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Background: Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes., Objectives: To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality., Methods: C57BL/6J mice received an iron-deficient diet (8 weeks; ±1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [F]II, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2-antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days., Results: Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with nonanemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice., Conclusion: These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA., (© 2024 The Author(s).)

Background: Mechanisms of iron clearance from hemophilic joints are unknown., Objectives: To better understand mechanisms of iron clearance following joint bleeding in a mouse model of hemophilia., Methods: Hemarthrosis was induced by subpatellar puncture in factor VIII (FVIII)-deficient (FVII -/- ) mice, +/- periprocedural recombinant human FVIII, and hypocoagulable ( Hypo BALB/c) mice. Hypo BALB/c mice experienced transient FVIII deficiency (anti-FVIII antibody) at the time of injury combined with warfarin-induced hypocoagulability. Synovial tissue was harvested weekly up to 6 weeks after injury for histological analysis, ferric iron and macrophage accumulation (CD68), blood and lymphatic vessel remodeling (αSMA; LYVE1). Synovial RNA sequencing was performed for FVIII -/- mice at days 0, 3, and 14 after injury to quantify expression changes of iron regulators and lymphatic markers., Results: Bleed volumes were similar in FVIII -/- and Hypo BALB/c mice. However, pronounced and prolonged synovial iron accumulation colocalizing with macrophages and impaired lymphangiogenesis were detected only in FVIII -/- mice and were prevented by periprocedural FVIII. Gene expression changes involved in iron handling (some genes with dual roles in inflammation) and lymphatic markers supported proinflammatory milieu with iron retention and disturbed lymphangiogenesis., Conclusion: Accumulation and delayed clearance of iron-laden macrophages were associated with defective lymphangiogenesis after hemarthrosis in FVIII -/- mice. The absence of such findings in Hypo BALB/c mice suggests that intact lymphatics are required for removal of iron-laden macrophages and that these processes depend on FVIII availability. Studies to elucidate the biological mechanisms of disturbed lymphangiogenesis in hemophilia appear critical to develop new therapeutic targets., Competing Interests: Declaration of competing interests A.v.D. has received honoraria for participating in scientific advisory board panels, consulting, and speaking engagements from BioMarin, Regeneron, Pfizer, Bioverativ/Sanofi, CSL-Behring, Novo Nordisk, Spark Therapeutics, Genentech, and UniQure. A.v.D. is a cofounder and member of the Board of Directors of Hematherix LLC., a biotech company that is developing (super)FVa therapy for bleeding complications. E.J.C., B.C.J., K.M.F., and C.A.N. have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acute traumatic coagulopathy (ATC) occurs in approximately 30% of patients with trauma and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond can reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by activated partial thromboplastin time (APTT) prolongation and reductions of factor V (FV), factor VIII (FVIII), and fibrinogen but not factor II and factor X. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as a consequence of severe bleeding. superFVa prophylaxis before liver laceration reduced bleeding and prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. superFVa intervention started after the development of ATC stabilized bleeding, reversed prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We have further characterized the Asian genotypes (Types 2 and 7) and subtypes of JC virus (JCV). Urine samples from 224 individuals with Han and Mongolian populations were collected in five regions in eastern China: Kunming, Chengdu, Shenyang, Chifeng, and Manzhouli. Also, 99 urine samples were collected from coastal and hill groups in Kerala, southern India, and 23 urine samples from Seoul, Korea. PCR products of four typing fragments were sequenced, including two in the VP1 gene, as well as one each in the VT intergenic region and regulatory region. It was possible to clone and sequence a total of 42 JCV whole genomes (approximately 5120 bp). Five genotypes of JCV (Types 7A, 7B, 7C, 2D, and 4) were found in China, four genotypes (Types 2D, 7C, 4, and 1B) in southern India, and three genotypes (Types 7B, 2A, and 1A) in Korea. Type 7A was most prevalent in South China (59-64%) and Type 7B was predominant in northeast China and Inner Mongolia (67-77%). Type 7C strains were spread throughout North and South China (3-14%), while Type 2D strains were found only in the two Mongolian groups (9-10%). In southern India, Type 2D was predominant in the coastal group (95%), and two major types, Type 7C (50%) and Type 2D (35%), were prevalent in the tribal hill groups. In Korea two major genotypes were found: Type 7B (50%) and Type 2A (43%). Phylogenetic reconstruction places the Chinese genotypes in the Afro-Asiatic supercluster, but distinct from the Mongolian and Indian strains (Type 2D), as well as the Korean and Japanese genotype (Type 2A) that predominates in the Americas.