Surgery As a Trigger for Incident Venous Thromboembolism: Results from a Population-Based Case-Crossover Study

Background Surgery is a major transient risk factor for venous thromboembolism (VTE). However, the impact of major surgery as a VTE trigger has been scarcely investigated using a case-crossover design. Aim To investigate the role of major surgery as a trigger for incident VTE in a population-based case-crossover study while adjusting for other concomitant VTE triggers. Methods We conducted a case-crossover study with 531 cancer-free VTE cases derived from the Tromsø Study cohort. Triggers were registered during the 90 days before a VTE event (hazard period) and in four preceding 90-day control periods. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to major surgery and after adjustment for other VTE triggers. Results Surgery was registered in 85 of the 531 (16.0%) hazard periods and in 38 of the 2,124 (1.8%) control periods, yielding an OR for VTE of 11.40 (95% CI: 7.42–17.51). The OR decreased to 4.10 (95% CI: 2.40–6.94) after adjustment for immobilization and infection and was further attenuated to 3.31 (95% CI: 1.83–5.96) when additionally adjusted for trauma, blood transfusion, and central venous catheter. In a mediation analysis, 51.4% (95% CI: 35.5–79.7%) of the effect of surgery on VTE risk could be mediated through immobilization and infection. Conclusions Major surgery was a trigger for VTE, but the association between surgery and VTE risk was in part explained by other VTE triggers often coexisting with surgery, particularly immobilization and infection

Hand grip strength in venous thromboembolism: risk of recurrence and mortality

Background - There is limited information on the relationship between muscle strength and recurrence and mortality after incident venous thromboembolism (VTE). Objectives - To investigate whether weak hand grip strength (HGS) was associated with risk of recurrence and mortality in patients with VTE recruited from the general population. Methods - Participants from the Tromsø Study with a first-time VTE (n = 545) were included, and all VTE recurrences and deaths among the participants were recorded in the period 1994 to 2020. Weak HGS was defined as lowest 25th percentile of the general population, and incidence rates for VTE recurrence and mortality according to weak vs normal (>25th percentile) HGS, with 95% CIs, were estimated. Results - There were 90 recurrences and 350 deaths during a median of 3.7 years of follow-up. The fully adjusted hazard ratio (HR) for overall VTE recurrence for those with weak HGS vs those with normal HGS was 2.02 (95% CI, 1.23-3.30). The corresponding HRs for recurrence were 2.22 (95% CI, 1.18-4.17) in patients with a first deep vein thrombosis and 1.60 (95% CI, 0.72-3.57) in patients with a first pulmonary embolism. The cumulative 1-year survival was 74.9% and 77.8% in those with weak and normal HGS, respectively. For overall mortality after incident VTE, the fully adjusted HR for those with weak HGS was 1.34 (95% CI, 1.04-1.72). Conclusion - Weak HGS was associated with an increased risk of recurrent VTE, and the association appeared to be particularly pronounced after incident deep vein thrombosis. There was a slightly lower survival probability among those with weak HGS than among those with normal HGS

Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review

Identification of individuals with ischemic stroke at particularly high risk of venous thromboembolism (VTE) is crucial for targeted thromboprophylaxis. To guide clinical decision-making and development of risk prediction models, increased knowledge on risk factors and biomarkers is needed. Therefore, we set out to identify risk factors and predictors for VTE in people with ischemic stroke by conducting a systematic review of the literature. Medline and Embase were searched from January 1990 and onwards. Studies investigating demographic, clinical, and/or laboratory factors for stroke-related VTE were considered. Two reviewers screened all retrieved records, independently and in duplicate. Risk of bias assessments were guided by a structured framework (PROSPERO-ID: CRD42020176361). Of 4674 identified records, 26 studies were included. Twenty-six demographic, clinical, and laboratory factors associated with increased risk of stroke-related VTE after multivariable adjustments were identified. The following factors were reported by ≥2 studies: prior VTE, cancer, prestroke disability, leg weakness, increasing lesion volume of the brain infarct, infection, low Barthel Index, increasing length of hospital stay, biochemical indices of dehydration, as well as elevated levels of D-dimer, C-reactive protein, and homocysteine. The majority of the studies were of poor quality with moderate or high risk of bias. In conclusion, this systematic review informs on several potential risk factors and predictors for VTE in people with ischemic stroke. To improve risk stratification and guide development of risk prediction models, further confirmation is needed because there were few high-quality studies on each factor

