Haemostasis Flashcards
Describe the structure of a platelet.
anuclear, discoid, fragments of a megakaryocyte
peripheral zone consists of a plasma membrane with deep invaginations allowing cell signalling.
contains integrins for cell signalling
contains alpha granules and microparticles
what comprises primary hsaemostasis?
the endothelium, the inner lining of blood vessels, platelets, and extracellular matrix components of the endothelium.
what are the three stages of platelet activation?
initiation
extension
stabilisation
what is involved with initiation?
sheer injury causing exposure of collage and vWF (from weibel palade bodies). plasma vWF then attach to collagen forming multimers
Then bind to platelets via GP1ba
this creates a monolayer and results in platelet activation
What is involved in extension?
local accumulation of thrombin, ADP, thromboxane and serotonin recruit and activate nearby platelets.
these agonists trigger activation of platelets resulting in the initial binding of fibrinogen to aIIbB3 - initiating aggregation
this activation also results in inside-out signal resulting in phospholipid membrane change creating a negative charge
What is involved in stabilisation?
Firm adhesion to fibrinogen via platelet integrins results in outside-in signaling, a cascade of events that occur downstream of integrins, and leads to the clustering of the platelet integrin within the lipid rafts and protein complexes that are linked to the actin/myosin filaments.
results in sinching down of the clot
What two processes are required for secondary hemostasis?
Disruption of membrane asymmetry and exposure of negatively charged phospholipids. - through flippase, flopase scramblase action
2. Gamma-carboxylation of glutamic acid of clotting factors. - γ-carboxylation is carried out by vitamin K-dependent carboxylase, which facilitates the addition of an extra negative charge on glutamic acid
Summary of cell-based model
A summary of the cell-based model of coagulation. A, Initiation: Tissue factor (TF)-bearing cells come into contact with FVIIa, which facilitates the formation of small amounts of thrombin (FIIa). B, Amplification: Thrombin activates platelets to degranulate and externalize phosphatidylserine, which facilitates their adhesion to subendothelial matrixes and activates other factors (FXI, V and VIII). C, Propagation: Formation of tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets propagates massive formation of thrombin. D, Termination: Thrombin generation is countered by endogenous anticoagulants including tissue factor pathway inhibitor (TFPI), protein C (PC), protein S (PS), and antithrombin.
what occurs during initiation
7 an TF
then activates 9 and 10
then 10 activates 5 to activate thrombin
this then results in amplification
what occurs during amplification?
hrombin, as a potent platelet agonist, maximizes platelet aggregation and formation of procoagulant membrane. Second, thrombin activates factors XI, V, and VIII, which become dissociated from vWF (Fig. 3.3B).14 Factors attached on the surface of platelets lead to the propagation phase.
what occurs during propagation?
production of a substantial amount of thrombin via formations of the tenase (FIXa-FVIIIa) and prothrombinase complexes (FXa-FVa) on activated platelets. leaving fibrinogen into fibrin monomers that eventually polymerize to form a fibrin clot. Factor XIII, which is activated by thrombin, is responsible for the crosslinking of fibrin monomers to further stabilize fibrin clots.
what are some antithrombotic mechanisms?
tissue factor pathway inhibitor (TFPI)
antithrombin (AT), which is produced by the liver, inhibits thrombin generation by forming molar complexes with thrombin, FIXa, FXa, FXIa, and FXIIa and is facilitated by the glycosaminoglycans, heparin, and heparin sulfate.
Protein C and protein S are vitamin K-dependent natural anticoagulants
what are two inhibitors of fibrinolysis?
plasminogen activator inhibitor 1 (PAI-1) and alpha-2 antiplasmin.
