Haemostasis Flashcards
What haemostasis mechanism molecules are found in the blood?
coagulation proteins (VIIa, IX, X, V, VIII) - triggers outside circulation (collagen and tissue factor on VSMC and fibroblasts)
VWF
- large, adhesive plasma protein with many anticoagulant binding sites (GP1b,IIb,IIIa on platelets, for collagen and FVIII)
- 20-40 monomers assembled to form multimer
- bundled up in plasma but unravels when binds to collagen
- soluble
platelet and their granules (10 day life span)
-granules of ADP, VWF, fibrinogen
Describe the overall process of haemostatic plug formation?
injury vessel constriction primary haemostasis - formation of unstable platelet plug (platelet adhesion, aggregation) - stabilisation of plug with fibrin (blood coagulation) secondary haemostasis - dissolution of clot (fibrinolysis) - vessel repair
Describe haemostatic plug formation
STEP 1 OF PRIMARY HAEMOSTASIS
- endothelial damage expose subendothelial collagen
- collagen binds to VWF to capture platelets via GP1b receptor and slow them down
- platelets also bind directly to exposed collage via GP1a
- binding signals Ca2+ influx and degranulation to activate platelet –> release ADP/prostaglandins/fibrinogen/TXA2 and VWF to capture more platelets (postive feedback)
- platelet aggregation using fibrinogen binding via glycoprotein 2b/3a on platelet
OR protease (thrombin) cleaves receptor on platelets to cause aggregation/activation
How does varying blood flow alter platelet activation method?
high shear stress in small blood vessels favours VWF binding
What is involved in platelet activation?
change shape, membrane composition (excess phospholipid)
present new/activated proteins on surface (G1p2b/3a)
Describe blood coagulation process
STEP 2 OF PRIMARY HAEMOSTASIS
intrinsic pathway
- zymogens are activated (protease precursor)
- F8a cofactor is made from F8 phospholipid on platelet which is activated to mediate thrombin formation via F9 and 10
extrinsic pathway
- TF activates F7
- F7 mediates F9/10 activation
- F10a mediated prothrombin –> thrombin to further activate platelets
- thrombin activates F5 to create +ve feedback thrombin activation
- thrombin also activated F13 to form cross linked fibrin that is more resistant to shear stress
ALL FUNCTION TO SECURE PRIMARY HAEMOSTATIC PLUG WITH FIBRIN MESH
Where are clotting and fibrinolytic factors/inhibitors made?
liver mostly
VWF, 8 = endothelial cells
megakaryocytes = VWF, 5
What is the main driver of blood coagulation cascade?
TF in vivo
F12 used in vitro lab testing
Describe the dissolution of clot and vessel repair?
= SECONDARY HAEMOSTASIS (fibrinolysis)
this is activated by fibrin formation/used therapeutically by stroke/MI
- tPA (tissue plasminogen activating factor) is protein made by endo cells that converts plasminogen (zymogen) to plasmin (protease)
- both proteins bind to fibrin that acts as a surface catalyst
Plasmin catalyses conversion of fibrin to fibrin degradation products (FDPs) that are measurable in thrombolytic therapy
What is streptokinase?
bacterial activator
treat thrombolysis in MI
What stops plasmin spreading?
antiplasmin
local effect
Describe the surface of endothelial cells?
anticoagulant
PGI2, ADPase, NO stop platelet activation
Describe direct inhibition of coagulation
antithrombin
stops activated enzymes by directly inhibiting thrombin and other proteinases (9, 10, 11a enzymes)
binds to 2a (thrombin) and neutralises it
heparin makes antithrombin a better target for 2a by promoting their binding (increases antithrombin binding x1000)
When is inhibition of coagulation initiated?
in presence of excess thrombin
What is the use of heparin?
for immediate anticoagulation in venous thrombosis and pulmonary embolism
