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PMY2106 > Thrombolytic therapies > Flashcards

Thrombolytic therapies Flashcards

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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?

Study These Flashcards
A

binds directly to the active site and exosite

25
example of vit. K reductase inhibitors
warafin
26
how does warafin work?
inhibits reformation of reduced Vit. K
27
what regulates plasmin?
alpha anti-2 plasmin plasminogen activator inhibitors
28
1st generation of plasminogen activator?
Urokinase Streptokinase
29
How does urokinase work?
cleaves the Arg-Val bond - allows thrombus to lyse from within
30
How does streptokinase work?
binding results in conformational change of Lys - plasmin dissolved fibrin clot
31
limitation of 1st gen?
- short half life - increased risk of bleeding - limited efficacy in breaking down bigger clots
32
2nd generation of plasma activators?
prourokinase - converts to urokinase APSAC tPA
33
limitations of 2nd gen?
- increased risk of bleeding - limited efficacy in breaking down bigger clots - drug-drug interactions - cost - complex dosing regimens
34
3rd gen?
Tencepteplase - resistance to plasminogen inhibitors Reteplase - long duration
35
when must thrombolytic therapies be administered?
rapidly after clot onset
36
other therapies?
combinatory therapies thrombectomy
37
2. Blood coagulation cascade: Intrinsic Pathway
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
2. Blood coagulation cascade: Extrinsic Pathway
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
2. Blood coagulation cascade: The final common pathway
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
What does the suffix 'a' mean after factors?
All components of of these pathways are coagulation factors that exist as inactive precursors before activated —> active forms = suffix 'a'
41
What coagulation cofactors are used to facilitate these conversions?
Tissue factor 5a and factor 8a
42
How is the blood coagulation cascade regulated?
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
Fibrinolysis
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
Outline the activation of plasminogen to plasmin
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
What therapeutic approaches can be taken to prevent blood clotting?
1. Anti-platelets therapies 2. Anti-coagulants therapies 3. Fibrolytics or thrombolytic therapies
46
How does the secretion of certain factors activate platelets?
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
How do anti-platelets work?
Anti-platelet approaches have aimed at preventing the synthesis of factors such as collagen, and or the synthesis of GP IIb/IIa antagonists.
48
Anti-platelet therapies: Thromboxane (TXA2) synthesis inhibitors
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
Anti-platelet therapies: ADP inhibitors
Examples = clopidogrel, ticlopidine, prasanagrel, ticagrelor
50
Anti-platelet therapies: GP IIb/IIa antagonists
- 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
Anti-coagulants therapies: Indirect thrombin inhibitors
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
Anti-coagulants therapies: Direct thrombin inhibitors
- 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
Anti-coagulants therapies: Vitamin K (Vit K) reductase inhibitors
- 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
Finbrinolytic or thrombolytic therapies: Streptokinase (SK)
- 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
Finbrinolytic or thrombolytic therapies: Urokinase Plasminogen Activators (uPA)
- 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
Finbrinolytic or thrombolytic therapies: Prourokinase (pro-uPA)
- 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
Finbrinolytic or thrombolytic therapies: Antitreplase (APSAC)
- 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
What is the disadvantage of thrombolytic therapies?
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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