothelium can continually synthesise COX-2

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26
Q

Action of P2Y12 receptors?

A

Full platelet aggregation and irreversible clot formation

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27
Q

How does ADP work on P2Y12 receptors?

A

It amplifies platelet aggregation initiated by P2Y12 and completes aggregation induced by all other platelet agonists

  • ADP
  • collagen
  • thrombin
  • TXA2
  • adrenaline
  • 5-HT
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28
Q

How can aggregation be blocked?

A

P2Y12 antagonists can block the P2Y12 receptor

P2Y12 is a subtype of the ADP receptors

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29
Q

Give examples of irreversible P2Y12 antagonists.

A

Clopidogrel and prasugrel

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30
Q

Examples of reversible P2Y12 antagonists

A

Ticagrelor and cangrelor

31
Q

Which enzymes are necessary to convert clopidogrel into its active metabolite?
And where are they found?

A

CYP450 and CYP2C19 in the liver

32
Q

Why is there a delayed inhibition of the P2Y12 receptors with clopidogrel

A

Due to clopidogrel requiring 2 CYP450 steps before forming the active metabolite

Clopidogrel on its own has to be metabolised by the liver for it to work, resulting in 2-3 days delay before full anti-platelet activity

33
Q

Actions of prasugrel

A
  • irreversible P2Y12 antagonist
  • improved efficacy
  • not affected by genetic variation of CYP450 enzymes
34
Q

Why is there a more rapid onset of action with prasugrel than with clopidogrel?

A

Increased rate of conversion to active metabolite as it only needs 1 metabolism step in the liver

35
Q

Ticagrelor

A
  • irreversible

- oral

36
Q

Cangrelor

A
  • reversible
  • i.v. function returns to normal 20 minutes post dose
  • non thienopyridine deivatives leads to rapid onset of action and do not require metabolism

Thienopyridine derivatives- clopidogrel + prasugrel

37
Q

What are the two classes of GPIIb-IIIa antagonists?

A

Fab fragments: abiximab & tirofiban (derived from antibodies)

Small molecular inhibitors: eptifibatide

all use IV

(glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids platelet activation)

38
Q

How do GPIIb-IIIa work?

A

Stop the final phase of platelet aggregation with the fibrinogen cross linking

Block immediate restenosis following coronary angioplasty

Inhibits aggregation irrespective of the agonist

However MAJOR thrombocytopenia, NOT FOR LONG TERM USE
(deficiency of platelets)
Derivation from antibodies means tendency to get an immune reaction from it.

Risk of haemorrhage so use in hospital requires monitoring

39
Q

Which anti-platelet drugs are used for secondary prevention?

A

Oral aspirin

P2Y12 antagonists

40
Q

Which anti-platelet drugs are used to block restenosis following angioplasty?

A

GPIIa-IIIa antagonists

P2Y12 antagonists

41
Q

Why is dual platelet therapy more effective?

A

Aspirin + clopiodgrel

Multiple pathways to platelet activation

this limits specific pathway inhibition

incomplete efficacy even though pharmacological inhibition is complete

42
Q

Which anti-platelet drugs have the potential for complete inhibition?

A

GPIIb-IIIa antagonists

43
Q

Which anti-platelet drugs showed limited clinical efficacy and variability in patient response and toxicity?

A

aspirin and clopidogrel

44
Q

Which anti-platelet drugs are at risk of haemorrhage?

A

All current drugs

  • aspirin
  • ticlopidine
  • clopidogrel
  • prasugrel
  • abiximab
  • epitifibatide
  • tirofiban
  • cliostazol
45
Q

How do anticoagulants work?

A
  • inhibit coagulation cascade
  • prophylaxis and treatment of venous thrombi
  • prevent propagation of the clot
  • BUT do not dissolve the clot
  • established anticoagulants: heparin, warfarin

Novel drugs: FX and thrombin inhibitors

46
Q

How do thrombolytics/ fibrinolytics work?

A

Thrombolytics used for rapid removal of the thrombus in coronary artery thrombosis

Thrombolytics act on the entire thrombus

Fibrinolytics break down the fibrin in the clot

47
Q

What is Vichow’s triangle?

A

Suggest that a patient is more likely to get a venous thrombi if they have:

  • decreased blood flow
  • endothelial disturbance
  • increased blood coagubility
48
Q

What does stasis lead to?

A

Decreased blood flow

Prevents dilution of coagulation proteins

49
Q

How does fibrinogen form fibrin?

A

Fibrinogen is cleaved to fibrin by thrombin

Thrombin acts on fibrinogen to form fibrin monomers

Ca acts to form fibrin polymers

FXIII stabilised the fibrin polymer mesh

50
Q

Why doesn’t all blood clot?

Mechanisms in place to prevent inappropriate clot formation?

A

Due to presence of anti-clotting systems

NO & PGI2

TFPI- tissue factor pathway inhibitor

APC/ active protein C/ thrombomodulin

Antithrombin III

51
Q

How does NO and PGI2 prevent inappropriate clot formation?

A

NO & PGI2 are released from endothelial cells

Prevent platelet aggregation and activation

52
Q

How does TFPI work?

A
  • from endothelial cells
  • inactivates and forms a complex with FXa
  • this inactivates membrane bound TF-VIIa complex
  • thought to limit process in extravascular space
53
Q

How does APC/ thrombomodulin work?

