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Pulmonary embolism is a leading cause of maternal morbidity and mortality in Western countries. In the United States, pulmonary embolism-related mortality rates have plateaued in the general population after an initial decrease in the past 20 years.This study aimed to describe the changes in pulmonary embolism-related maternal mortality rates in the United States over the past 2 decades.In this epidemiologic study of public vital registration data (death certificates encompassing underlying and contributing causes of death) from the Centers for Disease Control and Prevention Multiple Cause of Death database (2003-2020), we identified all maternal deaths with a pulmonary embolism code listed in any position of the death certificates. We investigated the changes in annual crude pulmonary embolism-related maternal mortality rates for the years 2003 to 2020, considering the effect of the introduction of the pregnancy checkbox in death certificates on the pulmonary embolism-related maternal mortality rates.Overall, 735 pulmonary embolism-related maternal deaths out of 12,871 total maternal deaths (5.7%) were recorded between 2003 and 2020; the overall pulmonary embolism-related maternal mortality rate was 1.02 (95% confidence interval, 0.95-1.10) per 100,000 live births. The pulmonary embolism-related maternal mortality rate increased from 0.93 in 2003 to 1.96 in 2020; however, when accounting for the implementation of the pregnancy checkbox in the death certificates, the trends in pulmonary embolism-related maternal mortality were largely unchanged from 2003 to 2020. The crude pulmonary embolism-related maternal mortality rates differed across maternal age groups (overall 0.61, 1.09, and 3.83 maternal deaths per 100,000 live births for those aged ≤24, 25-39, and ≥40 years, respectively) and racial/ethnicity groups (2.89, 0.47, 0.77, and 0.63 maternal deaths per 100,000 live births for Black non-Hispanics, other non-Hispanics, White non-Hispanics, and Hispanics, respectively).Maternal mortality rates related to pulmonary embolism did not decrease during the period from 2003 to 2020, as opposed to mortality rates related to pulmonary embolism in the general population. More research is required to assess whether improvement in venous thromboembolism prevention and pulmonary embolism diagnosis and management strategies might reduce death owing to pulmonary embolism in this vulnerable population.

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.

BackgroundStudies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown.MethodsIn a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.ResultsWe identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque.ConclusionsWe provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.CLINICAL PERSPECTIVEWhat is newWe identified genetic proxies for downregulated IL-6 signaling that had effects on upstream and downstream regulators of the IL-6 signaling pathway consistent with those of pharmacological IL-6R blockadeGenetically downregulated IL-6 signaling was associated with a lower risk of ischemic stroke, and in particular large artery and small vessel strokeSimilar associations were obtained for a broad range of other cardiovascular outcomesWhat are the clinical implicationsInhibition of IL-6 signaling is a promising therapeutic target for lowering risk of stroke and other cardiovascular outcomes and should be further investigated in clinical trials

BackgroundGenetic variation can be used to study causal relationships between biomarkers and diseases. Here, we identify new common and rare genetic variants associated with cardiovascular-related protein levels (protein quantitative trait loci [pQTLs]). We functionally annotate these pQTLs, predict and experimentally confirm a novel molecular interaction, and determine which pQTLs are associated with diseases and physiological phenotypes.Methods and resultsAs part of a larger case-control study of venous thromboembolism, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Tromsø Study. Exonic genetic variation near each protein's respective gene (cis) was identified using sequencing and arrays. Using single site and gene-based tests, we identified 27 genetic associations between pQTLs and the serum levels of 20 proteins: 14 associated with common variation in cis, of which 6 are novel (ie, not previously reported); 7 associations with rare variants in cis, of which 4 are novel; and 6 associations in trans. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein and with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro. Nine of the pQTLs have previously identified associations with 17 disease and physiological phenotypes.ConclusionsWe have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes.

