Page 1861 - Williams Hematology ( PDFDrive )

1836 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1837

thought to contain the sodium- and calcium-adenosine triphosphatase of these phenomena. Thus, the membrane of the open canalicular sys-
(ATPase) pumps that control the intracellular ionic environment of the tem most likely contributes to the increase in plasma membrane under
platelet. Approximately 60 percent of platelet phospholipids are con- these conditions; the membranes of α granules, dense bodies, and, to a
tained in the plasma membrane. The phospholipids are asymmetrically lesser extent, lysosomes may also contribute, but only if the stimulus is
organized in the plasma membrane; the negatively charged phospholip- sufficient to induce the fusion of these organelles with the plasma mem-
ids are almost exclusively present in the inner leaflet, whereas the others brane (release reaction). Finally, the membrane of the open canalicular
are more evenly distributed. The negatively charged phospholipids, system may serve as a storage site for plasma membrane glycoproteins.
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especially phosphatidylserine, are able to accelerate several steps in the For example, under certain conditions, platelet activation by thrombin
coagulation sequence and so their presence in the inner leaflet of rest- leads to a consistent, selective loss of GPIb/IX from the platelet surface
ing platelets, separated from the plasma coagulation factors, is thought and data from electron microscopy indicate that the GPIb/IX becomes
to be a control mechanism for preventing inappropriate activation of sequestered in the open canalicular system. 63,64,101 Plasmin may produce
the coagulation system. 80,81 During platelet activation induced by select a similar phenomenon. 101,102 Platelet activation leads to an increase in
agonists, the aminophospholipids may become exposed on the plate- surface integrin α β , and although much of this receptor is thought to
IIb 3
let surface or on the surface of microparticles (see “Platelet Coagulant derive from α-granule membranes, at least some may come from inte-
Activity” below). 80–83 grin α β in the membranes of dense bodies and the open canalicular
IIb 3
The phospholipid asymmetry in resting platelets may be main- system. 101,103 Similarly, GPVI, the P2Y ADP receptor, and the TXA
2
1
tained by an ATP-dependent aminophospholipid translocase that receptor, and perhaps other receptors are present in the open canalicular
actively moves phosphatidylserine and phosphatidylethanolamine from system and can be recruited to the platelet surface with activation. 104,105,
the outer to the inner leaflet. 80,84 Interactions of negatively charged phos- Dense Tubular System/Sarcoplasmic Reticulum The dense
pholipids with cytoskeletal or other cytoplasmic elements may also con- tubular system (DTS) is a closed-channel network of residual endoplas-
tribute to the asymmetry. 80,81,85,86 mic reticulum characterized histocytochemically by the presence of per-
Lipid rafts are dynamic, cholesterol- and sphingolipid-rich mem- oxidase activity. 76,106–108 The channels of the DTS are less extensive than
brane microdomains that are important in signaling and intracellular those of the open canalicular system and tend to cluster in regions in
trafficking. In platelets the cholesterol-to-phospholipid molar ratio is close approximation to the open canalicular system. The DTS is anal-
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twofold higher in rafts than in bulk membranes, with sphingomyelin ogous to the sarcoplasmic reticulum of muscle because it can sequester
87
accounting for the majority of total raft lipids. Platelet lipid rafts con- Ca and release it when platelets are activated, leading to shape change,
2+
tain the marker proteins flotillin 1, flotillin 2, stomatin, and the gan- granule centralization, and secretion. 109,110 Calreticulin, a calcium bind-
glioside GM ; the rafts are also notable for being devoid of caveolin. ing protein found in the DTS/sarcoplasmic reticulum, probably helps
1
Other proteins, such as CD36, CD63, CD9, integrin α β , and glucose to sequester ionized calcium. 111,112 Release of Ca from the DTS/sar-
2+
IIb 3
transporter (GLUT)-3, are present in rafts prepared from resting plate- coplasmic reticulum involves the binding of inositol-1,4,5-trisphos-
