13. Haemostasis 1 Flashcards
What is the role of Coagulation factors?
Help form clots to plug holes in vasculature
What is the role of Regulatory factors in haemostasis?
Stop coagulation system firing off prematurely
which would cause thrombosis
What prevents coagulation factors being triggered unnecessarily?
Triggers are outside the circulation in the sub endothelial tissue (Collagen and Tissue factor)
What is Von Willebrand Factor (vWF)?
A giant adhesive plasma protein
Has multiple binding sites for platelets, collagen and factor 8
How is Von Willebrand Factor found in blood normally?
In a rolled up form
Many of its binding sites are hidden
What happens when vWF binds to collagen?
Blood flow pushes it along and stretches it
vWF becomes long and thin
Describe platelets
Fragments of megakaryocytes Much smaller than RBCs No nucleus Granular Half life ~10 days
List 3 stimulatory receptors on platelets and what they bind to
P receptors: bind ADP
Thromboxane receptors: bind thromboxane
PGI2: binds prostacyclin
List 2 adhesive receptors on platelets and what they bind to
Integrin alpha-II-b-beta-3
GPIb-alpha
Both bind to vWF
What is exposed when the endothelial layer is damaged?
Collagen and tissue factor
What is required in primary haemostasis?
Collagen
Platelets
Von Willebrand Factor
(+ fibrin in larger vessels for stabilisation)
Describe the formation of a platelet plug in primary haemostasis
Rolled up vWF binds to exposed collagen and gets stretched out Exposes vWF binding sites for platelets Platelets bind as they flow by Platelets become activated Granules discharge, release more vWF vWF captures more platelets
What do platelets bind to other platelets in a platelet plug with?
Fibrinogen
What is platelet activation?
Conversion from a passive to an interactive cell
How are activated platelets different?
Change shape
Expose phospholipid
Present new or activated proteins on their surface
What happens inside platelets when they’re activated?
Ca2+ flux causes granules to degranulate
Release ADP, Fibrinogen and vWF
Takes phospholipid from its surface and makes thromboxane
What is coagulation?
Formation of a fibrin mesh (occurs in secondary haemostasis)
List the Sites of Synthesis of Clotting Factors, Fibrinolytic Factors and Inhibitors
Liver (primarily)
Endothelial cells (Factor VIII and vWF)
Megakaryocytes (to platelets) (vWF and factor V)
What is the co-factor needed to activate factor VII?
Tissue factor
When factor VII and tissue factor form a complex what happens?
Becomes activated (VIIa) Turns inactive proteins (factors IX and X) into active forms (IXa and Xa)
What is the dampening mechanism that turns off coagulation almost immediately?
TFPI
Binds to FVIIa and FXa
What can FXa make before the coagulation process is dampened by TFPI?
Thrombin
What does thrombin do if there is enough made before the dampening process?
Forms 2 complexes:
IXa enzyme, VIIIa cofactor, PL (phospholipid that platelets are providing)
+
Xa enzyme, Va cofactor on surface of PL with Ca2+
These make a lot more thrombin
What extra feedback can make more FIX if needed?
XI activated to XIa
Converted to IX
What does thrombin do haemostatically?
Thrombin cleaves fibrinogen (soluble, in blood) to form fibrin (insoluble, forms a mesh)
Rate of thrombin production
Lag while becoming activated
Then lots of thrombin produced in a burst
What does a thrombin burst generate?
A stronger, denser clot which is more resistant to fibrinolysis
What effect does thrombin have on factor XIII?
Thrombin activates factor XIII
Factor XIII cross links fibrin and inhibits fibrinolysis
What inhibitor does thrombin activate?
TAFI
An inhibitor of fibrinolysis
What does deficiency of coagulation factors cause?
Bleeding disorders due to failure of a thrombin burst
Why does blood not clot completely whenever clotting is initiated by vessel injury?
Coagulation inhibitory mechanisms prevent this
List 3 proteins on the surface of endothelial cells that prevent platelet activation and unnecessary clotting
Heparans/ Heparin
EPCR
TM
List 2 antiplatelet agents produced by the endothelium
PGI2
NO
What does ADPase on the surface of endothelial cells do to platelets?
Degrades platelets
What are the 2 direct inhibitory mechanisms for coagulation?
Antithrombin (AKA antithrombin III): an inhibitor of thrombin and other clotting proteinases, deals with enzymes
TFPI: in the initiation phase
What is the indirect inhibitory mechanism for coagulation?
Inhibition of thrombin generation by the protein C anticoagulant pathway, deals with cofactors
Describe the action of antithrombin (AT)
AT binds complexes with thrombin (IIa) and neutralises it
Describe the effect of heparin on the action of antithrombin (AT)
Heparin makes AT molecule more reactive and bridges AT and IIa
Abbreviation for thrombin
IIa
Which enzymes can antithrombin inactivate?
IXa
Xa
XIa
Describe the protein C pathway that down regulates thrombin generation
Thrombomodulin (TM) binds free thrombin
TM redirects thrombin activity from fibrinogen to protein C
Activated Protein C + cofactor protein S down-regulates thrombin generation by degrading factor Va and VIIIa
What do free thrombins bind to? (in termination of coagulation)
Free thrombin binds to antithrombin, which binds to heparans on the surface of epithelium
Fibrinolysis
Breaking a clot down
clots are temporary
Describe the process of fibrinolysis
When fibrin is formed, tissue plasminogen activator (tPA) and Plasminogen (Pgn) form a complex
tPA turns Pgn into Plasmin
Fibrin is the target of Plasmin
Plasmin breaks down fibrin, forming fibrin degradation products
Antiplasmin regulates this: stops plasmin degrading other healthy things (process is localised)
What happens when Coagulation Inhibitory Mechanisms Fail?
Inappropriate clot formation (thrombosis)
List 3 deficiencies increasing risk of thrombosis
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
What imbalances of haemostasis cause bleeding?
If not enough pro-coagulant factors
Or
There is too much anticoagulant activity
What imbalances of haemostasis cause thrombosis?
If there is too much FVIII (pro-coagulant factor)
or
Not enough antithrombin (anticoagulant)
