Vascular injury Flashcards
lecture 32 (40 cards)
what thing cooperate in heamostasis
platelets, plasma proteins of the coagulation cascade, endothelial cells.
what are platelets
discoid anuclear bodies produced by cytoplasmic fragmenattion of the megakaryocytes in the bone marrow. lifespan of about 7 days.
what activates platelets
ECM proteins particularly collagens. exposed following endothelial damage.
what do platelets adhere to in endothel damage
collage but mediated by Von willebrand factor. they then change their shape, shoot out long processes,and secrete chemicals like thromboxane A2, vasoactive amines (5HT) and ADP. promotes vasoconstriction and aggregation. a primary homeostatic plug is formed to temporarily fill the gap.
what happens after formation of the primary homeostatic plug?
platelet contraction, close apposition of the membranes and eventual fusion.
what mediates the phase of aggregation and fusion
a battery of receptor-ligand interactions and cell adhesion molecules :
- integrins (esp alpha2bbeta3)
- JAMs, ESAMs (endothelial cell-specific adhesion molecule)
- kinase-ligand combination of the eph and ephrin families
what causes the contraction of the platelet aggregation
the ntegrins and the eph/ephrins via cytoskeletal alteration via myosin dependent contraction.
what is purpura
bleeding from skin capillaries due to reduced platelets.
what types of granules do platelets release
dens granules and alpha granules
contents of alpha granules
PDGF
TGFbeta
factor 5, 8 and fibrinogen
PF4
contents of dense granules
ADP
calcium
5HT
ADR
what is the coagulation cascade
the series of proteolytic reactions through which circling inert zymogens are sequentially activated.
describe the common coagulation pathway
factor 10 activated to factor 10a by the intrinsic and extrinsic pathways on a phospholipid surface such as platelets in the primary haemostatic plug.
- 10a complexes with activated factor 5a in the presence of calcium and then catalyses prothrombin to thrombin.
- thrombin then does a whole load of things including cleving activation peptides from fibrin to activate it and cause it to polymerise.
- thrombin also activates factor 13 which catalyses the formation of covalent intermolecular bonds between the fibrin monomers to stabilise it.
- thrombin also activates more platelets, and catalyses the activation of factors 5 and 8. (8 is part of the intrinsic pathway).
what is the secondary haemostatic plug
the meshwork of crosslinked fibrin strands with fused platelets.
what system disassembles the haemostatic plug
the fibrinolytic system. plasminogen is precipitated with fibrin in the interior of the thrombus . plasminogen is activated here into the active protease plasmin.
what is the master regulator of the clotting cascade
thrombin!
describe the extrinsic pathway
exposure of subendothelium exposes tissue factor which binds factor 7 and causes it to autoactivate to factor 7a.
- factor 7a with calcium and on a phospholipid membrane, activates factor 10 to 10a
describe the intrinsic pathway
exposure of the subendothelium which is negatively charged. negative charge activates factor 12 to 12a.
- 12a activates prekallikrein to kallikrein which is anchored by HMW kininogen to the subendothelium.
- kallikrein does a number of things inc amplify factor 12 activation.
- factor 12 also activates 11 to11a which then cleaves its anchoring HMW kininogen to diffuse into the circulation and catalyse the activation of factor 9 to 9a in the presence of calcium.
- 9a complexes with 8a (released from VMF by thrombin) and calcium to activate factor 10 on phospholipids.
so what is a blood clot
the fibrin mesh with the platelet plug and caught platelets and RBCs.
how does normal endothelium inhibit clotting
1 - physical insulation
2 - enzymes
3 - chemical inhibitors
7 things made by the endothelium to inhibit clotting
1 - NO and PGI2 (prostacyclin) - inhibit platelet activation
2 - antithrombin - on cell surface binds and inactivates thrombin. complex released and cleared by the liver
3 - tissue factor pathway inhibitor (TFPI) blocks activation of factor 10 by tissue factor
4 - thrombomodulin - on cell surface, changes the conformation of thrombin so its less able to cleave fibrinogen and instead becomes able to activate protein C in the circulation
5 - protein C inactivates factor 5 and 8.
6 - protein S - a cofactor for protein C.
how do damaged endothelial cells promote coagulation
1 - exposed underlying tisses
2 - synthesising enzymes and chemicals such as
- Von willebrand factor - promotes platelet adhesion to proteins
- tissue factor (thromboplastin) which activates coagulation
- binding sites for factors 9 and 10.
define a thrombus
a mass formed from blood constituents within the circulation during life. composed of fibrin, platelets, with entrapped RBCs and WBCs
difference between a thrombus and a blood clot
a blood clot is formed in static blood and involves primarily the coagulation system, but without interaction with platelets and the vessel wall = glass in vitro and post mortem.
