Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic drug-induced platelet apoptosis: an overlooked issue in pharmacotoxicology

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The surfacing of the applied fields of biology such as, biotechnology, pharmacology and drug discovery was a boon to the modern man. However, it had its share of disadvantages too. The indiscriminate use of antibiotics and other biological drugs resulted in numerous adverse reactions including thrombocytopenia. One of the reasons for drug-induced thrombocytopenia could be attributed to an enhanced rate of platelet apoptosis, which is a less investigated aspect. The present essay sheds light on the adverse (pro-apoptotic) effects of some of the commonly used drugs and antibiotics on platelets viz. cisplatin, aspirin, vancomycin and balhimycin. Furthermore, the undesirable reactions resulting from chemotherapy could be attributed at least to some extent to the systemic stress induced by microparticles, which in turn are the byproducts of platelet apoptosis. Thereby, the essay aims to highlight the challenges in the emerging trend of cross-disciplinary implications, i.e., drug-induced platelet apoptosis, which is a nascent field. Thus, the different mechanisms through which drugs induce platelet apoptosis are discussed, which also opens up a new perspective through which the adverse effects of commonly used drugs could be dealt. The drug-associated platelet toxicity is of grave concern and demands immediate attention. Besides, it would also be appealing to examine the platelet pro-apoptotic effects of other commonly used therapeutic drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ahn YS, Jy W, Jimenez JJ, Horstman LL (2004) More on: cellular microparticles: what are they bad or good for? J Thromb Haemost 2:1215–1216

    Article  CAS  PubMed  Google Scholar 

  • Antoniak S, Boltzen U, Eisenreich A, Stellbaum C, Poller W, Schultheiss HP, Rauch U (2009) Regulation of cardiomyocyte full-length tissue factor expression and microparticle release under inflammatory conditions in vitro. J Thromb Haemost 7:871–878

    Article  CAS  PubMed  Google Scholar 

  • Aster RH, Curtis BR, McFarland JG, Bougie DW (2009) Drug induced thrombocytopenia: pathogenesis, diagnosis and management. J Thromb Haemost 7:911–918

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barabas K, Milner R, Lurie D, Adin C (2008) Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 6:1–18

    Article  CAS  PubMed  Google Scholar 

  • Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O’Donnell E, Farndale RW, Ware J, Lee DM (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327:580–583

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bonomini M, Dottori S, Amoroso L, Arduini A, Sirolli V (2004) Increased platelet phosphatidylserine exposure and caspase activation in chronic uremia. J Thromb Haemost 2:1275–1281

    Article  CAS  PubMed  Google Scholar 

  • Burger D, Schock S, Thompson CS, Montezano AC, Hakim AM, Touyz RM (2013) Microparticles: biomarkers and beyond. Clin Sci (Lond) 124:423–441

    Article  CAS  Google Scholar 

  • Candemir B, Aribuca A, Koca C, Ozcan OU, Gerede M, Kaya CT (2012) An unusual case of vancomycin-related systemic reaction accompanied with severe thrombocytopenia mimicking pacemaker-related infective endocarditis: a case report and review of literature. J Interv Card Electrophysiol 38(2):143–145

    Google Scholar 

  • Chatterjee S, Vijayakumar EKS, Nadkarni SR, Patel MV, Blumbach J, Ganguli BN (1994) Balhimycin a new glycopeptide antibiotic with an unusual hydrated 3-amino-4-oxoaldopyranose sugar moiety. Org Chem 59:3480–3484

    Article  CAS  Google Scholar 

  • Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345

    Article  CAS  PubMed  Google Scholar 

  • Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  CAS  PubMed  Google Scholar 

  • Creagh EM, Martin SJ (2001) Caspases: cellular demolition experts. Biochem Soc Trans 29:696–702

    Article  CAS  PubMed  Google Scholar 

  • Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  CAS  PubMed  Google Scholar 

  • Deavall DG, Martin EA, Horner JM, Roberts R (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012:645460

    PubMed Central  PubMed  Google Scholar 

  • Demain AL (2009) Antibiotics: natural products essential to human health. Med Res Rev 29:821–842

    Article  CAS  PubMed  Google Scholar 

  • dos Santos NA, Carvalho Rodrigues MA, Martins NM, dos Santos AC (2012) Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update. Arch Toxicol 86:1233–1250

    Article  PubMed  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Freyssinet JM (2003) Cellular microparticles: what are they bad or good for? J Thromb Haemost 1(7):1655–1662

