Research and Practice in Thrombosis and Haemostasis最新文献

{"title":"Formation of tight junction-like structures of zonula occludens 2 in platelet–platelet interaction","authors":"Magdolna Nagy ,&nbsp;Markus Bender ,&nbsp;Natalie S. Poulter ,&nbsp;Jeremy A. Pike ,&nbsp;Albert Sickmann ,&nbsp;Sonja Vondenhoff ,&nbsp;Natalia Bielicka ,&nbsp;Marc A.M.J. van Zandvoort ,&nbsp;Rory R. Koenen ,&nbsp;Hugo ten Cate ,&nbsp;Xavier Stéphenne ,&nbsp;Johan W.M. Heemskerk ,&nbsp;Constance C.F.M.J. Baaten","doi":"10.1016/j.rpth.2025.102845","DOIUrl":"10.1016/j.rpth.2025.102845","url":null,"abstract":"<div><h3>Background</h3><div>In tissues, cell–cell adhesion, barrier formation, and communication are regulated by gap, adherens, and tight junction (TJ) proteins. Platelets express several of these proteins. Platelets express key building blocks of gap junctions, the connexins, with known functions in integrin αIIbβ₃ regulation. While, for some expressed TJ proteins like junctional adhesion molecule A and endothelial cell-specific adhesion molecule, a role in platelets has been uncovered, for other TJ proteins, like zonula occludens (ZO)-2 a contribution to platelet function is still unknown.</div></div><div><h3>Objectives</h3><div>This study aimed to elucidate the role of ZO-2 in the stabilization of tight interplatelet contacts.</div></div><div><h3>Methods</h3><div>Isolated human platelets from healthy volunteers and a patient deficient in ZO-2 were spread on fibrinogen and laminin surfaces in the presence of platelet agonists and inhibitors. Samples were fixed and prepared for microscopy.</div></div><div><h3>Results</h3><div>Confocal and superresolution fluorescence microscopy indicated a redistribution of ZO-2 molecules forming clusters at sites of stable interplatelet contacts that was dependent on the platelet activation status. In the tight contacts, ZO-2 colocalized with endothelial cell-specific adhesion molecule and junctional adhesion molecule A. Furthermore, platinum replica electron microscopy revealed that interplatelet contacts resulted in compaction, detected as interwoven circumferential actin filaments, of interacting platelets. These changes were antagonized by cyclic adenosine monophosphate elevation and inhibition of αIIbβ₃ integrins. In a blood sample from a patient deficient in ZO-2, we observed an increased thrombus stability, suggesting a potential regulation of thrombus stability by these TJ-like structures.</div></div><div><h3>Conclusion</h3><div>Jointly, these data point to the assembly of TJ-like structures of interacting platelets, which enforce platelet adhesion contacts but lower 3-dimensional thrombus stability.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102845"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kindlin-3 phosphorylation is crucial for thrombosis and hemostasis in vivo","authors":"Elzbieta Pluskota ,&nbsp;Dorota Szpak ,&nbsp;Yunmei Wang ,&nbsp;Jun Qin ,&nbsp;Daniel I. Simon ,&nbsp;Edward F. Plow ,&nbsp;Katarzyna Bialkowska","doi":"10.1016/j.rpth.2025.102863","DOIUrl":"10.1016/j.rpth.2025.102863","url":null,"abstract":"<div><h3>Background</h3><div>A single phosphorylation in kindlin-3 at S⁴⁸⁴ (human) or S⁴⁸⁵ (mouse) has been shown to regulate its function in a variety of cells <em>in vitro.</em> However, whether this posttranslational modification of kindlin-3 plays a role in platelets and in hemostasis and thrombosis <em>in vivo</em> remains totally unknown.</div></div><div><h3>Objectives</h3><div>To create a strain of mice expressing kindlin-3 that bears the S⁴⁸⁵A substitution and utilize these mice to determine if kindlin-3 phosphorylation influences platelet responses, hemostasis, and thrombosis <em>in vivo</em>.</div></div><div><h3>Methods</h3><div>By clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 gene editing, we generated a mouse strain that expressed a kindlin-3 mutant bearing the S⁴⁸⁵A substitution. S⁴⁸⁵A kindlin-3 mice were born normally, and the platelet and red blood cells numbers were similar to their wild-type counterparts. Wild-type and S⁴⁸⁵A kindlin-3 platelets showed similar expression of α_IIbβ₃ integrin, kindlin-3, and talin.</div></div><div><h3>Results</h3><div>Platelets isolated from S⁴⁸⁵A kindlin-3 mice did not undergo agonist-induced kindlin-3 phosphorylation. Functional analysis revealed that S⁴⁸⁵A kindlin-3 mice exhibited prolonged tail bleeding time, increased blood loss, and delayed thrombosis in the carotid artery injury model <em>in vivo</em>. Platelets isolated from S⁴⁸⁵A kindlin-3 mice showed defective platelet function, including impaired integrin α_IIbβ₃ activation, platelet aggregation, clot retraction, and adhesion.