7: Haemostasis Flashcards
What is haemostasis
Cellular and biochemical processes that enables the SPECIFIC and REGULATED cessation of bleeding in response to vascular insult
What can cause bleeding?
Fibrinolytic factors
Anticoagulant proteins
What can cause thrombosis?
Coagulant factors
Platelets
Summarise plug formation in response to endothelial damage
Vessel constriction (limits blood flow)
Unstable platelet plug (platelet adhesion + aggregation)
Stabilisation of plug with fibrin (stops blood loss)
Vessel repair + Dissolution of clot
Describe the structure of a normal arterial vessel wall
Layer of endothelial cells - ‘anti-coagulant’
Subendothelium - contains tissue factor, ‘pro-coagulant’
Which cells are platelets derived from?
Haematopoietic stem cells -> pro-megakaryocytes -> Megakaryocytes -> platelet
What are present inside platelets?
Granules containing factors for coagulation as well as ATP/Ca to augment function of other platelets
What happens when a platelet is activated?
Converts from a passive to an INTERACTIVE cell
Describe platelet adhesion
- Vascular injury exposes sub-endothelial collagen
- Globular VWF binds
- Tethered VWF unravels by sheer force of blood flow and exposes platelet binding sites (Gp1b)
- Platlets bind - this binding recruits more platelets
Platelets can also bind directly to collagen via GPVI + a2b1 (only at LOW sheer force) and become activated, recruiting more platelets
Describe platelet activation
Collagen and thrombin activate platelets
Platelets bound to collagen/VWF release ADP + thromboxane which activates platelets
Activated platelets recruit additional platelets via aIIBb3
aIIBb3 also binds fibrinogen
Platelet plug develops (slows bleeding, provides surface for coagulation)
How does platelet change shape?
Flowing disc shape
Rolling ball shape
Hemisphere (Firm but reversible adhesion)
Spreading platelet (IRREVERSIBLE adhesion)
What does thrombin do?
Converts fibrinogen to fibrin
Where are plasma clotting factors produced?
Mostly the liver
Some in endothelial cells
Megakaryocytes
How do clotting factors circulate in the blood?
As inactive precursors
Activated by specific proteolysis
How is coagulation initiated?
Tissue damage exposes Tissue Factor to F7/7a
Activates Tissue factor
Where is tissue factor found?
Normally located at extravascular sites (not exposed to blood)
Describe the structure of Factor 7
Serine protease zymogen
Expressed/secreted by liver
Only around 1% of f7 circulates as f7a (active form)
Activated by proteolysis
Gla domain allows binding to phospholipid surfaces
Describe the Gla domain
Vitamin-K dependent - adds a COOH group, giving it extra charge, allowing it to bind to Ca2+
6/7 Ca2+ ions bound to it causes structural change
Folds up into phospholipid-binding conformation
How does warfarin work?
Vitamin K antagonist
Results in clotting factors with non-functional Gla domains meaning they can’t bind to phospholipid surfaces
What does TF/F7a do?
Activates F10, forming F10a
What does F10a do?
Activates pro-thrombin to generate THROMBIN
Very inefficient step, small amount of thrombin produced
What factors can activate f10 more efficiently?
f8a/9a activates f10 more efficiently than TF/f7a
What factors can activate pro-thrombin more efficiently?
f5a/10a
What are the 3 natural inhibitory systems involved in regulating coagulation?
- TFPI (Tissue factor pathway inhibitor)
- Protein C Pathway (APC)
- Antithrombin
What does TFPI do? How does it work?
Targets initiation phase of coagulation
TFPI/f10a complex INHIBITS TF/f7a
How does the protein C pathway work?
Thrombin escapes clot and binds to thrombomodulin on endothelial cells at the EDGE of the clot
Protein C activated by this complex
Activated protein C (APC) inactivates f5a/8a therefore DOWN-REGULATING (not inhibiting) thrombin generation
How does antithrombin work?
Anti-thrombin is a SERPIN (Serine protease inhibitor)
It ‘mops up’ and inhibits any thrombin/f10a that ESCAPES the clot to prevent initiation of coagulation elsewhere
How are clots broken down?
Fibrinolysis
tPA (tissue plasminogen activator) converts plasminogen to PLASMIN
Plasmin breaks down the fibrin clot