    Article  CAS  PubMed  Google Scholar 

  • Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G (2006) Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 13:1423–1433

    Article  CAS  PubMed  Google Scholar 

  • George JN, Aster RH (2009) Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematol Am Soc Hematol Educ Program 2009:153–158

    Article  Google Scholar 

  • Gupta A, Biyani M, Khaira A (2011) Vancomycin nephrotoxicity: myths and facts. Neth J Med 69:379–383

    CAS  PubMed  Google Scholar 

  • Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  CAS  PubMed  Google Scholar 

  • Italiano JE Jr, Mairuhu AT, Flaumenhaft R (2010) Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 17:578–584

    Article  PubMed Central  PubMed  Google Scholar 

  • Kim YK, Kim HJ, Kwon CH, Kim JH, Woo JS, Jung JS, Kim JM (2005) Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells. J Appl Toxicol 25:374–382

    Article  CAS  PubMed  Google Scholar 

  • Knijff-Dutmer EA, Koerts J, Nieuwland R, Kalsbeek-Batenburg EM, van de Laar MA (2002) Elevated levels of platelet microparticles are associated with disease activity in rheumatoid arthritis. Arthr Rheum 46:1498–1503

    Article  CAS  Google Scholar 

  • Leytin V (2012) Apoptosis in the anucleate platelet. Blood Rev 26:51–63

    Article  CAS  PubMed  Google Scholar 

  • Li X, Cong H (2009) Platelet-derived microparticles and the potential of glycoprotein IIb/IIIa antagonists in treating acute coronary syndrome. Tex Heart Inst J 36:134–139

    PubMed  Google Scholar 

  • Li J, Xia Y, Bertino AM, Coburn JP, Kuter DJ (2000) The mechanism of apoptosis in human platelets during storage. Transfusion 40:1320–1329

    Article  CAS  PubMed  Google Scholar 

  • Li S, Wang Z, Liao Y, Zhang W, Shi Q, Yan R, Ruan C, Dai K (2010) The glycoprotein Ib alpha-von Willebrand factor interaction induces platelet apoptosis. J Thromb Haemost 8:341–350

    Article  CAS  PubMed  Google Scholar 

  • Lin KH, Hsiao G, Shih CM, Chou DS, Sheu JR (2009) Mechanisms of resveratrol-induced platelet apoptosis. Cardiovasc Res 83:575–585

    Article  CAS  PubMed  Google Scholar 

  • López JJ, Redondo PC, Salido GM, Pariente JA, Rosado JA (2009) N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine induces apoptosis through the activation of caspases-3 and -8 in human platelets: a role for endoplasmic reticulum stress. J Thromb Haemost 7:992–999

    Article  PubMed  Google Scholar 

  • Mallat Z, Tedgui A (2001) Current perspective on the role of apoptosis in atherothrombotic disease Circ. Res 88:998–1003

    CAS  Google Scholar 

  • Marinho DS, Huf G, Ferreira BL, Castro H, Rodrigues CR, de Sousa VP, Cabral LM (2011) The study of vancomycin use and its adverse reactions associated to patients of a Brazilian university hospital. BMC Res Notes 4:236

    Article  PubMed Central  PubMed  Google Scholar 

  • Marković SD, Djačić DS, Cvetković DM, Obradović AD, Žižić JB, Ognjanović BI, Štajn AŠ (2011) Effects of acute in vivo cisplatin and selenium treatment on hematological and oxidative stress parameters in red blood cells of rats. Biol Trace Elem Res 142:660–670

    Article  PubMed  Google Scholar 

  • Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107:1047–1057

    Article  CAS  PubMed  Google Scholar 

  • Meier P, Finch A, Evan G (2000) Apoptosis in development. Nature 407:796–801

    Article  CAS  PubMed  Google Scholar 

  • Mintzer DM, Billet SN, Chmielewski L (2009) Drug-induced hematologic syndromes. Adv Hematol 2009:495863

    PubMed Central  PubMed  Google Scholar 

  • Morel O, Jesel L, Freyssinet JM, Toti F (2011) Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 31:15–26

    Article  CAS  PubMed  Google Scholar 

  • Nelson ML, Levy SB (2011) The history of the tetracyclines. Ann N Y Acad Sci 1241:17–32

    Article  CAS  PubMed  Google Scholar 

  • Nomura S, Nakamura T, Cone J, Tandon NN, Kambayashi J (2000) Cytometric analysis of high shear-induced platelet microparticles and effect of cytokines on microparticle generation. Cytometry 40:173–181

