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Flashcards in Platelet-endothelial interaction Deck (12)
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Pro-inflammatory cytokines and their effects

-ILs (particularly 1 and 6), TNFa, INFg, VEGF
-Cause: increased TF, fibrinogen, vEF, adhesion molecules on endothelium
-They also cause: decreased thrombomodulin (TM)
-Overall: increases chance of thrombus formation
-Also increases thrombus formation chance: bad genes, bad food, obesity


Formation of atherosclerosis: fatty streak

-Accumulation of cholesterol-rich lipids in sub endothelial (intima) space (usually at site of flow disturbances like bifurcation)
-The lipids become modified and oxidized, then invoke an inflammatory response by causing endothelium (EC) and smooth muscle cells (SMC) to release pro-inflammatory cytokines
-This stimulates the migration of macrophages to the lipids
-The macs ingest the oxidized lipids and become foam cells
-Accumulation of foam cells is the fatty streak


Formation of atherosclerosis: fibrous plaque 1

-Foam cells (activated macs) express high levels of TF
-The foam cells will cause thrombosis if they are exposed to blood, but this is limited by the endothelial cells
-If the endothelium is denuded microthrombi and platelets form over the fatty streak, the beginning of the fibrous plaque


Formation of atherosclerosis: fibrous plaque 2

-The platelets release PDGF and TGF-b and, combined w/ mitogenic effects of thrombin, stimulate proliferation of SMCs and fibroblasts and increase synthesis of interstitial collagen
-Platelets also release PAI1, leading to a local inhibition of fibrinolysis
-The decreased generation of plasmin also leads to depressed local activation of collagen-degrading metalloproteinases (MMPs)
-Overall effect is an uncontrolled accumulation of collagen in the lipid-rich plaque


Rupture of the fibrous plaque

-Continual growth of the plaque results in an atheroma (large plaque)
-Remodeling of the fibrous plaque leads to a cap over the surface of the plaque, with an underlying matrix of lipid and TF rich foam cells (and other proteins like collagen)
-Rupturing of the cap over the atheroma causes the majority of arterial thrombi and MI
-The exposed collagen can activate platelets, which can be amplified by the excessive TF leading to massive thrombin production
-Rupture of fibrous plaque could be in part due to excess expression of MMPs, leading to destabilization of the fibrous cap (?)


Hemostasis in the venous system

-Dependent on the expression of procoagulant factors, resulting in thrombin stimulation and platelet aggregation
-In the low shear venous system platelet aggregation is mediated by binding of platelets to fibrinogen (GPIIb/IIIa)
-The activated platelets provide a thrombogenic surface, further enhancing thrombin generation
-Prophylaxis and Rx for venous thrombi involved anticoagulants that inhibit formation of thrombin


Hemostasis in the arterial system

-Expression of endothelial procoagulants alone is insufficient to generate amount of thrombin needed for hemostatic plug
-Exposure of subendothelium (rich in collagen and vWF) allows for rapid adhesion (GPIb/IX to vWF and GPVI/GPIa/IIa to collagen) and activation of platelets
-Platelet aggregation is supported by the binding of vWF to GPIIb/IIIa (not fibrinogen)
-Since arterial clots are predominantly composed of platelets, Rx and prophylaxis inhibit platelet activation


Activation of platelets in hemostasis

-Activated platelets will express P-selectin on their membranes
-This will bing to mono/mac-derived micro vesicles that are rich in TF (via P-selectin binding to PSGL-1)
-Upon the binding of these two, their membranes will fuse and platelets will now express TF on their surface, greatly increasing their coagulability


Anti-platelet Rx

-Mostly for prevention and Rx of arterial thrombosis
-Targets: inhibition of primary agonist signaling (thrombin inhibition w/ Hirudin and Bivalrudin)
-Inhibition of secondary (amplifying) signaling (aspirin and thienopyridines)
-Inhibition of GPIIb/IIIa receptor aggregation (Abciximab, eptifibatide, tirofiban)


Aspirin (ASA)

-Irreversibly inhibits platelet COX1 to prevent the formation of TxA2
-Prevents aggregation and activation
-ASA is inactivated quickly in liver, so the only the platelets in the portal circulation are inactivated
-This is to our advantage, since all of our platelets pass through the portal circulation within a short period of time and thus many are inactivated
-This spares the rest of our cells (such as systemic endothelium) from having their COX irreversibly inhibited


Thienopyridines (ticlopidine,clopidogrel)

-Irreversible inhibitors of the ADP receptor (P2Y12)
-Active inhibitory agent is produced metabolically in the liver (gets activated in liver)
-Repeated doses are required before effective platelet ADP receptor blockade is active


Platelet GPIIb/IIIa receptor inhibitors

-Primary receptor for platelet aggregation in low and high shear blood flow
-Congenital deficiency (glanzman's thrombasthenia) results in severe life-long bleeding
-Both reversible (eptifibatide and tirofiban) and irreversible (abciximab) antagonists for the receptor exist
-These are usually only used in the short term due to their tendency to cause bleeding diatheses