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Thromb Haemost 2004; 91(03): 544-552
DOI: 10.1160/TH03-03-0156
Platelets and Blood Cells
Schattauer GmbH

Platelet function in mitochondriopathy with stroke and stroke-like episodes

Nicole Kotzailias
1   Department of Clinical Pharmacology, Vienna University, Vienna, Austria
4   Department of Neurology, Neurological Rehabilitation, Vienna University, Vienna, Austria Trial Center: Department of Clinical Pharmacology, University of Vienna, Austria
,
Josef Finsterer
2   Department of Neurology, Neurological Hospital Rudolfstiftung, Vienna, Austria
,
Maria Zellner
3   Department of Surgical Research, Vienna University, Austria
,
Claudia Marsik
1   Department of Clinical Pharmacology, Vienna University, Vienna, Austria
,
Tanja Dukic
1   Department of Clinical Pharmacology, Vienna University, Vienna, Austria
,
Bernd Jilma
1   Department of Clinical Pharmacology, Vienna University, Vienna, Austria
› Author AffiliationsFinancial support: This study was supported by a research grant from the Hans & Blanca Moser Stiftung.
Further Information

Publication History

Received 17 March 2003

Accepted after revision 12 February 2003

Publication Date:
05 December 2017 (online)

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Summary

Stroke and stroke-like episodes are frequent complications in mitochondriopathy, particulary in MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes) which is a disorder of the mitochondrial oxidative metabolism in diverse cell types. To clarify a possible pathological aspect of stroke in these patients, we investigated platelet function before and after physical exercise. Ten patients with mitochondriopathy and stroke and ten healthy sex and age matched controls were investigated in an analyst blinded, prospective cross-sectional trial. Exercise decreased intraplatelet adenosine triphosphate (ATP) concentrations by -22% from baseline in patients with mitochondriopathy (p<0.01 between groups) while exercise increased ATP-levels by 28% healthy controls (p=0.01 vs baseline). Thrombin receptor activating peptide (TRAP) stimulated P-selectin expression increased up to 50% (p<0.05) in healthy subjects following exercise compared to 39% (p>0.05) in patients with mitochondriopathy. Exercise trendwise decreased platelet plug formation under shear stress by 24% in patients as measured by the platelet function analyzer PFA-100®. Tromboelastography showed firm thrombus formation and delayed lysis in patients following exercise. In conclusion, this trial has shown that ATP depletion during and after exercise probably accounts for a defective oxidative metabolism in platelets of patients with mitochondriopathy and stroke. This might induce decreased platelet function in these patients but fails to explain the increased stroke rate. Therefore other mechanisms seem to be etiologically involved in the pathogenesis of stroke in patients with mitochondriopathy.

