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ETV6:ACSL6 fusion resulted from t(5;12)(q31;p13) is very rare and occurs in variety of myeloid malignancies, often associated with eosinophilia that mimics the found in ETV6:PDGFRB neoplasms. In most cases, t(5;12)/ETV6:ACSL6 occurs at diagnosis and is frequently observed as an isolated abnormality, suggesting that ETV6:ACSL6 is a primary event. The true frequency of cases with ETV6:ACSL6 gene fusion might be underestimated because some cases present t(5;12)(q31;p13) or normal karyotype with eosinophilia and/or basophilia did not perform molecular analysis to detect ETV6:ACSL6 fusion. Cases with t(5;12)(q31;p13)/ETV6:ACSL6 are very rare and so far 18 cases have been reported. [Extracted from the article]

Glanzmann's thrombasthenia (GT) is a severe hemorrhagic disease. It is caused by mutations in ITGA2B or ITGB3, which are the respective genes encoding integrin αIIb and β3. Despite widespread mutational analysis, the mechanisms underlying the extensive variability in bleeding severity observed among affected individuals remains poorly understood. In order to explore the mechanisms conferring for bleeding heterogeneity, three GT patients with ITGA2B c.2671C > T (p.Q891X) who possessed different bleeding scores were studied. Analysis showed that there was significant difference in nonsense‐mediated mRNA decay (NMD) efficiency among the three patients. These differences positively correlated with their bleeding score. Next, a knock‐in mouse model (KI mice) with the ITGA2B c.2659C > T (p.Q887X) was generated using CRISPR/Cas9. Importantly, this mutation is homologous to ITGA2B c.2671C > T (p.Q891X) in humans. The bleeding time of KI mice was significantly in comparison to the wide‐type mice. Interestingly, bleeding was stopped after treatment with caffeine, which is a known NMD inhibitor. This suggests that NMD efficiency potentially influences bleeding severity in ITGA2B c.2659C > T (p.Q887X) KI mice. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is a life-threatening condition that occurs when the liver sustains severe damage and rapidly loses its function. The primary cause of ALF is the overdose of acetaminophen (APAP), and its treatment is relatively limited. The involvement of the complement system in the development of ALF has been implicated. However, the related mechanisms remain poorly understood. Complement 3 (C3) knockout mice, complement 3a receptor (C3aR) knockout mice, platelet C-type lectin-like receptor 2 (Clec-2)-deficient mice, and myeloid cell podoplanin (Pdpn)-deficient mice were generated. Liver tissues were collected for histological analysis, RNA sequencing, confocal immunofluorescence, and immunoblot analyses. Our data demonstrated that APAP activated the C3/C3aR pathway, leading to intrahepatic hemorrhage, ultimately resulting in hepatocyte necrosis. Deletion of C3 or C3aR mitigated APAP-induced liver injury (AILI). C3/C3aR signaling upregulated the expression and phosphorylation of transcription factors STAT3 and c-Fos in hepatic Kupffer cells, which in turn increased PDPN expression, promoting platelet recruitment to the Kupffer cells via the interaction of PDPN and the CLEC-2 on platelets. Since the activation of platelets mediated by C3/C3aR occurs irrespective of the major hemostatic pathways, blocking the C3/C3aR pathway in ALF could be a coagulopathy-sparing and novel therapeutic approach. In summary, this study unveiled the critical roles of the C3/C3aR pathway in developing AILI, providing evidence that the C3/C3aR pathway could be an effective therapeutic target for AILI., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The glycoprotein, von Willebrand factor (VWF) is a carrier protein for factor VIII. When bound to platelets and the extracellular matrix, it promotes aggregation or adhesion of platelets to areas of vascular damage. A disintegrin and metalloproteinase with thrombospondin motif, member 13 (ADAMTS13) cleaves between the tyr1605 and met1606 residues in the central A2 domain of VWF decreasing its activity. The levels of ADAMTS13 and VWF are positively correlated with the risk of developing thrombosis and inversely correlated with the risk of bleeding. A total of 93 patients were observed, who underwent total hip arthroplasty or total knee arthroplasty. Blood samples were collected preoperatively and on postoperative days (PODs) 1, 2, 3, 5 and 7. Plasma levels of the ADAMTS13 antigen were determined using western blotting. The proteolytic activity was validated with the FRETS‑VWF73 assay. VWF:Ag and VWF:RCo activity were measured using an enzyme‑linked immunosorbent assay. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), antithrombin III and plasma fibrinogen levels were measured on a Sysmex® CA500 system with corresponding reagents. D‑dimer levels were measured on a STA‑R fully automated coagulation analyzer. The results demonstrated that, the levels of VWF antigen and activity in the patient increased from postoperative day (POD) 1. By contrast, the level of the ADAMTS13 antigen and its activity in the patients decreased significantly. Starting on POD1, fibrinogen and D‑dimer levels increased. No significant changes were observed in PT, APTT and TT. It was concluded that the ADAMTS13 and VWF levels exhibited a marked association with thrombosis risk. The levels of ADAMTS13 and VWF may be potentially useful as markers for predicting thrombotic complications following arthroplasty and inhibiting the activity of VWF may be a novel prophylaxis to reduce postoperative deep venous thrombosis and pulmonary embolism.