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PMY2106 > Thrombolytic therapies > Flashcards

Thrombolytic therapies Flashcards

1
Q

What is Haemostasis?

A

Normal process by which bodies control out bleeding

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2
Q

What is thrombosis?

A

The clotting of blood that may become pathological if haemostasis is dysregulated - a number of mechanisms to regulate thrombosis

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3
Q

Haemostasis and Thrombosis depend on 4 main factors what are they ?

A
  1. The vascular wall integrity (principles of blood clotting)
  2. Platelet response
  3. Blood coagulation cascade
  4. Fibrinolysis
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4
Q

Where are platelets derived from?

A

fragmentation of megakaryocytes

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5
Q

what do platelets do upon activiation?

A
  1. Change shape
  2. Secrete pro-clotting factors
  3. Aggregate to strengthen platelet plug
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6
Q

3 pathways?

A
  1. intrinsic
  2. extrinsic
  3. final common
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7
Q

All components are?

A

coagulation factors,
exist as inactive precursors that become activated
active forms have the suffix ‘a’

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8
Q
  1. Principles of blood clotting (4 steps )
A
  1. Injury damage to tissue
  2. Blood vessel contracts
  3. Formation of platelet plug
  4. Formation of fibrin clot
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9
Q

Principles of blood clotting: Injury damage to tissue

A

physical injury = puncture/ through
oxidative stress = leads to chronic inflammation of the tissue

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10
Q

Principles of blood clotting: Blood vessel contract

A

when tissue becomes injured or damaged, the blood vessels contract to restrict and contain circulating blood flow to injured site = vasoconstriction

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11
Q

Principles of blood clotting: Formation of platelet plug

A

platelets become activated and aggregate at the site of damage - bind to epithelium and provide temporary plug

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12
Q

Principles of blood clotting: Formation of fibrin clot

A

platelets contain high levels of clotting factors that will ultimately cleave fibrinogen into fibrin in order to strengthen the platelet plug - as a result blood coagulation occurs

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13
Q

Why are platelets vital for blood clotting?

A

Platelets result in the aggregation of platelets to form a temporary platelet plug. Few platelets could lead to excessive bleeding but too many platelets could lead to excessive clotting.

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14
Q

How is the platelet plug strengthened?

A

The platelet plug is strengthened by a network of insoluble fibrin. Fibrin forms as a result of the cleavage of soluble fibrinogen into insoluble fibrin protein by a serine protease known as thrombin.

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15
Q

serine proteases exist in:

A

inactive
active forms

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16
Q

co-factors required to facilitate coagulation

A

tissue factor
factor VIIIa
Factor Va
Vit. K

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17
Q

how is clotting regulated?

A

by deactivators
- protein c
- anti-thrombin III
- tissue factor pathway inhibitor
- plasmin

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18
Q

types of fibrinoolysis?

A

a) primary - normal bodily procedure
b) secondary - therapeutics

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19
Q

types of anti-platelet drugs

A

TXA2 synthesis - aspirin
ADP inhibitors - clopidogrel
GP IIB/IIIa antagonists - tirofiban

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20
Q

types of anti-coagulants

A
  • indirect thrombin inhibitor
  • direct thrombin inhibitors
  • Vit K reductase inhibitors
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21
Q

example of indirect thrombin inhibitors

A

apixaban, heparin and enoxaparin

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22
Q

example of direct thrombin inhibitors

A

Dabigatran - univalent
bivalarudin - bivalent

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23
Q

univalent?

A

bind directly to active site

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24
Q

bivalent?

A

binds directly to the active site and exosite

25
Q

example of vit. K reductase inhibitors

A

warafin

26
Q

how does warafin work?

A

inhibits reformation of reduced Vit. K

27
Q

what regulates plasmin?

A

alpha anti-2 plasmin
plasminogen activator inhibitors

28
Q

1st generation of plasminogen activator?

A

Urokinase
Streptokinase

29
Q

How does urokinase work?

A

cleaves the Arg-Val bond - allows thrombus to lyse from within

30
Q

How does streptokinase work?

