Sex-specific aspects of venous thromboembolism: What is new and what is next?

Men seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state-of-the-art research presented at the International Society on Thrombosis and Haemostasis Congress of 2021 with the available literature, we address potential explanations for this intriguing risk difference between men and women. We discuss the role of exogenous and endogenous sex hormones as the most important known sex-specific determinants of VTE risk. In addition, we highlight clues on the role of sex hormones and VTE risk from clinical scenarios such as pregnancy and the polycystic ovary syndrome. Furthermore, we address new potential sex-specific risk factors and unanswered research questions, which could provide more insight in the intrinsic risk difference between men and women, such as body height and differences in body fat distribution, leading to dysregulation of metabolism and inflammation.

ECTOPIC FAT DEPOSITION IN THE LIVER AND PANCREAS AND THE PRESENCE OF EXCESS VISCERAL ADIPOSE TISSUE SIGNIFICANTLY INCREASE HOSPITALISATION RISK FOLLOWING COVID-19

Background and Aims: In patients with COVID-19, obesity may increase risk of hospitalisation, use of mechanical ventilation and patient mortality. High liver fat, body mass index (BMI) and male sex are significant predictors of hospitalisation risk following COVID-19. However, BMI is a poor indicator of body fat distribution. Here, we studied ectopic fat accumulation within the liver and pancreas and body composition through multiparametric magnetic resonance (mpMR) and compared participants with and without hospitalisation for COVID-19. Method: Participants with laboratory-confirmed or clinically suspected SARSCoV- 2 infection were recruited to the COVERSCAN study (NCT04369807;median time from initial symptoms = 177 days) and underwent a multi-organ mpMR scan (CoverScan®, Perspectum Ltd). Measures of liver and pancreatic fat (PDFF), liver fibroinflammation (cT1) and body composition [visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle index (SMI)] were analysed. Differences between participants hospitalised (n = 59) and not hospitalised (n = 348) for COVID-19 were assessed using Wilcoxon signedrank tests. Univariate and multivariate analyses were performed on all biomarkers to assess the hospitalisation risk. Data presented are median values. Results: Approximately 6-months after initial symptoms, participants hospitalised following COVID-19 had significantly elevated pancreatic fat (3.8 % vs 2.8 %, p < 0.01), liver fat (3.8 % vs 2.4 %, p < 0.01) and liver cT1 (735ms vs 706ms, p < 0.01) compared to those who convalesced at home. Though hospitalised participants had a significantly elevated BMI (27 kg/m2 vs 25 kg/m2, p = 0.014), it was VAT, but not SAT, that was significantly elevated (132 cm2 vs 86 cm2, p < 0.01). Univariate analysis revealed that male sex, advanced age and elevated BMI, VAT, pancreatic fat, liver fat, and liver cT1 were all significantly predictive of hospitalisation following COVID- 19. In multivariate analysis, only age remained significantly predictive of hospitalisation. In hospitalised people with obesity (³ 30 kg/m2), VAT, liver cT1 and liver fat, but not BMI nor pancreatic fat, remained significantly elevated [VAT: 220 cm2 vs 152cm2, p = 0.01 (Figure 1);liver fat: 9.9 % vs 4.2 %, p = 0.003;liver cT1: 782ms vs 742ms, p = 0.012]. Conclusion: mpMR revealed significantly elevated visceral and ectopic fat deposition within the liver and pancreas in hospitalised participants following COVID-19. In obese participants, BMI was not significantly different in hospitalised, and non-hospitalised patients, whereas visceral fat, liver fibroinflammation and liver fat were significantly elevated. Our work highlights body fat distribution an important consideration for COVID-19 risk profiling, which cannot be sufficiently evaluated based on BMI alone. (Figure Presented) Figure 1. Comparison of liver fat (left), pancreatic fat (middle) and visceral adipose tissue (right) between participants hospitalised and not hospitalised following COVID-19.