</div></div><div><h3>Conclusion</h3><div>Our observations demonstrate that kindlin-3 phosphorylation on S⁴⁸⁵ in mice is crucial for supporting activation of α_IIbβ₃ integrin and α_IIbβ₃ integrin-dependent platelet responses and consequently contributes to hemostasis and thrombosis <em>in vivo</em>.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102863"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-type lectin-like receptor 2 in platelets amplifies inflammation in rheumatoid arthritis","authors":"Tomoyuki Sasaki ,&nbsp;Ewelina Golebiewska ,&nbsp;Toshiaki Shirai ,&nbsp;Nagaharu Tsukiji ,&nbsp;Kensuke Koyama ,&nbsp;Shogo Tamura ,&nbsp;Shimon Otake ,&nbsp;Makoto Osada ,&nbsp;Hirotaka Haro ,&nbsp;Yukio Ozaki ,&nbsp;Katsue Suzuki–Inoue","doi":"10.1016/j.rpth.2025.102866","DOIUrl":"10.1016/j.rpth.2025.102866","url":null,"abstract":"<div><h3>Background</h3><div>Platelets play a crucial role not only in thrombosis and hemostasis but also in inflammation, including rheumatoid arthritis. Although synovial cells in the joints express the membrane protein podoplanin, and platelets express the podoplanin receptor C-type lectin-like receptor 2 (CLEC-2), the role of CLEC-2 in arthritis has not been elucidated.</div></div><div><h3>Objectives</h3><div>This study investigated the role of CLEC-2 in arthritis.</div></div><div><h3>Methods</h3><div>Fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis were cocultured with washed human platelets, activated platelet supernatants, or recombinant CLEC-2 (rCLEC-2) to assess FLS proliferation and inflammatory cytokine mRNA levels. A KRN/B6xNOD (K/BxN) mice serum-transfer arthritis (STA) mouse model was used to study the in vivo roles of CLEC-2/podoplanin. Radiation bone marrow chimeric mice were generated by transplanting fetal liver cells from platelet/megakaryocyte-specific CLEC-2 conditional knockout (cKO) or wild-type (WT) embryos, to which serum from K/BxN was transferred. Arthritis was assessed by measuring the thicknesses of all 4 limbs.</div></div><div><h3>Results</h3><div>Coculture with platelets or rCLEC-2 significantly enhanced FLS proliferation and increased the mRNA levels of inflammatory cytokines including IL-6, IL-8, CXCL-2, CXCL-3, IL-1β, and tumour necrosis factor-α. Furthermore, platelets from wild-type mice showed increased mRNA levels of these cytokines in mouse FLSs. CLEC-2–deficient platelets partially, but significantly, inhibited this effect. In the STA model, CLEC-2 cKO mice showed reduced arthritis compared to WT mice. Immunohistological analysis confirmed the presence of platelets in the proliferative synovium.</div></div><div><h3>Conclusion</h3><div>CLEC-2 amplified arthritic platelets by stimulating the production of inflammatory cytokines and cell proliferation in FLSs.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102866"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An assessment of evidence to inform best practice for the communication of acute venous thromboembolism diagnosis: a scoping review","authors":"Samarth Mishra ,&nbsp;Frederikus A. Klok ,&nbsp;Grégoire Le Gal ,&nbsp;Kerstin de Wit ,&nbsp;Aviva Schwartz ,&nbsp;Dieuwke Luijten ,&nbsp;Parham Sadeghipour ,&nbsp;Julie Bayley ,&nbsp;Scott C. Woller","doi":"10.1016/j.rpth.2025.102835","DOIUrl":"10.1016/j.rpth.2025.102835","url":null,"abstract":"<div><h3>Background</h3><div>Physician communication with patients is a key aspect of excellent care. Scant evidence exists to inform best practice for physician communication in patients diagnosed with pulmonary embolism and deep vein thrombosis, collectively referred to as venous thromboembolism (VTE).</div></div><div><h3>Objectives</h3><div>The aim of this study was to summarize the existing literature on best practices for communication between healthcare providers and patients newly diagnosed with VTE.</div></div><div><h3>Methods</h3><div>We performed a scoping review to report existing literature on best practices for physician-patient communication and the diagnosis and management of acute VTE. Manuscripts on communication between healthcare professionals and patients presenting with acute VTE and acute vascular disease presentations that included atrial fibrillation and acute coronary syndrome were identified. Two authors independently reviewed studies for eligibility and a consensus determined article inclusion. The manuscripts were further categorized into 2 categories: best practices in communication and unmet needs in communication. Data aggregation was achieved by a modified thematic synthesis.