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PLATELET: 2 receptors for initial platelet adhesion
and activation in flowing blood
N-terminal GP1α: major binding region for:
vWF
leukocyte integrin aM2 (Mac-1)
-thrombin
P-selectin (activated endotelium and platelet)
GP1b-IX-V
2 GP1α
2 GP1
2 GPIX
1 GPV
GPVI
-Immunoglobulin superfamily
-2 extracellular immunoglobulin-like domain
-Binding collagen
Le piastrine inattive si presentano come piccoli frammenti discoidali.
Attivate presentano una superficie irregolare, con protrusioni piriformi.
Platelets
Platelets are blood cell fragments that originate from the cytoplasm of
megakaryocytes in the bone marrow and circulate in blood to play a
major role in the hemostatic process and in thrombus formation after
an endothelial injury.
Recent studies have provided insight into platelet functions in
inflammation and atherosclerosis. A range of molecules, present on the
platelet surface and/or stored in platelet granules, contributes to the
cross-talk of platelets with other cells,
Following adhesion, rapid signal transduction leads
to platelet activation, cytoskeletal changes associated with
shape change, spreading
- Secretion
- Inside–out activation of integrins that support adhesion and
aggregation. The major platelet integrin, aIIbh3 (GPIIb–IIIa),
binds vWF or fibrinogen to mediate platelet aggregation under
shear conditions
-Integrin aIIb3 (GPIIb–IIIa)
-binds vWF&fibrinogen
GP1b-IX-V
GPVI
Granules
Secretion (most of the substances that are contained within the granules are
synthesized in megakaryocytes, but it is possible that some of them are endocytosed
from the blood plasma)
- vWF
- ADP (enforces activation-aggregation)
-PDGF (is the major growth factor in platelets stimulating vascular smooth muscle cell
migration and proliferation associated with intimalhyperplasia. Also, PDGF is
chemotactic and activates monocytes. Therefore, PDGF has long been speculated to be
an important participant in the development of atherosclerosis.
Insertion:
- P-selectin
vWF&ADP
Integrin GPIIb–
IIIa
P2Y1-P2Y12
Granules
P2Y1, Gq, IP3, Ca2+
P-selectin
PDGF
P2Y12, adenyl ciclase inhibition
(A) Circulating platelets (a) interact with activated endothe
Cells (b) or subendothelial matrix (c) to form mural thromb
providing a substrate for adhesion of leukocytes (e) which
also adhere to activated endothelium (f) prior to
extravasation through the vessel wall (g). (B) Vascular
cell adhesion receptors: adhesive interactions in the
vasculature [(A), a–g] are mediated by specific receptors
on platelets, leukocytes, and/or endothelial cells, and
their ligands in plasma or subendothelial matrix, such as
fibrinogen, von Willebrand factor, or collagen. The
interaction of platelet GPIba (the major ligand-binding
subunit of GPIb-IX–V) or GPVI with von Willebrand factor
or collagen, respectively, initiates activation of the
integrin, aIIbh3, that binds von Willebrand factor or
fibrinogen and mediates platelet aggregation. GPIba can
also mediate platelet–endothelial cell adhesion by binding
to P-selectin, or P-selectin-bound von Willebrand
factor. GPIba can mediate platelet–leukocyte adhesion
by binding to the leukocyte integrin, aMh2 (Mac-1). The
leukocyte receptors PSGL-1 and aMh2 are involved in
leukocyte adhesion to endothelium by binding P-selectin
or ICAM-1, respectively, on endothelial cells, or by
binding to P-selectin or GPIba, respectively, on adhered
and activated platelets. This network of
receptor–counterreceptor or ligand interactions provides
Intricate regulation of platelet–leukocyte–endothelial cell
crosstalk.
Platelet Microparticles
Platelet microparticles, released from activated platelets, contain most of the
platelet adhesive molecules and proinflammatory factors, and cause a variety
of inflammatory reactions, as do activated platelets. The role of activated
platelets in the development of atherosclerosis may be partially attributed to
platelet microparticles.
SELECTIN
- The selectins (P-, E- and L-selectin) are cell-surface glycoproteins, able to bind carbohydrates
(selectin are lectins). Both selectin and selectin ligand are glycoprotein. L-selectin is
expressed on granulocytes and monocytes and on most lymphocytes. P-selectin is stored in αgranules of platelets and inWeibel–Palade bodies of endothelial cells, and is translocated to the
cell surface of activated endothelial cells and platelets.
