Hemostatic factors, inflammatory markers, and risk of incident venous thromboembolism: The Multi‐Ethnic Study of Atherosclerosis

Abstract

Background Several hemostatic factors and inflammatory markers are associated with the risk of incident venous thromboembolism (VTE), however, most existing data are from case‐control studies in Caucasian populations. Objectives We aimed to prospectively confirm previous findings and explore less studied biomarkers in relation to VTE risk in a multi‐racial/multi‐ethnic cohort. Methods Circulating levels of factor VIII, fibrinogen, D‐dimer, plasmin‐antiplasmin complex (PAP), C‐reactive protein (CRP), and interleukin‐6 (IL‐6) were measured at baseline (2000–2002) in 6706 participants of the Multi‐Ethnic Study of Atherosclerosis. Incident VTE was identified using hospitalization discharge codes from baseline to December 31, 2015. Hazard ratios (HRs) of VTE were estimated in Cox regression models. Results There were 227 events during a median of 14 years of follow‐up. Compared with participants in the lowest quartile, the HRs for those above the 95th percentile and p for trend across categories were 3.50 (95% confidence interval [CI] 1.98–6.19; p < .001) for D‐dimer, 1.49 (95% CI 0.84–2.63; p = .02) for factor VIII, 1.32 (95% CI 0.76–2.28; p = .99) for fibrinogen, 1.92 (95% CI 1.08–3.42; p = .15) for PAP, 1.68 (95% CI 0.81–3.48; p = .08) for CRP, and 2.55 (95% CI 1.15–5.66; p = .07) for IL‐6, after adjustment for demographics and body mass index. For CRP and IL‐6, follow‐up was restricted to 10 years because of violations of the proportional hazards assumption. No significant interactions by age/ethnicity were observed. Conclusions We demonstrated a fairly novel association between PAP and risk of incident VTE, and contributed further prospective confirmation regarding the associations of D‐dimer, factor VIII, and IL‐6 with VTE.

Elevated plasma D-dimer levels are associated with risk of future incident venous thromboembolism

“…Among several tested biomarkers, higher D-dimer levels were associated with increased risk of VTE in multivariable-adjusted models [15]. Our results are in line with the previous studies [13][14][15][16]35], as we found that higher D-dimer levels were associated with an increased risk of incident VTE, but according to our results, such an association was partly explained by BMI and inflammation. In fact, none of the aforementioned studies [13][14][15][16]35] made adjustment for low-grade systemic inflammation, as assessed by CRP levels.…”

“…The authors later expanded plasma D-dimer measurements in the ARIC population and found that D-dimer levels were related to increased risk of future VTE in a dose-response manner even with more than 10 years of follow-up, in analyses adjusted for age, race, and sex [14]. Additionally, results from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort with a median of 14 years of follow-up, showed that elevated D-dimer levels were associated with increased risk of incident VTE independently of age, sex, race/ethnicity, education, field center, BMI, diabetes, and estimated glomerular filtration rate [16]. In a nested case-control study (215 VTE cases and 867 controls) derived from the Women's Health Initiative hormone trials, which comprised postmenopausal women, Cushman et al investigated several biomarkers with regards to risk of future VTE [35].…”

“…In addition, multiple studies have found that elevated levels of D-dimer measured mainly after stopping anticoagulant treatment are associated with increased risk of recurrence in patients with unprovoked VTE [10][11][12]. Conversely, only a few studies have investigated the association between baseline D-dimer levels and the risk of a future first lifetime VTE in the general population [13][14][15][16]. In these studies, a higher baseline D-dimer value was associated with increased risk of incident VTE [13][14][15][16].…”

“…Conversely, only a few studies have investigated the association between baseline D-dimer levels and the risk of a future first lifetime VTE in the general population [13][14][15][16]. In these studies, a higher baseline D-dimer value was associated with increased risk of incident VTE [13][14][15][16].…”

High Levels of Complement Activating Enzyme MASP-2 Are Associated With the Risk of Future Incident Venous Thromboembolism

“…21 Second, in vitro studies have shown that activated MASP-2 can cleave prothrombin to thrombin with subsequent fibrin formation, 20,22,23 and several observational studies have shown that a high degree of coagulation activation is associated with the risk of future VTE. [51][52][53][54] Third, experimental studies in mouse models of arterial thrombosis have shown that inhibition of MASP-2, either by genetic deficiency or antibody neutralization, caused smaller myocardial infarct sizes 30,31 and less cerebral infarct volumes and neurological deficits. 28 Supporting these observations, the multiple interactions between the lectin complement pathway and the coagulation system, as well as key complement factors (eg, C3, C5, and the terminal complement complex) that have been shown to associate with the risk of future VTE, are summarized in Figure 6 and Table S4.…”