Thrombolytic Therapies Flashcards
Define heaemostasis
Normal process in which our bodies control bleeding
Define thrombosis
The clotting of blood that may become pathological if haemostasis is disregukated
What four main factors does haemostasis and thrombosis depend on
Vascular wall integrity
Platlet response
Blood coagulation cascade
Fibrinolysis
Main stages of maintenance of vascular wall
- Injury or damage to the tissue
Yhis may be due to a physical injury or through oxidative stress which could lead to chronic inflammation of the tissue.
2.blood vessels contract
When a tissue becomes damaged or injured , the blood vessels contract ti restrict and contain circulating blood to the injured site. Thus is known as vasoconstriction or vascular spasm
- Formation of the platelet plug.
Platelets become activated and aggregate at the site of injury. Here they bind to th endothelium to form a temporary platelet plug. - Formation of the fibrin clot.
Platelet contain hugh levels of clotting factors that cleave fibrinogen into fibrin in order to strengthen the platelet plug. As a result blood coagulation occurs.
What role does platelets play in the clotting of blood
Platelets secrete pro clotting factors which result in the blood coagulation cascade.
Furthermore platekts cause the aggregation of further platelets Leading to the formation of a temporary platelet plug.
Playwkts are derived from pro megakaryocytes that mature into megakaryocytes upon their activation.
Megakaryocytes adhere ti damaged blood vessels penetrating the wall with finger like projections call proplatelts which subsequently release platelets into the circulating blood
Too little - excessive bleeding
Too many - excessive clotting
How is the platelet plug strengthened
A network of insoluble fibrin. Fibrin is formed by the cleavage of soluble fibrinogen into insoluble fibrin by the serine protease thrombin.
Intrinsic pathway
Longer pathway.
Damaged surface of the endothelial becomes exposed revealing a collagen complex formed from kininogen and kallikrein.
Kininogen is a precursor of mining which are bio active peptides eg bradykinin an inflammatory mediator causing vasodilation.
Kallikriems are a family of Serine proteases
Both kallikrein and kininogen ctakyse the conversion of
Factor 12-12a
11-11a
9-91 and 10-10a
Known as a cascade of events
Extrinsic pathway
Shorter in comparison.
When external damage occurs
Tissue factors are release which convert
7-7a
10-10a
Where the 2 pathways merge.
Final common pathway
Meeges at factOr 10a leads to subsequent conversion
Prothrombin - thrombin
Fibriongen - fibrin
Leading to formation of cross link clot.
Distinguish embolus v embolism
Embolus is a travelling clot
Whenever it becomes lodged it is known as an embolism
Example of coagulation co factors
Tissue factor 8a and 5a
How is coagulation cascade regulated
Through deactivators
Protein c Deactuvates tissue factor 8a and 5a
Antithrombin 3 Deactivates 12a 11a 10a 9a 7a and thrombin 2a
Tissue factor pathway inhibitor inactivates 7a and 10a
Plasmin deactivates fibrin
Define Fibrinolysis
A normal bodily procedure that initiates the breakdown of clots. This occurs via activation of plasminogen into plasmin which is able to dissolve the fibrin clot.
Outline the activation of plasminogen into plasmin
Plasminogen is deposited on fibrin strands. Plasminogen is cleaved by plasminogen activators
These activator cleave plasma gems activation loop at Arg 561- val 562. Val 562 now forms a salt bridge with asp 740 and results in a conformational change and hence activation of plasmin.
Fibrin is now cleaved into fibrin degradation products by plasmin.
Clot lysis occurs
What therapeutic therapies can be taken to prevent blood clotting
Anti platelet therapies
Anti coagulant therapies
Fibrolytics and thrombolytic therapies
Anti platelet therapies overview
Platekts are derived and hence aggregate upon factors such as Thromboxane , ADP, thrombin , serotonin and collagen. These factors activate GP IIb/IIa receptors leading to a conformational change in the structure of these receptors. As a result , fibrinogen is able to bind to the receptor and results in the binding or aggregation of many platekts.
There for anti platelet therapies have been aimed at preventing the synthesis of GP IIb/IIa antagonists
Types of anti platelet therapies
Thromboxane synthesis inhibitors
ADP inhibitors
GP IIb/ IIa antagonists
Thromboxane synthesis inhibitors
TXA2 is formed as a result of the arachidonic acid metabolism during inflammation. The enzyme COX1 is responsible for the formation of TXA2.
THEREFORE , COX1 inhibitors would result in the inhibition of TXA2 synthesis . Aspirin is and examoke of a cox 1 enzyme inhibitors.
ADP inhibitors
Eg clopidogrel
GP IIb/IIa antagonists
Blocking GP IIb/IIa receptors from accepting fibrinogen will prevent the aggregation of platekts. This group of antagonist are usually delivered iv with heparin and aspirin eg abcixmab
Anti coagulant therapies overview
Target coagulation cascade of events
Types of anti coagulant therapies
Direct thrombin inhibitors
Indirect thrombin inhibitors
Vit k reductase inhibitors
Indirect thrombin inhibitors
Target 10a and the subsequent cascade of the final pathway. Eg apixaban
Direct thrombin inhibitors
Directly bind to thrombin either univalentky or bivalently at the active site or active site and exosite
Bivalent thrombin inhibitors have a higher affinity and specificity for thrombin over univalent inhibitors
Eg hirudin
Vit k reductase inhibitors
Vit k is required for the activation of cofactors along the coagulation cascade.
These factors are inactive until carboxylated by Vit k
As a result Vit k is oxidised and requires reduction by Vit k reductase to continue the CC
Abscence of Vit k reductase prevents the CC from occurring
Eg warfarin
Types of thrombolytic therapies
Streptokinase
Urokinase plasminogen activator uPA
Prourokinase
APSAC
Streptokinase
It was found that streptococcus aggregated to from clumps of plasma and that it could subsequently dissolve clots.
The protein streptokinase was isolated and purified and eventually used for treatment for MI, DVT etc
Cheap to produce and good patient response however risk of allergy so rarely used.
It was initially thought that SK causes direct degration of fibrin by dissolving the blood clot.
In contrast , it has an indirect role
Plasminogen upon binding to SK becomes activated into plasmin due to a conformational change ,
Plasmin can bid dissolve the fibrin clot.
No cleavage in the activation loop of plasminigen occurs.
Urokinase plasminogen activator
Follow discovery of SK, uPA was found to be synthesised in the kidneys and so was found preodominatejt in the urine but also in the blood. The Serine protease uPA , Cleaves the arg-val bond.
Prourokinase
2nd gen drug formed from uPA acts as a prodrug.
Inactivate protein that becomes activated into uPA upon the presence of plasmin or kallikrein
APSAC
formed from human plasminogen and SK complexed together.
SK in this form is acelyated to protect the active site from degradation
However upon administration SK is deaceylated and frees the plasminogen SK complex for activation of plasmin
It is used for rapid IV treatment and offers great clot selectivity on plasminogen associated clots and more thrombolytic activity
