Blood Vessels, Thrombosis & Hemostasis最新文献

{"title":"Treatment of severe bleeds with eptacog beta in hemophilia A or B with inhibitors: a post hoc analysis of the PERSEPT 1 and 2 trials","authors":"Guy Young ,&nbsp;Johnny Mahlangu ,&nbsp;Lisa N. Boggio ,&nbsp;Manuel Carcao ,&nbsp;Yesim Dargaud ,&nbsp;Miguel Escobar ,&nbsp;Adam Giermasz ,&nbsp;Cédric Hermans ,&nbsp;Philip Kuriakose ,&nbsp;Wolfgang Miesbach ,&nbsp;Danielle Nance ,&nbsp;Amina Rafique ,&nbsp;Robert F. Sidonio Jr. ,&nbsp;Kateryna V. Vilchevska ,&nbsp;Michael Wang ,&nbsp;Steven W. Pipe","doi":"10.1016/j.bvth.2025.100069","DOIUrl":"10.1016/j.bvth.2025.100069","url":null,"abstract":"<div><h3>Abstract</h3><div>Severe bleeding episodes (BEs) in persons with hemophilia A or B and inhibitors (PwHABIs) represent challenging clinical situations and can require treatment regimens lasting days or weeks before hemostatic control is achieved. Eptacog beta is a recombinant activated human factor VII bypassing agent approved for treating and controlling bleeding in PwHABIs aged ≥12 years. The aim of this study is to assess the efficacy and safety of eptacog beta for severe bleed treatment in PwHABIs during 2 phase 3 trials (PERSEPT 1 and PERSEPT 2). Patients could treat severe BEs with initial doses of 75 or 225 μg/kg eptacog beta at home, followed by subsequent 75 μg/kg eptacog beta infusions administered at predefined intervals in a hospital or hemophilia treatment center. Satisfactory treatment responses to eptacog beta were typically defined in this post hoc analysis by physician- and patient-reported hemostasis evaluations of “excellent” or “good.” Hemostatic control of an intracranial hemorrhage (ICH) in 1 patient was assessed by computed tomography. Seven PwHABIs (aged 1-50 years) treated 8 BEs considered severe or otherwise life threatening with eptacog beta during PERSEPT 1 and PERSEPT 2. Hemostatic control of 7 of these BEs (including 3 ICH events) was achieved. Eptacog beta treatment durations ranged from 25 minutes to 96 hours. No thrombotic events were reported, and eptacog beta was well tolerated. Most severe BEs resolved with eptacog beta treatment during PERSEPT 1 and PERSEPT 2. The PERSEPT 1 and PERSEPT 2 trials were registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #NCT02020369 and #NCT02448680, respectively.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100069"},"PeriodicalIF":0.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Japanese database analysis: effectiveness of early initiation of TPO-RA treatment in tapering corticosteroid dose in ITP","authors":"Kodai Suzuki ,&nbsp;Satoru Ito ,&nbsp;Stefano Carini ,&nbsp;Mami Shimizu ,&nbsp;Shigeki Hatanaka ,&nbsp;Yoshitaka Miyakawa","doi":"10.1016/j.bvth.2025.100066","DOIUrl":"10.1016/j.bvth.2025.100066","url":null,"abstract":"<div><h3>Abstract</h3><div>This longitudinal, descriptive study investigated the effect of the timing of thrombopoietin receptor agonist (TPO-RA) initiation on corticosteroid administration and related adverse events (AEs) in patients with immune thrombocytopenia (ITP) in Japan using real-world data from a health claim database. In total, 7696 patients were divided into 3 groups (early TPO-RA initiation, late TPO-RA initiation, and non–TPO-RA administration) by the presence and timing of TPO-RA administration. The early TPO-RA initiation group included patients first administered TPO-RA &lt;60, &lt;120, and &lt;180 days after the index date. The late TPO-RA initiation group included patients first administered TPO-RA ≥60, ≥120, and ≥180 days after the index date. The early TPO-RA initiation group received the highest daily average prednisolone dose, followed by a rapid decrease in dose, similar to that in the non–TPO-RA administration group. In the early TPO-RA initiation group, there was a long-term trend toward daily average prednisolone doses of ≤5 mg, and by approximately 10 to 11 months, the median dose was 0 mg. Diabetes (insulin-dependent) and hypertension tended to occur more frequently in the late TPO-RA (8.4% and 19.9%, respectively) than in the early TPO-RA initiation group (6.9% and 14.4%, respectively). Incidence rates of infections in the late TPO-RA and early TPO-RA initiation groups were similar (7.2% vs 7.6%). The incidence of AEs was similar between male and female patients; a trend toward a higher incidence was observed in those aged ≥60 years. Early initiation of TPO-RA administration can contribute to reducing total prednisolone dosage, treatment duration, and AEs (eg, hypertension and insulin-dependent diabetes).