lets. Upon activation of GPVI, Fc gamma chain, FcγRIIa, and GPIb/ phate (IP ), a messenger molecule formed during signal transduction,
87
3
IX/V partition into the lipid rafts, 88,89 as do c-Src, phosphatidic acid, to IP type II receptors on the DTS/sarcoplasmic reticulum membrane
90
3
2+
and phosphoinositol (PI) 3′-kinase (PI3K) products. 87,91 Factor XI binds (Fig. 112–3). 113,114 Cyclic AMP inhibits Ca release from the DTS/sar-
to extracellularly-oriented lipid rafts and undergoes activation. The coplasmic reticulum, either by enhancing the calcium pumping mecha-
92
115
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calcium entry channel hTRPc1 is associated with lipid rafts in platelets nism or by inhibiting release induced by IP 3 116 NO inhibits Ca uptake
and, upon platelet activation, contributes to calcium entry that is regu- by the DTS/sarcoplasmic reticulum at high concentrations and stimu-
lated by the state of intracellular calcium stores (store-mediated calcium lates uptake at low concentrations by effects on the calcium ATPase(s)
93
entry). The functionally detrimental effects of chilling platelets are SERCA26 and SERCA3. 117,118 Depletion of intracellular calcium stores
thought to be mediated, at least in part, by the temperature-dependent activates store-operated calcium entry (SOCE) into platelets (reviewed
coalescence of platelet lipid rafts. 94 in Ref. 119). The depletion of Ca from the DTS/sarcoplasmic reticulum
2+
Open Canalicular System The surface-connected open canalicu- is sensed by stromal interaction molecule 1 (STIM1), a transmembrane
2+
lar system is an elaborate series of conduits that begin as indentations of protein with a Ca binding motif (EF hand) in the DTS/sarcoplasmic
2+
the plasma membrane and tunnel throughout the interior of the plate- reticulum. 120–122 Loss of Ca binding to STIM1 results in translocation
let. 76,95,96 Tracer studies demonstrate that the open canalicular system is and activation of Orai1, a calcium release activated calcium (CRAC)
contiguous with the exterior of the platelet, even though elements of the channel in the plasma membrane, 123,124 that allows Ca entry into the
2+
open canalicular system may appear as closed vesicles or vacuoles by platelet. Although mice with defects in STIM1 and OraiI have demon-
electron microscopy of sectioned platelets. 76,95–97 strated abnormalities in platelet function, 120–122 humans with mutations
The open canalicular system may serve several functions. It pro- in these proteins have had immune dysfunction, but no overt hemo-
vides a mechanism for entry of external elements into the interior of static or thrombotic abnormalities. 125–127 The human canonical transient
the platelet. It also provides a potential route for the release of granule receptor potential 1 (hTRPC1) has also been implicated in regulating
contents to the outside, eliminating the need for granule fusion with the platelet SOCE, but mice deficient in this protein do not have a defect in
2+
plasma membrane itself. 97,98 This latter function is especially important platelet Ca entry. 128–130
because, under most circumstances, platelet granules appear to move The DTS membrane is also probably a major site of prostaglandin
to the center of the platelet upon platelet activation rather than to the and TX synthesis 109,131 ; in fact, the peroxidase activity used to identify
periphery. 76,95,99 Controversy remains, however, regarding the relative the DTS is an enzymatic component of prostaglandin synthesis. 131,132
frequency with which secretion occurs via the open canalicular system
versus direct fusion with the plasma membrane. 76,95,100 Cytoskeletal Elements
The open canalicular system also represents an extensive internal The discoid shape of the resting platelet is maintained by a well-defined
store of membrane. Both filopodia formation and platelet spreading and highly specialized cytoskeleton. This system of molecular struts and
after adhesion require a dramatic increase in surface plasma membrane girders preserves the shape and integrity of the platelet as it encounters
compared to the plasma membrane of resting platelets, and it is not pos- high shear forces in the circulation. The platelet cytoskeleton is oper-
sible for new membrane to be synthesized during the short time-course ationally defined as proteins that are insoluble in the presence of the

Kaushansky_chapter 112_p1829-1914.indd 1836 17/09/15 3:26 pm