Thromb Haemost 2019; 119(05): 766-778
DOI: 10.1055/s-0039-1681061
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Transferrin Saturation Inversely Correlates with Platelet Function

Cristina Barale
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
,
Rouslan Senkeev
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
,
Franca Napoli
2  San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
,
Marco De Gobbi
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
,
Angelo Guerrasio
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
,
Alessandro Morotti*
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
,
Isabella Russo*
1  Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy
› Author Affiliations
Funding This work was supported by grants from the Department of Clinical and Biological Sciences of Turin University (Ricerca Locale Ex-60%) to I.R. (RUSI_RILO_13, RUSI_RILO_15, RUSI_RILO_17), A.M. (MORA_RILO_16) and M.D.G. (DEGM_RILO_15).
Further Information

Publication History

27 August 2018

17 January 2019

Publication Date:
12 March 2019 (eFirst)

Abstract

Background The association between iron overload (IO) and risk of cardiovascular disease is controversial. Epidemiological studies have found a significant negative association of transferrin (Tf) saturation and cardiovascular events suggesting that higher body iron possibly confer a protective effect towards developing cardiovascular events. The biological mechanisms of this phenomenon are unknown.

Objective This article investigates the role of IO on platelet reactivity.

Materials and Methods This study was a prospective case–control study comparing 45 patients with IO, mostly characterized by the HFE gene mutations C282Y and/or H63D, with 32 healthy controls. We evaluated: (1) platelet aggregation in both platelet-rich plasma and whole blood, (2) platelet membrane expression of the activation marker CD62P, (3) activation of platelet signalling phosphoinositide 3-kinase /Akt and mitogen-activated protein kinase/extracellular signal-regulated kinases (Erk)-1/2 pathways, (4) a pattern of in vivo platelet activation markers, and (5) iron biomarker predictors of platelet reactivity.

Results IO patients had significantly lower platelet aggregability, expression of CD62P and phosphorylation amounts of pAkt and pErk-2 in response to agonists. Furthermore, patients with higher Tf saturation levels were characterized by lower circulating levels of sCD40L, PDGF-BB and thromboxane B2. Platelet aggregation and activation parameters inversely correlated with Tf saturation and the stepwise multivariate regression analysis underlined the role of Tf saturation in predicting platelet reactivity. We also found that in vitro platelet exposure to diferric Tf, but not to iron-depleted TF, dose-dependently inhibited platelet function in all investigated subjects.

Conclusion Tf saturation is inversely associated with platelet reactivity and this could explain, at least in part, the association of high Tf and lower risk of cardiovascular diseases in IO.

Authors' Contributions

Conception and study design: I.R. and A.M. Performing platelet function studies: C.B., R.S. and I.R. Statistical analyses: I.R. and R.S. Interpretation of the data: I.R., C.B., R.S., A.G. and A.M. Drafting the article: C.B., I.R. and A.M. Revising the manuscript critically for important intellectual content: M.D.G., F.N., A.G., A.M. and I.R. All authors gave their consent to the final version of the manuscript.


* Alessandro Morotti and Isabella Russo contributed equally to this work.