Hand grip strength and risk of incident venous thromboembolism: The Tromsø study

Background Hand grip strength (HGS), a common proxy of whole-body muscular strength, is associated with a wide range of adverse health outcomes and mortality. However, there are limited data on the association between HGS and risk of venous thromboembolism (VTE). Objectives We aimed to investigate the association between HGS and risk of incident VTE in a population-based cohort. Methods Participants (n = 13,704) from the fourth to seventh surveys of the Tromsø study (Tromsø4–Tromsø7, enrollment: 1994–2016) were followed throughout 2020, and all incident VTEs were recorded. HGS of the nondominant hand was measured using a Martin Vigorimeter (Tromsø4–Tromsø6) and a Jamar Digital Dynamometer (Tromsø7). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) according to weak HGS (less than 25th percentile) versus normal HGS (25th percentile or greater) were estimated using Cox regression models and adjusted for age, sex, body height, body mass index, physical activity, cardiovascular disease, and cancer. Results During a median of 6.5 years of follow-up, 545 incident VTEs occurred. Participants with weak HGS had a 27% higher risk of VTE (HR, 1.27; 95% CI, 1.03–1.57) compared to those with normal HGS. Subgroup analyses revealed that the point estimates were higher for unprovoked VTE (HR, 1.35; 95% CI, 0.96–1.91) and deep vein thrombosis (DVT; HR, 1.52; 95% CI, 1.14–2.01). Similar results were found in analyses restricted to men, women, and elderly (aged greater than 75 years). Conclusion A weak HGS was associated with increased risk of VTE, and particularly unprovoked VTE and isolated DVT. Our findings suggest that weak muscle strength may be a risk factor for VTE

Joint effect of myocardial infarction and obesity on the risk of venous thromboembolism: The Tromsø Study

Background: Myocardial infarction (MI) is associated with an increased risk of venous thromboembolism (VTE). Obesity is a recognized risk factor for both MI and VTE. Whether obesity further increases the risk of VTE in MI patients is scarcely investigated. Aim: To study the joint effect of MI and obesity on the risk of VTE. Methods: Study participants (n = 29 410) were recruited from three surveys of the Tromsø Study (conducted in 1994–1995, 2001, and 2007–2008) and followed up through 2014. All incident MI and VTE cases during follow-up were recorded. Cox regression models with MI as a time-dependent variable were used to estimate hazard ratios (HRs) of VTE (adjusted for age and sex) by combinations of MI exposure and obesity status. Joint effects were assessed by calculating relative excess risk and attributable proportion (AP) due to interaction. Results: During a median of 19.6 years of follow-up, 2090 study participants experienced an MI and 784 experienced a VTE. Among those with MI, 55 developed a subsequent VTE, yielding an overall incidence rate (IR) of VTE of 5.3 per 1000 personyears (95% confidence interval [CI]: 4.1–6.9). In the combined exposure group (MI+/ Obesity+), the IR was 11.3 per 1000 person-years, and the adjusted HR indicated a 3-fold increased risk of VTE (HR 3.16, 95% CI: 1.99–4.99) compared to the reference group (MI−/Obesity−). The corresponding AP was 0.46 (95% CI: 0.17–0.74). Conclusions: The combination of MI and obesity yielded a supra-additive effect on VTE risk of which 46% of the VTE events were attributed to the interaction

