TH open : companion journal to thrombosis and haemostasis最新文献

Introduction: Limited data are available on the relationship between bleeding outcomes and physical activity, and the quality of daily life (QoL), in children with haemophilia A (HA) receiving emicizumab prophylaxis.

Aim: TSUBASA evaluated physical activity, bleeding events, safety, and QoL in Japanese people with HA initiating emicizumab prophylaxis. This paper reports the results from the final analysis, focusing on children and adolescents with HA without factor VIII inhibitors, and their caregivers.

Methods: TSUBASA was a prospective, multicentre, observational study conducted across 50 medical institutions in Japan. Participants received emicizumab for 97 weeks. Bleeding events and physical activity data were obtained using an electronic patient-reported outcomes application; activity intensity was collected by wearable activity trackers worn over five 8-day monitoring periods. Adverse events (AEs) were documented on the electronic case report form and QoL was assessed using questionnaires.

Results: A total of 46 participants aged <18 years were enrolled; most (84.8%) had severe HA. Over a median observation period of 674 days (quartile 1-quartile 3: 665-690), the mean annualized bleed rate was 0.86 (standard deviation: 1.26). In all Twenty-six participants experienced 66 AEs, of which 2 were injection-site reactions deemed related to emicizumab. J-KIDSCREEN-52 questionnaire scores were maintained from baseline onwards. Of the completed caregiver questionnaires ( n  = 32), 43.8% reported increased activity and 56.3% reported unchanged activity. Additionally, 56.3% reported decreased anxiety about bleeding and 37.5% reported unchanged anxiety about bleeding. A total of 172 events of physical activity were recorded by 19 participants; 44 were high risk, 70 were moderate risk, and 42 were low risk. One activity-related traumatic bleed resulting from the impact of a basketball occurred, and more than 25 different types of physical activity were performed without bleeding.

Conclusion: Children and adolescents with HA who receive prophylaxis with emicizumab may be able to engage in consistent physical activity, with a low risk of experiencing bleeds. Additionally, the questionnaire responses from caregivers on physical activity and caregiver experience provide rare insights into the real-world impact of emicizumab prophylaxis. These findings present a more comprehensive view of the benefits of emicizumab. No new safety signals were observed and QoL was maintained for 2 years after emicizumab initiation.

Abstract:

Background: Fibrinolysis is the process of blood clot breakdown by the enzyme plasmin. Despite increased usage of large animals such as pigs to study fibrinolysis in human disease models, a comprehensive study comparing the human and porcine fibrinolytic factors has not been reported.

Objective: To directly compare and characterize structural and functional differences between human and porcine fibrinolytic factors.

Methods: Using human or porcine source of plasminogen, tissue-type plasminogen activator (tPA), and fibrinogen, we investigated how various permutations of the three fibrinolytic factors affect overall plasmin generation. Human or porcine plasmin breakdown of fibrin generated from human or porcine fibrinogen was also investigated using turbidity-based lysis assay and visualized using SDS-PAGE. Primary structures of the various proteins were also compared.

Results: All-human components had a 24-fold higher plasmin generation than all-porcine components. Species dependence on plasmin generation was the most dependent on fibrin source, where human fibrin presence led to a 2- to 34-fold higher plasmin generation than porcine fibrin. Porcine plasmin was the better enzyme for human or porcine fibrin breakdown due to a 2.7-fold and 6.7-fold higher k _cat , respectively. Peptide sequence analyses show the greatest differences lie in Kringle domain 1 for plasminogen and Kringle domain 2 for tPA, both of which bind fibrin. Fibrinogen chains also show the greatest difference within the αC domain, which has known plasminogen and tPA binding sites.

Conclusion: Although similar, there are notable and specific differences between the human and porcine fibrinolytic systems, particularly toward plasmin generation and fibrin breakdown.

Neonatal acute peritonitis is a leading cause of morbidity and mortality and poses challenges that demand prompt diagnosis and treatment, particularly in infants with disseminated intravascular coagulation. Here, we report a case series of four infants with acute peritonitis caused by necrotizing enterocolitis, gastrointestinal perforation, and meconium peritonitis. Laboratory tests for thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (t-PAIC) suggested the activation of the coagulation system followed by treatment with anticoagulant therapy in these infants. Overall, TAT, PIC, t-PAIC, and sTM may guide anticoagulant therapy, offering prospects for improving the outcomes in neonates with acute peritonitis.

