Hemostasis Flashcards
How can a venous bleed be slowed?
Raise bleed above the heart to reduce blood pressure. This decreases hydrostatic pressure and may stop hemorrhage.
What is a hematoma? Why may it stop a bleed?
This is when blood accumulates internally due to an internal wound. The accumulation may eliminate the pressure gradient so the bleed stops.
What happens when a blood vessel is injured?
1) It constricts, this slows blood flow to area so less blood is lost
The constriction also presses the opposed endothelial surfaces together inducing ‘stickiness’
2)Formation of the platelet plug
3)Blood coagulation - clotting cascade
How is the platelet plug formed?
1) Damage to endothelium -exposing collagen
2) Platelets adhere to collagen via intermediate von Willebrand factor (vWF). vWF is a plasma protein secreted by endothelial cells and platelets.
3) vWF forms a bridge between platelets and collagen on damaged vessel wall
4) Platelet binding triggers platelets to release the contents of their secretary vesicles
5) This vesicles contain a) adenosine diphosphate (ADP) b)serotonin and other chemicals
6) These chemicals act locally to change platelets, activating them. This causes platelet aggregation - when new platelets to adhere to old ones
7) Thus creating a platelet plug :)
8) Adhesion of platelets rapidly induces them to synthesize thromboxane A2 (thromboxane A2 is from the eicosoncid family, made from arachiolonic acid in platelet plasma membrane)
9) Thromboxane A is then released into the ECF
10) This stimulates platelet aggregation and secretory vesicle release
11) Platelets contain large amounts of actin and myosin, these are stimulated to intercat causing compression and strengthening
12) While the platelet clot is being build up the smooth muscle in the damaged wall is being stimulated to contract, this is mediated by thromboxane A and other chemicals from platelet vesicles
What 3 reactions does thrombin catalyse?
1) Fibrinogen to fibrin
2) factor XIII to factor XIIIa
(XIII a then catalyses loose fibrin into stable fibrin = plug)
3) +ve feedback, thrombin also activates more proteins and platelets. This means that the production of prothrombin to thrombin leads to even more thrombin
What happens when platelets are activated?
-Platelets display clotting factor receptors on their surfaces, therefore reactions occur on platelet surfaces.
-They also display platelet factors, these are phospholipids that act as cofactors.
(-Ca2+ is also required in clotting cascade)
What is the essential component of a clot?
Fibrin (the clot also contains erythrocytes and other cells trapped in fibrin meshwork)
What is the intrinsic pathway?
1) When factor XII comes into contract with collagen it is activated
2) factor XIIa catalyses factor XI to XIa
3) XIa catalyses factor X to Xa
4) Xa converts prothrombin to thrombin (thrombin catalyses 3 reactions)
What is the extrinsic pathway?
1) Tissue factor from the outer plasma membrane of various tissue cells, eg subendothelial cells, is exposed to collagen
2) Factor VII binds to these cells and is activated
3) Tissue factor - factor VIIa complexes are formed. These cataylse factor X activation (Xa converts prothrombin to thrombin)
They also catalyses factor IX to IXa, which can then activate more factor X
How do undamaged adjacent endothelial cells avoid clotting
Undamaged adjacent endothelial cells release:
1) Prostacyclin, this inhibits platelet aggregation
2) Nitric oxide (NO is a vasodilator and inhibitor of platelet aggregation)
What is blood coagulation
Blood coagulation or clotting occurs locally around the platelet plug to support and reinforce it. It also solidifies the blood remaining in the wound channels.
There are two ways this can occur; the intrinsic pathway or the extrinsic pathway.
(Intrinsic is when collagen activates XIIa, extrinsic is due to tissue factor - factor VIIa complexes )
What do molecules inhibit platelet aggregation
- NO
- Prostacyclin
What factors oppose clot formation? -3 mechanisms
- Tissue factor pathway inhibitor (TFPI)
-TFPI is secreted by endothelial cells
-binds to tissue factor - factor VIIa complexes
-This means that the complexes cannot catalyse factor X activation
(This is the mechanism of the extrinsic pathway and explains why it can only generate small amounts of thrombin) - Thrombomodulin
- A thrombin receptor on endothelial cells
- This eliminates all of thrombin’s clot producing effects
- It also causes thrombin to bind with protein C and another plasma protein. This inactivates factors VIIIa and Va - Antithrombin III
- This inactivates thrombin and other clotting factors
- When it binds to heparin Antithrombin III’s activity is greatly increased. (heparin is a substance found on the surface of endothelial cells)
- This prevents the spread of clots by rapidly inactivating clotting factors that are being carried away from the immediate site of the clot
What molecule digests clots? How is it formed?
Plasmin digests fibrin dissolving the clot.
Plasminogen (a proenzyme) is activated to plasmin by plasminogen activators
eg, tissue plasminogen activator (t-PA) is secreted by endothelial cells. During clotting both t-PA and plasminogen bind to fibrin. The presence of fibrin increases t-PA’s ability to catalyse plasminogen to plasmin.
Name some anti clotting drugs and their mechanisms
- Aspirin - Can prevent MIs, also given after MIs
Aspirin inhibits cyclooxyegnase (COX) enzyme; this stops the generation of prostaglandins and thromboxanes. thromboxane A2 is important for platelet aggregation and ensuring coagulation.
low doses = steady state decrease in PLATELET COX activity but not endothelial cell COX, so prostacyclin is not impaired
- Oral anticoagulants
Fibrinogen blockers
Heparin - (faster thrombin inactivation)
These all prevent clotting - Plasminogen activators - these dissolve clots that are already formed
