Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans

Susanna Lallukka; Panu K. Luukkonen; You Zhou; Elina Isokuortti; Marja Leivonen; Anne Juuti; Antti Hakkarainen; Marju Orho-Melander; Nina Lundbom; Vesa M. Olkkonen; Riitta Lassila; Hannele Yki-Järvinen

doi:10.1160/TH16-09-0716

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(02): 286-294
DOI: 10.1160/TH16-09-0716

Coagulation and Fibrinolysis

Schattauer GmbH

Obesity/insulin resistance rather than liver fat increases coagulation factor activities and expression in humans

Susanna Lallukka

¹Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

,

Panu K. Luukkonen

¹Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

,

You Zhou

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

,

Elina Isokuortti

¹Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

,

Marja Leivonen

³Department of Surgery, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

,

Anne Juuti

³Department of Surgery, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

,

Antti Hakkarainen

⁴Helsinki Medical Imaging Center, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

,

Marju Orho-Melander

⁵Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden

,

Nina Lundbom

⁴Helsinki Medical Imaging Center, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

,

Vesa M. Olkkonen

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

,

Riitta Lassila

⁶Coagulation Disorders Unit, Department of Hematology, and HUSLAB Laboratory Services, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

,

Hannele Yki-Järvinen

¹Department of Medicine, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

²Minerva Foundation Institute for Medical Research, Helsinki, Finland

› Author Affiliations

Abstract

Summary

Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant (‘IR’) versus insulin-sensitive (‘IS’)] and PNPLA3 genotype (PNPLA3^148MM/MI vs PNPLA3^148II). Liver fat content (¹H-MRS) was similarly increased in ‘IR’ (13 ± 1 %) and PNPLA3^148MM/MI (12 ± 2 %) as compared to ‘IS’ (6 ± 1 %, p < 0.05) and PNPLA3^148II (8 ± 1 %, p < 0.05), respectively. FVIII, FIX, FXIII, fibrinogen and VWF:RCo activities were increased, and PT and APTT shortened in ‘IR’ versus ‘IS’, in contrast to these factors being similar between PNPLA3^148MM/MI and PNPLA3^148II groups. In subjects undergoing a liver biopsy and entirely lacking the I148M variant, insulin-resistant subjects had higher hepatic expression of F8, F9 and FGG than equally obese insulin-sensitive subjects. Expression of pro-inflammatory genes in adipose tissue correlated positively with PT (% of normal), circulating FVIII, FIX, FXI, VWR:RCo and fibrinogen, and expression of anti-inflammatory genes negatively with PT (%), FIX and fibrinogen. We conclude that obesity/insulin resistance rather than an increase in liver fat is associated with a procoagulant plasma profile. This reflects adipose tissue inflammation and increased hepatic production of coagulation factors and their susceptibility for activation.

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

Keywords

Adipose tissue - inflammation - fibrinogen - insulin - Non-alcoholic fatty liver disease

Full Text

References

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