Page 199 - 2019_09-HaematologicaMondo-web

Dysfunction and disintegration of platelets
an essential part of apoptosis, but for the anucleate platelet the cell’s development and lifespan are determined by the intrinsic pathway of apoptosis.19 On the other hand, whether or not apoptosis is involved in the fate of platelets after activation has been controversial, but other death pathways cannot be excluded.45
Irrespective of the mechanisms underlying platelet death as an outcome of thrombin-induced activation, our data suggest a pathway for enhanced elimination of acti- vated platelets from the circulation in (pro)thrombotic conditions associated with thrombinemia. In severe thrombotic conditions, such as disseminated intravascular coagulation46 or trauma-induced coagulopathy,47 platelets may vanish due to removal of platelet fragments from the blood, perhaps by monocytes, dendritic cells and macrophages.48 Thrombin-induced platelet disintegration may therefore be a pathogenic mechanism that modulates platelet counts, functionality, and fate in disease states associated with hypercoagulability and high thrombin activity in blood.
In conclusion, following thrombin-induced platelet activation, a substantial fraction of platelets later undergo structural disintegration into subcellular particles. This fragmentation of platelets is accompanied by dramatic rearrangements of platelet cytoskeletal components, including redistribution of actin and microtubule dynam- ics. Thrombin-induced platelet fragmentation is concur-
rent with severe impairment of platelet functionality, including mitochondrial depolarization, metabolic ATP depletion, generation of ROS, and loss of platelet contrac- tility. The lack of caspase activity and increased calpain activity in energy-exhausted thrombin-treated platelets undergoing fragmentation suggests a calpain-dependent platelet death pathway. Fragmentation of activated platelets suggests that platelet death is an underappreciat- ed mechanism for enhanced elimination of platelets from the circulation in (pro)thrombotic conditions or under other conditions once these cells have performed their functions. Analogous to eryptosis, suicidal death of ery- throcytes, the platelet death pathway described here could be named “thromboptosis” or “plateleptosis”.
Acknowledgments
We would like to thank Dr. Xiaolu Yang for fruitful discus- sions. The work was supported by National Institutes of Health grants UO1HL116330 and R01 HL135254, National Science Foundation grant DMR1505662, the Program for Competitive Growth at Kazan Federal University, grant 18-415-160004 from the Russian Foundation for Basic Research, American Heart Association grants 17SDG33680177 and 16PRE30260002, and grant EPSRC EP/C513037/1 to P. R. Williams (Swansea University, Wales, UK) for the TA Instruments ARG2 rheometer. Transmission electron microscopy was carried out on the equip- ment of CSF-SAC FRC KSC RAS (Kazan, Russia).
References
1. Rosen ED, Raymond S, Zollman A, et al. Laser-induced noninvasive vascular injury models in mice generate platelet-and coagu- lation-dependent thrombi. Am J Pathol. 2001;158(5):1613–1622.
2. Brass LF, Ma P, Tomaiuolo M, Diamond SL, Stalker TJ. A systems approach to the platelet signaling network and the hemosta- tic response to injury. In: Platelets in Thrombotic and Non-Thrombotic Disorders. Springer. 2017;p.367–378.
3. Kim OV, Litvinov RI, Alber MS, Weisel JW. Quantitative structural mechanobiology of platelet-driven blood clot contraction. Nat Commun. 2017;8(1):1274.
4. Le Minh G, Peshkova AD, Andrianova IA, et al. Impaired contraction of blood clots as a novel prothrombotic mechanism in sys- temic lupus erythematosus. Clin Sci. 2018;132(2):243–254.
5. Peshkova AD, Minh GL, Tutwiler V, Andrianova IA, Weisel JW, Litvinov RI. Activated monocytes enhance platelet-dri- ven contraction of blood clots via tissuefac- tor expression. Sci Rep. 2017;7(1):5149.
6. Tutwiler V, Wang H, Litvinov RI, Weisel JW, Shenoy VB. Interplay of platelet contractility and elasticity of fibrin/erythrocytes in blood clot retraction. Biophys J. 2017;112(4):714– 723.
