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Thromb Haemost 2012; 108(01): 107-118
DOI: 10.1160/TH11-12-0860
Platelets and Blood Cells
Schattauer GmbH

Reactive leptin resistance and the profile of platelet activation in acute ischaemic stroke patients

Maria Lukasik
1   Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
,
Slawomir Michalak
1   Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
2   Department of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, Poznan, Poland
3   Neuroimmunological Unit, Polish Academy of Sciences, Poznan, Poland
,
Grzegorz Dworacki
4   Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
,
Karolina Siewiera
5   Department of Haemostasis and Haemostatic Disorders, Medical University, Lodz, Poland
,
Mariusz Kaczmarek
4   Department of Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
,
Cezary Watala
5   Department of Haemostasis and Haemostatic Disorders, Medical University, Lodz, Poland
,
Wojciech Kozubski
1   Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
› Author Affiliations
Further Information

Publication History

Received: 13 December 2011

Accepted after major revision: 05 April 2012

Publication Date:
22 November 2017 (online)

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Summary

Leptin is an adipokine that in vitro enhances agonist-induced platelet aggregation and adipokine expression. Hyperleptinaemia represents a risk factor for cardiovascular disease. We conducted a prospective evaluation of the potential link between blood platelet activation and plasma leptin levels in post-stroke patients. Using five-colour flow cyto-metry, the platelet surface expression of CD40L, CD62P, the subpopulations of monocyte-platelet aggregates and platelet-derived microparticles (PMPs) as well as the plasma leptin, soluble leptin receptor (sOb-R), leptin/sOb-R ratio, the plasma adiponectin, and leptin/adiponectin ratio were assessed in 98 stroke patients on the first (V0), 10th (V1) and 90th (V2) day after stroke and once in 78 age-, gender- and vascular risk factor-matched disease controls. We demonstrated that at V0 leptin resistance, defined as leptin/sOb-R ratio, was higher than in the controls [1.1 (0.5–1.8 vs. 0.5 (0.2–1.1); p=0.02]. After adjustment according to the factors which influence platelet activation, we confirmed the relationship between percentage of circulating PMPs and plasma leptin level (B=0.18; p=0.02) or the leptin/sOb-R ratio (B=0.23; p=0.02) in normal-weight subjects in the acute phase of stroke. No correlation could be demonstrated between the adipokine parameters and the percentage of monocyte-platelet aggregates or expression of platelet pro-inflammatory glycoproteins. In conclusion, formation of PMPs on the first day following an ischaemic stroke shows a positive correlation with leptin levels and with resistance to leptin. Leptin level does not seem to affect the expression of platelet surface proinflammatory glycoproteins.

Keywords

Leptin - platelet microparticles - P-selectin - CD40L - monocyte-platelet aggregates - ischaemic stroke
 

