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Editorials
References
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2. Diebolder CA, Beurskens FJ, de Jong RN, et al. Complement is acti- vated by IgG hexamers assembled at the cell surface. Science. 2014;343(6176):1260-1263.
3. Salles G, Barrett M, Foa R, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther. 2017;34(10):2232-2273.
4. Zent CS, Victoria Wang X, Ketterling RP, et al. A phase II random- ized trial comparing standard and low dose rituximab combined with alemtuzumab as initial treatment of progressive chronic lym- phocytic leukemia in older patients: a trial of the ECOG-ACRIN can- cer research group (E1908). Am J Hematol. 2016;91(3):308-312.
5. Witkowska M, Smolewski P, Robak T. Investigational therapies tar- geting CD37 for the treatment of B-cell lymphoid malignancies. Expert Opin Investig Drugs. 2018;27(2):171-177.
6. Yeung L, Hickey MJ, Wright MD. The many and varied roles of tetraspanins in immune cell recruitment and migration. Front Immunol. 2018;9:1644.
7. van Spriel AB, de Keijzer S, van der Schaaf A, et al. The tetraspanin CD37 orchestrates the alpha(4)beta(1) integrin-Akt signaling axis and supports long-lived plasma cell survival. Sci Signal. 2012;5(250):ra82.
9. RobakT,HellmannA,KloczkoJ,etal.Randomizedphase2studyof otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017;176(4):618-628.
10. Stilgenbauer S, Aurran Schleinitz T, Eichhorst B, et al. Phase 1 first- in-human trial of the anti-CD37 antibody BI 836826 in relapsed/refractory chronic lymphocytic leukemia. Leukemia. 2019 May 14. [Epub ahead of print]
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The secret afterlife of platelets
Nicholas A. Arce1,2 and Renhao Li1
17. Taylor RP, Lindorfer MA. Fcgamma-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments. Blood. 2015;125(5):762-766.
1Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine and 2Graduate Program of Molecular and Systems Pharmacology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA
E-mail: RENHAO LI - renhao.li@emory.edu doi:10.3324/haematol.2019.224170
Platelets express a wide variety of receptors and signal- ing molecules that enable responses to diverse physio- logical and pathological stimulants. For instance, in normal hemostasis, exposure of subendothelial collagen may elicit platelet activation at the site of injury via glyco- protein (GP)VI, integrin a2β1, and, through plasma von Willebrand factor, the GPIb-IX-V complex. Moreover, GPIb-IX-V in tandem with protease-activated receptors mediate thrombin-induced platelet signaling and activa- tion. GPIba serves as a receptor for low concentrations of thrombin, transmitting a mechanosensory signal to medi- ate calcium-dependent 14-3-3 signaling while GPIb-IX– dependent Rac1/LIMK1 signaling is modulated by pro- tease-activated receptors.1,2 Upon activation, platelets aggregate and form clots that are interwoven with fibrin strands. Over the last several decades, much of the research effort has been focused on how platelets are rapidly activat- ed by various agonists via their respective receptors and how activating, and sometimes inhibitory, signals amplify and propagate in the platelet. In most of these studies, the investigation ends at the cessation of blood flow, the for- mation of the clot, and/or the appearance of molecular signs that are well associated with platelet activation. A few minutes following platelet activation and aggregation, the blood clot contracts. In studies of clot contraction, the investigation often ends at the shrinkage of the platelet clot.3 However, little is known about the platelets in the clot
following the contraction of the platelet/fibrin clot. In other words, after the formation of a stable blood clot, where do platelets go?
A study by Kim et al., published in this issue of Haematologica, demonstrates that after activation and con- traction, thrombin-stimulated platelets break up into mem- brane particles, in a process termed platelet fragmentation.4 Thrombin is a major nexus between coagulation and platelet activation, as it generates fibrin to form a crosslinked fibrin plug and concurrently activates afore- mentioned receptors on the platelet surface.5 Platelet vesic- ulation and/or microparticle formation has been previously observed in response to thrombin and thrombin receptor activating peptide.6-8 The role that these platelet fragments play in hemostasis or platelet clearance has yet to be eluci- dated. In this new study, interestingly, Kim et al. observed a bimodal distribution of platelet fragments, the size of which can be attributed to the origin of the fragment. Filopodia as well as the main platelet body are two sources of platelet fragmentation, as smaller fragments were gener- ated by filopodia, and larger fragments were generated from the cell body. Thus, it appears that platelet break- down in response to thrombin stimulation is a regulated process of drastic morphological changes, platelet fragmen- tation, loss of function, and metabolic exhaustion. Platelet fragmentation may be a relatively newly discovered platelet behavior, adding to the ever-growing list of what
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