</div></div><div><h3>Results</h3><div>Among 345 initial publications, 22 manuscripts met inclusion criteria, with 11 addressing VTE, 5 pulmonary embolism, 4 deep vein thrombosis, 1 atrial fibrillation, and 1 acute coronary syndrome. Eleven manuscripts addressed communication of VTE diagnosis, while 12 focused on communication of VTE treatment. Eleven manuscripts identified unmet communication needs, and 14 addressed best practices. Our review showed that good communication enhanced satisfaction, while suboptimal communication was associated with emotional, cognitive, behavioral, social, and health systems adverse effects.</div></div><div><h3>Conclusion</h3><div>Scant literature guides best practices for communicating VTE diagnosis and treatment. Further research is necessary to establish practices for improving communication with VTE patients.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102835"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hematopoietic stem cell transplantation in a newborn suffering from severe combined immunodeficiency and severe hemophilia A: a case report and review of the literature","authors":"Sarah Schober ,&nbsp;Michaela Döring ,&nbsp;Peter Lang ,&nbsp;Johannes Schulte ,&nbsp;Martin Olivieri ,&nbsp;Vanya Icheva","doi":"10.1016/j.rpth.2025.102842","DOIUrl":"10.1016/j.rpth.2025.102842","url":null,"abstract":"<div><h3>Background</h3><div>Severe combined immunodeficiency (SCID) and severe hemophilia A are 2 rare and potentially life-threatening congenital diseases. The coincidence of these diseases has not been reported so far.</div></div><div><h3>Key Clinical Question</h3><div>We present the first case of a newborn with both diseases. SCID can be treated with hematopoietic stem cell transplantation (HSCT). However, how to successfully manage a newborn with severe hemophilia A during intensive HSCT treatment is the key clinical question of this case report.</div></div><div><h3>Clinical Approach</h3><div>Prophylactic factor (F)VIII substitution during HSCT was performed with an extended half-life FVIII product (efmoroctocog alfa). The platelet count was a major factor influencing the dosage of FVIII. No bleeding complications or FVIII inhibitors occurred during this individualized management.</div></div><div><h3>Conclusion</h3><div>This is the first case report of a newborn suffering from both SCID and severe hemophilia A. HSCT is feasible in this situation without bleeding complications if an individual substitution regimen with FVIII is applied.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102842"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin K deficiency bleeding in children with cholestatic liver disease: a systematic review and meta-analysis","authors":"Anusak Sakwit ,&nbsp;Pongpak Pongphitcha ,&nbsp;Patcharee Komvilaisak ,&nbsp;Masayuki Ochiai ,&nbsp;Daijiro Takahashi ,&nbsp;Shutaro Suga ,&nbsp;Ampaiwan Chuansumrit ,&nbsp;Marisol Betensky ,&nbsp;Stephen P. Pereira ,&nbsp;Amber Afzal ,&nbsp;C. Heleen van Ommen ,&nbsp;Neil Goldenberg ,&nbsp;Sasivimol Rattanasiri ,&nbsp;Nongnuch Sirachainan","doi":"10.1016/j.rpth.2025.102847","DOIUrl":"10.1016/j.rpth.2025.102847","url":null,"abstract":"<div><div>Vitamin K deficiency (VKD) in cholestatic liver disease affects up to 23% of pediatric patients. While several vitamin K (VK) prophylaxis regimens have been proposed, optimal therapeutic strategies remain undefined. The study aimed to identify the most effective VK prophylaxis for children with cholestatic liver disease. We conducted a systematic review of articles focusing on studies of children aged &lt;18 years with cholestatic liver disease who reported outcomes of either VKD or vitamin K deficiency bleeding (VKDB) after VK prophylaxis. The articles were sourced from PubMed, Scopus, and Embase. A meta-analysis was performed to determine the prevalence of VKD and the efficacy of each prophylactic protocol in preventing VKD/VKDB. The study was registered on PROSPERO (CRD 42021270048). Of the 889 articles, 37 were selected (2 comparative studies, 6 noncomparative studies, and 29 case reports/series). The results from the comparative studies indicated a lower incidence of VKD in the parenteral than that in the oral VK. The meta-analysis of the noncomparative