In the present study, coagulation proteins and interleukins were evaluated in different body phenotype groups. As expected, alterations in coagulation proteins were found in the MHO and MUO groups. However, it was also identified that participants with MUNW had alterations in their hemostasis and interleukin profiles.
The correlation between obesity and insulin resistance is widely acknowledged. However, research has demonstrated that individuals with a normal body weight can also develop insulin resistance, predisposing them to develop T2DM, a chronic proinflammatory state.10,11 While typical HOMA-IR ranges have been set at greater than 2.8 to determine insulin resistance, machine learning approaches have identified lower cut off values such as 1.62 as being indicative of individuals with early insulin resistance.12 In our results, MUNW and MUO had significantly higher median HOMA-IR values (3.4 and 4.4 respectively) in the ranges of insulin resistance, however, all measured groups had HOMA-IR ranges above the cut off value of 1.62, including in the MHNW and MHO (1.92 and 2.4 respectively). In similar population it has been observed elevated HOMA-IR it has been observed in a similar population.13 Studies have shown that HOMA-IR, is strictly related to visceral fat and is an index of metabolic impairment, a factor that directly contributes to the development of atherogenesis and vascular impairment in patients with and without obesity.14 Therefore irrespective of BMI composition, our results show that the utilization of HOMA-IR can serve as a predictive tool for early vascular damage.
Endothelial damage is significantly influenced by lipid levels, which are a prominent modifiable risk factor.15 Among these lipid measurements, triglycerides are particularly impacted by insulin resistance and independently contribute to the risk of developing T2DM.16 When stratifying by ethnic and racial category, Asian populations tend to develop T2DM and metabolic syndrome at lower BMI values than other populations, including those of Hispanic origin.17–19 Additionally, elevated triglycerides > 150 mg/dL, specifically in Hispanic populations, has been associated in past research with an increased risk of endothelial degeneration related to atheromatous changes in the vessels.20,21 High triglyceride levels (> 150 mg/dL) have been shown to be significantly associated with the development of endothelial dysfunction, including in MHNW and MUNW subjects.22,23 Our analysis revealed that both the MHNW and MUNW groups, as well as the MUO, exhibited triglyceride levels > 150 mg/dL. These findings based on previous studies, indicate that despite their non-obese status, these groups are at high risk for chronic inflammatory conditions that can potentially result in endothelial damage.24
Atherosclerotic disease can be induced by LDL-c, and groups with LDL-c levels equal to or exceeding 100 mg/dL have a significantly increased long-term risk of developing coronary heart disease (CHD) and experiencing cardiovascular mortality.25–27 Our results show LDL-c as > 100mg/dl in both MUO and MUNW with significantly higher levels in MUNW. The results suggest that MUNW individuals are also susceptible to endothelial damage and chronic inflammation as a result of significantly elevated LDL-c.
Excess adipose tissue is known to contribute to proinflammatory and procoagulant effects, resulting in a 2.5-fold higher risk of venous and arterial thromboembolism.28 Coagulation activation is largely mediated by inflammatory cytokines.29 BMI and recurrent venous thromboembolism (VTE) has also been shown to have a significant association.30 For example, in one analysis, a 10-point increase in BMI elevated the risk of recurrent VTE by 24%.31 Moreover, in a retrospective analysis focusing on young patients, obesity was linked to an increased likelihood of recurrent VTE.32 Patients with obesity demonstrate hypercoagulability compared to their similarly normal weight counterparts, as evidenced by increased factor IX activity, higher levels of functioning fibrinogen, relative thrombocytosis, stronger clot formation, and decreased evidence of clot lysis with increasing BMI.28 Additionally, in obesity, it is observed higher levels of factor VII, VIII, IX, and factor IX.28,32–37 The results of our study show these previously demonstrated obesity related increases in coagulation factors consistently in both MHO and MUO patients. Firstly, both FV and FIX, which play roles in fibrin clot formation, were found to be elevated in groups with obesity, regardless of their metabolic health status. This suggests a pro-thrombotic effect associated with obesity irrespective of metabolic health status. MUO patients showed higher levels of these factors compared to their metabolically healthy counterparts. FVIII, another pro-coagulant factor, was also found to be higher in MHO and MUO groups, consistent with the elevated levels of vWF, which is stabilized by FVIII. Conversely, MUO patients exhibited lower levels of vWF, likely due to the faster depletion of FVIII.
Metabolic syndrome leads to elevated inflammatory, endothelial, and pro-coagulant biomarkers, leading to a hypercoagulable state.38,39 Metabolic syndrome empirically has an impact on hyperglycemia and coagulation factors.37 Consistently, research has supported that an altered metabolism exerts a pro-thrombotic effect on coagulation factors.13 One of the mechanisms through which metabolic syndrome influences coagulation factor levels is the degradation of the glycocalyx, which is a protective layer present on the vessel wall, commonly seen in chronic states of inflammation such as obesity, sepsis and severe trauma.28,40 This degradation is induced by hyperglycemia and can lead to an elevation in coagulation factor levels. Our results showed that obesity led to an increase in PS, an anticoagulant, as a compensatory response to counteract the chronic pro-inflammatory state associated with obesity. These findings highlight the pro-thrombotic nature of obesity and emphasize the importance of distinguishing between MHO and MUO individuals in understanding their coagulation profiles. Consistent pro-coagulation markers in both MHO and MUO patients, as well as pathologically elevated metabolic markers in normal weight groups, underscores the need for comprehensive biochemical evaluations in patients with obesity and acknowledges the potential abnormalities present in both individuals with and without obesity.
IL-6 and IL-1 play pivotal roles in activating the coagulation cascade by up-regulating tissue factor expression.41–43 This leads to elevated levels of FVIII and FIX in part as seen from the correlation significance results.41–43 In the process of chronic inflammation IL-6 and IL-1 impair both the activity of PC and AT, explaining our findings.40,43 Furthermore, IL-1 and IL-6 enhances the production of tumor necrosis factor-alpha (TNF-α), which in turn induces procoagulant activity on endothelial cell surfaces.44,45 TNF-α was also analyzed and found to also be significantly correlated with coagulation factors FVIII and FIX, which aligns with its complementary mechanism of action with IL-6. TNF-α is a well-known pro-inflammatory protein that activates receptors on erythrocytes and platelets, core to disrupting macrovascular and microvascular circulation.46
Conversely, IL-10 acts as a suppressor of the coagulation cascade. It moderates the immune response by inhibiting (LPS)-induced tissue factor expression.47 Our findings show a significant negative correlation between IL-10 and coagulation factors FII, FV, FVII, FXI, and FXII. Additionally, IL-10 exerts its anti-inflammatory effects by inhibiting IL-6, TNF-α, and prostaglandins E1 and E2, thereby countering chronic inflammation.48
To our knowledge this is the first study to recognize the differences in coagulation proteins and their relationship with interleukins, according to body size phenotype. A limitation of the study is its cross-sectional design, so future studies with a case-control or follow-up design should be done to identify whether hemostatic and interleukin alterations could determine thrombotic events. Additionally, no male patients were included in this study, potentially resulting in lack of generalizability to the overall population. Future studies should include both male and female sexes.
Another limitation of the study is that the metabolically healthy groups, that is, MHNW and MHO, presented a low frequency, compared to other studies with populations where a higher frequency has been identified.49 In this regard, a high prevalence of metabolic diseases such as T2DM, dyslipidemia and obesity has been observed in our population, which according to the most recent National Health Survey 2022, is 18.3%, 30.6% and 36.9% respectively, in the adult population.50