Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 558

procoagulant complexes. Erythrocytes indeed promote platelet aggregation and
degranulation by releasing ATP and ADP under hypoxia and acidosis, as well as
in response to mechanical deformation.
Platelets contain cellular factor XIII and promote fibrin crosslinking by plasma
coagulation factor-XIII, thereby contributing to formation of a resistant fibrin
structure to avoid premature fibrinolysis.

9.8.2 Fibrinolysis

Fibrinolysis occurs after coagulation during healing. It involves plasmin, which
cleaves the fibrin clot. Plasmin is produced from plasminogen, which is synthe-
sized in the liver, by tissue plasminogen activator 139 (tPA). Tissue plasminogen
activator that activates fibrinolysis and thrombolysis is stored in small vesicles in
endothelial cells. It is released by thrombin, histamine, endothelin, and cytokines.
α 2-Antiplasmin and plasminogen activator inhibitor inhibit plasminogen activators

(tPA and uPA), thereby preventing the conversion of plasminogen to plasmin.
Inhibitor of fibrinolysis PAI1 is released by a calcium-dependent process primed
by thrombin, histamine, endothelin, and cytokines, such as TNF

. Endothelial
cells activate fibrinolysis by binding PAI. Activated protein-C deactivates PAI1.
Moreover, the inhibitory effect of PAI1 is reduced when fibrin, plasmin, and tPA
form ternary complexes.
During healing, activated clotting factor-XIIIa binds to fibrin and protects it
from plasmin. Similarly, myosin released by platelets interacts with fibrin fibers
and masks their plasmin-cleavage sites. Conversely, the free form of myosin binds
both tPA and plasminogen and accelerates plasminogen activation. Like fibrin-
bound plasmin, myosin-bound plasmin is protected against inhibitors of fibrinolysis.
Elastase degrades clotting factor-XIII and inactivates clotting factor-VII, -VIII, -IX,
and -XII [ 1008 ].
Trapped leukocytes in the clot modulate fibrinolysis. Leukocyte peptidases
not only digest fibrin, but also indirectly control fibrinolysis, as they degrade
zymogens and inhibitors of coagulation and fibrinolytic peptidases. Neutrophil
elastase promotes fibrinolysis directly by degrading fibrin and indirectly by cleaving
plasminogen into miniplasminogen that is more quickly activated to miniplasmin by
plasminogen activators without cofactors [ 1008 ]. Miniplasmin is much less sensitive
to inhibition by

α

α 2-antiplasmin than plasmin.

139 When stroke occurs, glutamate is released by ischemic neurons. Glutamate induces an excess in
receptor stimulation and a subsequent calcium ion influx. The latter leads to neuron death. tPA is
produced by endothelial cells and neurons. tPA released by damaged neurons increases glutamate
effects. Therefore, tPA administration after stroke must be carefully handled.