7. Kamath S, Blann A, Lip G. Platelet activa- tion: assessment and quantification. Eur Heart J. 2001;22(17):1561–1571.
8. Prevost N, Kato H, Bodin L, Shattil SJ. Platelet integrin adhesive functions and signaling. Methods Enzymol. 2007;426:103–115.
9. Shattil SJ. Integrins and Src: dynamic duo of adhesion signaling. Trends Cell Biol. 2005;15(8):399–403.
10. Siess W. Molecular mechanisms of platelet activation. Physiol Rev. 1989;69(1):58–178.
induces regression of solid tumours. Nature.
2005;435(7042):677–681.
21. McArthur K, Chappaz S, Kile BT. Apoptosis
in megakaryocytes and platelets: life and death of a lineage. Blood. 2018;131(12):605–
11. Pang A, Cui Y, Chen Y, et al. Shear-induced
integrin signaling in platelet phos- phatidylserine exposure, microvesicle
release and coagulation. Blood. 2018;132 610.
(5):533–543.
12. Aslan JE. Platelet shape change. In: Platelets
in Thrombotic and Non-Thrombotic
Disorders. Springer. 2017;p 321–336.
13. Shin E-K, Park H, Noh J-Y, Lim K-M, Chung J-H. Platelet shape changes and cytoskeleton dynamics as novel therapeutic targets for anti-thrombotic drugs. Biomol Ther.
2017;25(3):223–230.
14. Seifert J, Rheinlaender J, Lang F, Gawaz M,
Schäffer TE. Thrombin-induced cytoskele- ton dynamics in spread human platelets observed with fast scanning ion conduc- tance microscopy. Sci Rep. 2017;7(1):4810.
15. Sandmann R, Köster S. Topographic cues reveal two distinct spreading mechanisms in blood platelets. Sci Rep. 2016;6:22357.
16. Diagouraga B, Grichine A, Fertin A, Wang J, Khochbin S, Sadoul K. Motor-driven mar- ginal band coiling promotes cell shape change during platelet activation. J Cell Biol. 2014;204(2):177–185.
17. Edelstein LC. The role of platelet microvesi- cles in intercellular communication. Platelets. 2017;28(3):222–227.
18. Ponomareva A, Nevzorova T, Mordakhanova E, et al. Intracellular origin and ultrastructure of platelet-derived microparticles. J Thromb Haemost. 2017;15(8):1655–1667.
19. Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell. 2007;128(6):1173– 1186.
20. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins
22. Beigi R, Kobatake E, Aizawa M, Dubyak GR. Detection of local ATP release from acti- vated platelets using cell surface-attached firefly luciferase. Am J Physiol. 1999;276(1):C267–C278.
23. Leytin V, Allen DJ, Mykhaylov S, Lyubimov E, Freedman J. Thrombin-triggered platelet apoptosis. J Thromb Haemost. 2006;4(12):2656–2663.
24. Leytin V. Apoptosis in the anucleate platelet. Blood Rev. 2012;26(2):51–63.
25. White MJ, Kile BT. Apoptotic processes in megakaryocytes and platelets. In: Seminars in Hematology. Elsevier. 2010;p 227–234.
26. Vanags DM, Pörn-Ares MI, Coppola S, Burgess DH, Orrenius S. Protease involve- ment in fodrin cleavage and phos- phatidylserine exposure in apoptosis. J Biol Chem. 1996;271(49):31075–31085.
27. Wood D, Thomas A A, Devi L, et al. Bax cleavage is mediated by calpain during drug- induced apoptosis. Oncogene. 1998;17(9): 1069–1078.
28. Agbani EO, Williams CM, Hers I, Poole AW. Membrane ballooning in aggregated platelets is synchronised and mediates a surge in microvesiculation. Sci Rep. 2017;7(1):2770.
29. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alfa-granules. Blood. 1999;94(11):3791– 3799.
30. Brown SB, Clarke MCH, Magowan L,
haematologica | 2019; 104(9)
1877