Thromboinflammation or immunothrombosis is a concept that explains the existing link between coagulation and inflammatory response present in many situations, such as sepsis, venous thromboembolism, or COVID-19 associated coagulopathy. The purpose of this review is to provide an overview of the current data regarding the mechanisms involved in immunothrombosis in order to understand the new therapeutic strategies focused in reducing thrombotic risk by controlling the inflammation.

Objetivo: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. Metodo: El estudio multicentrico (18 SUH) ALTAMIRA (fActores de riesgo, compLicaciones y evaluación del manejo de la TVS de Miembros Inferiores en hospitales españoles atendidos en los seRvicios de urgenciAs) creó un cohorte retrospectivo de pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. Resultados: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1%) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6%). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). Conclusiones: El tratamiento en urgencias de la TVS aislada es heterogéneo y con frecuencia subóptimo. La incidencia de complicaciones de ETV es elevada. El tratamiento anticoagulante iniciado en urgencias supone un retraso en el desarrollo de complicaciones. Los pacientes con ETV previa tienen más riesgo de complicaciones.

Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.

Simple Summary Cancer is a widely heterogeneous disease, and the natural history of patients with cancer-associated thrombosis may differ according to the cancer site. Lung cancer is the most common malignancy, and a leading cause of death. A number of studies in the literature suggest that patients with adenocarcinoma may have a worse outcome than those with squamous or other types of lung cancer. The aim of the current study was to assess the potential impact of lung cancer histology on the incidence rates of VTE recurrences, major bleeding, or death appearing during the course of anticoagulation, in patients with lung cancer and VTE. Our findings, obtained from a large series of consecutive patients with lung cancer and VTE (482 patients), reveal important differences between patients with adenocarcinoma vs. other histologies in their outcomes during anticoagulation. This might likely help to design better therapeutic strategies for patients with lung cancer. Background: In patients with lung cancer and venous thromboembolism (VTE), the influence of cancer histology on outcome has not been consistently evaluated. Methods: We used the RIETE registry (Registro Informatizado Enfermedad TromboEmbolica) to compare the clinical characteristics and outcomes during anticoagulation in patients with lung cancer and VTE, according to the histology of lung cancer. Results: As of April 2022, there were 482 patients with lung cancer and VTE: adenocarcinoma 293 (61%), squamous 98 (20%), small-cell 44 (9.1%), other 47 (9.8%). The index VTE was diagnosed later in patients with squamous cancer than in those with adenocarcinoma (median, 5 vs. 2 months). In 50% of patients with adenocarcinoma, the VTE appeared within the first 90 days since cancer diagnosis. During anticoagulation (median 106 days, IQR: 45-214), 14 patients developed VTE recurrences, 15 suffered major bleeding, and 218 died: fatal pulmonary embolism 10, fatal bleeding 2. The rate of VTE recurrences was higher than the rate of major bleeding in patients with adenocarcinoma (11 vs. 6 events), and lower in those with other cancer types (3 vs. 9 events). On multivariable analysis, patients with adenocarcinoma had a non-significantly higher risk for VTE recurrences (hazard ratio [HR]: 3.79; 95%CI: 0.76-18.8), a lower risk of major bleeding (HR: 0.29; 95%CI: 0.09-0.95), and a similar risk of mortality (HR: 1.02; 95%CI: 0.76-1.36) than patients with other types of lung cancer. Conclusions: In patients with lung adenocarcinoma, the rate of VTE recurrences outweighed the rate of major bleeding. In patients with other lung cancers, it was the opposite.

El objetivo del presente documento es actualizar el consenso previo publicado en 2013, en relación con 12 áreas controvertidas en el manejo de la tromboembolia de pulmón (TEP). Para cada área se realizó una exhaustiva revisión bibliográfica y una propuesta de recomendación, sometida a un proceso de debate interno en dos teleconferencias sucesivas. En relación con el diagnóstico, recomendamos no utilizar la escala Pulmonary Embolism Rule Out Criteria (PERC) de forma aislada para descartar la TEP y, cuando haya indicación de dímero D, recomendamos emplear un punto de corte ajustado a la edad. Sugerimos utilizar la angiotomografía computerizada de tórax como prueba de imagen para el diagnóstico de la mayoría de los pacientes con sospecha de la enfermedad. Se recomienda utilizar anticoagulantes de acción directa (en vez de antagonistas de la vitamina K) para el tratamiento de la mayoría de los pacientes con TEP, y se sugiere utilizar anticoagulación para la mayoría de los pacientes con TEP subsegmentaria. Se recomienda no colocar un filtro de vena cava inferior en la mayoría de los pacientes. Si se indica tratamiento de reperfusión, el panel recomienda utilizar fibrinolisis sistémica a dosis completas. La duración de la anticoagulación está condicionada principalmente por la presencia (o ausencia) y el tipo de factor de riesgo para enfermedad tromboembólica venosa, y recomendamos no realizar estudios de trombofilia para decidir la duración de la anticoagulación a la mayoría de los pacientes con TEP. Finalmente, sugerimos no realizar cribado extendido de cáncer oculto en pacientes con TEP.

