Pub Date : 2024-09-01DOI: 10.1016/j.bvth.2024.100017
Margot DeBot , Christopher Erickson , Terry Schaid , Ian LaCroix , Ernest E. Moore , Christopher Silliman , Mitchell J. Cohen , Angelo D’Alessandro , Kirk C. Hansen
Abstract
Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at www.ClinicalTrials.gov as #NCT01838863.
{"title":"Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury","authors":"Margot DeBot , Christopher Erickson , Terry Schaid , Ian LaCroix , Ernest E. Moore , Christopher Silliman , Mitchell J. Cohen , Angelo D’Alessandro , Kirk C. Hansen","doi":"10.1016/j.bvth.2024.100017","DOIUrl":"10.1016/j.bvth.2024.100017","url":null,"abstract":"<div><h3>Abstract</h3><p>Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT01838863.</p></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 3","pages":"Article 100017"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950327224000172/pdfft?md5=5880916926772cd8bc0dccf15d720b5a&pid=1-s2.0-S2950327224000172-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141706753","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}
Pub Date : 2024-08-21DOI: 10.1016/j.bvth.2024.100024
Noelle I. Samia , Thomas J. Raife
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder involving pathological platelet–von Willebrand factor interaction, resulting in microvascular thrombosis. The consumption of platelets in TTP microthrombi results in severe thrombocytopenia which resolves with resolution of the microvascular thrombosis. Over the course of treatment, patient platelet counts often rise and fall multiple times before stable remission is achieved. On casual inspection, we noted that total leukocyte counts follow a pattern that appears to correspond to platelet counts. To explore whether changing leukocyte counts track significantly with changing platelet counts, we examined paired daily platelet counts and total leukocyte counts in 27 episodes of TTP in 13 patients across 2 institutions comprising 423 days of data. We modeled the nonlinear behavior in the data using a threshold mixed-effects regression model, in which we found a significant temporal relationship between total leukocyte counts and platelet counts. The model proved that, on a day when platelet counts were rising in previous days, the total leukocyte count is predictive of the rise in platelet count. The higher the total leukocyte count, the greater the rise in platelet count. Our results support the hypothesis that leukocytes play a role in the resolution of TTP microvascular thrombosis.
{"title":"Rising total leukocyte counts correspond with rising platelet counts in thrombotic thrombocytopenic purpura","authors":"Noelle I. Samia , Thomas J. Raife","doi":"10.1016/j.bvth.2024.100024","DOIUrl":"10.1016/j.bvth.2024.100024","url":null,"abstract":"<div><h3>Abstract</h3><div>Thrombotic thrombocytopenic purpura (TTP) is a rare disorder involving pathological platelet–von Willebrand factor interaction, resulting in microvascular thrombosis. The consumption of platelets in TTP microthrombi results in severe thrombocytopenia which resolves with resolution of the microvascular thrombosis. Over the course of treatment, patient platelet counts often rise and fall multiple times before stable remission is achieved. On casual inspection, we noted that total leukocyte counts follow a pattern that appears to correspond to platelet counts. To explore whether changing leukocyte counts track significantly with changing platelet counts, we examined paired daily platelet counts and total leukocyte counts in 27 episodes of TTP in 13 patients across 2 institutions comprising 423 days of data. We modeled the nonlinear behavior in the data using a threshold mixed-effects regression model, in which we found a significant temporal relationship between total leukocyte counts and platelet counts. The model proved that, on a day when platelet counts were rising in previous days, the total leukocyte count is predictive of the rise in platelet count. The higher the total leukocyte count, the greater the rise in platelet count. Our results support the hypothesis that leukocytes play a role in the resolution of TTP microvascular thrombosis.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100024"},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442253","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}