    Article  CAS  PubMed  Google Scholar 

  • Nomura S, Omoto S, Yokoi T, Fujita S, Ozasa R, Eguchi N, Shouzu A (2011) Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus. Int J Gen Med 4:539–545

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Olas B, Wachowicz B (2004) Resveratrol reduces oxidative stress induced by platinum compounds in blood platelets. Gen Physiol Biophys 23:315–326

    CAS  PubMed  Google Scholar 

  • Owens AP, Mackman N (2011) Microparticles in hemostasis and thrombosis. Circul Res 108:1284–1297

    Article  CAS  Google Scholar 

  • Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007

    Article  CAS  PubMed  Google Scholar 

  • Packham MA (1994) Role of platelets in thrombosis and hemostasis. Can J Physiol Pharmacol 72:278–284

    Article  CAS  PubMed  Google Scholar 

  • Patrono C, Rocca B (2009) Aspirin, 110 years later. J Thromb Haemost 7:258–261

    Article  CAS  PubMed  Google Scholar 

  • Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171

    Article  CAS  PubMed  Google Scholar 

  • Pirro M, Schillaci G, Bagaglia F, Menecali C, Paltriccia R, Mannarino MR, Capanni M, Velardi A, Mannarino E (2008) Microparticles derived from endothelial progenitor cells in patients at different cardiovascular risk. Atherosclerosis 197:757–767

    Article  CAS  PubMed  Google Scholar 

  • Pisetsky DS (2011) Platelet microparticles: making blood a bad humor. J Rheumatol 38:590–592

    Article  PubMed  Google Scholar 

  • Plenchette S, Moutet M, Benguella M, N’Gondara JP, Guigner F, Coffe C, Corcos L, Bettaieb A, Solary E (2001) Early increase in DcR2 expression and late activation of caspases in the platelet storage lesion. Leukemia 15:1572–1581

    Article  CAS  PubMed  Google Scholar 

  • Prasad KS, Andre P, He M, Bao M, Manganello J, Phillips DR (2003) Soluble CD40 ligand induces β3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 100:12367–12371

    Article  CAS  PubMed  Google Scholar 

  • Preston RA, Jy W, Jimenez JJ, Mauro LM, Horstman LL, Valle M, Aime G, Ahn YS (2003) Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 41:211–217

    Article  CAS  PubMed  Google Scholar 

  • Ramesh G, Reeves WB (2005) p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 289:F166–F174

    Article  CAS  PubMed  Google Scholar 

  • Rand ML, Wang H, Bang KW, Teitel JM, Blanchette VS, Freedman J, Nurden AT (2010) Phosphatidylserine exposure and other apoptotic-like events in Bernard–Soulier syndrome platelets. Am J Hematol 85:584–592

    Article  CAS  PubMed  Google Scholar 

  • Rautou PE, Vion AC, Amabile N, Chironi G, Simon A, Tedgui A, Boulanger CM (2011) Microparticles, vascular function, and atherothrombosis. Circ Res 109:593–606

    Article  CAS  PubMed  Google Scholar 

  • Reese JA, Li X, Hauben M, Aster RH, Bougie DW, Curtis BR, George JN, Vesely SK (2010) Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 116:2127–2133

    Article  CAS  PubMed  Google Scholar 

  • Rocha JL, Kondo W, Baptista MI, Da Cunha CA, Martins LT (2002) Uncommon vancomycin-induced side effects. Braz J Infect Dis 6:196–200

    Article  PubMed  Google Scholar 

  • Saraste A, Pulkki K (2000) Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res 45:528–537

    Article  CAS  PubMed  Google Scholar 

  • Schilling A, Neuner E, Rehm SJ (2011) Vancomycin: a 50-something-year-old antibiotic we still don’t understand. Cleve Clin J Med 78:465–471

    Article  PubMed  Google Scholar 

  • Shah RA, Musthaq A, Khardori NJ (2009) Vancomycin-induced thrombocytopenia in a 60-year-old man: a case report. Med Case Rep 3:7290

    Article  Google Scholar 

  • Sneader W (2000) The discovery of aspirin: a reappraisal. BMJ 321:1591–1594

    Article  CAS  PubMed  Google Scholar 

  • Straface E, Gambardella L, Metere A, Marchesi A, Palumbo G, Cortis E, Villani A, Pietraforte D, Viora M, Malorni W, Del Principe D (2010) Oxidative stress and defective platelet apoptosis in naïve patients with Kawasaki disease. Biochem Biophys Res Commun 392:426–430

