Masanori Matsumoto

Recombinant ADAMTS13 (rADAMTS13) was approved for prophylactic or on-demand ADAMTS13 replacement therapy for congenital thrombotic thrombocytopenic purpura (TTP) based on data from a preplanned interim analysis of a phase 3, open-label, crossover trial (NCT03393975). Here, we report results from the final analysis with 48 participants (3-68 years old) randomized 1:1 to two 6-month periods of prophylaxis with rADAMTS13 (40 IU/kg) or plasma-based therapy (PBT), followed by the alternate treatment at the same frequency; thereafter, all participants received 6 months of rADAMTS13. The primary outcome was acute TTP events. No participants experienced an acute event during rADAMTS13 prophylaxis, whereas 1 experienced an acute event during PBT prophylaxis (mean annualized event rate [AER], 0.04). A lower model-based mean AER of subacute TTP events was observed during rADAMTS13 prophylaxis (0.04) versus PBT (0.26). Thrombocytopenia was the most frequent TTP manifestation (model-based mean AER, 0.91 with rADAMTS13 and 1.62 with PBT). Treatment-related adverse events (AEs) occurred in 4.3% of participants with rADAMTS13 and in 45.8% with PBT. No serious AEs were considered related to rADAMTS13, whereas 1 serious AE (pyrexia) was considered related to PBT. No ADAMTS13-neutralizing antibodies were detected. Greater treatment satisfaction was reported for rADAMTS13 prophylaxis versus PBT (assessed using the 9-item Treatment Satisfaction Questionnaire for Medication). A ~6-fold increase in ADAMTS13 activity and prolonged time with ADAMTS13 activity of ≥10% was noted in participants receiving rADAMTS13 versus PBT. Consistent with the interim analysis, results with a longer follow-up support the continued clinical benefit of rADAMTS13 prophylaxis in congenital TTP.

We report a 33-year-old woman with systemic lupus erythematosus who developed fulminant multiorgan ischemic manifestations and hematologic abnormalities. She presented with persistent fever, newly developed painful fingertip cyanosis, and acute kidney injury. Laboratory tests showed severe thrombocytopenia, hemolytic anaemia with fragmented red blood cells, positive direct and indirect Coombs tests, hypocomplementemia, and positivity for multiple autoantibodies, including a triple-positive antiphospholipid antibody profile. Within the first week of hospitalisation, in addition to digital ischemia, she developed multiple cerebral infarctions and acalculous cholecystitis, findings consistent with catastrophic antiphospholipid syndrome. Unexpectedly, the activity of a disintegrin and metalloproteinase with thrombospondin type 1 motifs member 13 (ADAMTS13) was severely reduced to 5%, whereas ADAMTS13 inhibitor was not detected by the Bethesda assay. There was no past medical or family history suggestive of congenital thrombotic thrombocytopenic purpura. After treatment with high-dose glucocorticoids and nine sessions of plasma exchange, abdominal pain resolved and digital ischemia improved, accompanied by improvement in hematologic and renal abnormalities and disappearance of fragmented red blood cells. Subsequently, ADAMTS13 activity normalised to 63% and remained stable after completion of plasma exchange. Later, non-inhibitory anti-ADAMTS13 autoantibodies were detected by enzyme-linked immunosorbent assay in a stored serum sample obtained on admission. ADAMTS13 deficiency due to non-inhibitory anti-ADAMTS13 autoantibodies may modify the complications of systemic lupus erythematosus and antiphospholipid syndrome by promoting thrombotic microangiopathy.

Background and Objectives: Patient blood management (PBM) is an evidence-based, multidisciplinary approach to optimise patients' own blood across major clinical settings including surgery and obstetric care. The WHO 2021 policy brief and 2024 implementation guidance position PBM within a broader blood-health optimisation framework. Japan has advanced healthcare infrastructure, yet systematic PBM implementation aligned with this paradigm remains limited. Methods: We conducted a narrative review integrating WHO policy documents and peer-reviewed literature, Japanese governmental transfusion policies, reimbursement frameworks, and national blood utilisation data. Results: Four inter-connected barriers were identified: (1) conceptual misalignment rooted in a transfusion-avoidance framework; (2) structural limitations including absence of dedicated PBM policy and multidisciplinary PBM pathways, reimbursement structures that disincentivise intravenous iron therapy and repeated intraoperative viscoelastic testing (VET), and limited preoperative and antenatal iron-deficiency screening; (3) educational gaps among healthcare professionals; and (4) a cultural preference for consensus-driven change. At the same time, several enabling factors exist, including near-universal transfusion-therapy committees, universal health insurance coverage, advanced electronic medical record systems, and a strong quality-improvement culture. Japan's established autologous blood management infrastructure, combined with systematic correction of iron deficiency including intravenous iron therapy in both perioperative and obstetric settings, represents a contextually distinctive pathway for PBM development. Conclusions: Further evolution of Japan's PBM framework toward the WHO blood-health optimisation paradigm will likely require staged implementation strategies. Leveraging existing institutional strengths, a phased approach involving system readiness, pilot implementation, and national scale-up may provide a realistic pathway to sustainable, patient-centred blood-health optimisation.