  • References

  • 1 Auwerx J, Staels B. Leptin. Lancet 1998; 351: 737-741.
    CrossrefPubMedGoogle Scholar
  • 2 Considine RV, Sinha MK, Heiman ML. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New Engl J Med 1996; 334: 292-295.
    CrossrefPubMedGoogle Scholar
  • 3 Soderberg S, Ahren B, Jansson JH. et al. Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999; 159: 237-245.
    PubMedGoogle Scholar
  • 4 Wannamethee SG, Tchernova J, Whincup P. et al. Plasma leptin: associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007; 191: 418-426.
    CrossrefPubMedGoogle Scholar
  • 5 Soderberg S, Ahren B, Stegmayr B. et al. Leptin is a risk marker for first-ever hemorrhagic stroke in a population-based cohort. Stroke 1999; 30: 328-337.
    CrossrefPubMedGoogle Scholar
  • 6 Soderberg S, Stegmayr B, Stenlund H. et al. Leptin, but not adiponectin, predicts stroke in males. J Intern Med 2004; 256: 128-136.
    CrossrefPubMedGoogle Scholar
  • 7 Leyva F, Godsland IF, Ghatei M. et al. Hyperleptinemia as a component of metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol 1998; 18: 1919-1933.
    PubMedGoogle Scholar
  • 8 Ruige JB, Dekker JM, Blum WF. et al. Leptin and variables of body adiposity, energy balance and insulin resistance in a population based study. The Hoorn Study. Diabetes Care 1999; 22: 1097-1104.
    CrossrefPubMedGoogle Scholar
  • 9 Martin SS, Qasim A, Reilly MP. Leptin resistance. A possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Col l Cardiol 2008; 52: 1201-1210.
    PubMedGoogle Scholar
  • 10 Maamra M, Bidlingmaier M, Postel-Vinay MC. et al. Generation of human soluble leptin receptor by proteolytic cleavage of membrane-anchored receptors. Endocrinology 2001; 142: 4389-4393.
    CrossrefPubMedGoogle Scholar
  • 11 Giandomenico G, Dellas C, Czekay RP. et al. The leptin receptor system of human platelets. J Thromb Haemost 2005; 03: 1042-1049.
    CrossrefPubMedGoogle Scholar
  • 12 Bodary PF, Westrick RJ, Wickenheiser KJ. et al. Effect of leptin on arterial thrombosis following vascular injury in mice. J Am med Assoc 2002; 287: 1706-1709.
    CrossrefPubMedGoogle Scholar
  • 13 Konstantinides S, Schafer K, Koschnik S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540.
    CrossrefPubMedGoogle Scholar
  • 14 Corica F, Corsonello A, Lucchetti M. et al. Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients. Int J Obes 2007; 31: 842-849.
    CrossrefPubMedGoogle Scholar
  • 15 Dellas C, Schäfer K, Rohm I. et al. Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity. Thromb Haemost 2008; 100: 1123-1129.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Wallaschofski H, Lohmann T, Hild E. et al. Enhanced platelet activation by prolactin in patients with ischaemic stroke. Thromb Haemost 2006; 96: 38-44.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Bigalke B, Stellos K, Geisler T. et al. High plasma levels of adipocytokines with platelet activation in patients with coronary artery disease. Platelets 2010; 21: 1911-1917.
    PubMedGoogle Scholar
  • 18 Friedman JM. Obesity in the new millennium. Nature 2000; 404: 632-634.
    CrossrefPubMedGoogle Scholar
  • 19 Owecki M, Miczke A, Pupek-Musialik D. et al. Circulating serum adiponectin concentrations do not differ between obese and non-obese Caucasians and are unrelated to insulin sensitivity. Horm Metab Res 2007; 39: 25-30.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Kato H, Kashiwagi H, Shiraga M. et al. Adiponectin acts as an endogenous antithrombotic factor. Arteriosler Tromb Vasc Biol 2006; 26: 224-230.
    PubMedGoogle Scholar
  • 21 Restituto P, Colina I, Varo JJ. et al. Adiponectin diminishes platelet aggregation and sCD40L release. Potential role in metabolic syndrome. Am J Physiol Endocrinol Metab 2010; 298: E1072-E1077.
    CrossrefPubMedGoogle Scholar
  • 22 Riba R, Hughes CE, Graham H. et al. Globular adiponectin induces platelet activation through the collagen receptor GPVI-Fc receptor ? chain complex. J Thromb Haemost 2008; 06: 1012-1020.
    CrossrefPubMedGoogle Scholar
  • 23 Mirza S, Qu HQ, Li Q. et al. Adiponectin/leptin ratio and metabolic syndrome in Mexican American population. Clin Invest Med 2012; 34: E290.
    PubMedGoogle Scholar
  • 24 Marquardt L, Ruf A, Mansmann U. et al. Course of platelet activation markers after ischemic stroke. Stroke 2002; 33: 2570-2574.
    CrossrefPubMedGoogle Scholar
