Page 1889 - Williams Hematology ( PDFDrive )

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

probably include ligand- and/or cytoskeletal-mediated receptor clus- Integrin α β (Also Termed GPIa/IIa, Collagen Receptor, VLA-2
2 1
tering, are not well understood. 95,835,926,927 After ligands bind to integrin and CD49b/CD29)
α β , “outside-in” signaling through the integrin can occur, resulting in Integrin α β (GPIa/IIa) is widely distributed on different cell types and
IIb 3
2 1
a number of phosphorylation events, changes in the platelet cytoskele- can mediate adhesion to collagen. 19,20,952–957 The integrin α subunit (GPIa)
2
ton, platelet spreading, and even initiation of protein translation. 236,237,928 contains a region of 220 amino acids inserted in the aminoterminal
In addition to fibrinogen, several other proteins can bind to integ- β-propeller region (I domain) that is homologous to similar regions in
rin α β on activated platelets, including VWF, fibronectin, vitronectin, other proteins that are known to interact with collagen, including VWF
IIb 3
thrombospondin, and prothrombin 390,675,929 ; each of these contains an and cartilage matrix protein. This region has a MIDAS and crystallo-
958
RGD sequence in the region implicated in the initial interaction with graphic data of the α I domain in complex with a CRP containing the
2
platelets. There are subtle differences in the binding of each of these lig- type I collagen sequence GFOGER (where O indicates hydroxyproline)
ands, however, with regard to divalent cation preference and competent demonstrated that the glutamic acid in the peptide coordinates Mg
2+
activating agents. The binding of all of these other ligands can also be binding in the MIDAS. 959–961 The integrin α β I domain can assume a
2 1
inhibited by RGD-containing peptides, indicating a common require- variety of conformations, going from inactive (closed), through inter-
ment for the interaction between the RGD sequence in the protein and mediate or low affinity, to active high affinity. 952,962
the RGD-binding site in integrin α β . 930,931 Both integrin α β and GPVI appear to participate in platelet inter-
IIb 3
2 1
Platelet aggregation measured in the aggregometer ex vivo depends actions with collagen. 963–965 Bleeding defects have been described in
upon fibrinogen binding to integrin α β . It is less clear whether fibrin- patients with decreased levels of integrin α β and GPVI, but the pre-
IIb 3
2 1
ogen is the most important ligand supporting platelet aggregation in cise contributions of the decreases in these receptors is uncertain (Chap.
vivo since studies performed in model systems under flowing condi- 121). Although integrin α β is capable of supporting adhesion to col-
2 1
tions indicate that VWF is the major ligand at higher shear rates. Even lagen without exogenous activators, like integrin α β , it appears to be
932
IIb 3
in the aggregometer, VWF can partially substitute for fibrinogen if the able to increase its affinity for ligand in response to inside-out activa-
fibrinogen concentration is very low. In vivo, mice deficient in both tion. 966,967 Potential initiators of integrin α β activation include signaling
933
2 1
VWF and fibrinogen still make platelet thrombi in response to vascular after GPVI interaction with collagen and GPIb-mediated adhesion to
injury. 934–936 Although fibronectin was initially implicated in supporting VWF, perhaps acting via actin polymerization. 959,968–970 Thus, one pos-
the development of such thrombi, mice deficient in fibrinogen, VWF, sible scenario is that following GPIb-mediated adhesion to VWF and
and fibronectin have paradoxically increased platelet aggregation and collagen adhesion and activation mediated by GPVI, integrin α β may
2 1
thrombus formation, suggesting that fibronectin may play an inhibiting promote firm adhesion to collagen, stabilize thrombus growth on col-
role in thrombus formation under certain circumstances. 373 lagen, and promote procoagulant activity. 971,972 In addition, the affinity
Although resting platelets do not bind soluble fibrinogen (or other of integrin α β may also be modulated by alterations in disulfide bonds
2 1
adhesive glycoproteins) to an appreciable extent, they can adhere to since inhibition of platelet PDI and sulfhydryl blocking agents inhibit