Von Willebrand factor (VWF) is an essential contributor to hemostasis through its interaction with the platelet glycoprotein (GP) Ibα receptor. VWF is cleaved by ADAMTS13 to limit its prothrombotic properties. Failure to do so can result in platelet-VWF complexes that occlude the microcirculation, as seen in thrombotic thrombocytopenic purpura (TTP). In this setting, plasmin becomes active to cleave VWF, forming a distinct plasmin-generated cleavage product of VWF (cVWF) that is detectable during acute attacks in patients with TTP and following therapeutic plasminogen activation in a mouse model of TTP. However, it remains unclear whether plasmin-mediated proteolysis of VWF alone accounts for the breakdown of platelet-VWF complexes. Using ristocetin-induced platelet agglutinations, we show that plasmin cleavage of VWF does not impair its platelet-binding capacity, whereas plasmin-mediated cleavage of GPIbα reduces the ability of platelets released from agglutinates to bind VWF. Furthermore, platelets in suspension are relatively resistant to plasmin cleavage. We therefore propose that VWF binding may enhance GPIbα cleavage by recruiting plasmin(ogen) to the platelet surface. In a TTP mouse model, plasminogen activation led to a VWF-dependent reduction in GPIbα detectability, although to a lesser extent than observed in vitro. In patients with acute TTP, soluble GPIbα levels were elevated, indicating increased GPIbα shedding during attacks of thrombotic microangiopathy, although the extent to which this is plasmin-mediated remains unclear. Together, our findings demonstrate that plasmin cleavage of GPIbα drives the disruption of ristocetin-induced agglutinates, while its contribution to the breakdown of platelet-VWF complexes in vivo appears limited.

Background and Objectives: Haemoglobin‐based oxygen carriers (HBOCs) are intended to treat major bleeding, particularly in emergencies. While haemoglobin vesicles (HbVs)—liposome‐encapsulated haemoglobin with a long shelf life—and other HBOCs can cause colour‐related interference in chemistry testing, their effect on standardized pretransfusion assays remains unclear. Materials and Methods: We evaluated the impact of HbVs in blood on routine pretransfusion testing, including ABO blood group/Rhesus D (RhD) typing, antibody screening and cross‐matching, using tube and column agglutination techniques on samples collected from 10 healthy individuals and one patient with anti‐E antibodies. Whole blood was mixed with HbVs at 9:1 ratio for each sample. Results: Plasma treated with HbVs developed a dark‐red colouration, which interfered with the agglutination assessment. Manual replacement or automated washing of plasma containing HbVs effectively restored test clarity without compromising the accuracy of tube‐based assays for reverse ABO/RhD typing, antibody screening or major cross‐matching. In contrast, the washing process could not be applied to column‐based techniques. No interference was observed between the HbVs and commonly used reagents. Conclusion: Tube‐based pretransfusion testing with manual replacement or automated washing procedures is recommended for accurate compatibility assessment of blood samples treated with HbVs. However, further validation is required for broader clinical application.

Introduction: Haemoglobin vesicles (HbVs) (product name, NMU-HbVs [Nara Medical University-Haemoglobin Vesicles]), which contain purified human haemoglobin encapsulated within liposomes, have been developed as a potential alternative to blood transfusions in emergency situations. A previous phase I study examined doses up to 100 mL in 11 healthy volunteers. Here, we describe the protocol for a phase Ib study, wherein we will evaluate the safety and pharmacokinetics of NMU-HbV in healthy Japanese adults. Methods and analysis: This single-centre, open-label, dose-escalation study will enrol 16 healthy volunteers divided into four cohorts. Planned doses are 100 mL for cohorts 1 and 2, 200 mL for cohort 3 and 400 mL for cohort 4, with infusion rates gradually increasing to a maximum of 5.0 mL/min. The primary endpoint will be safety, which will be assessed as the incidence of adverse events within 14 days and significant clinical changes within 72 hours after administration. Safety evaluations will include subjective symptoms, vital signs, electrocardiograms and laboratory test results compared with the baseline. The secondary endpoint will be pharmacokinetics, which will be assessed as changes in NMU-HbV concentration immediately after infusion until day 4 to determine the maximum blood concentration, time to reach the maximum blood concentration, area under the blood concentration-time curve and elimination half-life. This study will provide data on the safety and pharmacokinetic profiles of NMU-HbV at doses up to 400 mL. The findings are expected to support the further development of NMU-HbV as a viable alternative to emergency transfusions. Ethics and dissemination: The study protocol was approved by the Institutional Review Board of Nara Medical University on 10 December 2024. Dissemination plans include publishing in peer-reviewed scientific journals and presentation at international conferences. Trial registration number: Japan Registry of Clinical Trials (jRCT2051240249). Registered on 27 January 2025 ( https://jrct.mhlw.go.jp/en-latest-detail/jRCT2051240249 ).