Background: Central venous catheter (CVC) insertion is a cornerstone procedure in hospitalized and critically ill adults. However, many patients requiring CVCs have coagulopathy, thrombocytopenia, liver disease, or hematologic malignancies, raising concerns about bleeding risk. The true incidence of hemorrhagic complications and the value of preventive measures in these populations remain uncertain.

Objective: The objective of this study is to systematically evaluate the incidence of bleeding related to CVC placement in adults at increased hemorrhagic risk and to assess the effectiveness of periprocedural preventive strategies.

Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from January 2000 to March 2025. Randomized trials and observational studies involving adults with elevated bleeding risk undergoing CVC placement were included. Data extraction and risk of bias assessment (RoB 2 and Newcastle-Ottawa Scale) were performed independently by two reviewers. Certainty of evidence was rated using GRADE (Grading of Recommendations Assessment, Development, and Evaluation), and random-effects meta-analyses were conducted when appropriate.

Results: Forty-one studies encompassing 7,603 patients and 8,796 CVC insertions were analyzed. Major bleeding occurred in 0.57% of procedures and minor bleeding in 8.1%. The pooled incidence of any bleeding across 22 studies was 6.8% (95% confidence interval, 3.7-10.7%). Bleeding was more frequent among patients with hematologic malignancies, severe thrombocytopenia, or critical illness. Ultrasound guidance markedly reduced complications compared with landmark technique. Platelet transfusion was effective only below 30 × 10 ⁹ /L, whereas fresh-frozen plasma showed no clear benefit.

Conclusions: CVC placement in adults with coagulopathy or thrombocytopenia is generally safe. Ultrasound guidance, restrictive transfusion thresholds, and thromboelastography-guided assessment enhance procedural safety and reduce unnecessary transfusions.

A rare prothrombin variant (c.1787G > A, p.Arg596Gln), also known as the prothrombin Belgrade variant, has been associated with an increased predisposition to thrombosis through resistance to antithrombin. This variant has been previously reported in individuals from Serbia, Japan, China, and India. In this case report, we described the first reported case of heterozygosity for the prothrombin Belgrade variant in a Mexican-American family. Affected individuals had negative results on standard hypercoagulable studies; however, they exhibited a history of early-onset and recurrent venous thromboembolism (VTE). Although rare, the prothrombin Belgrade variant-and other prothrombin variants associated with antithrombin resistance-may be underrecognized in patients with recurrent thrombotic events, particularly among individuals from ethnic backgrounds not previously associated with this variant. These findings support the consideration of comprehensive genetic thrombophilia testing, including full sequencing of the prothrombin gene, in patients with negative standard hypercoagulable studies but a strong personal and/or family history of VTE.

Background: Thrombin-antithrombin complex (TAT), a2-plasmininhibitor-plasmin complex (PIC), thrombomodulin (TM), tissue plasminogen activator-plasminogen activator inhibitor complex (t-PAIC) has been increasingly applied in clinical practice in recent years, especially in the diagnosis and treatment of diseases associated with thrombosis and hemorrhage. However, there is no universally accepted evaluation standard for the performance verification of these four indicators currently. Therefore, we designed experiments to verify the precision, trueness, carryover, linearity, and reference intervals of these four indicators. This study is expected to provide references for subsequent research in terms of data and experimental methods.

Methods: According to the Clinical and Laboratory Standards Institute (CLSI) guidelines EP15-A2, EP06-A, and C28-A, the precision, trueness, carryover, linearity, and reference intervals were evaluated.

Results: The within-laboratory CVs of TAT, PIC, TM, and t-PAIC were 3.67, 6.51, 3.64, and 2.46% on Control L and 4.68, 4.67, 5.08, and 3.87% on Control H. The assigned value of calibrations of TAT, PIC, TM, and t-PAIC were all included in the verification intervals. The biases of the four items of Calibration 1 were -6.67, -0.90, -3.58, and -6.78% and biases on Calibration 2 were -2.70, 1.63, 2.66, and -1.16%, respectively, compared with the assigned value provided by the manufacturer. The carryover rate of each indicator was less than 1%. Within the range that meets clinical use, the best fit curves of the four indicators were linear, and the correlation coefficients of all indicators were greater than 0.99. The reference intervals provided by the manufacturer were appropriate in our laboratory.