A

binding results in conformational change of Lys - plasmin dissolved fibrin clot

31
Q

limitation of 1st gen?

A
  • short half life
  • increased risk of bleeding
  • limited efficacy in breaking down bigger clots
32
Q

2nd generation of plasma activators?

A

prourokinase - converts to urokinase
APSAC
tPA

33
Q

limitations of 2nd gen?

A
  • increased risk of bleeding
  • limited efficacy in breaking down bigger clots
  • drug-drug interactions
  • cost
  • complex dosing regimens
34
Q

3rd gen?

A

Tencepteplase - resistance to plasminogen inhibitors
Reteplase - long duration

35
Q

when must thrombolytic therapies be administered?

A

rapidly after clot onset

36
Q

other therapies?

A

combinatory therapies
thrombectomy

37
Q
  1. Blood coagulation cascade: Intrinsic Pathway
A

A) This is a longer pathway - the damage led surface causes the endothelial to become exposed revealing collagen complex that is formed from kininogen and kallikrein.

Kininogen - a precursor of kinins which are bio active peptides E.g bradykin = inflammatory mediator causing vasodilation

Kallikrein - a family of serine proteases

Both kininogen and kallikrein catalyse activation of factor 12 —> 12a leading to the conversion of:
11 —> 11a
9 —> 9a
Finally 10 —> 10a
= cascade of events

38
Q
  1. Blood coagulation cascade: Extrinsic Pathway
A

B) In comparison is to the intrinsic pathway, it’s shorter. When external physical damage to the tissue occurs tissue factors are released to convert:
7 —> 7a
10 —> 10a
Which is where the 2 pathways merge.

39
Q
  1. Blood coagulation cascade: The final common pathway
A

C) The final common pathway merges at factor Xa and leads the the consequent conversion of:
Prothrombin—> Thrombin
Fibrinogen —> Fibrin
This leads to the formation of cross link clot forming

40
Q

What does the suffix ‘a’ mean after factors?

A

All components of of these pathways are coagulation factors that exist as inactive precursors before activated —> active forms = suffix ‘a’

41
Q

What coagulation cofactors are used to facilitate these conversions?

A

Tissue factor 5a and factor 8a

42
Q

How is the blood coagulation cascade regulated?

A

Through deactivators:
1. Protein C = deactivates 8a and 5a
2. Antithrombin 3 = deactivates 12a, 11a, 10a, 9a, 7a and thrombin 2a
3. Tissue factor pathway inhibitor = deactivates 7a and 10a
4. Plasmin = deactivates fibrin

43
Q

Fibrinolysis

A

A normal bodily procedure that initiates the breakdown of clots. This occurs via the activation of plasminogen —> plasmin which is able to dissolve the fibrin clot

44
Q

Outline the activation of plasminogen to plasmin

A

Plasminogen is deposited on fibrin strands
- Plasminogen is cleaved by plasminogen activators (serine proteases)
- These activators cleave plasminogens activation loop to Arg 561 - Val 562
- Val 562 now forms a salt bridge with Asp 760 which results in a conformational change —> activation of plasmin
- Fibrin is now cleaved into fibrin degradation by plasmin
- Clot lysis occurs

45
Q

What therapeutic approaches can be taken to prevent blood clotting?

A
  1. Anti-platelets therapies
  2. Anti-coagulants therapies
  3. Fibrolytics or thrombolytic therapies
46
Q

How does the secretion of certain factors activate platelets?

A

Platelets are activated and aggregated upon secretion if factors such as thromboxane, ADP, thrombin, serotonin and collagen. These factors activate IIb/IIa receptors leading to a conformational changed in the structure of these receptors. As a result, Fibrinogen is able to bind to the receptors which leads to binding or aggregation of many platelets.

47
Q

How do anti-platelets work?

A

Anti-platelet approaches have aimed at preventing the synthesis of factors such as collagen, and or the synthesis of GP IIb/IIa antagonists.

