Lecture 21: Hemostasis Flashcards
What are the two main cascade systems that are activated in response to tissue injury?
- adhesion and activation of platelets
- thrombotic system
these lead to the activation of fibrin and thrombus resulting in blood clots.
What is thrombosis?
- presence of a blood clot
- this can break off and go to smaller vessels such as the brain and lungs resulting in stroke, MI, etc
What are the two main pathways of the coagulation cascade?
-extrinsic and intrinsic.
these both meet in the final common pathway which starts at factor 10.
What is the intrinsic pathway of the coagulation cascade?
- usually initiated by contact with a foreign substance
- clotting factors 9, 11 and 12 are invovled
What is the extrinsic pathway of the coagulation cascade?
- the most commonly activated pathway
- clotting factor 6 is activated, leading down to factor 10
What does the final common pathway of the coagulation cascade involve?
- factor 10, 5 and factor 2 (thrombin)
- this pathway has two mechanisms which convert soluble fibrnogen to insoluble fibrin
- insoluble fibrin makes up the thrombus/blood clot
- also activates factor 13 which stabilises fibrin
- the two systems talk to each other predominantly through thrombin as this will further activate the platelet aggregation system
What is the main factor involved in the coagulation inhibition network?
-antithrombin 3. This can inhibit the activation of a large number of factors, particularly those in the intrinsic pathway like factor 9, 11, 12, 10 and
What does tissue factor pathway inhibitor in the coagulation inhibition network do?
-this inhibits factor 7 in the extrinsic pathway of the coagulation cascade
What do protein C and cofactor protein S do?
-these are activated by thrombin and inhibit factor 8 and factor 5.
What kind of gene deficiencies disrupt the the hemostasis balace?
- deficiency of protein C and cofactor protein S
- when these don’t get activated, they form unwanted blood clots so their blood has a higher risk of forming a thrombus
How are most pathologies with the hemostasis system caused?
- either spontaneously or through disease or injury like DVT.
- as we age, our vasculature loses its tone resulting in pooling of blood in the veins
- this can clot and cause DVT which can move and break off to cause embolism.
- a major concern/risk of OC is unwanted blood clots
- surgery is also a risk, particularly if you want a prosthetic device fitted
How can the risk of thrombo embolitic diseases be modified?
- modify blood coagulation
- platelet adhesion and activation
- move blood clot (not as effective, but there are agents which can break this bloodclot down.)
What are the mainline anticoagulant agents?
- warfarin, heparin
- they have wide uses e.g. in arterial thrombosis, embolism, surgery, esp if followed by long bed rest, and cardiomyopathy
what is the first line anti-coagulant?
Heparin
- binds to antithrombin 3 and increases its ability to inhibit the coagulation factors (9, 11, 12, 10, 2)
- Heparin mainly enhances AT3 to inhibit factor 10 and 2 which are the two main factors in the common pathway
- prevents thrombin from being able to produce fibrinogen to fibrin which will prevent blood clot.
What is the effect of heparin being more sensitive to factor 2?
- it has to bind and form a complex with AT3 and also bind to thrombin to form a tightly bound complex
- this complex is quite strong and irreversible
What is the effect of heparin being less sensitive to factor 10?
-factor 10 only needs to bind to AT3 to be inhibited. It has no binding site to heparin resulting in heparin being less sensitive.
What can thrombin do?
-activate platelets in the platelet activation cascade
Why do some patients not respond to full length heparin?
- it can result in thrombycytopenia, which is the reduction in platelet numbers
- in some cases they may form an immune response to the inhibition of thrombin
What is low molecular weight heparin?
- developed for patients who were intolerant to full length heparin
- has the binding site for factor 2 removed, resulting in little or no effect on thrombin due to loss of binding site,
- however it still retains the same inhibitory ability to factor 10 as it does not need to bind to heparin
When is wafarin used?
- often reserved for patients intolerant to heparin, or may be for temporary or long term use
- it is our main oral anticoagulant
Which blood coagulation factors are synthesised in the liver?
factors 2 and 19
- they need to undergo gamma carboxylation which requires a reduced form of vitamin K
- uses the enzyme vitamin K reductase.
- This synthesis is a circulation process
what is the mechanism of action of warfarin?
- inhibits vitamin K reductase and prevents vitamin K being reduced
- also prevents the synthesis of vitamin K from its oxidised form.
- gamma carboxylation cannot occur so we don’t synthesise factors 2 and 19
Which factors does wafarin not have an effect on?
factors 2, 7, 9 and 10 as warfarin does not affect any of the blood coagulation factors that are already synthesised.
- warfarin takes 5 days to have therapeutic effect.
- patients are often started on heparin therapy first, and then change over to oral warfarin when the two systems overlap
What are the problems with anticoagulant factors?
- there is a high degree of bleeding. This is often seen by bruises
- newer agents like antithrombin 3 independent agents have been developed to reduce this bruising
- the main groups are the direct thrombin inhibitors