Conclusion: The performance of HISCL-5000 analyzer for TAT, PIC, TM, and t-PAIC analysis were acceptable and the systems were suitable for clinical analysis.

[This corrects the article DOI: 10.1055/a-2719-9061.].

Background: Recent data on inferior vena cava filter (IVCF) placement mainly originate from the United States, with limited evidence from Europe.

Methods: We used nationwide, patient-level data from 2004 to 2023, including hospitalizations with mention of IVCF placement or venous thromboembolism (VTE). Placement was classified as secondary prevention if VTE was documented during the hospitalization, otherwise as primary prevention. We assessed IVCF placement rates overall and in patients with pulmonary embolism (PE), and studied in-hospital case fatality rates, retrieval rates, and length of hospitalization. Analyses were stratified by prevention type and sex.

Results: IVCF placement was recorded in 5,123 (81.1% secondary prevention) patients. The age-standardized rate of IVCF placement increased from 3.4 (95% confidence interval [CI]: 2.0; 4.8) per 1,000 PE-related hospitalizations in 2004 to 19.2 (95% CI: 16.7; 21.6) per 1,000 PE-related hospitalizations in 2023. The IVCF-related in-hospital case fatality rate increased from 7.1% (95% CI: 1.1; 13.2) in 2004 to 10.2% (95% CI: 7.2; 13.3) in 2023 and was higher after IVCF placement for secondary prevention than for primary prevention. The estimated retrieval rate within an average of 6 months was 31.9% (95% CI: 29.9; 34.0), peaking at 34.6% (95% CI: 32.4; 36.8) after excluding deaths during index hospitalization. The retrieval rate decreased progressively over time. IVCFs were less likely to be retrieved among older patients and in patients with intracranial hemorrhage or cancer, whereas the removal rate was higher among patients with recent trauma.

Conclusion: We showed an increasing trend of IVCF placement procedures. The IVCF retrieval rate decreased over time, emphasizing the need for improved follow-up protocols.

Background: Protein C concentrate (Ceprotin®; Baxalta US Inc., a Takeda company, Cambridge, MA; Takeda Manufacturing Austria AG, Vienna, Austria) is approved for intravenous (IV) use in severe congenital protein C deficiency (SCPCD), with pharmacokinetic (PK)-guided dosing. Subcutaneous (SC) administration may reduce treatment burden, especially for pediatric and neonatal patients; however, the use of SC protein C concentrate has so far been empirical, and PK data are required to support dose optimization.

Objectives: This study aimed to characterize the population PK (PopPK) of SC protein C concentrate in patients with SCPCD.

Methods: A PopPK model was developed for SC protein C concentrate, based on a previously developed model for IV administration. Simulations were conducted across eight three-stage dosing scenarios that patterned the IV dosing regimens in the U.S. product label (initial dose [stage 1]: 60-120 IU/kg; subsequent three doses [stage 2]: 60-80 IU/kg every 6 hours; maintenance dose [stage 3]: 45-120 IU/kg every 12 hours). Additional simulations were performed across six one-stage dosing scenarios that were based on dosing reported in clinical practice (50-60 IU/kg every 12 hours, 200-350 IU/kg every 48 hours). Target maximum ( C _max ) and trough ( C _trough ) concentration levels used as references were 100 IU/dL and 25 IU/dL, respectively.

Results: The dataset included 86 observations from 13 patients with SCPCD receiving SC protein C concentrate. Model-based simulations predicted that, after the first dose, 6-9% and 5-45% of patients in the three- and one-stage dosing scenarios, respectively, would attain C _max >100 IU/dL. At steady state, ≥83% of patients were predicted to attain C _trough >25 IU/dL for all scenarios. In three-stage dosing scenarios, while initial (stage 1 [dose 1]) and subsequent doses (stage 2 [doses 2-4]) determined speed to steady state, exposure at steady state was driven by the maintenance dose (stage 3 [dose 5 onwards]).

Conclusions: The PopPK model was robust and described SC protein C concentrate PK data well. Evidence provided by model-based simulations supports the use of various SC dosing regimens across age groups in acute or prophylactic settings according to the intended protein C activity levels. A high loading dose may be required to rapidly attain target therapeutic concentrations.