The Risk of Venous Thrombosis Related to Increase in Body Mass Index Is Mediated by Factor VIII Induced APC-Resistance.
Authors: Lijfering Willem M , Christiansen Sverre C , Naess Inger-Anne , Hammerstrøm Jens , van Hylckama Vlieg Astrid , Rosendaal Frits , Cannegieter Suzanne C 
Published: October 2019

Abstract
Abstract 453

Background:
The reason why a high BMI predisposes to venous thrombosis is not clarified. People with overweight or obesity tend to be more immobile which may lead to clot formation through stasis. It is also possible that these subjects acquire a prothrombotic state. Factor (F) VIII can be released by adipose tissue through inflammatory cytokines, which consequently might induce APC-resistance. This APC-resistance could be aggravated in case FV Leiden is also present. In addition, presence of high levels of FVIII in non-O blood group subjects could worsen this further.

Objective:
To determine whether an association exists between BMI and APC-resistance, and whether the combination of both high BMI and APC-resistance increased the risk of venous thrombosis in the Leiden Trombophilia Study (LETS). Whether increasing FVIII levels induced APC-resistance was also studied. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified if FV Leiden modified the risk of increasing BMI on the occurence of venous thrombosis and whether these risks were further increased by blood group non-O.

Methods:
Linear regression was used to determine the relation between increasing APC-resistance and BMI, increasing FVIII levels and BMI, increasing APC-resistance and FVIII levels, and between increasing APC-resistance and BMI adjusted for FVIII levels. Cut-off points needed to create tertile categories of APC-resistance were derived from the control-group of the LETS and the TROL population separately. Logistic regression was used to calculate odds ratios and their 95% confidence intervals, adjusted for age and sex. To make the TROL and LETS population more similar for the current analysis, we restricted the analysis in the TROL subjects to those who were younger than 70 and to those who had a DVT only (n=183 cases and n=696 controls).

Results:
APC-resistance increased linearly with increasing BMI. A same phenomenon was observed for FVIII, i.e. an increase of BMI led to higher FVIII levels. Increased APC-resistance was in its turn associated with an increase of FVIII levels. FVIII explained part of the relation between APC and BMI, as the slope of the regression line of APC-resistance on BMI levels decreased after adjustment for FVIII. To examine the effect of increasing BMI, independent of existing APC-resistance, on the risk of venous thrombosis, we restricted the analysis to subjects from the LETS in whom APC-resistance was not related to other factors such as FV Leiden or oral contraceptive use. In these subjects (n=237 cases and n=369 controls), the risk of venous thrombosis increased 1.4-fold for those with a BMI in the median tertile (odds ratio 1.4; 95% CI, 0.9-2.3) and 2.5-fold for those in the upper tertile (odds ratio 2.5; 95% CI, 1.6-3.9), as compared to subjects in the lowest tertile. Adjustment for APC-resistance or FVIII led to a slight decrease in these relative risk estimates. Non-FV Leiden-carriers with blood group O were only at risk of venous thrombosis when they had a BMI in the upper tertile compared to non-FV Leiden-carriers with blood group O and a BMI in the lowest tertile; (adjusted odds ratio 1.9). This risk was modestly increased when non FV Leiden carriers with non-O blood group were compared with this reference group, with adjusted odds ratios of 1.5, 2.4 and 3.4, respectively, within the BMI tertiles. This risk was strongly increased when FV Leiden carriers with blood group O were compared to the reference group, with adjusted odds ratios of 3.0, 8.3 and 9.7, respectively, within the BMI tertiles. Risk of FV Leiden carriers with non-O blood group showed the highest risk of venous thrombosis compared to the reference group, no longer in a dose-response way, with adjusted odds ratios of 40.6, 23.3 and 25.2, respectively, within the BMI tertiles.

Conclusion:
The increased risk of venous thrombosis in subjects with high BMI is mediated by FVIII induced APC-resistance. Subjects with FV Leiden and increasing BMI had a higher risk of venous thrombosis compared to non-carriers, and this risks was more than 20 fold increased in carriers of blood group non-O and FV Leiden. Future studies are needed to show if these risks can be downgraded by weight loss.

Disclosures:
No relevant conflicts of interest to declare.