Page 1899 - Williams Hematology ( PDFDrive )

1874 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1875

binding PPARγ. Both PPARβ/δ and PPARγ are present in platelets. AGONIST-INDUCED PLATELET ACTIVATION
PPARγ agonists decrease thrombin-induced platelet aggregation and Many platelet agonists initiate platelet activation by binding to seven-
release of ATP, TX, and CD40L. 1384 Thus, PPARγ appears to downreg- transmembrane heterotrimeric G-protein–coupled receptors (see
ulate platelet activation. Activated platelets release PPARγ complexed Fig. 112–15). 1394 When such receptors are activated, the Gα subunit
with the retinoid X receptor. 1385 Treatment with select thiazolidinedi- exchanges GDP for GTP and dissociates from the β/γ complex. The
ones has been associated with reductions in markers of platelet activa- free Gα subunit, and in some cases, the β/γ complex can activate some
tion, including aggregation and P-selectin expression. PPARβ ligands relatively common downstream pathways and initiate positive feed-
synergize with NO to inhibit platelet function. 1386,1387 The antiplatelet back loops. Activation of these pathways is usually intertwined. One
effects of the calcium channel blocker nifedipine may be mediated common pathway involves the activation of one or more isozymes of
through PPAR receptors. 348
PLC, leading to phosphoinositide hydrolysis. Three classes of PLC (β,
γ, and δ), have been described, and multiple isozymes exist within each
Matrix Metalloproteinases class. 1395 The best-studied PLCs in platelets include PLCβ and PLCγ .
Platelets contain a number of MMPs, as well as MMP activators and PLCβ is often activated downstream of the seven-transmembrane,
2
inhibitors. 1388,1389 MMP-1 can be activated by collagen and, in turn, G-protein–coupled, receptor family, whereas PLCγ can be activated
cleave PAR-1 at a site two amino acids N-terminal to the site of thrombin by phosphorylation on tyrosine, which is a downstream signal from
2
cleavage. 1390 This cleavage, like thrombin’s, activates PAR-1 by activating other types of agonist receptors. PLC of either type hydrolyzes phos-
a tethered ligand. Thus, MMP-1 can augment collagen-induced platelet pholipids between the glycerol backbone and the phosphate moiety; the
activation mediated by GPVI and integrin α β . MMP-2 cleavage has PLCβ class is relatively specific for phosphoinositides, whereas PLCγ
2 1
been implicated in enhancing platelet aggregation via cleavage of talin can cleave other types of phospholipids as well. The hydrolysis of one
and activation of integrin α β . 1389 It exists in an inactive form in resting particular phosphoinositide, PI 4,5-bisphosphate (PIP ), by either class
IIb 3
platelets and it is cleaved into its active form when platelets are activated, of PLC is critical in platelet function, since it results in the formation of
2
probably by platelet-type von Willebrand disease (MT1-MMP). 1391 It two important products, IP and DAG. IP binds to specific receptors on
then moves to the surface via binding to integrin α β and may then the DTS/sarcoplasmic reticulum, causing a release of intracellular Ca .
3
3
IIb 3
2+
go on to cleave CD40 ligand. 1339 MMP-2 is released into the coronary Increases in intracellular Ca are important for activation of a number
2+
circulation of patients with acute coronary syndromes. 1392 ADAM-17 of signaling enzymes and proteins involved in cytoskeletal reorganiza-
(TACE) is important in the cleavage of GPIb and the release glyco- tion. Increases in calcium are also important in granule fusion and the
calicin. 1076 MMP-9, which is increased in plasma in models of sepsis, can release reaction. DAG binds to PKC and participates in its conversion
also cleave platelet CD40L. 1393 Other related proteins in platelets include to an active enzyme. For many agonists, activation of one or more of the
MMP-9 and -14, ADAM-10, and tissue inhibitor of metalloproteinase multiple isozymes of PKC is an obligatory step in the conversion of inte-
(TIMP)- 1, -2, and -3. Platelets also contain ADAMTS-13, which cleaves grin α β to a high affinity fibrinogen receptor and subsequent platelet
VWF, thus controlling hemostasis and thrombosis (Chap. 126). IIb 3
aggregation. 918,1396,1397 One consequence of PKC activation is to cause
the release of ADP from dense granules. Released ADP acts at its own
SIGNALING PATHWAYS IN PLATELETS seven-transmembrane G-protein–coupled receptor(s) to potentiate the
action of numerous agonists. The precise mechanism(s) by which PKC
OVERVIEW causes integrin α β activation, however, remains unclear.
IIb 3
Activation of a number of receptors also leads to the activation
Platelets generally circulate in a quiescent state, but are poised to be of PLA , which releases arachidonic acid from membrane lipid stores.
2
activated in response to a variety of agonists that become available at Arachidonic acid is rapidly converted to prostaglandin (PG) products,
sites of vascular injury or ruptured atherosclerotic plaques. Agonists PGH and TXA , which are themselves potent activators of platelet
2
differ in their intrinsic ability to produce these phenomena, and added aggregation. 2
complexity derives from differences in dose responses to each agonist
and the synergistic effects of agonists used in combination. Agonists are Adenosine Diphosphate: P2Y , P2Y , P2X
1
1
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diverse and include small and large soluble molecules, enzymes, and Platelets express receptors for both ADP and ATP. Both nucleotides
immobilized adhesive glycoproteins. They can be classified as either are present in platelet dense granules and are secreted when platelets
“strong” or “weak,” depending on whether full activation, including are activated by adequate concentrations of most, if not all, agonists.
the release reaction, can be initiated without the augmenting effect of Another source of these nucleotides is the red blood cell (RBC); dam-
platelet aggregation itself. Low doses of strong agonists behave like weak aged RBCs or those subjected to high shear stress, may release ADP
agonists. Most agonists are released, synthesized, or formed at the site and ATP, increasing their local concentrations. ADP is an especially
of vascular injury, and this undoubtedly serves to localize the response. important physiologic agonist, not only because it can induce plate-
Agonists bind to receptors of two general categories: seven- let aggregation independent of other agonists, but because secreted
transmembrane G-protein–coupled receptors and receptors that can ADP contributes significantly to the full aggregation response induced
initiate phosphorylation of target proteins (Fig. 112–15). In both cases, by many other agonists. This has been convincingly demonstrated in
a sequence of signaling events ultimately leads to platelet activation. experimental systems in which secreted ADP is rapidly degraded or
Physiologic responses of platelets to agonists lead to the activation of inhibited. Moreover, submaximal concentrations of ADP synergize
the integrin α β receptor to a high-affinity ligand binding state and with other agonists, and this has been best studied with epinephrine.
IIb 3
subsequent platelet aggregation. Moreover, binding of ligands to plate- ADP induces or contributes to a variety of responses in platelets: shape
lets and platelet aggregation itself further propagates signals that are change, granule release, TXA production, activation of integrin α β ,
IIb 3
2
required for stabilization of the platelet aggregates and clot retraction. and platelet aggregation. 1398,1399 Recent pharmacologic and cloning and
In this section, the major agonists, receptors, and signaling pathways sequencing studies suggest that ADP exerts its full effect on platelets
involved in early stages of platelet activation that lead to shape change, through at least two different receptors. These receptors, P2Y and
1
granule secretion, and platelet aggregation, as well as postaggregation P2Y , are G-protein–coupled, and are responsible for most of the phys-
12
signaling events are described. iologic effects of ADP. 1400

Kaushansky_chapter 112_p1829-1914.indd 1874 17/09/15 3:30 pm