Page 1992 - Williams Hematology ( PDFDrive )

1967

CHAPTER 115 VASCULAR FUNCTION IN HEMOSTASIS:

INTRODUCTION
VASCULAR FUNCTION IN The endothelium represents a dynamic interface between flowing blood
HEMOSTASIS and the vessel wall, and produces a variety of factors that regulate blood
fluidity (Fig. 115–1). Endothelial cells are subject to unique shear stress
forces, to soluble factors in the blood, and to signals emanating from
cells in the circulation, vascular wall, and tissues, all of which create
Katherine A. Hajjar, Aaron J. Marcus*, and region-specific phenotypes. In addition to modulating vascular
1–3
William Muller permeability and fragility, the endothelium regulates the fluid state of
blood through its thromboresistant nature, profibrinolytic properties,
and antiinflammatory potential. These activities maintain vascular p
atency. 4
SUMMARY
ENDOTHELIAL CELL HETEROGENEITY
Blood vessels, especially their endothelial lining, play a critical role in the The heterogeneity of endothelial cells is mediated by two mecha-
maintenance of vascular fluidity, arrest of hemorrhage (hemostasis), pre- nisms. First, extracellular biochemical and biomechanical signals
5,6
vention of occlusive vascular phenomena (thrombosis), and regulation of trigger posttranscriptional and/or posttranslational changes that vary
inflammatory cell processes. The endothelium extends to all recesses of the across the vascular tree. Second, certain site-specific properties of the
body and maintains an intimate association with flowing blood and blood endothelium are genetically programmed, and therefore, independent
cells. However, endothelial cell morphologies, gene-expression profiles, of the extracellular milieu. This phenotypic variability serves at least
and functions vary among different vascular beds. For example, in straight two important purposes: (1) It allows endothelial cells to meet the spe-
arterial segments, but not at branch points or curvatures of the arteries cific metabolic needs of the surrounding tissue. For example, the tight
or veins, endothelial cells align themselves in parallel to the direction of junctions of the blood–brain barrier protect neurons from fluctuations
blood flow. Similarly, endothelial cells in post capillary venules are primar- in composition of the aqueous blood supply, whereas the fenestrated
discontinuous endothelium of hepatic sinusoids allows ready access of
ily responsible for mediating adhesion and transmigration of leukocytes, nutrient-rich portal venous blood for the metabolic systems in hepa-
whereas arteriolar endothelium is important for regulation of vasomotor tocytes; and (2) phenotypic variability provides endothelial cells with
tone. Proteomic studies have revealed that endothelial cells have the unique site-specific mechanisms for thriving within many different microen-
capacity to express and elaborate thromboregulatory molecules, which vironments. For example, endothelial cells in the inner medulla of the
can be classified according to their chronologic appearance following vas- kidney must survive the relatively hypoxic and hyperosmolar local envi-
cular injury. Early thromboregulators appear prior to thrombin formation ronment, whereas endothelial cells in the pulmonary capillary bed have
and late thromboregulators arrive after thrombin has formed. This chap- adapted to an oxygen-rich environment.
ter reviews some of the mechanisms by which the vascular wall regulates A rapid endothelial cell response is required for sudden envi-
hemostasis, and discuss their implications for vascular health and disease ronmental perturbations. Translational control mechanisms, which
(Table 115–1). are more immediate than transcriptional changes, provide regulatory
responses for up to 10 percent of genes expressed in endothelial cells.
7
Because of their close association with both flowing blood and solid
tissues, endothelial cells are subject to a broad spectrum of agonistic
and inhibitory external signals that frequently require rapid functional
and phenotypic responses. Clinically, such stimuli are associated with
sepsis, inflammation, ischemia–reperfusion injury, and direct mechan-
ical vascular trauma induced clinically by stents, balloon catheters, and
Acronyms and Abbreviations: APC, activated protein C; Apo, apolipoprotein; graft procedures.
APS, antiphospholipid syndrome; C5a, complement factor 5a; CAM, cell adhesion
molecule; COX, cyclooxygenase; DAG, diacylglycerol; DDAVP, deamino D-arginine
vasopressin; EPCR, endothelial protein C receptor; GMP, guanosine monophosphate; ENDOTHELIAL PRODUCTION OF
IL, interleukin; IP , inositol triphosphate; Lp(a), lipoprotein(a); NFκB, nuclear factor THROMBOREGULATORY MOLECULES
3
kappa B; NO, nitric oxide; NOS, nitric oxide synthase; PAF, platelet-activating fac-
tor; PDGF, platelet-derived growth factor; PECAM, platelet endothelial cell adhe- Thromboregulatory compounds, such as eicosanoids, nitric oxide,
sion molecule; PGI , prostacyclin; PGIS, prostacyclin synthase; PSGL, P-selectin and the ecto-ATP/Dase-1/CD39, control platelet and vascular reac-
2
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glycoprotein ligand; scu-PA, single-chain urokinase-type plasminogen activator; tivity during the early stages of thrombus formation (Table 115–2).
TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor Eicosanoids are hydrocarbon compounds derived from essential fatty
pathway inhibitor; TM, thrombomodulin; TNF, tumor necrosis factor; t-PA, tissue- acids in the diet. The most important endothelial eicosanoid is prostacy-
type plasminogen activator; VWF, von Willebrand factor. clin (PGI ), which blocks platelet reactivity, induces vascular relaxation,
2
and stimulates cytokine production. Nitric oxide (NO) is a naturally
9
occurring gas released from vascular endothelial cells in response to
binding of vasodilators to endothelial cell membrane receptors. Thus,
*Dr. Aaron Marcus died on May 6, 2015 it is a short-lived vasodilator and inhibitor of platelet reactivity. By

Kaushansky_chapter 115_p1967-1984.indd 1967 9/18/15 10:07 AM