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Thromb Haemost 2017; 117(10): 1970-1980
DOI: 10.1160/TH17-05-0314
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Erythrocyte-heme proteins and STEMI: implications in prognosis

Judit Cubedo
1   Cardiovascular Science Institute – ICCC, CiberCV and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain
,
Rosa Suades
1   Cardiovascular Science Institute – ICCC, CiberCV and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain
,
Teresa Padró
1   Cardiovascular Science Institute – ICCC, CiberCV and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain
,
Victoria Martin-Yuste
2   Department of Interventional Cardiology, Hospital Clinic, Barcelona, Spain
,
Manel Sabate-Tenas
2   Department of Interventional Cardiology, Hospital Clinic, Barcelona, Spain
,
Juan Cinca
3   Cardiology Department Santa Creu i Sant Pau Hospital and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona
,
Jordi Sans-Roselló
3   Cardiology Department Santa Creu i Sant Pau Hospital and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona
,
Alessandro Sionis
3   Cardiology Department Santa Creu i Sant Pau Hospital and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona
,
Lina Badimon
1   Cardiovascular Science Institute – ICCC, CiberCV and Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain
4   Cardiovascular Research Chair UAB; Barcelona, Spain
› Author Affiliations Financial support: This work was supported by grants from the Spanish Ministry of Economy and Competitiveness of Science [SAF2016–76819-R to L. B.]; Institute of Health Carlos III, ISCIII [TERCEL RD16/00110018 and CB16/11/0041 to L. B.; and FIS PI16/01915 to T. P.]; FEDER “Una Manera de Hacer Europa”; the Secretary of University and Research, Department of Economy and Knowledge of the Government of Catalonia [2014SGR1303 to L. B.]; and “CERCA Programme/Generalitat de Catalunya” Spain. We thank FIC-Fundacion Jesús Serra, Barcelona, Spain, for their continuous support.
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Publication History

Received: 06 May 2017

Accepted after minor revision: 16 June 2017

Publication Date:
28 November 2017 (online)

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Summary

The role of erythrocytes in thrombus formation has been often neglected, but some studies have highlighted their active role in thrombotic events. Free-haemoglobin (Hb) has shown to induce oxidative-stress damage. Herein we have investigated the coordinated changes in heme-related proteins in patients with acute-coronary-syndromes (ACS), their association to ongoing thrombosis and their impact on patients’ prognosis. The serum proteome of STEMI-patients (N=27) within the first 6h after event-onset and 3d after were compared to controls (N=60). Changes in heme-metabolism were characterized in a second STEMI-group by a dual proteomic approach analyzing in-vivo aspirated coronary thrombi at PCI (N=24) and the associated peripheral-blood changes (N=10). A third STEMI-group (N=132) was studied to analyze the impact of the observed changes in prognosis at 6-months-follow-up. The haptoglobin/hemopexin(Hpg/Hpx)-scavenging-system revealed a time-dependent response after STEMI with an early increase in Hpg circulating levels in the acute phase (P=0.01) and a late increase in Hpx levels 3d after (P=0.045). Beta-Hb content in coronary thrombi was directly correlated with systemic beta-Hb and Hpg (R=0.804,P=0.0029; R=0.859,P=0.0007) levels. The presence of a fully-occlusive thrombus was associated to higher circulating levels of beta-Hb (P=0.03) and unbound-Hpg (P=0.03). ELISA validation demonstrated a decreased survival rate at 6-months follow-up in STEMI-patients with lower Hpg plasma levels at admission (P=0.027). Our results show active Hb-release form erythrocytes in ACS. This release is followed by a systemic early increase in Hpg levels and a late increase in Hpx levels that can co-ordinately help to prevent systemic pro-oxidative effects. The Hb-scavenging ability of haptoglobin is related to patients’ prognosis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Key words

Acute Myocardial Infarction - haptoglobin - heme-metabolism - hemopexin - free-heme

 