- Only P-selectin glycoprotein ligand 1 (PSGL-1) has been extensively characterized. In addition
to being responsible for 90% of P-selectin binding, PSGL-1 is also the most important L-selectin
ligand in inflammatory settings. PSGL-1 can also bind to E-selectin, but is not the major Eselectin ligand, which remains to be discovered.
- Activated platelet and endothelial cells have both selectins and PSGL-1, whereas leucocytes
have only PSGL-1.
- Monocytes express functional PSGL-1 and use selectins to leave the vascular system. The
selectins participate in the capture, rolling and slow rolling of leucocytes
Platelet P-selectin is required for efficient interaction with monocytes and endothelial cells.
- Inhibition of P-selectins (by antibody, inhibitors or "false" PSGL-1 may be of therapeutical use)
The role of selectins in inflammation and disease (TRENDS in Molecular Medicine 2003)
The selectins are cell-surface glycoproteins, able to bind carbohydrates (i.e., lectins)
There are 3 types of selectin: E-, L- and P-selectin. L-selectin is expressed on all granulocytes
and monocytes and on most lymphocytes. P-selectin is stored in α-granules of platelets and
inWeibel–Palade bodies of endothelial cells, and is translocated to the cell surface of activated
endothelial cells and platelets. E-selectin is not expressed under baseline conditions, except in
skin microvessels, but is rapidly induced by inflammatory cytokines.
Fig. 1. Selectin structure. (a) Selectins are composed of an N-terminal lectin domain
(lime green), which binds sugars, an epidermal growth factor (EGF) domain (dark
green), two (L-selectin), six (E-selectin) or nine (P-selectin) consensus repeats with
homology to complement regulatory (CR) proteins (yellow), a transmembrane
domain (red) and a cytoplasmic domain (purple).
There are many candidate ligands for selectins, but only P-selectin glycoprotein ligand 1 (PSGLhas been extensively characterized (Fig. 2). L-selectin ligands have been identified in high
endothelial venules of secondary lymphatic organs
Ligando
Fig. 2. Structure of PSGL-1 homodimer.
N-terminal tyrosine sulfates (purple) are followed by a long glycoprotein backbone (lime
green) with many O-linked carbohydrates (dark green) and some N-linked carbohydrates
(yellow). A functionally important O-glycan is indicated. A stabilizing disulfide bond (S–S)
(vertical orange line) is located near the plasma membrane.
In most organs, leukocyte recruitment proceeds in a cascade-like fashion from capture to rolling
to a systematic decrease of rolling velocity to firm adhesion and transmigration. The selectins
participate in the capture, rolling and slow rolling steps.
Selectin-dependent platelet functions
Activated platelets express P-selectin, which binds PSGL-1 on leukocytes and monocytes. This
interaction is responsible for the recruitment of inflammatory leukocytes to thrombi, where they
are thought to help organize and resolve the thrombus, An additional function of platelet Pselectin is in the recruitment of monocyte-derived microparticles, which are a rich source of the
blood-clotting element ‘tissue factor’, to the forming thrombus (Fig. 3). Furthermore, platelet Pselectin is required for efficient interaction with monocytes and endothelial cells, in the context of
atherosclerotic lesions. Activated platelets deposit proinflammatory chemokines on the surface of
endothelial cells and monocytes and accelerate atherosclerosis; blockade or elimination of
platelet P-selectin function reduces atherosclerosis in mouse models. It appears likely that some
of the beneficial preventative effects of drugs such as aspirin and clopidogrel are mediated by a
reduction in platelet–leukocyte and platelet–endothelial interactions.
Selectins are crucial for the innate immune response, as demonstrated in
selectin-deficient and selectin-ligand deficient patients and in mouse
models. Disease treatment using selectin inhibition showsappears to be
promising. However, chronic selectin inhibition will probably produce
unfavorable consequences by suppressing the innate immune system.
The effects of transient selectin inhibition in well controlled clinical
settings, such as organ transplantation, or balloon angioplasty with or
without stent placement, have not yet been sufficiently explored.