Moderate alcohol consumption has been shown to protect against cardiovascular diseases. The association between alcohol consumption, especially types of alcoholic beverages, and venous thromboembolism (VTE) is less well described. The aim of this study was to investigate the impact of alcohol consumption and different alcoholic beverages on risk of VTE. Information on alcohol consumption were collected by a self-administrated questionnaire in 26 662 subjects, aged 25-97 years, who participated in the Tromsø Study, in 1994-95. Subjects were followed through September 1, 2007 with incident VTE as the primary outcome. There were 460 incident VTE-events during a median of 12.5 years of follow-up. Total alcohol consumption was not associated with risk of incident VTE. However, subjects consuming ≥3 units of liquor per week had 53% increased risk of VTE compared to teetotalers in analyses adjusted for age, sex, BMI, smoking, diabetes, cancer, previous cardiovascular disease, physical activity and higher education (HR: 1.53, 95% CI: 1.00-2.33). Contrary, subjects with a wine intake of ≥3 u/week had 22% reduced risk of VTE (HR: 0.78, 95% CI: 0.47-1.30), further adjustment for liquor and beer intake strengthened the protective effect of wine (HR: 0.53, 95% CI: 0.30-1.00). Frequent binge drinkers (≥1/week) had a 17% increased risk of VTE compared to teetotallers (HR 1.17, 95% CI: 0.66-2.09), and a 47% increased risk compared to non-binge drinkers (HR 1.47, 95% CI: 0.85-2.54). In conclusion, liquor consumption and binge drinking was associated with increased risk of VTE, whereas wine consumption was possibly associated with reduced risk of VTE.

Venøs tromboembolisme (VTE) er en samlebetegnelse på dyp venetrombose (DVT) og lungeemboli. D-dimer, en blodprøve for koagulasjon og fibrinolyse, har vært en sentral del av VTE-diagnostikken i flere tiår. Blodprøven D-dimer har flere bruksområder og kan dermed reflektere ulike aspekter ved VTE. I denne avhandlingen har vi undersøkt i) om det er trygt og effektivt å bruke D-dimer uten samtidig bruk av risikoskår for å utelukke DVT hos pasienter med mistenkt DVT, ii) sammenhengen mellom D-dimer-nivå og førstegangs VTE og hvordan overvekt og inflammasjon påvirker denne sammenhengen, og iii) betydningen av D-dimer målt ved diagnosetidspunktet på risikoen for residiverende VTE. I artikkel I inkluderte vi pasienter henvist til Universitetssykehuset Nord-Norge med mistenkt DVT. Basert på de faktiske DVT-diagnosene ved det første besøket eller i løpet av de påfølgende tre månedene, estimerte vi hvor mange DVTer som ville ha blitt oversett (udiagnostisert) hvis D-dimer alene hadde vært den diagnostiske strategien. I artikkelen fant vi at D-dimer alene er trygt for å utelukke proksimal DVT hos ikke-innlagte pasienter og at denne strategien har potensiale til å forenkle og øke effektiviteten av utredningen. I artikkel II utførte vi en befolkningsbasert nøstet kasus-kontroll studie med VTE-kasuser og tilhørende matchende kontroller fra Tromsøundersøkelsen. D-dimer ble målt i blodprøver som var tatt ved inklusjon og odds ratioer for VTE ble beregnet utfra D-dimer-kvartiler. I studien fant vi at høyere D-dimer ved inklusjon er assosiert med økt risiko for førstegangs VTE, og at D-dimer-nivåene delvis reflekterer underliggende tilstander relatert til overvekt og inflammasjon. I artikkel III inkluderte vi pasienter med førstegangs symptomatisk VTE fra TROLL-studien ved Sykehuset Østfold. Alle tilfeller av residiverende VTE i oppfølgingstiden ble registrert, og den samlede insidensen av residiv ble estimert etter henholdsvis D-dimer ≤1900 ng/mL (≤25 persentilen) og >1900 ng/mL på diagnosetidspunktet. I studien fant vi at lav D-dimer på diagnosetidspunktet trolig kan identifisere pasienter med lav risiko for residiverende VTE. Hos disse kan blodfortynnende behandling trolig stoppes etter den første behandlingsfasen. Funnene i denne avhandlingen viser bredden i bruken av D-dimer og dens viktige plass både i diagnostikken av førstegangs DVT og prediksjonen av residiverende hendelser. De foreslåtte strategiene i avhandlingen har potensiale til å forbedre dagens håndtering av VTE.