  • References

  • 1 Aleman MM, Byrnes JR, Wang JG. et al. Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 2014; 124: 3590-3600.
    CrossrefPubMedGoogle Scholar
  • 2 Walton BL, Byrnes JR, Wolberg AS. Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost 2015; 13 (Suppl. 01) S208-S215.
    CrossrefPubMedGoogle Scholar
  • 3 Peyrou V, Lormeau JC, Herault JP. et al. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost 1999; 81: 400-406.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Horne 3rd MK, Cullinane AM, Merryman PK. et al. The effect of red blood cells on thrombin generation. Br J Haematol 2006; 133: 403-408.
    CrossrefPubMedGoogle Scholar
  • 5 Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R. et al. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10: 1355-1362.
    CrossrefPubMedGoogle Scholar
  • 6 Zecher D, Cumpelik A, Schifferli JA. Erythrocyte-derived microvesicles amplify systemic inflammation by thrombin-dependent activation of complement. Arterioscler Thromb Vasc Biol 2014; 34: 313-320.
    CrossrefPubMedGoogle Scholar
  • 7 Gersh KC, Nagaswami C, Weisel JW. Fibrin network structure and clot mechanical properties are altered by incorporation of erythrocytes. Thromb Haemost 2009; 102: 1169-1175.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Wohner N, Sotonyi P, Machovich R. et al. Lytic resistance of fibrin containing red blood cells. Arterioscler Thromb Vasc Biol 2011; 31: 2306-2313.
    CrossrefPubMedGoogle Scholar
  • 9 Suades R, Padro T, Vilahur G. et al. Growing thrombi release increased levels of CD235a(+) microparticles and decreased levels of activated platelet-derived microparticles. Validation in ST-elevation myocardial infarction patients. J Thromb Haemost 2015; 13: 1776-1786.
    CrossrefPubMedGoogle Scholar
  • 10 Yunoki K, Naruko T, Sugioka K. et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33: 1480-1490.
    CrossrefPubMedGoogle Scholar
  • 11 Reeder BJ, Svistunenko DA, Cooper CE. et al. The radical and redox chemistry of myoglobin and hemoglobin: from in vitro studies to human pathology. Antioxid Redox Signal 2004; 06: 954-966.
    CrossrefPubMedGoogle Scholar
  • 12 Jeney V, Balla J, Yachie A. et al. Pro-oxidant and cytotoxic effects of circulating heme. Blood 2002; 100: 879-887.
    CrossrefPubMedGoogle Scholar
  • 13 Schaer DJ, Buehler PW, Alayash AI. et al. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 2013; 121: 1276-1284.
    CrossrefPubMedGoogle Scholar
  • 14 Tolosano E, Fagoonee S, Morello N. et al. Heme scavenging and the other facets of hemopexin. Antioxid Redox Signal 2010; 12: 305-320.
    CrossrefPubMedGoogle Scholar
  • 15 Graw JA, Mayeur C, Rosales I. et al. Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells. Circulation 2016; 134: 945-960.
    CrossrefPubMedGoogle Scholar
  • 16 Cavusoglu E, Chopra V, Gupta A. et al. Usefulness of anemia in men as an independent predictor of two-year cardiovascular outcome in patients presenting with acute coronary syndrome. Am J Cardiol 2006; 98: 580-584.
    CrossrefPubMedGoogle Scholar
  • 17 Lee PC, Kini AS, Ahsan C. et al. Anemia is an independent predictor of mortality after percutaneous coronary intervention. J Am Coll Cardiol 2004; 44: 541-546.
    CrossrefPubMedGoogle Scholar
  • 18 Stone GW, Maehara A, Lansky AJ. et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011; 364: 226-235.
    CrossrefPubMedGoogle Scholar
  • 19 Cao RY, Zheng H, Guo J. et al. Prognostic value of plasma biomarkers in patients with acute coronary syndrome: a review of advances in the past decade. Biomark Med 2016; 10: 525-535.
    CrossrefPubMedGoogle Scholar
  • 20 Cubedo J, Padro T, Garcia-Arguinzonis M. et al. A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients. J Lipid Res 2015; 56: 1762-1773.
    CrossrefPubMedGoogle Scholar
  • 21 Cubedo J, Padro T, Cinca J. et al. Retinol-binding protein 4 levels and susceptibility to ischaemic events in men. Eur J Clin Invest 2014; 44: 266-275.
    CrossrefPubMedGoogle Scholar
  • 22 Cubedo J, Ramaiola I, Padro T. et al. High-molecular-weight kininogen and the intrinsic coagulation pathway in patients with de novo acute myocardial infarction. Thromb Haemost 2013; 110: 1121-1134.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Badimon L, Badimon JJ. Mechanisms of arterial thrombosis in nonparallel streamlines: platelet thrombi grow on the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J Clin Invest 1989; 84: 1134-1144.
    CrossrefPubMedGoogle Scholar
