Journal of Thrombosis and Haemostasis最新文献

Background: Intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator prior to endovascular thrombectomy treatment (EVT) failed to improve treatment effect in acute ischemic stroke (AIS) patients compared with EVT alone.

Objectives: We investigated whether primary and secondary hemostasis biomarkers are associated with the effect of intravenous thrombolytics on clinical and radiological outcomes after EVT.

Methods: In the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN)-NO IV, AIS patients were randomized to receive IVT plus EVT or EVT alone. We measured hemostatic biomarkers before and 24 hours postreperfusion to determine changes in biomarkers and the association of the biomarkers with short term stroke severity on National Institutes of Health Stroke Scale score, long-term functional outcome (modified Rankin scale [mRS] score), post-EVT extended Thrombolysis in Cerebral Infarction score, and final infarct size.

Results: This substudy included 214 of the 539 AIS patients who underwent IVT + EVT (n = 108/266) or EVT alone (n = 106/273). In the EVT group, low soluble glycoprotein VI (sGPVI) and high factor (F)VIII levels before treatment were associated with severe National Institutes of Health Stroke Scale score at 24 hours and poor mRS score at 90 days posttreatment, respectively. Also, in this group, sGPVI levels 24 hours after treatment were negatively associated with final infarct size. In the IVT + EVT group, high fibrinogen before treatment was associated with good extended Thrombolysis in Cerebral Infarction score, and low a disintegrin and metalloprotease with thrombospondin motif repeats 13 activity 24 hours posttreatment was associated with an unfavorable mRS score at 90 days.

Conclusion: Our findings suggest that patients with high FVIII and fibrinogen and low sGPVI levels might be the most suitable candidates for IVT + EVT and that patients with low a disintegrin and metalloprotease with thrombospondin motif repeats 13 activity might be suitable for EVT alone.

Background: Despite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations.

Objectives: To evaluate the role of ctDNA in risk stratification for cancer-associated VTE.

Methods: We analyzed data from 1038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the United States. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine-Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC).

Results: The presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratios of 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared with none; P < .0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared with the clinical-only model (AUC, 0.71; 95% CI, 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC, 0.74; 95% CI, 0.67-0.80).

Conclusion: ctDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.

In the last couple of decades, numerous investigations have shed considerable light on how precisely factor (F)VIIa mediates the initiation of blood coagulation upon association with its cofactor, tissue factor (TF). The role of the cofactor in this process is indispensable under physiological conditions, serving as a membrane-tethering allosteric activator of FVIIa also interacting with substrates (eg, FX). Available evidence reveals the induction and manifestation of complex allostery within FVIIa when stimulated by TF, involving at least 2 connected pathways spanning the interactive interface of the FVIIa-TF complex and the functional segments of FVIIa. Carefully designed FVIIa variants demonstrate corresponding modulations of their properties and response to TF-triggered allostery and activation. In addition, antibodies can stimulate FVIIa activity in both similar and distinctly different ways compared to that employed by TF. The mechanistic insights obtained through basic biochemical investigations have been validated through select engineered FVIIa constructs which, even in vivo, demonstrate beneficial, proof-of-concept effects. Altogether, we have recently gained unprecedented knowledge about and control over FVIIa allostery, enabling us to influence FVIIa activity in advanced manners and in a desired direction. Here, we summarize our current understanding of the allosteric activation of FVIIa ending up with some prospects of future investigations.

A growing number of patients receiving antithrombotic therapy require dental procedures. Dental interventions in these patients can be challenging, as the risk of bleeding from the continuation of antithrombotic therapy needs to be weighed against the thromboembolic risk associated with drug interruption or de-escalation. Most minor dental procedures, including simple dental cleaning and filling, pose minimal bleeding risk, and antiplatelet or anticoagulation therapy can be continued without interruption. Local hemostatic measures, such as tranexamic mouthwash, can be used, as needed, to reduce bleeding events following these interventions. Managing antithrombotic therapy during more invasive dental interventions and oral surgeries with a higher risk of perioperative bleeding necessitates the consideration of specific factors influencing the bleeding risk and thromboembolism. In patients receiving antithrombotic therapy for primary prevention, temporary interruption is reasonable. In others, the decisions may be more complex and more nuanced. In this article, we review the current evidence for managing patients receiving oral antiplatelet or anticoagulant drugs scheduled for various dental procedures and present a practical approach for the periprocedural management of antithrombotic treatments.

Background: Variations in light exposure are associated with changes in inflammation and coagulation. The impact of light spectra on venous thrombosis (VT) and arterial thrombosis is largely unexplored.

Objectives: To investigate the impact of altering light spectrum on platelet function in thrombosis.