During the past decades, extensive data from the general population have revealed that patients with acute myocardial infarction (MI) are at increased risk of venous thromboembolism (VTE, i.e., deep vein thrombosis [DVT] and pulmonary embolism [PE]). The risk is highest in the initial 0-6 months following an acute MI, and declines rapidly thereafter. The explanation for the observed association between MI and future risk of incident VTE is yet unknown. The overall aim of the present thesis was to identify triggers and risk factors of VTE in patients with MI that potentially can be used to identify MI patients with high risk of VTE. In Paper I, we used a case-crossover designed study with the incident VTE cases recruited from the fourth survey of the Tromsø Study. A case-crossover design is well-suited for studying transient risk factors or triggers on the risk of acute events. The study populations for Paper II and Paper III were recruited from the fourth, fifth and sixth surveys of the Tromsø Study. In Paper II, the participants consisted of a subgroup with extended genetic information. Study subjects in Paper II and Paper III were followed from the first survey they attended to the date of an incident VTE, the date of death or migration, or until administrative censoring at the end of follow-up. First, we found that an MI is a strong trigger factor for VTE, and that indirect risk factors related to the MI, in particular acute infections and immobilization, may to a large extent explain the observed association between MI and VTE. Second, we showed that five prothrombotic genotypes did not explain the increased risk of VTE in MI patients, implying that the prothrombotic genotypes may not play a crucial role in the development of VTE after MI. Third, we demonstrated that the combined effect of MI and obesity on overall VTE risk exceeded the sum of the separate effects. In non-obese subjects, MI was not associated with DVT and unprovoked VTE. Thus, the increased risk of these subtypes of outcomes in MI patients appeared to be dependent on the presence of obesity. Our findings imply that an acute MI is a strong trigger factor for VTE, and that indirect factors related to hospitalization for MI (i.e., acute infections and immobilization) and concomitant obesity could be essential in the risk assessment of VTE after MI.

Venous thromboembolism (VTE), encompassing both deep vein thrombosis and pulmonary embolism, is a major public health concern due to substantial morbidity and mortality. Around half of all VTE cases are hospital-related. Importantly, VTE also has life-long implications, as a large proportion of VTE-patients suffer either a recurrent event or chronic complications. The first aim of the thesis was to investigate hospitalization as a trigger of incident VTE. Secondly, we aimed to provide new insights to the epidemiology of recurrence, and to identify novel risk factors for recurrent VTE. The study population was derived from one or more of the first six surveys of the Tromsø Study, with nearly 40.000 participants. All potential cases of first lifetime and recurrent VTE events during this time-period were recorded. The target population for all papers were participants who had suffered a first lifetime VTE in the in the period 1994-2012. We found that hospitalization was a major trigger factor for incident VTE, and that the VTE risk was mainly influenced by the length of hospital stay rather than the frequency of hospital admissions in the 90-days prior to VTE. Furthermore, hospitalization was a high-risk situation also in the absence of immobilization, although immobilization contributed substantially to the VTE risk among hospitalized patients. Secondly, we discovered that the rates of recurrence and mortality after a first VTE remain high, particularly in the following year after a VTE. In paper III, we found that patients with a VTE related to hospitalization for medical illness had a high risk of recurrence, even after the competing risk of death was taken into account. Finally, we identified that d-dimer, measured at first VTE diagnosis, could be a potential biomarker to identify patients at low risk of recurrence, in whom short-term anticoagulant therapy could be sufficient.

Background: Several studies have investigated the association between coffee consumption and cardiovascular disease, but little is known about coffee intake and risk of venous thromboembolism (VTE). Objective: The aim of this prospective cohort study was to investigate the association between coffee consumption and risk of incident VTE in a general population. Methods: Information about coffee consumption habits was obtained by a self-administered questionnaire in 26 755 subjects, aged 25-97 years, who participated in the fourth survey of the Tromsø study (1994-95). Incident VTE events were registered until the end of follow-up, 1 September 2007. Results: There were 462 incident VTE events (1.60 per 1000 person-years, 95% CI: 1.46-1.75) during a median of 12.5 years of follow-up. A daily consumption of 3-4 cups was borderline associated (HR: 0.70; 95% CI: 0.48-1.02), while 5-6 cups (HR: 0.67; 95% CI: 0.45-0.97) of coffee was significantly associated with reduced risk of VTE compared to coffee abstainers in multivariable analysis adjusted for age, sex, BMI, smoking status, physical activity, diabetes, history of cardiovascular disease and cancer. Similar risk estimates were found for provoked and unprovoked VTE, and in sex-stratified analyses. Conclusion: Our findings suggest a possible U-shaped relation between coffee consumption and VTE, and that moderate coffee consumption may be associated with reduced risk of VTE. However, more studies are needed to establish whether a moderate coffee consumption is inversely associated with the risk of VTE.