Pub Date : 2024-08-02DOI: 10.1016/j.bvth.2024.100023
Joanna Deng ∗ , Luca Ramelli ∗ , Pei Ye Li , Ali Eshaghpour , Allen Li , Giovanna Schuenemann , Mark A. Crowther
Abstract
Oral iron (Fe) supplementation is one of the mainstays of treatment for iron deficiency anemia (IDA). However, its therapeutic effects are limited when there is poor absorption from the gastrointestinal tract. Vitamin C is hypothesized to improve uptake when combined as an adjunct agent. We aimed to determine the difference in hematologic outcomes in patients with IDA receiving oral iron, with or without vitamin C. MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched from database inception to July 2023 for studies investigating the use of oral iron supplements with vitamin C in patients with IDA. The primary outcome was the change in serum hemoglobin (Hb). Secondary outcomes include change in serum ferritin, reticulocyte percentage, and incidence of adverse events. A total of 2231 studies were retrieved; 10 randomized control trials (n = 1782), and 1 prospective cohort study (n = 148) comprising 1930 patients were included. Vitamin C supplementation was associated with a significant increase in serum Hb level (mean differences [MDs], 0.14 g/dL; 95% confidence interval [CI], 0.08-0.20; P < .01; 10 studies, 1490 patients) and serum ferritin levels (MD, 3.23 μg/L; 95% CI, 1.63-4.84; P < .01; 9 studies, 1682 patients) in the iron plus vitamin C group compared with the iron-only group. The addition of vitamin C to iron supplementation was associated with a small and likely clinically insignificant increase in serum Hb. The results of this study do not support routine supplementation of oral iron therapy with vitamin C in the treatment of IDA.
摘要口服铁（Fe）补充剂是治疗缺铁性贫血（IDA）的主要方法之一。然而，如果胃肠道吸收不良，其治疗效果就会受到限制。据推测，维生素 C 作为一种辅助药物可提高吸收率。我们的目的是确定口服铁剂（含或不含维生素 C）的 IDA 患者在血液学结果方面的差异。我们检索了 MEDLINE、Embase、Web of Science 和 Cochrane Central Register of Controlled Trials 数据库中从开始到 2023 年 7 月有关 IDA 患者口服铁剂和维生素 C 的研究。主要结果是血清血红蛋白（Hb）的变化。次要结果包括血清铁蛋白、网织红细胞百分比和不良事件发生率的变化。共检索到 2231 项研究；其中包括 10 项随机对照试验（n = 1782）和 1 项前瞻性队列研究（n = 148），共涉及 1930 名患者。与单纯铁剂组相比，补充维生素 C 可显著提高铁剂加维生素 C 组的血清 Hb 水平（平均差 [MDs], 0.14 g/dL; 95% 置信区间 [CI], 0.08-0.20; P <.01；10 项研究，1490 名患者）和血清铁蛋白水平（MD, 3.23 μg/L; 95% CI, 1.63-4.84; P <.01；9 项研究，1682 名患者）。在补充铁剂的同时添加维生素 C 可使血清 Hb 略有增加，但这种增加在临床上可能并不显著。这项研究结果并不支持在口服铁剂治疗中常规补充维生素 C 来治疗 IDA。
{"title":"Efficacy of vitamin C with Fe supplementation in patients with iron deficiency anemia: a systematic review and meta-analysis","authors":"Joanna Deng ∗ , Luca Ramelli ∗ , Pei Ye Li , Ali Eshaghpour , Allen Li , Giovanna Schuenemann , Mark A. Crowther","doi":"10.1016/j.bvth.2024.100023","DOIUrl":"10.1016/j.bvth.2024.100023","url":null,"abstract":"<div><h3>Abstract</h3><div>Oral iron (Fe) supplementation is one of the mainstays of treatment for iron deficiency anemia (IDA). However, its therapeutic effects are limited when there is poor absorption from the gastrointestinal tract. Vitamin C is hypothesized to improve uptake when combined as an adjunct agent. We aimed to determine the difference in hematologic outcomes in patients with IDA receiving oral iron, with or without vitamin C. MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched from database inception to July 2023 for studies investigating the use of oral iron supplements with vitamin C in patients with IDA. The primary outcome was the change in serum hemoglobin (Hb). Secondary outcomes include change in serum ferritin, reticulocyte percentage, and incidence of adverse events. A total of 2231 studies were retrieved; 10 randomized control trials (n = 1782), and 1 prospective cohort study (n = 148) comprising 1930 patients were included. Vitamin C supplementation was associated with a significant increase in serum Hb level (mean differences [MDs], 0.14 g/dL; 95% confidence interval [CI], 0.08-0.20; <em>P</em> < .01; 10 studies, 1490 patients) and serum ferritin levels (MD, 3.23 μg/L; 95% CI, 1.63-4.84; <em>P</em> < .01; 9 studies, 1682 patients) in the iron plus vitamin C group compared with the iron-only group. The addition of vitamin C to iron supplementation was associated with a small and likely clinically insignificant increase in serum Hb. The results of this study do not support routine supplementation of oral iron therapy with vitamin C in the treatment of IDA.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100023"},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142420675","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}