</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 2","pages":"Article 100066"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world analysis of strategies to prevent thrombosis and bleeding in adults with ALL treated with asparaginase","authors":"Joseph F. Mort ,&nbsp;David Brighton ,&nbsp;Benjamin Mautner ,&nbsp;Eric Pierce ,&nbsp;Farid Ghamsari ,&nbsp;Cecily Allen ,&nbsp;Darren D’Souza ,&nbsp;Imari Patel ,&nbsp;Justin Lawson ,&nbsp;Clayton Jackson ,&nbsp;Karin Abernathy ,&nbsp;Bradley Yelvington ,&nbsp;Ryan Miller ,&nbsp;Bhagirathbhai Dholaria ,&nbsp;Heather Wolfe ,&nbsp;Jordan Infield ,&nbsp;Susan C. Locke ,&nbsp;Rory M. Shallis ,&nbsp;Vu H. Duong ,&nbsp;Daniel R. Reed ,&nbsp;Firas El Chaer","doi":"10.1016/j.bvth.2025.100065","DOIUrl":"10.1016/j.bvth.2025.100065","url":null,"abstract":"<div><h3>Abstract</h3><div>The prognosis of adult patients with acute lymphoblastic leukemia (ALL) has improved with the incorporation of pediatric-inspired regimens that contain PEGylated asparaginase (PEG-Asp). However, PEG-Asp administration is associated with an increased rate of thrombosis. Data regarding the benefits of antithrombin (AT) repletion and prophylactic anticoagulation in adults receiving PEG-Asp–based regimens are limited. We performed a retrospective study to evaluate the rates of induction thrombosis and bleeding among adults receiving ALL therapy containing Asp at 6 academic centers in the United States. Of 233 patients who met the inclusion criteria, 98.3% received PEG-Asp. Ninety-six patients (41.2%) had their AT levels monitored, 58 patients (24.9%) received AT repletion, and 41 patients (17.6%) received prophylactic anticoagulation. Thirty-two patients (13.7%) experienced thrombotic events, with half (53.1%) being line-associated thromboses. In multivariate analysis, the odds of thrombosis did not differ between patients who received AT monitoring, AT repletion, or prophylactic anticoagulation. The odds of thrombosis were 4 times higher for patients with peripherally inserted central catheters than for those with other types of central lines (odds ratio, 4.112; 95% confidence interval, 1.622-10.427; <em>P</em> = .01). Thrombotic risk did not differ based on age, cumulative Asp dose, type of steroid administered, or whether transfusions were performed. Bleeding occurred in 12 patients (5.2%), and major bleeding occurred in 8 patients (3.4%). The odds of bleeding did not increase in the patients who received prophylactic anticoagulation. Our study brings into question whether prophylactic AT repletion and anticoagulation are beneficial strategies for reducing PEG-Asp–associated thrombosis, and large randomized prospective studies are needed.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100065"},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-dimer after 3 months of anticoagulation therapy and outcomes in cancer-associated isolated distal deep vein thrombosis","authors":"Tatsuya Nishikawa ,&nbsp;Yugo Yamashita ,&nbsp;Masashi Fujita ,&nbsp;Takeshi Morimoto ,&nbsp;Nao Muraoka ,&nbsp;Michihisa Umetsu ,&nbsp;Yuji Nishimoto ,&nbsp;Takuma Takada ,&nbsp;Yoshito Ogihara ,&nbsp;Nobutaka Ikeda ,&nbsp;Kazunori Otsui ,&nbsp;Daisuke Sueta ,&nbsp;Yukari Tsubata ,&nbsp;Masaaki Shoji ,&nbsp;Ayumi Shikama ,&nbsp;Yutaka Hosoi ,&nbsp;Yasuhiro Tanabe ,&nbsp;Ryuki Chatani ,&nbsp;Kengo Tsukahara ,&nbsp;Naohiko Nakanishi ,&nbsp;Takeshi Kimura","doi":"10.1016/j.bvth.2025.100063","DOIUrl":"10.1016/j.bvth.2025.100063","url":null,"abstract":"<div><h3>Abstract</h3><div>Cancer-associated isolated distal deep vein thrombosis (IDDVT) is a common complication in patients with cancer. The Optimal Duration of Anticoagulation Therapy for Isolated Distal Deep Vein Thrombosis in Patients with Cancer study revealed the superiority of 12- over 3-month edoxaban treatment with respect to thrombotic risk. However, it remains unclear whether D-dimer levels during anticoagulation influence the efficacy of extended anticoagulation. In this post hoc subgroup analysis, we stratified 519 patients into the low D-dimer (&lt;1.0 μg/mL) (n = 308) and high D-dimer (≥1.0 μg/mL) (n = 211) subgroups based on D-dimer levels at 3 months. The cumulative