48
Q

Anti-platelet therapies: Thromboxane (TXA2) synthesis inhibitors

A

TXA2 is formed as a result of Arachidonic Acid metabolism during inflammation
- The enzyme COX-1 is responsible for the formation of TXA2
- Therefore COX-1 enzyme inhibitors would result in the inhibition of TXA2
- Example of COX-1 enzyme inhibitor = Aspirin

49
Q

Anti-platelet therapies: ADP inhibitors

A

Examples = clopidogrel, ticlopidine, prasanagrel, ticagrelor

50
Q

Anti-platelet therapies: GP IIb/IIa antagonists

A
  • Blocking GP 11b/IIa receptors from accepting fibrinogen will prevent the aggregation of platelets
  • This group of antagonists are typically delivered through IV with heparin and aspirin
  • Examples = abcixmab, eptifatide, tirofiban
51
Q

Anti-coagulants therapies: Indirect thrombin inhibitors

A

They target Xa pathway preventing subsequent cascade of final pathway.
Examples include:
1. Heparin - also binds to anti-thrombin but inhibits formation of thrombin
2. Low molecular weight Heparin (LMWH)
3. Fondaparinux
4. Apixiban/Rivaroxaban

52
Q

Anti-coagulants therapies: Direct thrombin inhibitors

A
  • Bind directly to thrombin either univalently or bivalently at the active site or the active site and exosite, respectively.
  • Bivalent thrombin inhibitors have a higher affinity and specificity for thrombin over univalent inhibitors
    Examples include:
  • Dabigatran (univalent)
  • Bivalarudin (bivalent)
  • Hirudin (bivalent)
53
Q

Anti-coagulants therapies: Vitamin K (Vit K) reductase inhibitors

A
  • Vit K is required for the activation of Co-factors along the coagulation cascade including : II, VII, IX and X
  • These factors are inactive until carboxylated by Vit K
  • As a result, Vit K is subsequently oxidised to the epoxide and requires reduction by Vit K reductase to continue the coagulation cascade
  • Absence of Vit K reductase prevents the coagulation cascade from occurring
    Example = Warfarin us an inhibitor of Vit K reductase and hence prevents coagulation process from occurring
54
Q

Finbrinolytic or thrombolytic therapies: Streptokinase (SK)

A
  • Initially it was thought that SK causes direct degradation of fibrin dissolving the blood clot
  • In contrast, SK has an indirect role
  • Plasminogen upon binding to SK becomes activated into plasmin due to conformational change
  • Plasmin can now dissolve the fibrin clot
  • No cleavage in the activation loop of plasminogen
55
Q

Finbrinolytic or thrombolytic therapies: Urokinase Plasminogen Activators (uPA)

A
  • Following the discovery of SK, uPA was found to be synthesised in the kidney so was found mainly in the urine but also in the blood
  • The serine protease, uPA cleaves to Arg 561-Val 562 bond and is large in size
  • However, an advantage that uPA offers over SK is that plasmin formed inside the thrombus is protected from anti-plasmins and so allows clot to lose from within
56
Q

Finbrinolytic or thrombolytic therapies: Prourokinase (pro-uPA)

A
  • 2nd generation drug formed from uPA - acts as a pro-drug
  • It is an inactive protein (zymogen) that becomes activated into uPA in the presence of kallikrein or plasmin
57
Q

Finbrinolytic or thrombolytic therapies: Antitreplase (APSAC)

A
  • APSAC is formed from human plasminogen and SK
  • Plasminogen and SK are complexed together
  • SK in this form is acetylated to prevent the active site from degradation
  • However, upon administration, SK is deacetylated and this frees the plasminogen-SK complex for activation of plasmin
  • This is used for rapid IV treatment and offers greater clot selectivity in plasminogen associated clots and more thrombolytic activity
58
Q

What is the disadvantage of thrombolytic therapies?

A

This treatment is only applicable for fresh clots
- When clots are formed, they are cross linked with factor 3a which renders them resistant to degradation by plasmin.
- Therefore, thrombolytic therapies are advised to be only administered within 30 mins of hospitalisation

PMY2106 (15 decks)

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