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Recent advancements in deep learning have led to a resurgence of medical imaging and Electronic Medical Record (EMR) models for a variety of applications, including clinical decision support, automated workflow triage, clinical prediction and more. However, very few models have been developed to integrate both clinical and imaging data, despite that in routine practice clinicians rely on EMR to provide context in medical imaging interpretation. In this study, we developed and compared different multimodal fusion model architectures that are capable of utilizing both pixel data from volumetric Computed Tomography Pulmonary Angiography scans and clinical patient data from the EMR to automatically classify Pulmonary Embolism (PE) cases. The best performing multimodality model is a late fusion model that achieves an AUROC of 0.947 [95% CI: 0.946–0.948] on the entire held-out test set, outperforming imaging-only and EMR-only single modality models.

Although arterial and venous thromboembolic disorders are among the most frequent causes of mortality and morbidity, there has been little description of how the composition of thrombi and emboli depends on their vascular origin and age. We quantified the structure and composition of arterial and venous thrombi and pulmonary emboli using high-resolution scanning electron microscopy. Arterial thrombi contained a surprisingly large amount of fibrin, in addition to platelets. The composition of pulmonary emboli mirrored the most distal part of venous thrombi from which they originated, which differed from the structure of the body and head of the same thrombi. All thrombi and emboli contained few biconcave red blood cells but many polyhedrocytes or related forms of compressed red blood cells, demonstrating that these structures are a signature of clot contraction in vivo . Polyhedrocytes and intermediate forms comprised the major constituents of venous thrombi and pulmonary emboli. The structures within all of the thrombi and emboli were very tightly packed, in contrast to clots formed in vitro . There are distinctive, reproducible differences among arterial and venous thrombi and emboli related to their origin, destination and duration, which may have clinical implications for the understanding and treatment of thrombotic disorders.

Mechanical stress from haemodynamic perturbations or interventional manipulation of epicardial coronary atherosclerotic plaques with inflammatory destabilization can release particulate debris, thrombotic material and soluble substances into the coronary circulation. The physical material obstructs the coronary microcirculation, whereas the soluble substances induce endothelial dysfunction and facilitate vasoconstriction. Coronary microvascular obstruction and dysfunction result in patchy microinfarcts accompanied by an inflammatory reaction, both of which contribute to progressive myocardial contractile dysfunction. In clinical studies, the benefit of protection devices to retrieve atherothrombotic debris during percutaneous coronary interventions has been modest, and the treatment of microembolization has mostly relied on antiplatelet and vasodilator agents. The past 25 years have witnessed a relative proportional increase in non-ST-segment elevation myocardial infarction in the presentation of acute coronary syndromes. An associated increase in the incidence of plaque erosion rather than rupture has also been recognized as a key mechanism in the past decade. We propose that coronary microembolization is a decisive link between plaque erosion at the culprit lesion and the manifestation of non-ST-segment elevation myocardial infarction. In this Review, we characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for prevention and treatment.In this Review, Kleinbongard and Heusch characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for the prevention and treatment of this phenomenon.

Pulmonary embolism (PE) is caused by emboli, which have originated from venous thrombi, travelling to and occluding the arteries of the lung. PE is the most dangerous form of venous thromboembolism, and undiagnosed or untreated PE can be fatal. Acute PE is associated with right ventricular dysfunction, which can lead to arrhythmia, haemodynamic collapse and shock. Furthermore, individuals who survive PE can develop post-PE syndrome, which is characterized by chronic thrombotic remains in the pulmonary arteries, persistent right ventricular dysfunction, decreased quality of life and/or chronic functional limitations. Several important improvements have been made in the diagnostic and therapeutic management of acute PE in recent years, such as the introduction of a simplified diagnostic algorithm for suspected PE as well as phase III trials demonstrating the value of direct oral anticoagulants in acute and extended treatment of venous thromboembolism. Future research should aim to address novel treatment options (for example, fibrinolysis enhancers) and improved methods for predicting long-term complications and defining optimal anticoagulant therapy parameters in individual patients, and to gain a greater understanding of post-PE syndrome. Pulmonary embolism (PE) is a form of venous thromboembolism in which an embolus occludes pulmonary arteries. This Primer by Huisman and colleagues discusses the epidemiology, mechanisms, diagnosis and prevention of PE and describes patient management and quality of life.