incidence of a composite of symptomatic recurrent venous thromboembolism (VTE) or VTE-related death was lower in the 12-month edoxaban group than in the 3-month edoxaban group in both the low D-dimer (0.8% vs 5.6%; <em>P</em> = .02; odds ratio [OR], 0.12; 95% confidence interval [CI], 0.01-0.66) and high D-dimer (0.9% vs 10.2%; <em>P</em> = .01; OR, 0.11; 95% CI, 0.01-0.62) subgroups without interaction. Furthermore, there was no significant difference in the cumulative incidence of major bleeding between the 12- and 3-month groups in both the low D-dimer (3.6% vs 1.8%; <em>P</em> = .64; OR, 1.96; 95% CI, 0.47-9.67) and high D-dimer (18.3% vs 14.6%; <em>P</em> = .29; OR, 1.27; 95% CI, 0.60-2.75) subgroups without interaction. In conclusion, a 12-month edoxaban treatment for cancer-associated IDDVT was superior to a 3-month treatment in reducing thrombotic events, irrespective of D-dimer levels after 3 months of anticoagulation therapy. There was no significant increased risk of major bleeding in the 12-month edoxaban group relative to the 3-month edoxaban group regardless of the D-dimer levels at 3 months. This trial was registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #NCT03895502.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 2","pages":"Article 100063"},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refractoriness to eltrombopag in adult primary immune thrombocytopenia: utility of next-generation sequencing techniques","authors":"Tomás José González-López ,&nbsp;Ricardo Sanchez ,&nbsp;Carmen Pastoriza ,&nbsp;Pavel Olivera ,&nbsp;Silvia Bernat ,&nbsp;Fernando Fernandez-Fuertes ,&nbsp;Isabel Socorro Caparrós-Miranda ,&nbsp;Gloria Pérez-Rus ,&nbsp;Isidro Jarque ,&nbsp;Maria Esperanza Moreno-Beltrán ,&nbsp;Emma López-Abadía ,&nbsp;Erik De Cabo ,&nbsp;Shally Marcellini ,&nbsp;Gloria Pérez-Segura ,&nbsp;Carmen Fernández-Miñano ,&nbsp;María Jesús Peñarrubia ,&nbsp;Sergio Matarraz ,&nbsp;María Pérez-Caro ,&nbsp;Alberto Orfao ,&nbsp;Drew Provan ,&nbsp;Joaquín Martínez-López","doi":"10.1016/j.bvth.2025.100061","DOIUrl":"10.1016/j.bvth.2025.100061","url":null,"abstract":"<div><h3>Abstract</h3><div>Thrombopoietin receptor agonists, for example eltrombopag, are standard second-line treatment for immune thrombocytopenia (ITP). Eltrombopag has demonstrated high response rates, both in clinical trials and in routine practice studies. However, some patients with ITP are refractory to this drug. Next-generation sequencing (NGS) may help us identify underlying molecular biology variants that may be involved in eltrombopag refractoriness. Our multicenter national NGS study investigated 110 genes of the most important cell-signaling pathways involved in the mechanism of action of eltrombopag in 35 refractory cases and 35 eltrombopag-responsive controls. Our refractory population comprised 51.4% men with a median age at diagnosis of 48 (range, 38-69) years and a median platelet count of 7 × 10⁹/μL (range, 4 × 10⁹/μL to 16 × 10⁹/μL). At eltrombopag initiation, 78.3% had chronic ITP with a median platelet count of 8 × 10⁹/μL (range, 5× 10⁹/μL to 30 × 10⁹/μL). Treatment with eltrombopag was maintained for a median of 3 (range, 1-9) months before discontinuation. No major grade 3-4 side effects were observed. Several statistical differences were observed in relation to the control responders. Of the total sum of the NGS variants found, 13 variants with statistical significance (<em>P</em> ≤ .05) between case and controls were observed. Two of these have been shown to be associated with cancer. Seven variants are considered benign. Four variants are not previously described, and their significance is unknown. To our knowledge, none of the 13 variants described here has ever been correlated with ITP or eltrombopag refractoriness. Further studies are required to establish their role in this setting.