studies showed the prevalence of VKD in high prothrombin induced by vitamin K absence-II group was 56% (95% CI, 45%-68%; <em>I</em>² = 0.0%; <em>H</em>² = 1.0; <em>Q</em> test: χ² = 1.93; <em>P</em> = .38) and a prevalence of VKD in abnormal coagulation test was 10% (95% CI, 5%-14%; <em>I</em>² = 0%, <em>H</em>² = 1.0; <em>Q</em> test: χ² = 0.82; <em>P</em> = .66), respectively. Among the 3 administrative routes, the analysis from case reports/series showed the median onset of VKDB in cholestatic infants was the earliest in the oral (44.5 days; IQR, 13.0-240.0 days) compared with intramuscular (86.0 days; IQR, 36.0-120.0) and intravenous routes and intravenous (97.0 days; IQR, 74.0-120.0 days) VK prophylaxis. Available studies to determine the optimal route of VK administration in children with cholestatic liver disease were limited. The result from the review indicated that parenteral VK demonstrated a noticeable advantage over oral VK for VKD/VKDB prevention in cholestatic children.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102847"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The diagnostic utility of genetic testing in inherited thrombocytopenia: regional multicenter tertiary experience","authors":"Eman Hassan ,&nbsp;Carl Fratter ,&nbsp;Will Lester ,&nbsp;Charles Percy ,&nbsp;Walaa Saad ,&nbsp;Afrah Alkhedir ,&nbsp;Jayashree Motwani ,&nbsp;Patricia Bignell ,&nbsp;Phillip L.R. Nicolson ,&nbsp;Neil V. Morgan ,&nbsp;Sandeep Potluri ,&nbsp;Gillian Lowe","doi":"10.1016/j.rpth.2025.102869","DOIUrl":"10.1016/j.rpth.2025.102869","url":null,"abstract":"","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102869"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of 2 thromboelastography methods using patient and control samples","authors":"Robert Frick ,&nbsp;Brittany Washburn ,&nbsp;Dennis Plocher ,&nbsp;Jonathan K. Zoller ,&nbsp;Jason Gillihan ,&nbsp;Michael Dombrowski ,&nbsp;Charles Eby ,&nbsp;Christopher W. Farnsworth","doi":"10.1016/j.rpth.2025.102843","DOIUrl":"10.1016/j.rpth.2025.102843","url":null,"abstract":"<div><h3>Background</h3><div>Viscoelastic testing at point-of-care is associated with reduced blood loss and blood product transfusions. The ROTEM (Werfen) sigma is a cartridge-based system that may facilitate point-of-care use, but limited studies exist comparing the sigma with the predicated ROTEM delta.</div></div><div><h3>Objectives</h3><div>We compared the performance of the ROTEM delta with that of the sigma.</div></div><div><h3>Methods</h3><div>Citrated blood was collected from 20 healthy donors and patients during liver transplants (<em>n</em> = 17), obstetrics (<em>n</em> = 15), cardiovascular (<em>n</em> = 9), and trauma surgeries (<em>n</em> = 10). A method comparison was performed using the delta as the predicate. Imprecision was assessed at 2 levels for each assay. Manufacturer reference intervals were verified using 20 healthy donors. An algorithm used for cardiovascular surgery with the delta was compared with the sigma.</div></div><div><h3>Results</h3><div>The coefficient of variation was &lt;10% for all assays/parameters except for the thromboelastometry with extrinsic activation (EXTEM) clotting time (10.3%) and EXTEM amplitude (A)5 (10.2%). Reference intervals for the delta and sigma were comparable to manufacturer claims. The Pearson r comparing the delta and sigma exceeded .85 for all parameters/assays except for thromboelastometry with cytochalasin D-mediated platelet inhibition (FIBTEM) A10 (.77; 95% CI, .66-.86), FIBTEM A20 (.78; 95% CI, .65-.87), and thromboelastometry with heparinase clotting time (.77; 95% CI, .61-.87). No difference was observed in extrapolated thresholds from the delta-guided algorithm. However, extrapolated sigma A5 parameters for EXTEM were 5 mm lower, and for FIBTEM were 1 mm lower than delta A10 parameters.</div></div><div><h3>Conclusion</h3><div>The ROTEM delta and sigma devices had comparable performance. A negative bias was observed in the FIBTEM assay with lower extrapolated clinical decision points for a delta-guided treatment algorithm for the FIBTEM and EXTEM A5.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102843"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of pharmacokinetics of intravenous protein C concentrate in protein C deficiency: implications for treatment initiation and maintenance","authors":"Zhaoyang Li ,&nbsp;Inmaculada C. Sorribes ,&nbsp;Jennifer Schneider ,&nbsp;Adekemi Taylor","doi":"10.1016/j.rpth.2025.102859","DOIUrl":"10.1016/j.rpth.2025.102859","url":null,"abstract":"<div><h3>Background</h3><div>Dosing of intravenous protein C concentrate (Ceprotin) in patients with protein C deficiency is guided by pharmacokinetics (PK) of plasma protein C activity.