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

Background: Experimental studies have shown that the complement activating enzyme MASP-2 (mannose-binding lectin associated serine protease 2) exhibits a thrombin-like activity and that inhibition of MASP-2 protects against thrombosis. In this study, we investigated whether plasma MASP-2 levels were associated with risk of future venous thromboembolism (VTE) and whether genetic variants linked to MASP-2 levels were associated with VTE risk. Methods: We conducted a population-based nested case-control study involving 410 VTE patients and 842 age- and sex-matched controls derived from the Norwegian Tromsø Study. Logistic regression was used to estimate odds ratios (ORs) of VTE across MASP-2 quartiles. Whole-exome sequencing and protein quantitative trait loci analyses were performed to assess genetic variants associated with MASP-2 levels. A 2-sample Mendelian randomization study, also including data from the INVENT consortium (International Network of Venous Thrombosis), was performed to assess causality. Results: Subjects with plasma MASP-2 in the highest quartile had a 48% higher OR of VTE (OR, 1.48 [95% CI, 1.06–2.06]) and 83% higher OR of deep vein thrombosis (OR, 1.83 [95% CI, 1.23–2.73]) compared with those with MASP-2 levels in the lowest quartile. The protein quantitative trait loci analysis revealed that 3 previously described gene variants, rs12711521 (minor allele frequency, 0.153), rs72550870 (minor allele frequency, 0.045; missense variants in the MASP2 gene), and rs2275527 (minor allele frequency, 0.220; exon variant in the adjacent MTOR gene) explained 39% of the variation of MASP-2 plasma concentration. The OR of VTE per 1 SD increase in genetically predicted MASP-2 was 1.03 ([95% CI, 1.01–1.05] P=0.0011). Conclusions: Our findings suggest that high plasma MASP-2 levels are causally associated with risk of future VTE

High plasma levels of C1-inhibitor are associated with lower risk of future venous thromboembolism

Background - C1-inhibitor (C1INH) is a broad-acting serine protease inhibitor with anticoagulant activity. The impact of C1INH plasma levels within the normal physiological range on risk of venous thromboembolism (VTE) is unknown. We assessed the association of plasma C1INH levels and VTE risk and evaluated the impact of C1INH on thrombin and plasmin generation in ex vivo assays. Methods - A nested case-control study with 405 patients with VTE and 829 age- and sex-matched controls was derived from the Tromsø Study. Odds ratios (ORs) with 95% confidence intervals (95% CI) for VTE were estimated across plasma C1INH quartiles. Genetic regulation of C1INH was explored using quantitative trait loci analysis of whole exome sequencing data. The effect of plasma C1INH levels on coagulation was evaluated ex vivo by calibrated automated thrombography. Results - Individuals with C1INH levels in the highest quartile had a lower risk of VTE (OR 0.68, 95% CI: 0.49-0.96) compared with those with C1INH in the lowest quartile. In subgroup analysis, the corresponding ORs were 0.60 (95% CI: 0.39-0.89) for deep vein thrombosis and 0.85 (95% CI: 0.52-1.38) for pulmonary embolism, respectively. No significant genetic determinants of plasma C1INH levels were identified. Addition of exogenous C1INH to normal human plasma reduced thrombin generation triggered by an activator of the intrinsic coagulation pathway, but not when triggered by an activator of the extrinsic coagulation pathway. Conclusions - High plasma levels of C1INH were associated with lower risk of VTE, and C1INH inhibited thrombin generation initiated by the intrinsic coagulation pathway ex vivo

Role of microRNAs in venous thromboembolism

MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets

Platelet count and risk of major bleeding in venous thromboembolism

The relationship between platelet count and risk of major bleeding in patients with venous thromboembolism (VTE) during anticoagulation remains unclear. We therefore investigated the association between platelet count, measured at VTE diagnosis and before the thrombotic event, and risk of major bleeding. Participants comprised 744 patients with incident VTE derived from the Tromsø Study. Major bleedings were recorded during the first year after VTE. Cox-regression was used to calculate hazard ratios (HRs) for major bleeding across platelet count quartiles. There were 55 major bleedings (incidence rate 9.1/100 person-years, 95% confidence interval [CI] 7.0–11.8). The major bleeding risk increased across quartiles of platelet count measured at VTE diagnosis (P for trend<0.02). In the age- and sex-adjusted model, subjects with platelet count in the highest quartile (≥300x109/L) had a 4.3-fold (95% CI 1.7–10.9) higher risk of major bleeding compared to those with platelet count in the lowest quartile (≤192x109/L), and exclusion of patients with cancer yielded similar results. When platelet count was measured on average 7 years before a VTE, the corresponding HR was 2.5 (95% CI 0.9–6.7). Our results suggest that increasing platelet count, assessed several years before and at VTE diagnosis, is associated with a higher risk of major bleeding, and could be a stable individual marker of major bleeding risk in VTE-patients