Endothelium• Normally exhibits antiplatelet, anticoagulant, and fibrinolytic

properties. Injury → procoagulant activities

Antiplatelet activity of endotheliumprostacyclin (PGI2) and nitric oxide• prevent platelet adhesion/aggregation. • vasodilation • Synthesis stimulated by thrombin, cytokine

Anticoagulant activity of endothelium• endothelial membrane-associated heparin-like molecules.• Cofactors, enhance inactivation of thrombin, other coagulation

factors. Protein S (cofactor for protein C)

Fibrinolytic activity of endothelium• t-PA, cleaves plasminogen → plasmin (cleaves fibrin, degrades

thrombi)

Prothrombotic properties of endothelium• Platelet effects - vWF binds platelets

• Procoagulant effects - TNF, IL-1 → tissue factor synthesis (by endothelial cells) → activation of extrinsic clotting cascade.

• Antifibrinolytic - plasminogen activator inhibitors (PAIs)

Platelet Adhesion• to ECM,• mediated by interactions with vWF. GpIb binds vWF. (binding

necessary to overcome shear forces of flowing blood!)

Platelet Secretion• Release Alpha granules (contain finbrinogen, fibronectin, factor V, VII,

PF-4, PDGF) • Dense granules (ADP and ATP, ionized calcium, histamine, serotonin,

epinephrine) • Ca needed for coag cascade, ADP activates platelet aggregation

Platelet Aggregation• ADP and TxA2 stimulates aggregation.

• Activation by ADP → conformation change in GpIIb-IIIa receptor → induces binding to fibrinogen• Aspirin blocks thromboxane A2 (TxA2) synthesis (TxA2 → amplifies

aggregation)

Location of Coagulation Cascade (and role of calcium)• Components (enzyme, substrate and cofactors) are held together by

calcium, and assembled on platelet phospholipid surface.