Page 2085 - Hematology_ Basic Principles and Practice ( PDFDrive )

1854 Part XII Hemostasis and Thrombosis

Flow

Activation Diapedesis
Tethering and rolling Firm adhesion
Selectins
Integrins – IgSF
CD31 JAM-1 Other
SLe x
Leukocyte ESAM PVR CD47 CD99
PSGL-1 L-selectin α 4 β 7 α 4 β 1 α L β 2 α M β 2 α 4 β 7 α 4 β 1 CD99L2

P-selectin E-selectin PNAd Nepmucin MAdCAM-1 VCAM-1 ICAM-2 ICAM-1 MAdCAM-1 VCAM-1
Endothelium
Fig. 123.3 ADHESION CASCADE. Under conditions of flow, leukocytes first tether to endothelial ligands
and then roll along the vessel wall. Tethering is mediated predominantly by interaction of P-selectin and
x
L-selectin with their cognate glycoconjugate ligands. P-selectin binds to SLe and sulfate residues expressed
on PSGL-1. L-selectin binds to an uncharacterized ligand(s) on inflamed endothelium and to sulfated SLe -like
x
moieties on PNAd and MAdCAM-1 and sialomucin nepmucin on high endothelial venules. E-selectin, α 4 β 1
(very late antigen 4 [VLA-4]), and α 4β 7 stabilize rolling initiated by P-selectin and L-selectin. E-selectin rec-
x
ognizes SLe on PSGL-1 and other glycoproteins or glycolipids. After tethering and rolling, leukocyte integrin
receptors are activated, most often by chemoattractants (e.g., chemokines) via G protein–coupled receptors.
After activation, integrin receptors engage endothelial immunoglobulin gene superfamily ligands to promote
firm adhesion. Leukocyte α L β 2 (leukocyte function antigen 1 [LFA-1]) binds to ICAM-1 and ICAM-2, α Mβ 2
(macrophage 1 [Mac-1]) to ICAM-1, α 4β 1 (VLA-4) to VCAM-1, and α 4β 7 to MAdCAM-1. The adherent
leukocyte then migrates across endothelium to interendothelial junctions, where it diapedeses between endo-
thelial cells via leukocyte integrin receptors and their endothelial immunoglobulin gene superfamily ligands
as well as endothelial junctional proteins such as CD31 (PECAM-1), CD99, CD99L2, ESAM, and JAM-1.
ESAM, endothelial cell-selective adhesion molecule; ICAM, intercellular adhesion molecule; IgSF, immuno-
globulin gene superfamily; JAM-1, junctional adhesion molecule 1; MAdCAM, mucosal addressin cell adhesion
molecule; PNAd, peripheral node addressin; PSGL, P-selectin glycoprotein ligand; PVR, poliovirus receptor;
SLe , sialyl Lewis X; VCAM, vascular cell adhesion molecule 1.
x
clinical trials in a variety of diseases. However, results were disap- endothelial denudation or retraction, platelets rapidly adhere to the
pointing overall, with many unsuccessful clinical trials of various exposed subendothelium. As discussed in greater detail in Chapters
adhesion antagonists in multiple disease indications. 274,275 Moreover, 115 and116, at high shear rates this initial adhesion does not require
the report of progressive multifocal leukoencephalopathy, a rare viral platelet activation and involves platelet glycoprotein Ib/V/IX
infection of the CNS, in several patients treated with the α4-integrin (GPIb–V–IX) binding to vWF in the subendothelial matrix and
276
antagonist natalizumab highlights the risks of targeting molecules platelet GPVI binding to collagen in the injured arterial wall. Platelet
that are pivotal in host defense and repair as well as in disease. activation occurs after adhesion, leading to platelet spreading medi-
Nevertheless, the potential of antiadhesion therapy is demonstrated ated by integrin receptors binding to matrix components and
by the approval of two integrin antagonists: efalizumab for treatment aggregation mediated by fibrinogen binding to GPIIb/IIIa (αIIbβ3).
277
of psoriasis and natalizumab for treatment of multiple sclerosis. 278 Evidence indicates that platelets can bind directly to activated
279
280
endothelium in vivo via endothelial P-selectin and PECAM-1 ,
and to roll on venular endothelium via interaction of platelet GPIbα
Platelets and endothelial P-selectin. Platelets have been shown to bind to
281
282
high endothelial venules in vivo via platelet P-selectin. In vitro
Similar to neutrophils, unactivated platelets do not interact with platelets can adhere to intact endothelium via a platelet GPIIb/IIIa-
unperturbed endothelium. After a vascular injury that produces dependent bridging mechanism involving platelet-bound adhesive