Editorial : Women in Thrombosis

Funding CSW is supported by the British Heart Foundation (PG/20/17/35050).Peer reviewedPublisher PD

BMI variability and cardiovascular outcomes within clinical trial and real-world environments in type 2 diabetes:an IMI2 SOPHIA study

Background BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real-world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability. Methods We investigated the association between BMI variability and 3P-MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA-REG OUTCOME (n = 2333) trials, followed by real-world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome. Results After adjusting for cardiovascular risk factors, a + 1 SD increase in BMI variability was associated with increased 3P-MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08–1.17, P &lt; 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P &lt; 0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA-REG OUTCOME trial did not replicate this association. BMI variability’s impact on 3P-MACE risk was independent of HbA1c variability. Conclusions In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P-MACE across cardiovascular outcome trials and real-world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.</p

Promotion of arterial stiffness by childhood cancer and its characteristics in adult long‐term survivors

BACKGROUND Vascular alterations induced by antineoplastic treatment might be considered as a possible underlying mechanism of increased cardiovascular sequelae in childhood cancer survivors (CCSs). We aimed to evaluate arterial stiffness among long‐term CCSs and to compare the data against a population‐based sample. METHODS AND RESULTS Arterial stiffness was assessed by digital photoplethysmography (stiffness index; m/s) among 1002 participants of the CVSS (Cardiac and Vascular Late Sequelae in Long‐Term Survivors of Childhood Cancer) study, diagnosed with neoplasia (1980–1990) before an age of 15 years. A population‐based sample from the GHS (Gutenberg Health Study) (n=5252) was investigated for comparison. All subjects underwent a comprehensive, standardized clinical examination in the same study center. CCSs had higher stiffness index (β=0.66 m/s; 95% CI, 0.51–0.80 m/s) in multivariable linear regression analysis after adjustment for cardiovascular risk factors compared with the population sample of comparable age range. Stiffer vessels were found among CCSs also in absence of arterial hypertension (β=0.66; 95% CI, 0.50–0.81) or history of chemotherapy/radiotherapy (β=0.56; 95% CI, 0.16–0.96) in fully adjusted models. Moreover, stiffness index differed by tumor entity, with highest values in bone and renal tumors. Almost 5.2‐fold higher prevalence of stiffness index values exceeding age‐specific, population‐based reference limits was observed among CCSs compared with GHS participants. CONCLUSIONS This is the first study demonstrating increased arterial stiffness among long‐term CCSs. The data suggest that vascular compliance might differ in survivors of childhood cancer from the established development concept for arterial stiffness in the population; cancer growth and antineoplastic treatment might be relevant determinants of the pathobiological features

Cardiovascular profiling in the diabetic continuum : results from the population-based Gutenberg Health Study

Aims To assess the prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in the general population and to investigate the associated cardiovascular burden and clinical outcome. Methods and Results The study sample comprised 15,010 individuals aged 35–74 years of the population-based Gutenberg Health Study. Subjects were classified into euglycaemia, prediabetes and T2DM according to clinical and metabolic (HbA1c) information. The prevalence of prediabetes was 9.5% (n = 1415) and of T2DM 8.9% (n = 1316). Prediabetes and T2DM showed a significantly increased prevalence ratio (PR) for age, obesity, active smoking, dyslipidemia, and arterial hypertension compared to euglycaemia (for all, P < 0.0001). In a robust Poisson regression analysis, prediabetes was established as an independent predictor of clinically-prevalent cardiovascular disease (PRprediabetes 1.20, 95% CI 1.07–1.35, P = 0.002) and represented as a risk factor for asymptomatic cardiovascular organ damage independent of traditional risk factors (PR 1.04, 95% CI 1.01–1.08, P = 0.025). Prediabetes was associated with a 1.5-fold increased 10-year risk for cardiovascular disease compared to euglycaemia. In Cox regression analysis, prediabetes (HR 2.10, 95% CI 1.76–2.51, P < 0.0001) and T2DM (HR 4.28, 95% CI 3.73–4.92, P < 0.0001) indicated for an increased risk of death. After adjustment for age, sex and traditional cardiovascular risk factors, only T2DM (HR 1.89, 95% CI 1.63–2.20, P < 0.0001) remained independently associated with increased all-cause mortality. Conclusion Besides T2DM, also prediabetes inherits a significant cardiovascular burden, which translates into poor clinical outcome and indicates the need for new concepts regarding the prevention of cardiometabolic disorders

Platelet-associated hypercoagulability in patients with Essential Thrombocythemia and Polycythemia Vera

Thrombosis is a frequent complication in patients with cancer. In patients with hematological malignancies, such as Essential Thrombocythemia (ET) and Polycythemia Vera (PV), thrombotic events are a major cause of increased morbidity and mortality. The pathogenesis of the activation of blood coagulation in these patients is complex. Platelets have an important role in this process. This thesis presents studies exploring the platelet-associated hypercoagulability in patients with ET and PV. The acquired JAK2V617F mutation, which has been reported in nearly all patients with PV and in more than half of patients with ET has been associated with severity of disease and increased expression of soluble or cellular biomarkers of clotting system activation. This thesis confirmed a hypercoagulable state in patients positive for the JAK2V617F mutation, associated with the highest thrombin generation values

Rivaroxaban Effects Illustrate the Underestimated Importance of Activated Platelets in Thrombin Generation Assessed by Calibrated Automated Thrombography

International audienceBackground: The direct oral anticoagulant rivaroxaban inhibiting specifically activated factor X (FXa) causes delayed thrombin generation (TG) as measured by calibrated automated thrombography (CAT). The implications of these changes for assessing bleeding or residual prothrombotic risks of patients are unclear in the absence of a better understanding of the underlying mechanism. Methods: We compared platelet rich plasma (PRP) without or with prior collagen-induced platelet aggregation (agPRP) in the CAT assay to better characterize TG in the presence of rivaroxaban. Results: In the presence of rivaroxaban, TG curves in agPRP showed a distinct profile with a rapidly ascending phase followed with a protracted phase. Inhibition of tissue factor pathway inhibitor amplified the first phase of the curve which was also modulated by procoagulant phospholipids. Inhibition of FXIIa-dependent FXI activation revealed that aggregated platelets influenced the first phase by a combination of extrinsic and intrinsic coagulation pathway initiations. Thrombin-dependent amplification of TG (even prior collagen activation) was responsible for the second phase of the TG curve. Conclusions: AgPRP fully includes platelet ability to support TG and reveal distinct TG phases in the presence of direct FXa inhibitors highlighting its potential use in an anticoagulated setting