Page 1865 - Williams Hematology ( PDFDrive )

1840 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1841

continuous polymerization and depolymerization of actin involves bones and muscles. Table 112–1 lists the major components of the plate-
conversion of ATP to ADP, and this may account for as much as 40 let contractile system. These elements are thought to contribute to plate-
percent of the ATP consumption in resting platelets. The continuous let shape change, secretion, and clot retraction after platelet activation.
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polymerization and depolymerization of tubulin that occurs in the coil When exposed to a variety of agonists, platelets undergo dramatic
of resting platelet involves conversion of guanosine triphosphate (GTP) changes in shape within seconds. Shape change follows a reproduc-
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to guanosine diphosphate (GDP), and thus consumes energy. Contin- ible sequence of events during which the resting platelet cytoskeleton
uing dephosphorylation and rephosphorylation of phosphatidylinosi- is dismantled and reorganized. The first noticeable change following
tols, which are important in signal transduction, has been estimated to activation is the dismantling of the microtubule coil and conversion
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consume as much as 7 percent of the total ATP produced. Protein from discs to spheres. Filopodia and lamellipodia, generated by new
phosphorylation also occurs as an ongoing process, but its fractional actin filament assembly, then extend from the plasma membrane. At
use of ATP is not clear in resting cells. Platelet stimulation leads to a the same time, intracellular organelles and granules, and the dismantled
marked increase in both glycolytic activity and oxidative ATP produc- microtubule coil, are compressed into the center of the platelet. Once
tion, perhaps as a result of the abrupt decrease in ATP that occurs with shape change is finished, the actin cytoskeleton is used as a platform
platelet activation or the increase in cytoplasmic pH. The increased for contraction, and contractile tension is exerted between platelets and
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ATP appears to be used, at least in part, for phosphatidylinositide and between platelets and the adjacent fibrin strands.
protein phosphorylation.
Platelet stimulation is accompanied by a marked increase in both PLATELET SHAPE CHANGE
glycolytic activity and oxidative ATP production, perhaps through a
feedback mechanism in response to the abrupt decrease in ATP that Platelet shape change occurs in response to many different agonists. It
occurs with platelet activation or as a result of the increase in cytoplas- involves loss of the platelet’s normal discoid shape (approximately 1.5
mic pH. The increased ATP appears to be utilized, at least in part, in to 2.5 μm diameter and approximately 0.5 to 0.9 μm width) and trans-
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phosphoinositide phosphorylation and protein phosphorylation. formation to a spiny sphere with long, thin filopodia extending sev-
eral micrometers out from the platelet and ending in points that are as
Organelles small as 0.1 μm in diameter (see Fig. 112–2). 95,212 In the aggregometer,
Peroxisomes In platelets, some of the main metabolic functions of it has been generally assumed that the initial decrease in light trans-
peroxisomes include fatty acid β-oxidation, plasmalogen (a phospho- mission immediately after adding certain agonists is a reflection of
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lipid) synthesis, and synthesis of platelet-activating factor (PAF). They platelets undergoing shape change, but this interpretation has been
contain acyl-CoA:dihydroxyacetone phosphate acyltransferase, which challenged by the suggestion that microaggregation rather than shape
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catalyzes the first step in the synthesis of ether-containing phospholip- change accounts for this phenomenon. Although the reason platelets
ids. Deficiencies of this enzymatic activity have been identified in the undergo shape change is unclear, one possibility is that it reduces elec-
cerebrorenal Zellweger syndrome, and the platelet activity can be used trostatic repulsion between two negatively charged platelets or between
to diagnose the disorder. 195,196 a platelet and a negatively charged surface or cell without the need to
Mitochondria Platelets contain approximately four to seven reduce surface charge density. Thus, after changing shape, the tip of a
mitochondria of relatively small size, often located near the plasma platelet filopodium can more easily approach and make contact with a
membrane; they are involved in oxidative energy metabolism. 197–199 surface or a cell because the great bulk of the repulsive surface charge is
Control of mitochondrial Bcl-2 family proteins, including Bcl-x1 and now at a distance from the tip. 215
Bak, directly affects a platelet’s life span and alterations in these pro- A change in platelet shape from disk to sphere is the first event
teins can produce thrombocytopenia (Chaps. 111 and 117). Release that is observed as the platelet is activated. Agonist binding to select
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of mitochondria upon platelet activation, either in microparticles or receptors activates phospholipase (PL) Cβ, which hydrolyzes mem-
free in the circulation, may contribute to inflammation and nonhemo- brane-bound PI-4,5-bisphosphate to inositol-1,4,5-triphosphate (IP )
3
lytic transfusion reactions. Abnormalities of mitochondrial enzymes, and diacylglycerol. IP then binds to receptors on the DTS/sarcoplasmic
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3
including the reduced form of nicotinamide adenine dinucleotide reticulum, generating a rise in cytosolic calcium concentrations to 5 to
(NADH) coenzyme Q reductase (complex I), have been implicated 10 μM. While calcium can influence the activity of many actin-binding
in the pathophysiology of aging and several neurodegenerative disor- proteins, one of the major proteins that is activated is gelsolin, which
ders, including Alzheimer disease, schizophrenia, and some forms of is present in platelets at a concentration of approximately 5 μM. Actin
Parkinson disease. Assays of platelet mitochondrial enzyme levels have filaments in resting platelets are relatively stable because their barbed
been used in these studies. 201–206 In addition, hyperglycemia-induced ends (the end from which they can grow by adding additional actin
mitochondrial superoxide generation may contribute to the enhanced monomers), are capped with the protein CapZ and α,γ-adducins (see
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platelet aggregation observed in diabetes. Loss of the mitochondrial Fig. 112–5). Calcium-activated gelsolin both severs existing actin fila-
inner leaflet potential has been associated with surface expression of ments and caps the newly created barbed ends. This increases the num-
platelet procoagulant activity and coated platelet formation (see “Plate- ber of actin filaments by an estimated 10-fold, and substitutes gelsolin
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let Coagulant Activity” below). 208–211 for CapZ and α,γ-adducins as the actin filament capping protein. Sev-
ering of actin filaments that interact with the planar lattice composed of
filamin A (actin binding protein), GPIb/IX, and spectrin in the mem-
PLATELET SHAPE CHANGE, SPREADING, brane cytoskeleton releases the constraints on the spectrin network.
CONTRACTION, AND CLOT RETRACTION This allows the membrane skeleton to swell (but not produce filopodia)
(see Fig. 112–5) by incorporating into the plasma membrane the mem-
OVERVIEW branes from the open canalicular system, and later the membranes from
the granules that release their contents.
The cytoskeleton establishes the platelets native structure and its ability The protrusive force for lamellipodia and filopodia formation
to respond to stimuli through changes in shape and force generation; comes from new actin polymerization, such that there is a doubling of
as such, the cytoskeleton can be considered analogous to an animal’s actin filament content. This burst of actin filament assembly is powered

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