Page 1879 - Williams Hematology ( PDFDrive )

1854 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1855

protein may be vestigial from the megakaryocyte. Some of these could Activated platelets synthesize tissue factor by splicing pre-mRNA
be translated subsequently by the platelet under physiologic demands. into mature mRNA and then translating the tissue factor protein. 660,661
Combining “multiomic” data with phenotyping can provide important Additionally, platelet thrombi can recruit tissue factor from blood by
insights as demonstrated by a study in which transcriptomic and pro- binding leukocyte-derived, tissue factor-containing microparticles or by
teomic analysis identified six platelet transcripts associated with aspirin binding an alternatively spliced, soluble form of tissue factor. 466,472,662–665
resistance. The expression of these genes was associated with death The interaction between PSGL-1 on the surface of leukocyte-derived
641
or MI. In addition, platelet phenotyping and genome-wide genotyping microparticles and P-selectin on the surface of activated platelets
and platelet mRNA and miRNA profiling led to the identification of appears to play an important role in the binding of microparticles to
664
novel protein-coding and noncoding transcripts associated with plate- platelet thrombi. Interactions between platelets and leukocytes,
let activation. 596 and perhaps leukocyte-derived microparticles, reportedly enhance
(“de-encrypt” or decrypt) tissue factor activity, probably by supplying
666
negatively charged phopholipids and/or the oxidoreductase enzyme
PLATELET COAGULANT ACTIVITY protein disulfide isomerase (PDI). 667
Platelet dense granules contain polyphosphate, a linear polymer of
In resting platelets, negatively charged phospholipids, including phos- inorganic phosphate synthesized by inositol hexakisphosphate 6 kinase.
phatidyl serine (PS) and phosphatidylethanolamine (PE), are almost Polyphosphates are released during platelet activation and promote clot
exclusively present in the inner leaflet of the cell membrane and phos- formation. Polyphosphates affect many steps in coagulation. Polyphos-
phatidylcholine predominates in the outer leaflet. This asymmetry is phates accelerate factor V and factor XII and alter the structure of
668
maintained by ATP-dependent “flippase” transporters, which restrict fibrin clots. In the presence of polyphosphates, fibrin clots have thicker
PS to the inner membrane surface and “floppases,” which promote out- fibers and are more resistant to fibrinolysis. In contrast to bacterial
669
ward-directed lipid transport. 84,85,642,643 When platelets are activated by polyphosphates, which are long-chain structures, platelet polyphos-
strong agonists, negatively charged phospholipids redistribute to the phates have shorter chain length and are more effective in increasing
outer leaflet of the platelet plasma membrane. This involves a putative factor V and TFPI activity.
calcium-dependent “scramblase” that transports lipids bidirectionally Incontrovertible evidence exists that platelets accelerate thrombin
and, when active, collapses membrane asymmetry and results in PS formation. 658,659,670–672 Platelets accelerate the activation of factor X by
exposure on the outer leaflet. The eight transmembrane domain con- factors IXa and VIIIa and the activation of prothrombin by factors
2+
taining protein TMEM16F serves as a Ca -activated, nonselective cat- Xa and Va. 659,670 However, only a subpopulation of platelets develops
ion channel that is crucial for Ca -dependent phospholipid scrambling a procoagulant phenotype with activation, as only a fraction of acti-
2+
and PS exposure on activated platelets. 644 vated platelets display high levels of factors Va and Xa, termed “coat”
Platelet activation with strong agonists also results in the forma- platelets. 464,465,670,673 The assembly of the factor IXa/factor VIIIa/platelet
tion of microparticles, which are particularly rich in surface-exposed complex increases the catalytic efficiency of factor X activation (k /K
cat
negatively charged phospholipids. Microparticles also are rich in factor [turnover number/Michaelis-Menten dissociation constant]) by a fac- m
Va and thus actively support thrombin generation. 82,645,646 Microparticle tor of 2.4 × 10 . Prothrombin binds to approximately 20,000 sites on
6 670
formation can be induced in vitro by activation of platelets with iono- activated platelets with a K equal to its plasma concentration (approx-
D
phore A23187, complement C5b-9, or the combination of thrombin and imately 0.15 μM). Integrin α β binds prothrombin through its RGD
674
IIb 3
collagen; by adding tissue factor to recalcified platelet-rich plasma; or by domain, and may contribute to the localization of prothrombin to the
2+
high shear stress. 645,647–652 Elevations of cytosolic Ca , calpain activation, surface of unactivated and activated platelets. 675
cytoskeletal reorganization, protein phosphorylation, and phospholipid In addition to accelerating coagulation, the binding of activated
translocation have all been implicated in microparticle formation. coagulation factors to the surface of platelets appears to protect them
The biologic relevance of platelet microparticles is supported by from inactivation by inhibitors in plasma and platelets. The bleeding
399
the finding of increased circulating levels of platelet microparticles in diathesis in patients with Quebec platelet syndrome, who have prote-
patients with activated coagulation and fibrinolysis, diabetes mellitus, olysis of their platelet α-granule factor V, supports the potential impor-
sickle cell anemia, human immunodeficiency virus infection, unsta- tance of platelet factor V in normal hemostasis (Chap. 121), as do the
ble angina, heparin-induced thrombocytopenia with thrombosis, and studies of another patient with abnormal platelet factor V. 659
respiratory distress syndrome. 645,653 Microparticles can bind to fibrin Other connections between platelets and the coagulation sys-
thrombi via one or more of the receptors present on their surface, tem include: (1) the presence of fibrinogen in platelet α granules and
including integrin α β , GPIb/IX, P-selectin, and possibly P-selectin perhaps on the surface of platelets, where it is strategically located for
IIb 3
glycoprotein ligand (PSGL)-1. 654 interactions with locally generated thrombin 371,399 ; (2) the presence of
Microparticles bind factors VIII, Va, and Xa, allowing them to intracellular VWF and the binding of extracellular VWF to platelets
form both the factor Xase and prothrombinase complexes on their sur- (via GPIb/X and integrin α β ), with the potential colocalization of
IIb 3
face. They can also bind protein S and facilitate inactivation of factors factor VIII attached to the VWF (Chap. 126); (3) activation of factor
645
Va and VIIIa which could serve an anticoagulant function. 655,656 In addi- XI by thrombin on the platelet surface, 676,677 with the dimeric structure
tion, microparticles can activate platelets by supplying arachidonic acid. of factor XI allowing it to interact both with the platelet and factor IX
Evidence supporting the importance of platelet microparticle simultaneously ; (4) a factor XI-like protein associated with platelet
678
formation to platelet coagulant activity has been gathered from obser- membranes, which may be an alternatively spliced form of factor XI
vations of patients who have significant bleeding diatheses in associa- lacking exon V; the level of this factor appears to correlate better with
tion with defects in platelet microparticle formation (Scott syndrome; hemorrhagic symptoms than does the level of plasma factor XI 399,679 ;
Chap. 121). 657–659 Platelets from the most intensively studied patient (5) the presence of cytoplasmic factor XIII (Chap. 113); (6) the presence
had an impaired ability to accelerate the activation of both factor X and of inhibitors of coagulation (α -protease inhibitor, C-1 inhibitor, TFPI,
1
prothrombin. In addition, this patient’s platelets exhibited both abnor- the thrombin inhibitor protease nexin I, and the factors IXa and XIa
mal factor V binding and abnormal exposure of negatively charged inhibitor protease nexin II or β-APP) 399,448 ; and (7) promotion of factor
phospholipids. XII activation by ADP-treated platelets. 399

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