Page 2086 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 123 The Blood Vessel Wall 1855

TABLE Endothelial Cell Activation a adhesion to endothelium, sickle RBC binding to adherent leukocytes
294
123.1 has been proposed as a mechanism for sickle cell vascular occlusion.
As with leukocyte adhesion to endothelium in inflammatory and
Agonist Response immune disease, drugs targeting sickle RBC adhesive interactions
Thrombin Secretion of vWF, P-selectin, TFPI, and PDGF with endothelial cells or leukocytes may prove useful in preventing
Synthesis of PAF, IL-8, IL-6, and E-selectin or treating vasoocclusive crises.
IL-1β, TNF-α, LPS Synthesis of adhesion molecules (ICAM-1,
VCAM-1, E-selectin), chemokines (IL-8, Endothelial Cell Activation and Dysfunction
MCP-1), cytokines (IL-6, CD40), procoagulant
proteins (TF, PAI-1, t-PA, u-PA), and Although once viewed as a passive barrier between blood and tissue,
cytoprotective molecules (A1, IAP) the endothelium now is evident to be a dynamic and heterogeneous
Downregulation of anticoagulant proteins (TM)
organ that responds to diverse stimuli, ranging from coagulation
Reduced/disturbed Increased expression of proinflammatory genes proteins and cytokines to hemodynamic forces and growth factors.
shear stress (e.g., VCAM-1, ICAM-1, MCP-1) Activation of endothelial cells induces a complex proinflammatory
VEGF Decreased eNOS activity and prothrombotic phenotype as well as expression of certain cyto-
295,296
Increased expression of cytoprotective genes protective genes (see Table 123.1). 297 Multiple transcription
(A1, MnSOD), Ang2, COX-2 factors, particularly nuclear factor-κB and early growth response
295
298
1, regulate these responses. Endothelial activation undoubtedly
a Selected agonists and responses. Many other stimuli (e.g., lipoproteins,
hypoxia, microbes, and microbial products) have been reported to upregulate is an important event in host defense and repair, but it also may
or downregulate various endothelial responses. contribute to the pathogenesis of diverse diseases, ranging from
299
Ang, Angiopoietin; A1, Bcl-2 homologue; COX-2, cyclooxygenase 2; sepsis to atherosclerosis. 300
eNOS, endothelial nitric oxide synthase; IAP, inhibitor of apoptosis protein; Endothelial dysfunction is characterized by a reduction in the
ICAM, intercellular adhesion molecule; IL, interleukin; LPS, lipopolysaccharide;
MCP, monocyte chemoattractant protein; MnSOD, manganese superoxide bioavailability of vasodilators, particularly NO, leading to impair-
dismutase; PAF, platelet-activating factor; PAI, plasminogen activator inhibitor; ment of endothelium-dependent vasodilation, or by an increase in
PDGF, platelet-derived growth factor; TF, tissue factor; TFPI, tissue factor endothelium-derived contracting factors. Endothelial dysfunction
301
pathway inhibitor; TM, thrombomodulin; TNF, tumor necrosis factor; is prominent in atherosclerosis but also has been described in diabetes,
t-PA, tissue plasminogen activator; u-PA, urokinase-type plasminogen activator;
VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth preeclampsia, hypertension, uremia, and other diseases. In a broader
factor; vWF, von Willebrand factor. sense, endothelial dysfunction encompasses proinflammatory and
procoagulant changes as well as apoptotic cell death. 227,302,303
A number of noninvasive approaches for assessing endothelial
function in vascular diseases have been developed. Endothelial
proteins and the endothelial cell receptors ICAM-1, αVβ3 integrin, vasodilatory responses can be evaluated by high-resolution ultrasound
283
and GPIbα. Platelet adhesion to intact endothelium via these measurement of flow-mediated vasodilation or by plethysmography
304
various pathways may contribute to thrombus formation in the cir- of changes in forearm blood flow during reactive hyperemia.
culation and may provide a link between thrombosis and inflamma- Endothelial activation can be assessed in plasma by circulating
284
tion in diseases such as atherosclerosis. Platelet–endothelial markers such as soluble endothelial adhesion molecules (e.g.,
interactions also may contribute to the pathogenesis of thrombotic sVCAM-1, sICAM-1, sE-selectin) and endothelial coagulation pro-
305
thrombocytopenic purpura. Normally, ultra-large vWF remains teins (e.g., vWF and thrombomodulin) or endothelial micropar-
306
attached to endothelium via P-selectin until it is cleaved by the ticles. Circulating endothelial cells reflect significant vascular
plasma metalloproteinase a disintegrin and metalloproteinase with damage or cell death. 307
thrombospondin (ADAMTS-13). Failure of this mechanism in
thrombotic thrombocytopenic purpura because of a deficiency of
ADAMTS-13 may lead to spontaneous platelet adhesion to endothe- SUGGESTED READINGS
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