Pub Date : 2024-07-31DOI: 10.1016/j.bvth.2024.100022
Nigel Mackman , Ana T. A. Sachetto
Abstract
Tissue factor (TF) is a transmembrane protein that, in association with its ligand factor VII (FVII)/activated factor VII (FVIIa), activates blood coagulation. TF is highly procoagulant and even very small amounts can activate blood coagulation. Levels of TF–positive extracellular vesicles (EVs) are increased in blood in diseases associated with thrombosis. However, it is challenging to accurately quantify the very low levels of TF in blood. Activity-based assays have higher sensitivity and specificity than antigen-based assays. Many anti-human TF antibodies have been generated but they differ in their affinity for TF and bind to different epitopes. They can be divided into 2 groups: those that compete with FVII/FVIIa binding to TF, and those that bind to both TF and the TF-FVII/VIIa complex. Commercial enzyme-linked immunosorbent assays are commonly used to measure TF antigen in plasma but have low sensitivity and specificity for the detection of TF antigen in plasma. Flow cytometry is used to measure TF antigen on EVs but also has low sensitivity and specificity. Functional TF activity assays should be performed in the presence and absence of an inhibitory anti-TF antibody to distinguish between TF-dependent and TF-independent FXa generation because FVIIa can activate FX in the absence of TF. TF pathway inhibitor inhibits the TF-FVIIa complex and reduces TF activity of isolated EVs. Two commercial assays are available for the measurement of TF activity of EVs isolated from human plasma. Measurement of TF activity of EVs isolated from plasma may be a useful biomarker of thrombotic risk in different diseases.
{"title":"Challenges with measuring tissue factor antigen and activity in human plasma","authors":"Nigel Mackman , Ana T. A. Sachetto","doi":"10.1016/j.bvth.2024.100022","DOIUrl":"10.1016/j.bvth.2024.100022","url":null,"abstract":"<div><h3>Abstract</h3><div>Tissue factor (TF) is a transmembrane protein that, in association with its ligand factor VII (FVII)/activated factor VII (FVIIa), activates blood coagulation. TF is highly procoagulant and even very small amounts can activate blood coagulation. Levels of TF–positive extracellular vesicles (EVs) are increased in blood in diseases associated with thrombosis. However, it is challenging to accurately quantify the very low levels of TF in blood. Activity-based assays have higher sensitivity and specificity than antigen-based assays. Many anti-human TF antibodies have been generated but they differ in their affinity for TF and bind to different epitopes. They can be divided into 2 groups: those that compete with FVII/FVIIa binding to TF, and those that bind to both TF and the TF-FVII/VIIa complex. Commercial enzyme-linked immunosorbent assays are commonly used to measure TF antigen in plasma but have low sensitivity and specificity for the detection of TF antigen in plasma. Flow cytometry is used to measure TF antigen on EVs but also has low sensitivity and specificity. Functional TF activity assays should be performed in the presence and absence of an inhibitory anti-TF antibody to distinguish between TF-dependent and TF-independent FXa generation because FVIIa can activate FX in the absence of TF. TF pathway inhibitor inhibits the TF-FVIIa complex and reduces TF activity of isolated EVs. Two commercial assays are available for the measurement of TF activity of EVs isolated from human plasma. Measurement of TF activity of EVs isolated from plasma may be a useful biomarker of thrombotic risk in different diseases.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100022"},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326630","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}
Pub Date : 2024-07-26DOI: 10.1016/j.bvth.2024.100021
Silvia Verhofste , Ahmad Al-Huniti , Marci Novak , Amy L. Conrad , Ellen van der Plas , Lyndsay Harshman , Janice M. Staber
