Page 1868 - Williams Hematology ( PDFDrive )

1842 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1843

cytoskeletal and contractile elements. 301,302 It is also possible that GPIb/ biologic phenomena including vasospasm, platelet coagulant activity,
IX contributes to clot retraction by virtue of the binding of GPIbα to the and liver regeneration. 315
thrombin and/or VWF bound to the fibrin. 303,304 Thus, while integrin The membrane of dense granules contains glycoproteins that are
α β is required for clot retraction, the process is not a simple reflection also found on the plasma membrane and the membranes of α granules
IIb 3
of fibrinogen binding to integrin α β . and lysosomes, including CD36, LAMP-2, CD63, P-selectin, α β , and
IIb 3
IIb 3
GPIb/IX. Abnormalities of eight different genes have been implicated
PLATELET SECRETORY MACHINERY in the Hermansky Pudlak syndrome (HPS) (Chap. 121), an autosomal
AND SECRETION disorder characterized by a deficiency of dense bodies, and so these
genes are presumed to participate in dense body formation. As with lys-
osomes, dense bodies are thought to derive from endosomes, via differ-
Platelets possess secretory granules and mechanisms for cargo release
to amplify responses to stimuli and influence the surrounding environ- ent types of multivesicular bodies (MVBs). The eight genes associated
ment. Platelet granule structures include α- and dense granules, lys- with HPS are thought to affect sorting and/or trafficking of membrane
osomes, and peroxisomes. structures through participation in protein complexes that mediate
these phenomena. 316,317 These complexes include three biogenesis of lys-
osome-related organelles complexes (BLOCs) and the activator protein
SECRETARY ORGANELLES 3 (AP3) complex. Similarly, the product of the LYST gene, which is
305
Lysosomes abnormal in some patients with Chediak-Higashi syndrome (who also
Lysosomes are produced from the endosomal membrane system have abnormal dense bodies), has been proposed to associate with the
318
through a complex mechanism involving membrane and protein sort- dense granule membrane (Chap. 121). The LYST gene product may
ing and trafficking. Platelets lysosomes contain acid hydrolases typi- associate with the AP3 complex. 305
305
cal of these organelles (e.g., β-glucuronidase, cathepsins, aryl sulfatase, The abnormalities of in vitro platelet function in patients
β-hexosaminidase, β-galactosidase, endoglucosidase [heparitinase], with HPS suggest that released dense granule contents contrib-
β-glycerophosphatase, elastase, and collagenase). With activation, ute to platelet activation through a positive feedback mechanism.
197
platelets secrete some of these enzymes; however, lysosomal contents are Release of ADP, which is a potent platelet activator, and serotonin, a
more slowly and less completely released than are those from α granules weaker agonist (see section “Signaling Pathways in Platelets” below),
and dense bodies. 306–308 Thus, stronger agonists are required to induce probably account for most of the positive feedback effects on
lysosomal enzyme release than release from the other granules, and platelet aggregation. ATP is a partial antagonist of ADP-induced acti-
their appearance on the platelet plasma membrane serves as a marker vation, but as ATP is rapidly catabolized to ADP in plasma (T =
1/2
of high-level platelet activation. 309,310 The elastase and collagenase activi- 1.5 min), and ADP is rapidly catabolized to AMP (T = 4 min) and
1/2
319
197
ties released from platelet lysosomes may contribute to vascular damage then to adenosine, a platelet inhibitor, it is difficult to predict the
at sites of platelet thrombus formation. The heparitinase may be able overall effect of ATP release. Adding to the complexity in vivo is the
311
to cleave heparin-like molecules from the surface of endothelial cells, presence of an ecto-ADPase (CD39; ecto-ADPase) present on endothe-
and the resulting soluble molecules appear to inhibit growth of smooth lial and lymphoid cells, which can metabolize ATP and ADP to AMP
74
muscle cells. 312 and thus probably limits the amount of ADP present. ATP released
from platelets may also serve as a high energy phosphate source for
Dense Bodies platelet ecto-protein kinases, which can phosphorylate several proteins,
Platelets contain approximately three to eight electron-dense organ- including CD36 (GPIV). 320–322
elles, 20 to 30 nm in diameter (see Fig. 112–2). 76,262 The intrinsic elec-
tron density of dense bodies when viewed as unstained whole mounts α Granules
derives from their high content of calcium 76,197 ; the granules are also An important platelet function is storage and release of a variety of
dense when viewed by transmission electron microscopy because they bioactive substances packaged in α granules. α Granules are the most
are highly osmophilic. Dense granules contain high concentrations abundant granule type of platelets, numbering approximately 50 to 80
262
of serotonin, which is taken up from plasma by a plasma membrane per platelet. 323,324 They are approximately 200 nm in diameter on cross-
carrier and then trapped in the dense bodies. Trapping of serotonin section and demonstrate internal variation in electron density, often
262
may occur as a result of the lower pH (approximately 6.1) maintained with an eccentric area of accentuated electron density, termed a nucle-
in dense granules as a result of the action of a proton pumping ATPase oid, in which β-thromboglobulin, platelet factor 4 (PF4), and proteo-
325
on the dense-body membrane. ADP and ATP are also highly con- glycans are concentrated (see Fig. 112–2). The more electron-lucent
262
centrated in dense bodies. There is more ADP than ATP in the dense areas contain tubular elements in which VWF, multimerin, and factor
197
76
bodies (ATP to ADP ratio = 2:3), which is the reverse of their relative V are preferentially localized. Proteomic analysis of the releasate of
concentrations in the cytoplasm (ATP to ADP ratio = 8:1). As there is activated human platelets has identified more than 300 proteins, most
little connection between the pools of adenine nucleotides in the cyto- of which are stored within α granules. 326–328 The list of α-granule proteins
plasm and the dense bodies, they have been respectively designated includes adhesive proteins, coagulation factors, protease inhibitors,
as the metabolic and storage pools of adenine nucleotides. Storage chemokines, and angiogenesis regulatory proteins. Some of the most
197
of adenine nucleotides at such a high concentration in dense bodies important proteins present in α granules are described in detail below.
appears to be achieved by stacking the ATP and ADP purine rings verti- Platelets contain distinct subpopulations of α granules that undergo
cally in aggregates that are stabilized by the interactions of calcium ions differential release of α-granule cargo during activation. For exam-
with the polyphosphate groups. 313,314 The planar hydroxyindole rings ple, some α granules contain proangiogenic proteins, such as vascular
of serotonin may also enter these stacks, providing a molecular basis endothelial growth factor (VEGF), whereas others contain antiangio-
329
for the trapping mechanism. Trapping of serotonin must differ from genic factors, such as endostatin (Fig. 112–6). These two subclasses
that of adenine nucleotides, however, because dense granule serotonin of α granules can be differentially induced to undergo degranulation by
exchanges readily with external serotonin. Transport and delivery of exposure of human platelets to agonists specific for either protease-ac-
197
platelet-derived serotonin may play an important role in a variety of tivated receptor (PAR)-1 or PAR-4. Fibrinogen and VWF are localized

Kaushansky_chapter 112_p1829-1914.indd 1843 17/09/15 3:26 pm