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 3","pages":"Article 100061"},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acquired (autoimmune) hemophilia: demographics, outcomes, and readmissions","authors":"Aditi Sharma ,&nbsp;Nikhil Vojjala ,&nbsp;Vijendra Singh","doi":"10.1016/j.bvth.2025.100062","DOIUrl":"10.1016/j.bvth.2025.100062","url":null,"abstract":"<div><h3>Abstract</h3><div>Acquired hemophilia (AHA) is a rare bleeding disorder characterized by autoantibodies against coagulation factors. It predominantly affects older adults and is associated with autoimmune disorders or malignancies. Achieving hemostasis and inhibiting autoantibody production through immunosuppression are the mainstays of treatment.We conducted a retrospective cohort study using the Nationwide Readmissions Database from 2016 to 2019 to perform a descriptive analysis of AHA, including the estimation of the 30-day readmission rate and primary diagnoses at readmission.Of 1450 admissions for AHA, 803 (55.4%) were male, and the median age at admission was 73 years. Approximately 21% had an underlying solid malignancy, 3.9% had hematologic malignancy, and 13.5% had autoimmune disease. Acute myocardial infarction occurred in 9.5%, disseminated intravascular coagulation in 1.2%, intracranial hemorrhage in 1.5%, ischemic stroke in 2.5%, and venous thromboembolism in 4.4%. Bleeding occurred in 30.2% of admissions, with 27% requiring blood transfusion. The median length of hospital stay was 7 days, and there were 101 deaths during the index admission, resulting in a 7% inpatient mortality rate. Mortality was higher in the older age group at 8% compared with 3% in those aged &lt;65 years (<em>P</em> = .03). The 30-day readmission rate was 27%, with a 10.8% mortality rate during readmission. Infections followed by bleeding were the most common causes for readmission. High rates of bleeding and thrombotic complications are seen in AHA, with bleeding and infection being the primary reasons for the elevated 30-day readmission rate, indicating significant treatment-related toxicity and disease relapse.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 2","pages":"Article 100062"},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of cardiovascular risk factors in persons with venous thromboembolism aged 50 years or younger","authors":"Eng Soo Yap ,&nbsp;Frits R. Rosendaal ,&nbsp;Suzanne C. Cannegieter ,&nbsp;L. J. J. Scheres","doi":"10.1016/j.bvth.2025.100059","DOIUrl":"10.1016/j.bvth.2025.100059","url":null,"abstract":"<div><h3>Abstract</h3><div>The risk of cardiovascular disease (CVD) is elevated in individuals with a history of venous thromboembolism (VTE). It is uncertain whether younger patients, aged ≤50 years, have an increased prevalence of potentially modifiable CVD risk factors, which could be targeted for prevention. We aimed to estimate the prevalence of potentially modifiable CVD risk factors (ie, overweight/obesity, smoking, alcohol use, physical inactivity, hypertension, diabetes mellitus, and dyslipidemia) in persons aged ≤50 years with a history of VTE (cases) and compare with those without VTE (controls). Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis case-control study comprising 2627 case patients with first VTE and 1908 random digit dialing control patients, all aged ≤50 years, we estimated the prevalence of risk factors. Analyses were stratified by sex and were performed separately for unprovoked and provoked events. The prevalence of hypertension, diabetes, dyslipidemia, and excessive alcohol intake was low and similar between case and control patients. The prevalence of overweight and obesity, sedentary behavior, and current smoking was higher in case than control patients. When stratified for sex, obesity was highest in women: 24.9% in case vs 9.9% in control patients. Sedentary behavior was more common in case patients than control patients: women, 57.8% vs 41.1%; and men, 48.7% vs 41.5%, respectively. In persons aged ≤50 years with recent VTE, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and alcohol intake was similar to that of control patients from the general population, suggesting limited benefits from screening these factors in young patients with VTE. Weight reduction and smoking cessation strategies are key targets for CVD prevention.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 2","pages":"Article 100059"},"PeriodicalIF":0.