Keywords

Platelet function - ATP - exercise - mitochondriopathy - stroke
 

  • References

  • 1 Abe K, Matsuo Y, Kadekawa J. et al.. Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry. J Neurol Sci 1999; 162: 65-8.
    CrossrefPubMedGoogle Scholar
  • 2 Majamaa K, Turkka J, Karppa M. et al.. The common MELAS mutation A3243G in mitochondrial DNA among young patients with an occipital brain infarct. Neurology 1997; 49: 1331-4.
    CrossrefPubMedGoogle Scholar
  • 3 James AM, Sheard PW, Wei YH. et al.. Decreased ATP synthesis is phenotypically expressed during increased energy demand in fibroblasts containing mitochondrial tRNA mutations. Eur J Biochem 1999; 259: 462-9.
    CrossrefPubMedGoogle Scholar
  • 4 Smith PR, Cooper JM, Govan GG. et al.. Platelet mitochondrial function in Leber’s hereditary optic neuropathy. J Neurol Sci 1994; 122: 80-3.
    CrossrefPubMedGoogle Scholar
  • 5 Tomasiak M. Importance of the malate-aspartate shuttle for the reoxidation of glycolytically produced NADH and for cell aggregation in porcine blood platelets. Acta Biochim Pol 1987; 34: 269-84.
    PubMedGoogle Scholar
  • 6 Valanne L, Paetau A, Suomalainen A. et al.. Laminar cortical necrosis in MELAS syndrome: MR and neuropathological observations. Neuropediatrics 1996; 27: 154-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Garcia JH, Pantoni L. Strokes in childhood. Semin Pediatr Neurol 1995; 02: 180-91.
    CrossrefPubMedGoogle Scholar
  • 8 Barak Y, Arnon S, Wolach B. et al.. MELAS syndrome: peripheral neuropathy and cytochrome C-oxidase deficiency: a case report and review of the literature. Isr J Med Sci 1995; 31: 224-9.
    PubMedGoogle Scholar
  • 9 Huang CC, Wai YY, Chu NS. et al.. Mitochondrial encephalomyopathies: CT and MRI findings and correlations with clinical features. Eur Neurol 1995; 35: 199-205.
    CrossrefPubMedGoogle Scholar
  • 10 Horiguchi Y, Fujii T, Imamura S. Purpuric cutaneous manifestations in mitochondrial encephalomyopathy. J Dermatol 1991; 18: 295-301.
    CrossrefPubMedGoogle Scholar
  • 11 Williams AJ, Coakley JC, Christodoulou J. Flow cytometric evaluation of defects of the mitochondrial respiratory chain. J Child Neurol 1999; 14: 518-23.
    CrossrefPubMedGoogle Scholar
  • 12 Griesshammer M, Bangerter M, Sauer T. et al.. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999; 245: 295-300.
    CrossrefPubMedGoogle Scholar
  • 13 Selak MA. Neutrophil-platelet interactions in inflammation. Receptor 1994; 04: 3-7.
    PubMedGoogle Scholar
  • 14 Stohlawetz P, Horvath M, Pernerstorfer T. et al.. Effects of nitric oxide on platelet activation during plateletpheresis and in vivo tracking of biotinylated platelets in humans. Transfusion 1999; 39: 506-14.
    CrossrefPubMedGoogle Scholar
  • 15 Reiter R, Derhaschnig U, Spiel A. et al.. Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans. Thromb Haemost 2003; 90 (05) 898-903.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Hergovich N, Aigner M, Eichler H. et al.. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther 2000; 68: 435-42.
    CrossrefPubMedGoogle Scholar
  • 17 Homoncik M, Jilma B, Hergovich N. et al.. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83: 316-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital and acquired platelet dysfunction. J Lab Clin Med 2001; 138 (03) 152-63.
    CrossrefPubMedGoogle Scholar
  • 19 Jilma B, Eichler HG, Vondrovec B. et al.. Effects of desmopressin on circulating Pselectin. Br J Haemotol 1996; 93 (02) 432-6.
    CrossrefPubMedGoogle Scholar
  • 20 Jilma B, Eichler HG, Stohlawetz P. et al.. Effects of exercise on circulating vascular adhesion molecules in healthy men. Immunobiology 1997; 197 (05) 505-12.
    CrossrefPubMedGoogle Scholar
  • 21 Majamaa K, Moilanen JS, Uimonen S. et al.. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet 1998; 63: 447-54.
    CrossrefPubMedGoogle Scholar
  • 22 Dalby MCD, Davidson SJ, Burman JF. et al.. Diurnal variation in platelet aggregation with the PFA-100 platelet function analyser. Platelets 2000; 11: 320-4.
    CrossrefPubMedGoogle Scholar
  • 23 Gilchrist JM, Sikirica M, Stopa E. et al.. Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 1996; 27: 1420-3.
    CrossrefPubMedGoogle Scholar
  • 24 Akkerman JW, van Brederode W, Gorter G. et al.. The Wiskott-Aldrich syndrome: studies on a possible defect in mitochondrial ATP resynthesis in platelets. Br J Haematol 1982; 51: 561-8.
    CrossrefPubMedGoogle Scholar
  • 25 Holmsen H. Biochemistry and function of platelets. In: Williams WJ, Bentler E, Ersten AJ, Lichtmann MA. Haematology. McGraw Hill Publ Comp; New York: 1182-1200.
    Google Scholar
  • 26 Rusanen H, Majamaa K, Hassinen IE. Increased activities of antioxidant enzymes and decreased ATP concentration in cultured myoblasts with the 3243A → G mutation in mitochondrial DNA. Biochim Biophys Acta 2000; 1500: 10-6.
    CrossrefPubMedGoogle Scholar
  • 27 Tzima E, Walker JH. Platelet annexin V: the ins and outs. Platelets 2000; 11: 245-51.
    CrossrefPubMedGoogle Scholar
  • 28 Raynal P. Pollard HB: Annexins. the problem of assessing the biological role for a gene family of multifunctional calcium-and phospholipid-binding proteins. Biochim Biophys Acta 1994; 1197: 63-93.
    CrossrefPubMedGoogle Scholar
  • 29 Storey F. The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 2001; 12 (04) 197-209.
    CrossrefPubMedGoogle Scholar
  • 30 Clemetson KJ, Polgar J. Platelet adhesion and aggregation receptors. In: Platelets and their factors. Springer Verlag; 1997: 155-80.
    Google Scholar
  • 31 Li N, Wallen NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation 1999; 100: 1374-9.
    CrossrefPubMedGoogle Scholar
  • 32 Wang JS, Jen CJ, Kung HC. et al.. Different effects of strenous exercise and moderate exercise on platelet function in men. Circulation 1994; 90 (06) 2877-85.
    CrossrefPubMedGoogle Scholar
  • 33 Thaulow E, Erikssen J, Sandvik L. et al.. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991; 84: 613-7.
    CrossrefPubMedGoogle Scholar
  • 34 Michielis JJ. Aspirin and platelet lowering agents for the prevention of vascular complications in essential thrombocytemia. Clin Appl Thromb Hemost 1999; 05 (04) 247-51.
    CrossrefPubMedGoogle Scholar
  • 35 Sharma SK, Philip J, Whitten C. et al.. Assessment of changes in coagulation in parturients with preeclampsia using thromboelastography. Anesthesiology 1999; 90: 385-90.
    CrossrefPubMedGoogle Scholar
  • 36 Khurana S, Mattson JC, Westley S. et al.. Monitoring platelet glycoprotein IIb/IIIafibrin interaction with tissue factor-activated thromboelastography. J Lab Clin Med 1997; 130 (04) 401-11.
    CrossrefPubMedGoogle Scholar
  • 37 Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol 1989; 25 (06) 594-601.
    CrossrefPubMedGoogle Scholar
  • 38 vanHellenberg JLHubar, Gabreels FJ, Ruitenbeek W. et al.. MELAS syndrome. Report of two patients, and comparison with data of 24 patients derived from the literature. Neuropediatrics 1991; 22 (01) 10-4.
    Article in Thieme ConnectPubMedGoogle Scholar