Methods: Wild-type C57BL/6J mice were exposed to ambient (mice^white, 400 lux), blue (mice^blue, 442 nm, 1400 lux), or red light (mice^red, 617 nm, 1400 lux) with 12:12 hour light:dark cycle for 72 hours. After 72 hours of light exposure, platelet aggregation, activation, transcriptomic, and metabolomic changes were measured. The ability of released products of platelet activation to induce thrombosis-generating neutrophil extracellular trap formation was quantified. Subsequent thrombosis was measured using murine models of VT and stroke. To translate our findings to human patients, light-filtering cataract patients were evaluated over an 8-year period for rate of venous thromboembolism with multivariable logistic regression clustered by hospital.

Results: Exposure to long-wavelength red light resulted in reduced platelet aggregation and activation. RNA-seq analysis demonstrated no significant transcriptomic changes between mice^red and mice^white. However, there were global metabolomic changes in platelets from mice^red compared with mice^white. Releasate from activated platelets resulted in reduced neutrophil extracellular trap formation. Mice^red also had reduced VT weight and brain infarct size following stroke. On subgroup analysis of cataract patients, patients with a history of cancer had a lower lifetime risk of venous thromboembolism after implantation with lenses that filter low-wavelength light.

Conclusion: Light therapy may be a promising approach to thrombus prophylaxis by specifically targeting the intersection between innate immune function and coagulation.

Background: Despite appropriate treatment, up to 50% of patients with proximal deep vein thrombosis will develop postthrombotic syndrome (PTS). Once PTS occurs, there is no specific treatment, and some patients constantly experience intolerable symptoms. Hence, prevention of PTS is important.

Objectives: To characterize vein wall remodeling after thrombus and investigate the effects of antiproliferative agent on postthrombotic vein wall remodeling in murine and human subjects.

Methods: Features of postthrombotic vein wall remodeling in murine and human subjects were characterized using imaging and histologic examinations. Paclitaxel-loaded hydrogels were used to assess the effects of antiproliferative agent on the remodeling in murine model. Based on the abovementioned results, a pilot study was conducted to assess the effects of paclitaxel-coated balloon dilation in patients with severe PTS experiencing intolerable symptoms. The control cohort was obtained by 1:1 propensity score matching from a prospective database.

Results: Structural and functional alterations in postthrombotic vein wall were verified by imaging and histologic examinations, and predominant active α-smooth muscle actin-positive cells and fibroblast-specific protein 1-positive cells proliferation was observed. In the murine model, the application of paclitaxel-loaded hydrogels inhibited the remodeling. In the pilot clinical study, patients receiving drug-coated balloon demonstrated benefits in Villalta scores and venous clinical severity scores compared with those not receiving drug-coated balloon, and no severe adverse events were reported except for thrombosis recurrence.

Conclusion: Cell proliferation plays an important role in postthrombotic vein wall remodeling. Inhibition of cell proliferation inhibits the remodeling in murine model and may reduce signs and symptoms in patients with severe PTS.

Background: Thrombocytopenia is common for patients in the intensive care unit (ICU) and is associated with adverse outcomes. ICU thrombocytopenia in pediatric patients who underwent cardiac surgeries with cardiopulmonary bypass (CPB) is inadequately studied.

Objectives: We aimed to investigate the incidence, risk factors, and prognostic role of ICU thrombocytopenia after congenital cardiac surgeries with CPB.

Methods: A retrospective study involving 11 761 patients was conducted. Patients were categorized into 4 groups of thrombocytopenia based on platelet counts tested during ICU: non (>150 × 10⁹/L), mild (100-150 × 10⁹/L), moderate (50-100 × 10⁹/L), and severe (<50 × 10⁹/L). Logistic and Cox regression analyses were utilized to explore the risk factors of thrombocytopenia and the association of ICU thrombocytopenia with 30-day mortality.

Results: ICU thrombocytopenia was observed in 4007 patients (34.1%), with mild, moderate, and severe thrombocytopenia occurring in 2773 (23.6%), 987 (8.4%), and 247 (2.1%) patients, respectively. Younger age, cyanotic congenital heart disease, CPB duration, and preoperative laboratory findings (red blood cell, thrombocytopenia, red cell distribution width, hematocrit, and coagulation disorder) were identified as independent risk factors of ICU thrombocytopenia. Patients with moderate (hazard ratio [95% CI]: 11.38 [3.02-42.87]; P < .001) and severe thrombocytopenia (hazard ratio [95% CI]: 49.54 [13.11-187.14]; P < .001) had a significantly higher risk of 30-day mortality. Furthermore, with the increase in the severity of ICU thrombocytopenia, there was an incremental increase in the incidence of postoperative critical bleeding and thrombosis, perioperative blood transfusions, length of ICU stays, and duration of mechanical ventilation.

Conclusion: ICU thrombocytopenia occurred in one-third of children after congenital cardiac surgery with CPB, and it was associated with multiple adverse outcomes.