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose-dependent effects of eltrombopag iron chelation on platelet formation","authors":"Elisabetta Bassi ,&nbsp;Vittorio Abbonante ,&nbsp;Alicia Aguilar ,&nbsp;Hana Raslova ,&nbsp;James B. Bussel ,&nbsp;Christian Andrea Di Buduo ,&nbsp;Alessandro Malara ,&nbsp;Alessandra Balduini","doi":"10.1016/j.bvth.2025.100060","DOIUrl":"10.1016/j.bvth.2025.100060","url":null,"abstract":"<div><h3>Abstract</h3><div>Iron deficiency is associated with thrombocytosis in patients, although thrombocytopenia can occur in cases of severe iron deficiency anemia. Eltrombopag (EP), a thrombopoietic agent approved for immune thrombocytopenia, also acts as an iron chelator. Our study demonstrates that megakaryocytes (MKs) exhibit an increased requirement for iron as they mature and acquire the ability to form proplatelets and release platelets. Although low EP concentrations maintain MK functions, high EP concentrations disrupt iron homeostasis, reducing proplatelet formation. Mechanistically, EP-dependent iron chelation impairs MK cytoskeletal dynamics, induces higher extracellular signal–regulated kinase 1/2 (ERK1/2) signaling, and reduces posttranslational glutathionylation of tubulin protein. Addition of exogenous iron or oxidized glutathione to high-dose EP-treated MKs counteracts the negative effect on iron status and ERK1/2 signaling, thereby rescuing proplatelet formation. Overall, these data reveal the complex role of iron status on MK cytoskeletal dynamics and platelet biogenesis and may explain the varied clinical manifestations of iron deficiency on platelet counts.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 2","pages":"Article 100060"},"PeriodicalIF":0.0,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A nonactivating ITGB3 mutation in the β3 cytoplasmic region causes macrothrombocytopenia with an impaired αIIbβ3/RhoA pathway","authors":"Keiichi Nakata ,&nbsp;Keigo Akuta ,&nbsp;Takaya Endo ,&nbsp;Midori Koike ,&nbsp;Daisuke Motooka ,&nbsp;Daisuke Okuzaki ,&nbsp;Hisashi Kato ,&nbsp;Yoshiaki Tomiyama ,&nbsp;Naoki Hosen ,&nbsp;Hirokazu Kashiwagi","doi":"10.1016/j.bvth.2024.100036","DOIUrl":"10.1016/j.bvth.2024.100036","url":null,"abstract":"<div><h3>Abstract</h3><div>Almost all mutations of <em>ITGA2B</em> or <em>ITGB3</em> identified in congenital macrothrombocytopenia induce constitutive activation of αIIbβ3. However, whether concomitant αIIbβ3 activation is essential for macrothrombocytopenia development remains unknown. Recently, we identified the β3(R760C) mutation that does not induce αIIbβ3 activation in a patient with macrothrombocytopenia. The family study showed that macrothrombocytopenia with reduced expression of αIIbβ3 and glycoprotein IV (GPVI) appeared to be associated with patients heterozygous for β3(R760C). We generated β3(R760C) knockin (KI) mice and investigated the effects of the mutation on platelet/megakaryote biology. Macrothrombocytopenia was decreased to 76% and 40% of platelet counts in heterozygous (Hetero) and homozygous (Homo) KI mice, respectively, when compared with the wild-type mice. Platelet αIIbβ3 and GPVI expression were decreased in KI mice, and αIIbβ3 activation was not detected in nonstimulated KI platelets. Thus, the hetero KI mice reproduced the phenotype of the human participant, indicating that the β3(R760C) mutation is responsible for the macrothrombocytopenia. Platelet aggregation, agonist-induced JON/A binding, and P-selectin expression were impaired in KI mice. Platelet spreading on fibrinogen was also impaired in Homo mice with adenosine 5′-diphosphate or thrombin stimulation. Filopodia and lamellipodia formation was impaired in fibrinogen-adhered megakaryocytes of Homo mice with significantly impaired RhoA activation. Proplatelet formation in Homo mice was impaired with abnormal morphology. In addition, platelet life span was shortened in Homo mice. These data indicate that the β3(R760C) mutation impairs the inside-out and outside-in signaling of αIIbβ3, and abnormal actin rearrangement and impaired RhoA activation may play major roles in macrothrombocytopenia.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100036"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Podoplanin and microthrombi in lung injury","authors":"Jahnavi Gollamudi ,&nbsp;Ricardo Gonzalez Delgado ,&nbsp;Min Soon Cho ,&nbsp;Brianne Wharton ,&nbsp;Hani Lee ,&nbsp;Animesh Vadaparti ,&nbsp;Swapan K. Dasgupta ,&nbsp;Miguel A. Cruz ,&nbsp;Perumal Thiagarajan ,&nbsp;Vahid Afshar-Kharghan","doi":"10.1016/j.bvth.2024.100034","DOIUrl":"10.1016/j.bvth.2024.100034","url":null,"abstract":"","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"2 1","pages":"Article 100034"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143093756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}