Journal of Thrombosis and Haemostasis最新文献

Background: Platelets are critical for thrombosis and hemostasis. The THPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent and its activity may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration.

Objectives: We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering mechanisms that bypass THPO-MPL pathways.

Methods: We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify Food and Drug Administration-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. Bromodeoxyuridine assays, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and RNA sequencing analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes.

Results: We found that paclitaxel expands thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish and elevates platelet levels in mice. This effect occurs by bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis, potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis.

Conclusion: Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the JAK2-ERK1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.

Background: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events, including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathologic aspects of human disease.

Objectives: To evaluate DVT severity and hypercoagulability in murine and human MASH.

Methods: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a standard chow diet or a high-fructose, high-fat, and high-cholesterol MASH diet for 24 weeks. Plasma analyses of coagulation markers and thrombin generation assays were performed in a well-characterized cohort of patients with or without MASH.

Results: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased levels of plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs 11/15 in controls, P = .0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased levels of plasma coagulation markers and delayed thrombin generation.

Conclusion: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased venous thromboembolic events in patients with MASH.

Background: A considerable number of patients with chronic thromboembolic pulmonary hypertension (CTEPH) lack a history of venous thromboembolism (VTE).

Objectives: We aimed to examine the annual incidence and prevalence of CTEPH in Denmark and to compare the rates of VTE, bleeding, and mortality between CTEPH patients with and without a history of VTE.

Methods: The Danish National Patient Registry covering all Danish hospitals was used to identify all CTEPH cases between 2009 and 2018, based on combinations of discharge diagnoses using International Classification of Diseases, 10th Revision codes for CTEPH and relevant diagnostic and/or therapeutic interventions. Incidence rates of CTEPH per 100 000 person-years, rates of VTE and bleeding, and 5-year survival estimates were calculated.

Results: In total, 509 CTEPH patients were identified, of whom 82% had a history of VTE. The yearly incidence rate of CTEPH was 0.5 to 0.8 per 100 000 person-years during the study period. Patients with a history of VTE experienced a 2.5-fold rate of VTE compared with those without prior VTE (2571 vs 980 per 100 000 person-years), while the rate of bleeding events was lower (5008 vs 7139 per 100 000 person-years). The 5-year survival of CTEPH patients with a VTE history was 65% (95% CI, 58%-71%) compared with 45% (95% CI, 31%-58%) in patients without a history of VTE.

Conclusion: The Danish incidence rate of CTEPH was comparable with that of other European countries. We identified notable differences in the prognosis of patients with CTEPH with or without a history of VTE. These findings may support generation of hypotheses regarding the pathophysiology of CTEPH and inform current patient care.

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Background: Adjunctive catheter-directed thrombolysis shows variable efficacy in preventing postthrombotic syndrome (PTS), despite restored patency.

Objectives: This Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome (CAVA) trial subanalysis investigated the effect of ultrasound-accelerated catheter-directed thrombolysis (UACDT) on patency, reflux, and their relevance in PTS development.

Methods: This multicenter, randomized, single-blind trial enrolled patients (aged 18-85 years) with a first iliofemoral deep vein thrombosis and symptom duration ≤14 days. Patency and reflux were assessed by duplex ultrasound at 12 months (T12) and long-term (LT) follow-up (median, 39.5 months; IQR, 24.0-63.0 months). PTS was diagnosed using the Villalta score.

Results: UACDT significantly improved patency in all vein segments at T12 (60.3% UACDT vs 25.9% standard treatment [ST]; P = .002) and LT (45.2% UACDT vs 11.9% ST; P < .001). Popliteal patency, however, was similar between groups (87.9% UACDT vs 83.3% ST; P = .487). Reflux was similar between groups at T12 and LT; only popliteal reflux was significantly reduced in the UACDT group at LT (22.6% UACDT vs 44.8% ST; P = .010). Absent iliac patency at T12 was associated with increased PTS risk in the ST group only (odds ratio [OR], 10.84; 95% CI, 1.93-60.78; P = .007). In the UACDT group, popliteal reflux at T12 was associated with moderate-to-severe PTS at T12 (OR, 4.88; 95% CI, 1.10-21.57; P = .041) and LT (OR, 5.83; 95% CI, 1.44-23.63; P = .009). Combined popliteal reflux and absent iliac patency significantly amplified PTS risk (OR, 10.79; 95% CI, 2.41-48.42; P < .001).

Conclusion: UACDT improved patency and reduced popliteal reflux. Iliac patency and popliteal reflux are independently associated with moderate-to-severe PTS and contribute synergistically to its development. However, a proportion of moderate-to-severe PTS cases lacks an evident underlying cause.