  • 25 Fateh-Moghadam S, Htun P, Tomandl P. et al. Hyperresponsivenes of platelets in ischemic stroke. Thromb Haemost 2007; 97: 974-978.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Marquardt L, Anders C, Buggle F. et al. Leukocyte-platelet aggregates in acute and subacute ischemic stroke. Cerebrovasc Dis 2009; 28: 276-282.
    CrossrefPubMedGoogle Scholar
  • 27 Lukasik M, Rozalski M, Luzak B. et al. Platelet activation and reactivity in the convalescent phase of ischaemic stroke. Thromb Haemost 2010; 103: 644-650.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Adams Jr HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute is-chaemic stroke. Definitions for use in a multicenterclinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
    CrossrefPubMedGoogle Scholar
  • 29 Bamford J, Sandercock P, Dennis M. et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521-1526.
    CrossrefPubMedGoogle Scholar
  • 30 Lukasik M, Dworacki G, Kufel-Grabowska J. et al. Upregulation of CD40 ligand and enhanced monocyte-platelet aggregate formation are associated with worse clinical outcome after ischaemic stroke. Thromb Haemost 2012; 107: 346-355.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Lukasik M, Dworacki G, Michalak S. et al. Aspirin treatment influences platelet-related inflammatory biomarkers in healthy individuals but not in acute stroke patients. Thromb Res 2011; 128: e73-78.
    CrossrefPubMedGoogle Scholar
  • 32 Lukasi kM, Dworacki G, Michalak S. et al. Chronic hyper-reactivity of plate lets resulting in enhanced monocyte recruitment in patients after ischaemic stroke. Platelets 2012; 23: 132-142.
    CrossrefPubMedGoogle Scholar
  • 33 Lee SA, Kallianpur A, Xiang YB. et al. Intra-individual variation of plasma adipokine levels and utility of single measurement of these biomarkers in population-based studies. Cancer Epidemiol Biomarkers Prev 2007; 16: 2464-2470.
    CrossrefPubMedGoogle Scholar
  • 34 Ogawa T, Hirose H, Yamamoto Y. et al. Relationship between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism 2004; 53: 879-888.
    CrossrefPubMedGoogle Scholar
  • 35 McConway MG, Johnson D, Kelly A. et al. Differences in circulating concentrations of total, free and bound leptin relate to the gender and body composition in adult humans. Ann Clin Biochem 2000; 37: 717-723.
    CrossrefPubMedGoogle Scholar
  • 36 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 06: 772-783.
    CrossrefPubMedGoogle Scholar
  • 37 Zhang F, Basinski MB, Beals JM. et al. Crystal structure of the obese protein leptin-E100. Nature 1997; 387: 206-209.
    CrossrefPubMedGoogle Scholar
  • 38 Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol. 2077 04. 1-13.
    PubMedGoogle Scholar
  • 39 Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis 2004; 19: 151-167.
    CrossrefPubMedGoogle Scholar
  • 40 Worthmann H, Tryc AB, Goldbecker A. et al. The temporal profile of inflammatory markers and mediators in blood after acute ischaemic stroke differs depending on stroke outcome. Cerebrovasc Dis 2010; 30: 85-92.
    CrossrefPubMedGoogle Scholar
  • 41 Smith CJ, Emsley HC, Vail A. et al. Variability of the systemic acute phase response after ischaemic stroke. J Neurol Sci 2006; 251: 77-81.
    CrossrefPubMedGoogle Scholar
  • 42 Chen K, Li F, Li J. et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 2006; 12: 425-432.
    CrossrefPubMedGoogle Scholar
  • 43 Dellas C, Schäfer K, Rohm IK. et al. Leptin signalling and leptin-mediated activation of human platelets: importance of JAK2 and the phospholipases Cγ2 and A2 . Thromb Haemost 2007; 98: 1063-1071.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Del Conde I, Shrimpton CN, Thiagarajan P. et al. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106: 1604-1611.
    CrossrefPubMedGoogle Scholar
  • 45 Tans G, Rosing J, Thomassen MC. et al. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77: 2641-2648.
    PubMedGoogle Scholar
  • 46 Lubsczyk B, Kollars M, Hron G. et al. Low dose acetylsalicylic acid and shedding of microparticles in vivo in humans. Eur J Clin Invest 2010; 40: 477-482.
    CrossrefPubMedGoogle Scholar
  • 47 Kuriyama N, Nagakane Y, Hosomi A. et al. Evaluation of factors associated with elevated levels of platelet-derived microparticles in the acute phase of cerebral infarction. Clin Appl Thromb Hemost 2010; 16: 26-32.
    CrossrefPubMedGoogle Scholar