Page 1859 - Williams Hematology ( PDFDrive )

1834 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1835

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ADP and TXA . Alternatively, a platelet may become activated and bind and coagulation factors may concentrate are prothrombogenic. Endo-
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VWF or fibrinogen while still circulating, in which case the platelet- thelial cells can synthesize two potent inhibitors of platelet activation,
ligand complex may bind directly to an activated integrin α β receptor prostacyclin and nitric oxide (Chap. 115). 69–72 Generation of prostacy-
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on the luminal surface. The binding of adhesive ligands to platelet recep- clin at sites of vascular injury or inflammation may provide a mecha-
tors then repeats itself, resulting in the recruitment of additional layers nism to limit platelet accumulation. Nitric oxide, which is synthesized
of platelets, and ultimately the formation of a hemostatic plug. Intravital by endothelial cells, is a potent inhibitor of ex vivo platelet adhesion
videomicroscopy of the mesenteric and cremasteric circulations of mice and aggregation. Endothelial cells and lymphocytes also have CD39, an
after endothelial cell damage demonstrates that, at least in these vascu- ecto-ATP diphosphohydrolase (ecto-ADPase) that can digest ATP and
lar beds, platelet thrombus formation is initially a very dynamic process, ADP to adenosine monophosphate (AMP), and thus limit the effects of
with many platelets depositing but then embolizing. The thrombus released ADP. 73,74 They also have CD73, which can convert AMP into
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grows relatively slowly compared to what its growth would be if all of the the platelet inhibitor adenosine.
platelets that deposited remained attached to the surface. 39–41
The integrin α β receptor occupies a central role in determin- PLATELET MORPHOLOGY AND
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ing the extent of platelet aggregation, in part because it is present at
an extraordinarily high density on the platelet surface (approximately BIOCHEMISTRY
50,000 receptors per platelet, such that receptors are probably less than
20 nm apart). 30,42–45 This permits it to rapidly initiate platelet aggre- MICROSCOPIC APPEARANCE
gation. On the other hand, the receptor is not in its high-affinity lig- On films made from blood anticoagulated with the strong calcium
and-binding state on resting platelets but rather needs to be activated chelating agent ethylenediaminetetraacetic acid (EDTA) and treated
by agonists, including ADP, serotonin, thrombin, collagen, and TXA , with Wright stain, platelets appear as small bluish-gray, oval-to-round
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that are localized to sites of vascular injury. 34,44,46 As a result, platelets can shaped cell fragments with several purple-red granules. The mean diam-
circulate in plasma containing high concentrations of the integrin α β eter of platelets varies in different individuals, ranging from approx-
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ligands fibrinogen and VWF without ongoing platelet thrombus forma- imately 1.5 to 3.0 μm, approximately one-third to one-fourth that of
tion. The agonists that activate the integrin α β receptor are likely to erythrocytes. There is also considerable variability in the size of platelets
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work in combination in vivo. In fact, the mixture of agonists present in a single individual, with occasional platelets in normal blood sam-
is likely to change as the process unfolds, with collagen perhaps more ples having diameters greater than half the diameter of erythrocytes.
important at the beginning, thrombin more important later on, and the Overall, platelet size appears to follow a log normal distribution with an
other agonists in varying mixtures throughout. The platelet activation average volume of approximately 7 fL. When unanticoagulated blood
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effects of multiple agonists may be additive or synergistic, depending on is used to prepare blood films, platelets undergo variable activation and
the mechanism(s) involved. 47,48 spreading, and thus platelet aggregates are commonly seen; platelets
A number of mechanisms stabilize platelet aggregates. These from such specimens may demonstrate three or four very long finger-
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include absence of fibrinogen (presumably limiting fibrin formation), like processes extending out from the body of the platelet (filopodia),
leptin, 49–51 CD40 ligand, growth arrest-specific gene 6 product (Gas6) and some platelets may be devoid of granules.
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and its receptors (Axl, Sky, and Mer), 53–57 Eph kinases and ephrins, fac- Electron microscopy reveals a fuzzy coat (glycocalix) extending 14
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tor XII, plasminogen activator inhibitor-1 and vitronectin, or inhibi- to 20 nm from the platelet surface, which is thought to be composed
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tion of select regions of fibrinogen. 60 of membrane GPs, glycolipids, mucopolysaccharides, and adsorbed
Activated platelets can facilitate thrombin generation by one or plasma proteins (Fig. 112–2). Platelets move in an electric field as if
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more different mechanisms, including recruitment of bloodborne tissue they have a net negative surface charge; sialic acid residues attached to
factor, synthesis or activation of tissue factor, formation of procoagu- proteins and lipids are major contributors to this negative charge. The
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lant microvesicles, exposure of activated factor V, exposure of negatively electrostatic repulsion created by the negative surface charge may help
charged phospholipids, and perhaps activation of the contact system. The prevent resting platelets from attaching to each other or to negatively
thrombin thus generated further activates platelets, leading to more exten- charged endothelial cells.
sive degranulation; it also further activates coagulation and initiates the Indentations on the platelet surface are thought to be the open-
deposition of fibrin strands that reinforce the platelet thrombus and serve ings of the open canalicular system, which is an elaborate channel sys-
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as sites for additional VWF deposition. Thrombin also helps to consol- tem composed of invaginations of the plasma membrane that extend
idate the plug by initiating platelet-mediated clot retraction (see section throughout the platelet (see Fig. 112–2 and “Membrane Systems”
“Platelet Shape Change, Spreading, Contraction and Clot Retraction” below). The contents of platelet granules can gain access to the outside
below). Finally, thrombin affects the surface membrane receptors, down- when the granules fuse with either the plasma membrane or any region
regulating GPIb/IX and upregulating integrin α β , perhaps facilitating of the open canalicular system. Similarly, glycoproteins contained
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the transition from platelet adhesion to platelet aggregation. 62–65 within granule membranes can join the plasma membrane after granule
Release of vasoactive and mitogenic agents, as well as chemok- fusion with either the plasma membrane or the open canalicular system.
ines, from platelets contributes to the inflammatory response, as does
the appearance of P-selectin on the surface of activated platelets and
endothelial cells, because P-selectin and other platelet receptors recruit MEMBRANE SYSTEMS
leukocytes to the damaged region. 66–68 Finally, after contributing to The Plasma Membrane
hemostasis and initiating an inflammatory response, platelet-fibrin The plasma membrane is a trilaminar unit composed of a bilayer of phos-
thrombi eventually resolve, most likely by a combination of emboliza- pholipids embedded with cholesterol, glycolipids, and glycoproteins. 76,78
tion, fibrinolysis, and macrophage removal of debris. Platelets prepared by the freeze–fracture technique demonstrate more
Several inhibitory factors serve to balance platelet activation and intramembranous particles embedded in the outer platelet membrane
thus prevent excessive platelet deposition. The dilutional effects of flow- leaflet than in the inner leaflet, which is the reverse of findings in ery-
ing blood are probably most important; thus, alterations in the surface throcytes; this observation presumably reflects the many external
of the blood vessel that produce local areas of stasis in which platelets receptors that mediate platelet interactions. The plasma membrane is

Kaushansky_chapter 112_p1829-1914.indd 1834 17/09/15 3:25 pm