Blood clots, which are composed of blood cells and a stabilizing mesh of fibrin fibers, are critical in cessation of bleeding following injury. However, their action is transient and after performing their physiological function they must be resolved through a process known as fibrinolysis. Internal fibrinolysis is the degradation of fibrin by the endogenous or innate presence of lytic enzymes in the bloodstream; under healthy conditions, this process regulates hemostasis and prevents bleeding or clotting. Fibrin-bound tissue plasminogen activator (tPA) converts nearby plasminogen into active plasmin, which is bound to the fibrin network, breaking it down into fibrin degradation products and releasing the entrapped blood cells. It is poorly understood how changes in the fibrin structure and lytic protein ratios influence the biochemical regulation and behavior of internal fibrinolysis. We used turbidity kinetic tracking and microscopy paired with mathematical modeling to study fibrin structure and lytic protein ratios that restrict internal fibrinolysis. Analysis of simulations and experiments indicate that fibrinolysis is driven by pore expansion of the fibrin network. We show that this effect is strongly influenced by the ratio of fibrin:tPAwhen compared to absolute tPA concentration. Thus, it is essential to consider relative protein concentrations when studying internal fibrinolysis both experimentally and in the clinic. An improved understanding of effective internal lysis can aid in development of better therapeutics for the treatment of bleeding and thrombosis.

Venous thromboembolism is associated with formation of denser fibrin clots resistant to lysis. We investigated whether prothrombotic plasma clot properties are associated with the severity of acute pulmonary embolism (PE). We enrolled 126 normotensive acute PE patients (aged 58 ± 14 years) and 25 age- and sex-matched healthy controls. Plasma fibrin clot permeability (K s ), clot lysis time (CLT), endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1), and citrullinated histone H3 (citH3) were evaluated on admission. PE patients compared to controls had 370% higher citH3 levels, 41% higher ETP, 16.5% reduced K s , and 25.6% prolonged CLT. Patients with intermediate-high (n = 29) and intermediate-low (n = 77) PE mortality risk had reduced K s and prolonged CLT, increased PAI-1 and ETP as compared to low-risk PE (n = 20) patients. Prolonged CLT was predicted by PAI-1 and citH3, while low K s by C-reactive protein. During a 12-month follow-up 9 (7.1%) patients who had 24% higher ETP, 45% higher citH3 levels, and 18% prolonged CLT at baseline died. High ETP combined with elevated citH3 levels and prolonged CLT was associated with eightfold increased risk of PE-related death. Prothrombotic fibrin clot properties and enhanced neutrophil extracellular traps formation are associated with higher early mortality risk in acute PE patients, which suggests a prognostic role of these biomarkers.

Venous thromboembolism (VTE) encompasses deep-vein thrombosis (DVT) and pulmonary embolism. VTE is the leading cause of lost disability-adjusted life years and the third leading cause of cardiovascular death in the world. DVT leads to post-thrombotic syndrome, whereas pulmonary embolism can cause chronic pulmonary hypertension, both of which reduce quality of life. Genetic and acquired risk factors for thrombosis include non-O blood groups, factor V Leiden mutation, oral contraceptive use, hormone replacement therapy, advanced age, surgery, hospitalization and long-haul travel. A combination of blood stasis, plasma hypercoagulability and endothelial dysfunction is thought to trigger thrombosis, which starts most often in the valve pockets of large veins. Animal studies have revealed pathogenic roles for leukocytes, platelets, tissue factor-positive microvesicles, neutrophil extracellular traps and factors XI and XII. Diagnosis of VTE requires testing and exclusion of other pathologies, and typically involves laboratory measures (such as D-dimer) and diagnostic imaging. VTE is treated with anticoagulants and occasionally with thrombolytics to prevent thrombus extension and to reduce thrombus size. Anticoagulants are also used to reduce recurrence. New therapies with improved safety profiles are needed to prevent and treat venous thrombosis. For an illustrated summary of this Primer, visit: http://go.nature.com/8ZyCuY Venous thrombosis and its potentially debilitating or even fatal consequences can pose diagnostic and therapeutic challenges. Here, Mackman and colleagues discuss not only the clinical implications of thrombosis but also new insights into thrombogenesis and how to inhibit this process.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major complication following surgery and in high-risk scenarios. Aspirin may provide an alternative for extended VTE prophylaxis, but its risk-benefit profile remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials, following PRISMA guidelines, to evaluate aspirin’s efficacy and safety for extended VTE prevention. Subgroup analyses included primary and secondary prevention, provoked and unprovoked VTE, and low-dose aspirin. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model, and trial sequential analysis was used to assess the robustness of the evidence. Five trials including 68,554 patients were analyzed. Aspirin (100–160 mg) significantly reduced the risk of VTE, DVT, PE, and VTE-related mortality compared to placebo, particularly in primary prevention and provoked VTE cases. No benefit was observed in secondary prevention, while some benefit emerged for unprovoked VTE, limited to overall VTE risk. Low-dose aspirin (100 mg) did not significantly reduce the incidence of VTE, DVT, or PE. Aspirin increased the risks of overall and major bleeding but did not elevate blood transfusion requirements or major cardiovascular events. These findings suggest that prolonged aspirin therapy may have a role in extended VTE prevention, particularly in patients at risk for provoked VTE. However, careful patient selection remains crucial, and further studies are needed to refine its indications and optimal dosing strategy.

Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation.

Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73–1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65–1.02) per doubling of LMWH dose. This dose–response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose–response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.