Haemostasis Flashcards
When will blood contain coagulation factors/platelets etc. for clot formation?
All the time
But these things are not active until damage to BV occurs
What is the main job of the endothelium lining the BV walls?
Encourage flow
Prevent things sticking to the BV wall
How does the endothelium prevent things sticking to it?
Produces: heparans, TFPI, thrombomodulin, nitric oxide, prostacyclin
What occurs when you cut yourself?
Bleeding which stops after 2-3 mins and then forms a clot (thanks to platelets, vWF, coagulation factors), clot remains confined to area of damage (thanks to natural anticoagulants) and after 1 week clot disappears (thanks to fibrinolytic system)
How does damage to the BVs lead to the activation of clotting factors and platelets?
Signals -
Abnormal surface of damaged BV
Physiological activators of coagulation which are present at the site
Why do platelets adhere to the site of vessel damage?
As subendothelial collagen is exposed which is sticky so platelets stick and become activated
vWF has binding sites for collagen and platelets so sticks everything together too
What surface proteins are present on the surface of a platelet?
Glycoproteins: 2b/3a - binds fibrinogen 1b-9-5 - binds vWF 1a/2b - binds collagen 6 - binds collagen
What structures are present inside platelets?
Sources of energy
Granules containing chemicals involved in coagulation, e.g. alpha or dense granules
Granules are next to open canalicular systems that allow for their expulsion
What are the three steps that platelets take in haemostasis?
Adhere
Activate
Aggregate
and also provide a surface phospholipid layer for coagulation proteins to be activated on
What is involved in adhering of a platelet?
GP1a binds collagen
GP1b binds vWF
This holds the platelet in place where the tissue damage is
What is involved in activation and aggregating of the platelets?
Activation is via the ADP pathway (via ADP/P2Y12 receptor) –> activates platelets through cyclooxygenase pathway
Where arachidonic acid is converted into thromboxane A2 via COX enzyme
Thromboxane A2 allows the platelets to aggregate (stick together)
How does the platelet produce a surface for coagulation factor activation to take place on?
Scramblase enzyme allows phospholipids to be externalised to outside of cell
What is the role of vWF?
Big sticky protein that sticks to many things, including factor 8
Also adheres sticks clot to collagen and allows platelets to stick to each other
What is the primary haemostatic (platelet) plug?
Straight after BV damage, platelets adhere and become activated
This clot is too weak and needs reinforcement by fibrin
What is the definitive haemostasis?
Fibrin clot forms on top of platelet clot
Coagulation cascade activated to eventually cleave fibrinogen to form fibrin
How does the coagulation cascade work?
Physiological activator activates first factor, which activates the next one and so on (like dominoes)
If one coagulation factor is missing what happens to the clotting cascade?
Might not work at all/will be reduced`
I.e. will be unable to make proper fibrin clot –> bleeding diathesis
How do anticoagulants work?
They remove a clotting factor and hence halt the clotting cascade
Describe the events that occur in the clotting cascade?
Tissue factor is produced by damaged tissues
TF binds to factor 7 and activates it (–> 7a)
7a activates 10
10a along with 5a turns prothrombin –> thrombin
Thrombin cleaves fibrinogen –> fibrin
Thrombin activates 11, then 8 and 9 leading to even more activation of prothrombin –> thrombin leading to even more fibrin
Forms a strong clot
What are the three main natural anticoagulant pathways?
TFPI - tissue factor pathway inhibitor
Protein C and S
Antithrombin
How does TFPI work?
Binds to 7a and 10a and switches them off and prevents them becoming activated –> reduced thrombin –> stops clot forming
How does protein C and S work?
Targets activated factor 5 and 8 –> reduced thrombin –> reduced clot
How does antithrombin work?
Activates lots of proteases (mainly 10a) and directly inactivates thrombin
What is fibrinolysis?
Breaking down of the clot
How is fibrinolysis carried out?
Endothelial cells produce activators of plasminogen (tPA and uPA)
Plasminogen is a zymogen in the blood
tPA cleaves plasminogen –> plasmin –> breaks down
What substances result from clot breakdown?
Fibrin degradation products, including D-dimer
To ensure there is not excessive fibrinolysis, what mechanisms are in place?
Inhibitors of plasminogen - PA1-1 and PA1-2
Inhibitors of plasmin - alpha2-antiplasmin, alpha2-macroglobulin
Why might someone need antithrombotic drugs?
Vascular disease (esp. old age, diabetes, HTN)
What are common presentations of abnormal clotting in hospital?
DVT, stroke, MI, PE
How does aspirin work?
Inhibits cyclooxygenase
Arachidonic acid comes from platelet wall and COX catalyses it into thromboxane A2 –> platelet aggregation but aspirin blocks COX
How do clopidogrel, ticagrelor, and prasugrel work?
P2Y12 inhibitors (ADP receptor) which is important for activation of platelets
How do abciximab/tirofiban/eptifibatide work?
GP2b/3a inhibitors - prevents platelet aggregation/binding to fibrin
In which patients would you use clopidogrel etc?
Tends to be stented patients
How does warfarin work?
Vitamin K antagonist –> reduced vitamin K dependent clotting factors (2, 4, 7, 9)
If someone is on warfarin and are bleeding uncontrollable what can you give them?
Vitamin K
If really acute - IV prothrombin
Why might you give warfarin?
If patient has prosthetic heart valve
What are examples of DOACs?
Rivaroxaban, edoxaban, apixaban
How do Rivaroxaban, edoxaban and apixaban work?
Target activated factor 10
What are the DOACs used for?
Prevention of stroke/systemic embolism in AF, prevention and treatment of DVT/PE
How do Dabaigataran/bivalirudin/argatroban work?
Act directly on thrombin to deactive it