A
  • thrombomodulin protein on endothelial cells bind excess thrombin
  • complex binds APC (anti-clotting/ active protein C)
  • co-factor protein S
  • causes inhibition of FVa & FVIIIa
54
Q

How does antithrombin III work?

A

Gets activated by heparans on endothelial cells and heparin

  • inactivates thrombin and FIXa, FXa, FXIa, FXIIa when not in clot or combined in prothrombinase
  • binds to surface of nearby endothelial cells and inactivates clotting factors diffusing away from the damaged area
55
Q

Action of heparin on clotting cascade?

A

Heparin activates antithrombin

(UF is variable in effect)
(LMWH more predictable + more effective on FXa than on thrombin)

Inhibits tenase complex

Inactivates FXa and thrombin

56
Q

Action of fondaparinux on clotting cascade

A

A synthetic polysaccharide that acts like LMWH

- inactivates FXa and then tenase complex

57
Q

Action of warfarin on clotting cascade

A

Oral, Vit K antagonists

Inhibits vitamin K reductase in the liver

Vitamin K reductase is required for y-carboxylation of FIIa, FVII, FIX and FX

Inactivates:
FTF:VIIIa complex
FX
Prothrombin

58
Q

Name some direct thrombin inhibitors

A

Dabigatran

Bivalirudin

59
Q

Name some direct FXa inhibitors

A

Rivaroxaban

60
Q

How does fibrinolysis work?

A
  • endothelium produces a protein called thrombomodulin
  • converst thrombin to its inactive form
  • converts inactive protein C to active protein C at the same time
61
Q

What does plasmin do?

A

Plasmin degrades the fibrin clot

only occurs after a certain period of time, after the clot has formed

62
Q

What does tPA do?

A

Tissue plasminogen activator converts plasminogen to plasmin

63
Q

Action of PAI?

A

Plasminogen activator inhibitor inhibtis tissue plasminogen activator

64
Q

Action of Active protein C

A

Inhibits plasminogen activator inhibitor

65
Q

Action of alpha 2- antiplasmin

A

inhbits plasmin

66
Q

Products of fibrin degradation?

A

Fibrin degradation products (FDP) and D dimers

67
Q

HEPARIN

A

mixture of glycosaminoglycans

large charged molecules

inhibits serine- protease factors
XIIa 
XIa
Xa
IXa
thrombin

1) directly
2) potentiation of plasma serine-protease inhibitor anti-thrombin III

Used for prevention, rapid treatment

68
Q

adv & disadv of UF

A

Unfractionated heparin

Pro
- effective, cheap, short half-life, reversible with antidote- protamine

Con
- continous infusion, variab;e bioavailability, monitoring required, unpredictable PK, HIT, haemorrhage

69
Q

pros and cons of LMWH

A

e.g. enoxaparin

pro
increased bioavailability
increased half life
decreased risk of HIT

cons
expensive
partial reversal with protamine
haemorrhage

70
Q

What is HIT

A

heparin induced thrombocytopaenia

  • platelets express a protein called platelet factor 4
  • can combine as a complex with heparin
  • body tried to produce antibodies against the complex
  • subsequent exposure to heparin will have an immune mediated response
  • antibodies will recognise the complex stuck on the surface of platelets
  • body will try to take platelets out of the body causing bleeding, platelet activation, formation of inappropriate thrombi
71
Q

Factor Xa inhibitor

A

By injection: fondaparinux, idraparinux

  • pentasaccharides
  • active moiety of heparin based on antithrombin binding sequence
  • act indirectly via antithrombin
  • iv or sc (100% bioavailability)
  • more predictable PK than heparin
  • HIT rarely observed
  • superior to LMWH

orally available: rivaroxaban, apixaban

  • directly inhibit FXa
  • favourable safety do not require frequent blood monitoring
72
Q

Vitamin K antagonists

A

Coumarin (Warfarin) inhibits Vit K dependent epoxide reductase activity,
which modifies FVII, FIX, FX, and prothrombin (FII) during synthesis in liver
• Long term anticoagulant therapy
• Orally active
• Takes 1-3 days for full effect
• Requires frequent monitoring
• 1-3% of warfarin patients have major bleeding events
• Activity affected by diet and genetic variation
• Drug interactions (displacement from plasma albumin, alteration in metabolism in liver)
• Antidote with Vit K , or replace clotting factors by plasma transfusion (if haemorrhage
severe)

73
Q

Thrombin inhibitors

A

AKA: Factor IIa inhibitors, Direct Thrombin Inhibitors (DTIs)

Block active site of thrombin, inhibit both clot bound and free thrombin

I.V. Infusion: hirudin, lepirudin, desirudin (short acting)

  • As effective as LMWH
  • Used for anticoagulant therapy and treatment of patients with HIT

Orally active: dabigatran.

  • Licensed for AF and DVT
  • As effective as warfarin
  • Less chance of haemorrhage
74
Q

Fibrinolytics

A

• Activate plasminogen
• Used to remove (Lyse) arterial thrombi
o AMI: upto 12hrs
o Stroke: upto 3hrs

  • High risk of haemorrhage
  • I.V. Infusion

• Antidote: Severe haemorrhage treated with transexamic acid (inhibits activation of plasminogen)

• Streptokinase
o Non-enzyme protein from streptococci
o Binds and activates plasminogen → plasmin
o Allergenic

  • Alteplase (r-tPA)
  • Non-allergenic
  • Clot selective? (only activates plasminogen bound to fibrin in thrombus)
  • Increased safety as it only affects the plasminogen at the site of the thrombus

CVR (12 decks)

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