Hemostatic alterations linked to body fat distribution, fatty liver, and insulin resistance.

OBJECTIVE: Obesity, in particular visceral obesity, and insulin resistance emerged as major risk factors for severe coronavirus disease 2019 (COVID-19), which is strongly associated with hemostatic alterations. Because obesity and insulin resistance predispose to thrombotic diseases, we investigated the relationship between hemostatic alterations and body fat distribution in participants at risk for type 2 diabetes. SUBJECTS: Body fat distribution (visceral and subcutaneous abdominal adipose tissue) and liver fat content of 150 participants - with impaired glucose tolerance and/or impaired fasting glucose - were determined using magnetic resonance imaging and spectroscopy. Participants underwent precise metabolic characterization and major hemostasis parameters were analyzed. RESULTS: Procoagulant factors (FII, FVII, FVIII, and FIX) and anticoagulant proteins (antithrombin, protein C, and protein S) were significantly associated with body fat distribution. In patients with fatty liver, fibrinogen (298 mg/dl vs. 264 mg/dl, p = 0.0182), FVII (99% vs. 90%, p = 0.0049), FVIII (114% vs. 90%, p = 0.0098), protein C (124% vs. 111%, p = 0.0006), and protein S (109% vs. 89%, p < 0.0001) were higher than in controls. In contrast, antithrombin (97% vs. 102%, p = 0.0025) was higher in control patients. In multivariate analyses controlling for insulin sensitivity, body fat compartments, and genotype variants (PNPLA3I148MM/MI/TM6SF2E167kK/kE), only protein C and protein S remained significantly increased in fatty liver. CONCLUSIONS: Body fat distribution is significantly associated with alterations of procoagulant and anticoagulant parameters. Liver fat plays a key role in the regulation of protein C and protein S, suggesting a potential counteracting mechanism to the prothrombotic state in subjects with prediabetes and fatty liver.

Impact of body composition on COVID-19 susceptibility and severity: A two-sample multivariable Mendelian randomization study.

OBJECTIVES: Recent studies suggested obesity to be a possible risk factor for COVID-19 disease in the wake of the coronavirus (SARS-CoV-2) infection. However, the causality and especially the role of body fat distribution in this context is still unclear. Thus, using a univariable as well as multivariable two-sample Mendelian randomization (MR) approach, we investigated for the first time the causal impact of body composition on the susceptibility and severity of COVID-19. METHODS: As indicators of overall and abdominal obesity we considered the measures body mass index (BMI), waist circumference (WC), and trunk fat ratio (TFR). Summary statistics of genome-wide association studies (GWASs) for these body composition measures were drawn from the GIANT consortium and UK Biobank, while for susceptibility and severity due to COVID-19 disease data from the COVID-19 Host Genetics Initiative was used. For the COVID-19 cohort neither age nor gender was available. Total and direct causal effect estimates were calculated using Single Nucleotide Polymorphisms (SNPs), sensitivity analyses were done applying several robust MR techniques and mediation effects of type 2 diabetes (T2D) and cardiovascular diseases (CVD) were investigated within multivariable MR analyses. RESULTS: Genetically predicted BMI was strongly associated with both, susceptibility (OR = 1.31 per 1 SD increase; 95% CI: 1.15-1.50; P-value = 7.3·10-5) and hospitalization (OR = 1.62 per 1 SD increase; 95% CI: 1.33-1.99; P-value = 2.8·10-6) even after adjustment for genetically predicted visceral obesity traits. These associations were neither mediated substantially by T2D nor by CVD. Finally, total but not direct effects of visceral body fat on outcomes could be detected. CONCLUSIONS: This study provides strong evidence for a causal impact of overall obesity on the susceptibility and severity of COVID-19 disease. The impact of abdominal obesity was weaker and disappeared after adjustment for BMI. Therefore, obese people should be regarded as a high-risk group. Future research is necessary to investigate the underlying mechanisms linking obesity with COVID-19.