haemostasis Flashcards
define haemostasis and importance
process allowing cessation of bleeding due to a vascular injury- prevents blood loss from injured vessels, allowing tissue repair
when balance of haemostasis goes wrong
increase in fibrinolytic factors/anticoagulant factors= too much bleeding, increase in coagulant factors/platelets= too much thrombosis
summary of haemostatic plug formation
vessel constriction (VCSM contracts= blood limited) unstable platelet plug formed (platelete adhesion+ aggregation= blood loss limited+ SURFACE for coagulant factors)- PRIMARY haemostasis plug stabilisation with fibrin (coagulation to stop blood loss) dissolution of clot once vessel repaired (cell migration+ fibrinolysis )
components of vessel wall
endothelium (ANTIcoagulant barrier with things like thrombomodulin/EPCR) subendothelium (PROcoagulant- elastin, collagen, TF)
platelets DIAGRAM
derived from megakaryocytes in bone marrow (multilobular)- megakaryocytes go from bone marrow to vessel, where platelets are released from them they have MANY receptors which are responsive to different stimuli- have well developed cytoskeleton, hence they can change shape easily from resting/quiescent to active- goes from disc shapes to rolling, then spreads out
platelet adhesion
when there is vessel injury, the coiled VWF binds to collagen, and unravels VWF to make it linear and expose its platelet bnding site (GP1b in platelet) platelets also bind directly to collagen via GP1a alpha 2 beta 1, but this is in LOW FLOW
platelet activation D
GP1a binding activates platelet, changes platelet shape- thrombin released to further activate platelets- ADP and thromboxane release to recruit platelets
platelet aggregation DIAGRAM
activated plateleets bind to other platelets via alpha 2 beta 3 (GP 11B/111A) alpha 2 beta 3 binds fibrinogen as well to help form platelet plug
VWD+ platelet disorders
leads to problem with platelet recruitment, as VWF needed not enough platelets/missing receptors
platelet count thresholds
normal- 150 to 400*10^9/L below 40 is spontaenous bleeding, below 10 severe
sites of production of coagulation proteins
liver (most important), endothelial cells (VWF, TFPI, thrombomodulin), and megakaryocytes (VWF)
proteases, cofactors and inhibitors
F7,9,10,11,12,13 (zymogens which when active become eg F7a) cofactors- TF, F5/8a inhibitors- TFPI, protein C/S, antithrombin
initiation and propagation of coagulation DIAGRAM
TF (ONLY present on extravascular cells) exposed to F7 in plasma- F7 binds via GLA DOMAIN to form complex complex activates F9=F9A (intrinsic pathway) AND F10=F10A (extrinsic) F10A converts PROTHROMBIN to THROMBIN- this process inefficient, so thrombin activates F5/8A (cofactors)- F8A activates F9A, which activates LOTS of F10 A, complex with F5A leads to HUGE production of thrombin- thus small production of thrombin leads to large production of thrombin thrombin makes fibrinogen turn into fibrin
common feature of F7, 9, 10 and protein C/S, as well as prothrombin+ relevance to warfarin
all share Gla domain (can bind to phospholipid surface on activated platelets)- Gla domain can only form by VITAMIN K dependent carboxylase- warfarin has an anti-coagulant is vit K antagonist ie produces clotting factors with no GLA domain= cannot bind
haemophilia A vs B
A= F8 deficiency B= F9 deficiency
regulation of coagulation+ deficiencies DIAGRAM
TFPI prevents TF-F7a complex ie initiation Protein C/S inhibits F5/8 by cleaving it- does NOT inhibit thrombin antithrombin inhibits 10a and thrombin- HEPARIN supports antithrombin prevents thrombosis- deficiencies present in Protein C/S, antithrombin, NOT TFPI in humans