fibrinogen immobilized on a surface. 825,937 This activation-independent integrin α β -mediated platelet adhesion to type I collagen and to the
2 1
adhesion may be from alterations in the structure of fibrinogen when it related peptide GFOGER. 883,973 The state of the collagen may also influ-
is immobilized on a surface. 836,938 Alternatively, there may always be a few ence whether integrin α β or GPVI mediates the interaction with col-
2 1
integrin α β receptors that are transiently in the proper conformation lagen, because GPVI appears to mediate adhesion to fibrillar collagen
IIb 3
to bind fibrinogen, and immobilization may result in high local density whereas integrin α β preferentially adheres to collagen that has been
2 1
of fibrinogen and favorable kinetics for adhesion. Finally, it is possible treated with partial protease digestion. 28,974
that even low-affinity fibrinogen interactions with integrin α β are suf- Ligand binding to integrin α β is enhanced in the presence of
IIb 3
2 1
ficient to initiate integrin interactions with the cytoskeleton such that magnesium or manganese and is inhibited by calcium, and thus the
actin-myosin-induced contraction provides the energy required for the conditions in human blood, where calcium concentrations are higher
conformational changes needed to achieve higher affinity binding. 250 than those of magnesium, do not provide optimal cation concentrations
Fibrinogen and/or fibrin have been identified on the surface of for the receptor’s function. Integrin α β can, however, mediate plate-
975
2 1
damaged blood vessels; thus it is possible that integrin α β mediates let adhesion to collagen in heparinized blood 956,975 and inhibitors of inte-
IIb 3
939
platelet adhesion under those circumstances. In contrast, integrin grin α β inhibit thrombus formation in animal models. 976–978 Regions of
2 1
α β on resting platelets does not appear to be able to mediate adhe- collagen type I have been implicated as potential binding sites for inte-
IIb 3
940
sion to VWF or fibronectin ; if platelets are activated, however, inte- grin α β 979 ; the peptide sequence 502 to 516 of collagen type I α chain,
2 1
1
930
grin α β can support adhesion to these glycoproteins. In models of which contains a Gly-Glu-Arg (GER) sequence, may be of particular
IIb 3
platelet accumulation under flowing conditions, α β acts in synergy importance, but other regions of the collagen molecule may also be
980
IIb 3
with GPIb/IX, VWF, and fibrinogen at the apex of thrombi, where shear important. In type III collagen, amino acids 522 to 528 of fragment α
981
forces are greatest. 28,941,942 The integrin α β has also been implicated (III) CB4 contains a binding region for α β . 982 1
IIb 3
2 1
in platelet spreading after adhesion, 227,228,943 and it is necessary for clot Three different alleles for the integrin α gene, which differ at
2
retraction (see above) and the uptake of plasma fibrinogen into platelet nucleotides 807 (T or C) and 1648 (G or A), have been described.
983
α granules. 818,944 The 807 substitution does not affect the amino acid sequence, but the
Less-well-defined roles for integrin α β have been suggested in 1648 substitution causes a change from Glu to Lys, resulting in the Br
b
IIb 3
the binding of plasminogen, calcium transport across the platelet and Br alloantigens (HPA-5a and HPA-5b) (Chap. 137). Allele 1 (T-G)
688
a
membrane, 945–947 IgE binding to platelets leading to parasite cytotoxic- is present in 39 percent of individuals, allele 2 (C-G) in 53 percent, and
948
ity, and interactions with the Borrelia species spirochetes that cause allele 3 (C-A) in 7 percent. 984,985 Individuals with allele 1 have higher
950
949
Lyme disease and hantavirus. Integrin α β also mediates factor integrin α β platelet density than individuals with allele 2, and indi-
IIb 3
2 1
XIIIa binding to platelets, but this is primarily as a result of factor XIII’s viduals with allele 3 have the lowest density; the density of integrin
456
association with fibrinogen. Factor XIIIa and calpain have also been α β correlates with platelet deposition on collagen under flow. The asso-
2 1
implicated in limiting platelet–platelet interactions after activation by ciation of these polymorphisms with cardiovascular disease morbidity
adhesion to collagen. 951 and mortality, including the risk of developing MI 986,987 and stroke, has
988
Kaushansky_chapter 112_p1829-1914.indd 1864 17/09/15 3:29 pm