BACKGROUND: A recently published, large prospective study showed unexpectedly high prevalence of acute pulmonary embolism (APE) among patients hospitalized for syncope. In such a case, a high incidence of recurrent pulmonary embolism is expected among patients who were discharged without APE workup.

OBJECTIVES: To determine the incidence of symptomatic APE among patients hospitalized for a first episode of syncope and discharged without APE workup or anticoagulation.

METHODS: This retrospective cohort study included patients hospitalized at Rambam Health Care Campus between January 2006 and February 2017 with a primary admission diagnosis of syncope, who were not investigated for APE and were not taking anticoagulants. The patients were followed up for up to three years after discharge. The occurrence of venous thromboembolism (VTE) during the follow-up period was documented.

RESULTS: The median follow-up duration was 33 months. 1,126 subjects completed a three-year follow-up. During this period, 38 patients (3.38%) developed VTE, 17 (1.51%) of them had APE. The cumulative incidence of VTE and APE was 1.9% (95% CI 1.3%-2.5%) and 0.9% (95% CI 0.4%-1.3%) respectively. Only seven subjects developed APE during the first year of follow-up. The median times from the event of syncope to the development of APE and VTE were 18 and 19 months respectively.

CONCLUSIONS: The cumulative incidence of VTE during a three-year follow-up period after an episode of syncope is low. In the absence of clinical suspicion, a routine diagnostic workup for APE in patients with syncope cannot be recommended.

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.