  • 24 Badimon L, Badimon JJ, Turitto VT. et al. Platelet thrombus formation on collagen type I. A model of deep vessel injury. Influence of blood rheology, von Willebrand factor, and blood coagulation. Circulation 1988; 78: 1431-1442.
    CrossrefPubMedGoogle Scholar
  • 25 Suades R, Padro T, Vilahur G. et al. Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques. Thromb Haemost 2012; 108: 1208-1219.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Ramaiola I, Padro T, Pena E. et al. Changes in thrombus composition and profilin-1 release in acute myocardial infarction. Eur Heart J 2015; 36: 965-975.
    CrossrefPubMedGoogle Scholar
  • 27 Cubedo J, Padro T, Alonso R. et al. ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia. J Lipid Res 2016; 57: 1059-1073.
    CrossrefPubMedGoogle Scholar
  • 28 Cubedo J, Padro T, Badimon L. Glycoproteome of human apolipoprotein A-I: N- and O-glycosylated forms are increased in patients with acute myocardial infarction. Transl Res 2014; 164: 209-222.
    CrossrefPubMedGoogle Scholar
  • 29 Cubedo J, Padro T, Garcia-Moll X. et al. Proteomic signature of Apolipoprotein J in the early phase of new-onset myocardial infarction. J Proteome Res 2011; 10: 211-220.
    CrossrefPubMedGoogle Scholar
  • 30 Barr JD, Chauhan AK, Schaeffer GV. et al. Red blood cells mediate the onset of thrombosis in the ferric chloride murine model. Blood 2013; 121: 3733-3741.
    CrossrefPubMedGoogle Scholar
  • 31 Yunoki K, Naruko T, Komatsu R. et al. Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes. Eur Heart J 2009; 30: 1844-1852.
    CrossrefPubMedGoogle Scholar
  • 32 Wagner KR, Sharp FR, Ardizzone TD. et al. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 2003; 23: 629-652.
    CrossrefPubMedGoogle Scholar
  • 33 Watanabe J, Grijalva V, Hama S. et al. Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein. J Biol Chem 2009; 284: 18292-18301.
    CrossrefPubMedGoogle Scholar
  • 34 Hare GM, Mu A, Romaschin A. et al. Plasma methemoglobin as a potential biomarker of anemic stress in humans. Can J Anaesth 2012; 59: 348-356.
    CrossrefPubMedGoogle Scholar
  • 35 Li RC, Saleem S, Zhen G. et al. Heme-hemopexin complex attenuates neuronal cell death and stroke damage. J Cereb Blood Flow Metab 2009; 29: 953-964.
    CrossrefPubMedGoogle Scholar
  • 36 Fokkema ML, Vlaar PJ, Svilaas T. et al. Incidence and clinical consequences of distal embolization on the coronary angiogram after percutaneous coronary intervention for ST-elevation myocardial infarction. Eur Heart J 2009; 30: 908-915.
    PubMedGoogle Scholar
  • 37 Vallelian F, Pimenova T, Pereira CP. et al. The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways. Free Radic Biol Med 2008; 45: 1150-1158.
    CrossrefPubMedGoogle Scholar
  • 38 Rother RP, Bell L, Hillmen P. et al. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. J Am Med Assoc 2005; 293: 1653-1662.
    CrossrefPubMedGoogle Scholar
  • 39 Patel RP, Gladwin MT. Physiologic, pathologic and therapeutic implications for hemoglobin interactions with nitric oxide. Free Radic Biol Med 2004; 36: 399-401.
    CrossrefPubMedGoogle Scholar
  • 40 Meyer C, Heiss C, Drexhage C. et al. Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function. J Am Coll Cardiol 2010; 55: 454-459.
    CrossrefPubMedGoogle Scholar
  • 41 Da Q, Teruya M, Guchhait P. et al. Free hemoglobin increases von Willebrand factor-mediated platelet adhesion in vitro: implications for circulatory devices. Blood 2015; 126: 2338-2341.
    CrossrefPubMedGoogle Scholar
  • 42 Yedgar S, Hovav T, Barshtein G. Red blood cell intercellular interactions in oxidative stress states. Clin Hemorheol Microcirc 1999; 21: 189-193.
    PubMedGoogle Scholar
  • 43 Chiang KH, Kao YT, Leu HB. et al. Higher post-acute myocardial infarction plasma haptoglobin level is associated with poor long-term overall survival. Int J Cardiol 2017; 229: 102-107.
    CrossrefPubMedGoogle Scholar
  • 44 Mehta NU, Reddy ST. Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases. Curr Opin Lipidol 2015; 26: 384-387.
    CrossrefPubMedGoogle Scholar
  • 45 Swedberg K, Young JB, Anand IS. et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013; 368: 1210-1219.
    CrossrefPubMedGoogle Scholar
  • 46 Silverberg DS, Wexler D, Blum M. et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003; 18: 141-146.
    CrossrefPubMedGoogle Scholar
  • 47 Cubedo J, Padro T, Pena E. et al. High Levels of Antifibrinolytic Proteins Are Found in Plasma of Older Octogenarians With Cardiovascular Disease and Cognitive Decline. J Am Coll Cardiol 2015; 65: 2667-2669.
    CrossrefPubMedGoogle Scholar