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1968 Part XII: Hemostasis and Thrombosis Chapter 115: Vascular Function In Hemostasis 1969

Figure 115–2. Following injury to the blood vessel wall, platelets
adhere to the damaged surface of the endothelial cell. Concomitant
with adhesion platelets and endothelial cells become activated.
P-selectin is expressed on the endothelial cell surface. Platelet sur-
face receptors glycosylphosphatidylinositol (GPI)bα and P-selectin
glycoprotein ligand (PSGL)-1 interact with endothelial P-selectin,
thereby mediating platelet rolling. Firm adhesion is mediated by
the integrin α β . In parallel with these intercellular events, platelet
IIb 3
activation and release occur. The enzyme CD39 on the endothe-
lial surface modulates the ambient concentration of adenosine
7,8
diphosphate (ADP) by metabolizing it. 5-HT, 5-hydroxytryptam-
ine; TXA , thromboxane A . (Adapted with permission from Gawaz M,
2
2
Langer H, May AE: Platelets in inflammation and atherogenesis. J Clin
Invest 11(12):3378–3384, 2005.)

THE EICOSANOID PATHWAY IN thromboxane, namely vasodilation and inhibition of platelet aggrega-
tion.
The biologic half-life of PGI was found to be 10 to 20 seconds.
26,27
BIOLOGY AND MEDICINE: CELL–CELL In addition, it was determined that the first step in arachidonic acid oxi-
2
INTERACTIONS AND TRANSCELLULAR dation and conversion, which is carried out by cyclooxygenase (COX)-1,
is inhibited by aspirin (acetylsalicylic acid), which donates an acetyl
METABOLISM group that inactivates COX-1 and inhibits platelet function. 28
Dietary fatty acids give rise to arachidonic acid, the starting point for BIOSYNTHESIS OF PROSTACYCLIN IN
synthesis of other eicosanoids. Originating from different cells, inter-
mediates in the arachidonic acid pathway can interact with each other ENDOTHELIAL CELLS
to produce new products with new biologic activities. Oxygenation PGI is the major and most important eicosanoid produced by endothe-
2
and further enzymatic transformation of arachidonic acid gives rise lial cells. A broad range of stimuli, including hormones, biochemicals,
to eicosanoids (formerly classified as PGs) and hydroxy acids, such or physical forces such as shear stress can elicit release of PGI . Kinetic
2
as the leukotrienes. Eicosanoids are autocoids, an important group of studies revealed two distinct patterns of PGI production: (1) rapid
2
transient, physiologically active endogenous substances, that act within release, independent of new COX-1 mRNA or protein synthesis, and
the immediate environment of the cell, where they promote or inhibit a (2) slower production reflecting increased COX-2 expression.
biologic function. These autacoids have a very short life span and may In the case of rapid stimulation of PGI production, as induced
24
2
act within a few seconds, a phenomenon that is clinically important but by thrombin, histamine, bradykinin, and ionophore, the response pla-
difficult to study experimentally. teaus at 10 minutes. These agonists activate phospholipase C which
29
In 1975, Hamberg and colleagues discovered that a new eicosanoid, generates inositol trisphosphate (IP ) and diacylglycerol (DAG). The
3
PGI , was derived from arachidonic acid in endothelial cells. Soon released IP induces an elevation of intracellular calcium, which translo-
25
3
2
thereafter, Moncada realized that the effects of PGI opposed those of cates phospholipase A to the outer portion of the nuclear envelope and
2
Figure 115–3. Adherent activated platelets induce an
inflammatory response in endothelial cells. Platelet adhesion
involving α β induces exposure of P-selectin (CD62P) and
IIb 3
release of platelet CD40 ligand (CD40L) and interleukin (IL)-1β
which then stimulate endothelial cells to respond with an
inflammatory reaction that supports prothrombotic and
proatherogenic alterations in the endothelium. IL-8 and MCP-1
(monocyte chemoattractant protein-1) are the principal che-
moattractants for neutrophils and monocytes. ICAM, intercel-
lular adhesion molecule; MMP, matrix metalloproteinase; u-PA,
urokinase plasminogen activator; uPAR, urokinase plasmino-
gen activator receptor; VCAM, vascular cell adhesion mole-
cule. (Adapted with permission from Gawaz M, Langer H, May AE:
Platelets in inflammation and atherogenesis. J Clin Invest 11(12):
3378–3384, 2005.)

Kaushansky_chapter 115_p1967-1984.indd 1969 9/18/15 10:08 AM