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

Thromb Haemost 2017 01 8;117(2):286-294. Epub 2016 Dec 8.

Susanna Lallukka, MD, Minerva Institute for Medical Research, Biomedicum Helsinki 2U, Room DP02b, Tukholmankatu 8, 00290 Helsinki, Finland, Tel.: +358 2941 25708, Fax: +358 9 471 71896, E-mail:

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 vs PNPLA3). Liver fat content (H-MRS) was similarly increased in 'IR' (13 ± 1 %) and PNPLA3 (12 ± 2 %) as compared to 'IS' (6 ± 1 %, p<0.05) and PNPLA3 (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 and PNPLA3 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.

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http://dx.doi.org/10.1160/TH16-09-0716DOI Listing

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January 2017
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