In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.

Background: To analyze the long-term outcomes for advanced cancer patients admitted to an intermediate care unit (ImCU), an analysis of a do not resuscitate orders (DNR) subgroup was made. Methods: A retrospective observational study was conducted from 2006 to January 2019 in a single academic medical center of cancer patients with stage IV disease who suffered acute severe complications. The Simplified Acute Physiology Score 3 (SAPS 3) was used as a prognostic and severity score. In-hospital mortality, 30-day mortality and survival after hospital discharge were calculated. Results: Two hundred and forty patients with stage IV cancer who attended at an ImCU were included. In total, 47.5% of the cohort had DNR orders. The two most frequent reasons for admission were sepsis (32.1%) and acute respiratory failure (excluding sepsis) (38.7%). Mortality in the ImCU was 10.8%. The mean predicted in-hospital mortality according to SAPS 3 was 51.9%. The observed in-hospital mortality was 37.5% (standard mortality ratio of 0.72). Patients discharged from hospital had a median survival of 81 (30.75-391.25) days (patients with DNR orders 46 days (19.5-92.25), patients without DNR orders 162 days (39.5-632)). The observed mortality was higher in patients with DNR orders: 52.6% vs. 23.8%, p 0 < 0.001. By multivariate logistic regression, a worse ECOG performance status (3-4 vs. 0-2), a higher SAPS 3 Score and DNR orders were associated with a higher in-hospital mortality. By multivariate analysis, non-invasive mechanical ventilation, higher bilirubin levels and DNR orders were significantly associated with 30-day mortality. Conclusion: For patients with advanced cancer disease, even those with DNR orders, who suffer from acute complications or require continuous monitoring, an ImCU-centered multidisciplinary management shows encouraging results in terms of observed-to-expected mortality ratios.

Background: The natural history of patients with hematologic cancer and venous thromboembolism (VTE) has not been consistently evaluated. We aimed to compare the rates of symptomatic recurrent VTE, major bleeding or death during anticoagulant therapy in patients with VTE associated to hematologic vs. solid cancers. Methods: Consecutive patients with active cancer recruited in RIETE were evaluated. Their baseline characteristics, treatments and outcomes during the course of anticoagulation were compared. Univariate and multivariate competing-risk analysis were performed. Results: As of December 2020, 16,694 patients with cancer and VTE were recruited. Of these, 1,062 (6.4%) had hematologic cancers. Hematologic patients were less likely to initially present with pulmonary embolism (48% vs. 63%) and more likely with upper-extremity deep vein thrombosis (25% vs. 18%). They also were more likely to have severe thrombocytopenia at baseline (5.6% vs. 0.7%) or to receive chemotherapy (67% vs. 41%). During the course of anticoagulation (median, 150 vs. 127 days), 1,071 patients (6.4%) developed VTE recurrences, 806 (4.8%) suffered major bleeding and 4,136 (24.8%) died. Patients with hematologic cancers had lower rates of recurrent VTE (rate ratio [RR]: 0.73; 95% confidence interval [CI]: 0.56-0.95), major bleeding (RR: 0.72; 95%CI: 0.53-0.98) or all-cause death (RR: 0.49; 95%CI: 0.41-0.57) than those with solid cancers. Patients with multiple myeloma showed the best outcomes. Conclusions: Patients with hematologic cancers, particularly multiple myeloma, and VTE had better outcomes than those with solid cancers. These findings are relevant for the interpretation of previous clinical trials and the design of future studies.

Thromboprophylaxis with low molecular weight heparin in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with nonsevere COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/kg daily) versus standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress, and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic dose and 33 to standard prophylactic dose. The primary efficacy outcome occurred in 7 patients (22%) in the therapeutic-dose group and 6 patients (18%) in the prophylactic-dose (absolute risk difference 3.6% [95% confidence interval [CI], -16% -24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p = 0.95). Discharge in the first 10 days was possible in 66 and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with nonsevere pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin does not appear to improve clinical outcomes compared with standard prophylactic doses. Trial Registration: ClinicalTrials.gov NCT04604327.