Page 1890 - Williams Hematology ( PDFDrive )

1864 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1865

been extensively study without firm conclusions, although there is some N-terminal β-propeller region of α and the βA (I-like) domain of inte-
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suggestion that they may be associated with cardiovascular risk. 983,989–992 grin β , lies near the legs of the integrin α and β subunits, and (2)
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3
993
Integrin α β is probably linked to the membrane skeleton. Its the RGD peptide binds to the headpiece with the Arg (R) making con-
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ligand specificity appears to be determined by the cell on which it is tact with integrin α and the Asp (D) making contact with the MIDAS
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expressed, since on endothelial cells it functions as a laminin recep- domain in β . Current evidence suggests that the bent conformation is
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tor as well as a collagen receptor. 994,995 Engagement of integrin α β is the inactive one and that activation results in extension of the head-
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capable of initiating platelet protein synthesis. Integrin α β has been piece and pivoting between the integrin β βA and hybrid domains in
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3
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implicated in megakaryocyte development and platelet formation. In association with leg separation. 827,843,1007,1009 Integrin α β can mediate
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particular, loss of activated integrin α β receptors on the surface of adhesion to vitronectin, but only in the presence of magnesium or man-
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megakaryocytes, as a result of interacting with collagen, has been impli- ganese, not calcium. 1011 It can also mediate interactions with fibrinogen,
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cated in the transition from the marrow to the peripheral circulation, VWF, prothrombin, and thrombospondin. 389,1012–1015 Platelet stimulation
and conditional targeting of megakaryocyte and platelet integrin α β in can activate integrin α β , analogous to activation of integrins α β
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IIb 3
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mice is associated with reduced MPV. 996 and α β . Activated integrin α β may uniquely mediate adhesion to
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osteopontin, a protein found in high concentrations in atherosclerotic
Integrin α β (Also Termed GPIc*/IIa, Fibronectin Receptor, plaque. 1016 The receptor’s role in platelet physiology is not defined, but
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VLA-5 and CD49e/CD29) it may contribute to the development of platelet coagulant activity. 1017
Integrin α β is a receptor that is expressed on a wide variety of differ- The integrin α β receptor is also present on endothelial cells, 822,1013
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ent cells and mediates adhesion to fibronectin. 804,819,820 It is important for osteoclasts, 1018 smooth muscle cells and other cells; it has been impli-
interactions with extracellular matrix, and data from cells other than cated in bone resorption, 1019–1021 endothelial–matrix interactions, 822,1013
platelets indicate a role for this receptor in developmental biology and lymphoid cell apoptosis, 1022 neovascularization, 1023 tumor angiogen-
metastasis formation. The RGD sequence in fibronectin is crucial for esis, 1023–1025 intimal hyperplasia after vascular injury, 1026–1028 sickle
cell adhesion, but other regions in fibronectin probably also contribute. cell disease, 1029–1031 focal segmental glomerulosclerosis 1032,1033 and
RGD-containing peptides can inhibit cell adhesion mediated by integ- scleroderma. 1034
rin α β . As with other integrin receptors, adhesion depends on the pres- The presence or absence of integrin α β on the platelets of
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ence of divalent cations. Integrin α β is competent to mediate adhesion patients with Glanzmann thrombasthenia can help localize the abnor-
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of resting platelets to fibronectin, 997,998 but its affinity may be modulated mality to either integrin α (if integrin α β is present in normal or
IIb
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999
by activation. The biologic role of this receptor on platelets is not clear. increased amounts) or integrin β (if integrin α β is reduced or absent)
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Although it may be involved in hemostasis and/or thrombosis, it is also (Chap. 121).
possible that its function is primarily related to megakaryocyte binding
to marrow matrix and proplatelet formation. 1000 Integrin α β is not the LEUCINE-RICH REPEAT GLYCOPROTEIN
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only fibronectin receptor on platelets, since with appropriate activation,
integrin α β can also bind fibronectin. 804,1001 RECEPTORS
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GPIb/GPIX/V (CD42)
Integrin α β (Also Termed GPIc/IIa, Laminin Receptor, VLA-6 GPIb is composed of GPIbα (CD42b) (610 amino acids) disulfide-
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and CD49f/CD29) bonded to two GPIbβ subunits (CD42c) (122 amino acids). 801,1035–1043
Platelet adhesion to select laminins, which are variably found in base- GPIb appears to exist on the surface of platelets in a 1:1 complex with
ment membranes and extracellular matrix, can be mediated by integ- GPIX (160 amino acids) and a 2:1 complex with GPV (Fig. 112–13). The
rin α β . 804,1002–1004 Because VWF can bind to some laminins, GPIb can GPIbα gene is on the short arm of chromosome 17 and the GPIbβ gene
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also contribute to platelet adhesion to laminin. 1002 This adhesion is best is on the long arm of chromosome 22. The GPIX gene is on the long arm
demonstrated with magnesium and manganese; calcium does not sup- of chromosome 3. 1044–1046 GPIX is required for efficient surface expres-
port adhesion. This receptor is competent on resting platelets, but its sion of GPIb, 1047 but beyond that, its function is unknown. GPIb/IX is
role in platelet physiology is not clear. Mice deficient in integrin α β do expressed on megakaryocytes and platelets; there is controversy as to
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not bleed pathologically but are protected against thrombosis. 1002 The whether GPIb/IX is expressed on endothelial cells, either constitutively
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integrin appears to be able to signal in platelets via PI3 kinase to induce or after cytokine activation. The promoters for GPIb/IX lack TATA or
morphological changes. 1005 An approximate Mr 67,000 laminin receptor CAAT boxes, but contain binding sites for the GATA and ETS families
has also been identified on platelets; this receptor is present on other of transcription factors, which, along with the expression of the cofac-
cells as well. 1006 tor FOG (friend of GATA-1), may account for the limited expression of
GPIb/IX. 1048–1056
Integrin α β (Also Termed Vitronectin Receptor and CD51/ A genetic polymorphism in GPIbα affects the number of repeating
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CD61) 13-amino-acid units (1, 2, 3, or 4) and produces changes in the molecu-
Integrin α β receptor shares the same β subunit as integrin α β3 lar weight of GPIbα. 1057 The 2 repeat variant is most common, but there
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IIb
(GPIIb/IIIa) (see Fig. 112–11). 804,855,1007–1009 The integrin α and α sub- is considerable ethnic variation in the frequency of the different num-
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IIb
units display 36 percent sequence identity. 1010 Integrin α β differs dra- bers of repeats. This molecular weight polymorphism has been linked
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matically, however, from integrin α β in its platelet surface density, to the Sib and Ko alloantigens, which have been localized to a T→M
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because there are only approximately 50 to 100 integrin α β receptors variation at amino acid 145 of GPIbα, with M associated with either
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984
per platelet. 1011 The crystal structure of the external domains of integ- 3 or 4 repeats and T associated with either 1 or 2 repeats. Some, but
rin α β alone and in complex with a peptide containing the RGD cell not all reports suggest an association between the alleles with the larger
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recognition sequence found in a number of ligands have been solved number of repeats and vascular disease. 983,991,1058,1059 Two other GPIbα
at high resolution. 844,845 Such RGD peptides inhibit ligand binding to polymorphisms have been described: (1) C or T at position –5 from
integrin α β . The most important findings were: (1) the receptor adopts the ATG start codon (RS system), and (2) a nucleotide dimorphism at
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a bent conformation in which the globular headpiece composed of the the third bases of the codon for Arg 358. 1038,1060,1061 A C at position –5 is
Kaushansky_chapter 112_p1829-1914.indd 1865 17/09/15 3:29 pm