    Article  CAS  PubMed  Google Scholar 

  • Suliman A, Lam A, Datta R, Srivastava RK (2001) Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways. Oncogene 20:2122–2133

    Article  CAS  PubMed  Google Scholar 

  • Taguchi T, Nazneen A, Abid MR, Razzaque MS (2005) Cisplatin-associated nephrotoxicity and pathological events. Contrib Nephrol 148:107–121

    Article  CAS  PubMed  Google Scholar 

  • Takano K, Asazuma N, Satoh K, Yatomi Y, Ozaki Y (2004) Collagen-induced generation of platelet-derived microparticles in whole blood is dependent on ADP released from red blood cells and calcium ions. Platelets 15:223–229

    Article  CAS  PubMed  Google Scholar 

  • Terrisse AD, Puech N, Allart S, Gourdy P, Xuereb JM, Payrastre B, Sié P (2010) Internalization of microparticles by endothelial cells promotes platelet/endothelial cell interaction under flow. J Thromb Haemost 8:2810–2819

    Article  CAS  PubMed  Google Scholar 

  • Towhid ST, Schmidt EM, Tolios A, Münzer P, Schmid E, Borst O, Gawaz M, Stegmann E, Lang F (2013a) Stimulation of platelet death by vancomycin. Cell Physiol Biochem 31:102–112

    Article  CAS  PubMed  Google Scholar 

  • Towhid ST, Tolios A, Münzer P, Schmidt EM, Borst O, Gawaz M, Stegmann E, Lang F (2013b) Stimulation of platelet apoptosis by balhimycin. Biochem Biophys Res Commun 435:323–326

    Article  CAS  PubMed  Google Scholar 

  • Tschuor C, Asmis LM, Lenzlinger PM, Tanner M, Härter L, Keel M, Stocker R, Stover JF (2008) In vitro norepinephrine significantly activates isolated platelets from healthy volunteers and critically ill patients following severe traumatic brain injury. Crit Care 12:R80

    Article  PubMed  Google Scholar 

  • Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, Fukuda K, Kanai H, Kishihara K, Hirakata H, Iida M (2003) Direct involvement of the receptor-mediated apoptotic pathways in cisplatin-induced renal tubular cell death. Kidney Int 63:72–82

    Article  CAS  PubMed  Google Scholar 

  • VanWijk MJ, VanBavel E, Sturk A, Nieuwland R (2003) Microparticles in cardiovascular diseases. Cardiovasc Res 59:277–287

    Article  CAS  PubMed  Google Scholar 

  • Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I, Baker KR, Aster RH (2007) Vancomycin-induced immune thrombocytopenia. N Engl J Med 356:904–910

    Article  Google Scholar 

  • Warner TD, Mitchell JA (2002) Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum? Proc Natl Acad Sci USA 99:13371–13373

    Article  CAS  PubMed  Google Scholar 

  • Zahra S, Anderson JA, Stirling D, Ludlam CA (2011) Microparticles, malignancy and thrombosis. Br J Haematol 152:688–700

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Zhao L, Liu J, Du J, Wang Z, Ruan C, Dai K (2012) Cisplatin induces platelet apoptosis through the ERK signaling pathway. Thromb Res 130:81–91

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Zhang W, Chen M, Zhang J, Zhang M, Dai K (2013) Aspirin induces platelet apoptosis. Platelets 24(8):637–642

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

Authors declare that there exist no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Studies in Biochemistry, University of Mysore, Mysore, 570006, India

    R. M. Thushara, M. Hemshekhar, K. Kemparaju & K. S. Girish

  2. Department of Studies in Chemistry, University of Mysore, Mysore, 570006, India

    K. S. Rangappa

  3. Department of Studies and Research in Biochemistry, Tumkur University, Tumkur, 572103, India

    S. Devaraja & K. S. Girish

Authors
  1. R. M. Thushara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Hemshekhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Kemparaju
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. S. Rangappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Devaraja
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. S. Girish
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. S. Girish.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thushara, R.M., Hemshekhar, M., Kemparaju, K. et al. Therapeutic drug-induced platelet apoptosis: an overlooked issue in pharmacotoxicology. Arch Toxicol 88, 185–198 (2014). https://doi.org/10.1007/s00204-013-1185-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-013-1185-3

Keywords

Search

Navigation