</div></div><div><h3>Objectives</h3><div>This study aimed to characterize PK of intravenous Ceprotin in patients with severe congenital protein C deficiency (SCPCD) and severe acquired protein C deficiency (SAPCD).</div></div><div><h3>Methods</h3><div>An exploratory analysis was conducted to assess effects of demographic and disease-related factors on PK of Ceprotin (<em>n</em> = 35 patients with SCPCD or SAPCD), followed by a population PK analysis on data from 4 prospective clinical trials of Ceprotin in SCPCD or SAPCD (<em>n</em> = 58). Model-based simulations were conducted across 3-stage or 1-stage dosing scenarios based on label-recommended doses in acute or maintenance settings.</div></div><div><h3>Results</h3><div>Age, body weight, and symptomatic state of disease appeared to influence PK of Ceprotin, including endogenous production of (active) protein C. Model-based simulations predicted that after the first doses, 15% to 76% of patients in the 3-stage dosing scenarios (initial dose: 60-120 IU/kg) and 15% of patients in the 1-stage dosing scenario (60 IU/kg every 12 hours) would attain the recommended target <em>C</em>_max of &gt;100 IU/dL. At steady state, ≥86% of patients were predicted to attain the recommended maintenance <em>C</em>_trough of &gt;25 IU/dL. The steady-state protein C concentration was driven by the maintenance dose, regardless of the level of initial loading doses.</div></div><div><h3>Conclusion</h3><div>Age, body weight, and symptomatic disease state should be considered in dose optimization. Model-based simulations support the use of various combined loading and maintenance regimens to quickly and effectively achieve target protein C plasma levels.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102859"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomics in patients with von Willebrand disease and hemophilia A highlights von Willebrand factor as main determinant of response to desmopressin treatment","authors":"Jessica del Castillo Alferez ,&nbsp;Eva R. Smit ,&nbsp;Alexander B. Meijer ,&nbsp;Karin Fijnvandraat ,&nbsp;Marieke J.H.A. Kruip ,&nbsp;Tirsa T. van Duijl ,&nbsp;Maartje van den Biggelaar","doi":"10.1016/j.rpth.2025.102738","DOIUrl":"10.1016/j.rpth.2025.102738","url":null,"abstract":"<div><h3>Background</h3><div>Desmopressin, 1-deamino-8-D-arginin vasopressin (DDAVP), is a treatment option for people with von Willebrand disease (VWD) and hemophilia A (HA) with a large interindividual variation in response. DDAVP elicits the release of von Willebrand Factor (VWF) from endothelial cells, thereby increasing the levels of circulating VWF and coagulation factor (F)VIII. However, we currently lack detailed insight on additional systemic effects of DDAVP administration on plasma protein levels.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate plasma proteomic profiles associated with DDAVP administration.</div></div><div><h3>Methods</h3><div>Longitudinal plasma samples of 13 patients with VWD and 9 people with mild HA up to 24 hours after DDAVP infusion were analyzed using mass spectrometry–based proteomics.</div></div><div><h3>Results</h3><div>Among 408 proteins quantified in plasma, only VWF and VWF propeptide (pp) increased significantly at 1 and 2 hours after DDAVP infusion in people with HA and VWD, respectively. VWF antigen levels were in agreement with mass spectrometry–based VWF intensity levels (<em>ρ</em> = 0.89). A slower clearance was observed for VWF compared with that for VWFpp, accompanied with higher interindividual variation. In 4 people with HA, C-reactive protein levels increased 24 hours after DDAVP infusion, which correlated with serum amyloid A1/A2 levels.</div></div><div><h3>Conclusion</h3><div>This study showed the selective increase of VWF and VWFpp 1 to 2 hours after DDAVP infusion and highlighted the interindividual variance in VWF clearance. Additionally, a delayed acute-phase response in a subgroup of patients suggested the potential role of inflammatory mechanisms contributing to heterogeneity of response.</div></div>","PeriodicalId":20893,"journal":{"name":"Research and Practice in Thrombosis and Haemostasis","volume":"9 3","pages":"Article 102738"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}