Abstract
The effect of factor VIII (FVIII) deficiency on neurocognitive outcomes in children with hemophilia A (HA) is not well characterized. This study aimed to examine differences in brain volume and neurocognition between children with severe HA and healthy controls.This single-center study included 32 males aged 6 to 16 years, 9 with severe FVIII deficiency and 23 healthy controls. Volumetric data from magnetic resonance imaging and neurocognitive testing were compared using linear models including age to evaluate the association between regional brain volume and function. Cerebellar gray matter volume was significantly smaller in the HA cohort than in healthy controls (estimate, –0.375; 95% confidence interval [CI], –0.732 to –0.019; t(26) = 2.07; P = .049). A reduction in cerebellar gray matter was associated with neurocognitive executive dysfunction as noted by abnormal scores on 2 executive function assessments: the Delis-Kaplan Executive Function System, total switching accuracy (estimate, 0.549; 95% CI, –0.876 to 0.221; t(25) = –3.28; P = .003) and total correct category switching (estimate, 0.538; 95% CI, –0.868 to 0.207; t(25) = –3.19; P = .004), and the Behavior Rating Inventory of Executive Function, behavioral regulation index score (estimate, 0.531; 95% CI, 0.228-0.835; t(25) = 3.44; P = .002). Our study provides key insights into the lower brain volumes found in patients with HA and the corresponding executive dysfunction. Quantitative brain volume assessment in patients with HA may provide an integrated measure and with further research could be a useful clinical tool when assessing risk for neurocognitive dysfunction.
{"title":"Regional brain volumes and their relationship to neurocognitive outcomes in children with severe hemophilia A","authors":"Silvia Verhofste , Ahmad Al-Huniti , Marci Novak , Amy L. Conrad , Ellen van der Plas , Lyndsay Harshman , Janice M. Staber","doi":"10.1016/j.bvth.2024.100021","DOIUrl":"10.1016/j.bvth.2024.100021","url":null,"abstract":"<div><h3>Abstract</h3><div>The effect of factor VIII (FVIII) deficiency on neurocognitive outcomes in children with hemophilia A (HA) is not well characterized. This study aimed to examine differences in brain volume and neurocognition between children with severe HA and healthy controls.This single-center study included 32 males aged 6 to 16 years, 9 with severe FVIII deficiency and 23 healthy controls. Volumetric data from magnetic resonance imaging and neurocognitive testing were compared using linear models including age to evaluate the association between regional brain volume and function. Cerebellar gray matter volume was significantly smaller in the HA cohort than in healthy controls (estimate, –0.375; 95% confidence interval [CI], –0.732 to –0.019; t<sub>(26)</sub> = 2.07; <em>P</em> = .049). A reduction in cerebellar gray matter was associated with neurocognitive executive dysfunction as noted by abnormal scores on 2 executive function assessments: the Delis-Kaplan Executive Function System, total switching accuracy (estimate, 0.549; 95% CI, –0.876 to 0.221; t<sub>(25)</sub> = –3.28; <em>P</em> = .003) and total correct category switching (estimate, 0.538; 95% CI, –0.868 to 0.207; t<sub>(25)</sub> = –3.19; <em>P</em> = .004), and the Behavior Rating Inventory of Executive Function, behavioral regulation index score (estimate, 0.531; 95% CI, 0.228-0.835; t<sub>(25)</sub> = 3.44; <em>P</em> = .002). Our study provides key insights into the lower brain volumes found in patients with HA and the corresponding executive dysfunction. Quantitative brain volume assessment in patients with HA may provide an integrated measure and with further research could be a useful clinical tool when assessing risk for neurocognitive dysfunction.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100021"},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845275","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}
Pub Date : 2024-07-26DOI: 10.1016/j.bvth.2024.100020
Laura F. Newell , Najla El Jurdi , Brian C. Betts , Corey Cutler , Joseph H. Antin , John E. Levine , Angela Panoskaltsis-Mortari , Shernan G. Holtan
Abstract
Posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis regimens are associated with very low rates of severe acute and chronic GVHD after hematopoietic cell transplant (HCT). However, concerns about cardiac and other organ toxicities persist. This study aimed to compare the vascular biomarker profile of PTCy with other GVHD regimens, including tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), to generate hypotheses for toxicity mitigation strategies. Plasma samples from day +28 after transplant were analyzed against pretransplant baseline measurements in patients receiving PTCy-based GVHD prophylaxis as part of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 (n = 112) vs Tac/MTX (n = 98) and Tac/Sir (n = 95) regimens from BMT CTN 0402. Compared with Tac/MTX, PTCy was associated with increasing angiopoietin-2 levels and decreasing epidermal growth factor levels at day +28. In contrast, Tac/Sir displayed increasing follistatin and endoglin levels and decreasing vascular endothelial growth factor receptor 2 (VEGFR2) plasma levels after HCT. Across all cohorts, increasing epidermal growth factor was protective from nonrelapse mortality, and decreasing VEGFR2 was associated with subsequent development of extensive chronic GVHD. These distinct biomarker profiles offer insights that could guide strategies to mitigate unique GVHD prophylaxis–associated toxicities.
{"title":"Vascular biomarkers reveal a unique toxicity profile of posttransplant cyclophosphamide: secondary analysis of BMT CTN 0402 and 1202","authors":"Laura F. Newell , Najla El Jurdi , Brian C. Betts , Corey Cutler , Joseph H. Antin , John E. Levine , Angela Panoskaltsis-Mortari , Shernan G. Holtan","doi":"10.1016/j.bvth.2024.100020","DOIUrl":"10.1016/j.bvth.2024.100020","url":null,"abstract":"<div><h3>Abstract</h3><p>Posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis regimens are associated with very low rates of severe acute and chronic GVHD after hematopoietic cell transplant (HCT). However, concerns about cardiac and other organ toxicities persist. This study aimed to compare the vascular biomarker profile of PTCy with other GVHD regimens, including tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), to generate hypotheses for toxicity mitigation strategies. Plasma samples from day +28 after transplant were analyzed against pretransplant baseline measurements in patients receiving PTCy-based GVHD prophylaxis as part of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1202 (n = 112) vs Tac/MTX (n = 98) and Tac/Sir (n = 95) regimens from BMT CTN 0402. Compared with Tac/MTX, PTCy was associated with increasing angiopoietin-2 levels and decreasing epidermal growth factor levels at day +28. In contrast, Tac/Sir displayed increasing follistatin and endoglin levels and decreasing vascular endothelial growth factor receptor 2 (VEGFR2) plasma levels after HCT. Across all cohorts, increasing epidermal growth factor was protective from nonrelapse mortality, and decreasing VEGFR2 was associated with subsequent development of extensive chronic GVHD. These distinct biomarker profiles offer insights that could guide strategies to mitigate unique GVHD prophylaxis–associated toxicities.</p></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 3","pages":"Article 100020"},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950327224000202/pdfft?md5=01eb3abe1f0fcdbe3c0117bbf8ef11b8&pid=1-s2.0-S2950327224000202-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141850752","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}
Pub Date : 2024-07-16DOI: 10.1016/j.bvth.2024.100019
Wenjing Cao , Malay K. Basu , Elizabeth Staley , X. Long Zheng
Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13. However, the contribution of genetic variations that may modulate its clinical presentations remains unknown. This study aimed to determine the potential contribution of variants in the genes associated with coagulation, complement activation or regulation, and platelet activation to pathophysiology of iTTP. Multicenter case series, whole-exome sequencing, and bioinformatic approaches were used. We focused on analysis of 20 genes that are involved in regulation of coagulation (eg, ADAMTS13, THBD, MMACHC, INF2, and PLG), complement activation (eg, C3, C3AR1, C5, CFB, CFH, CFI, C4BPA, CD46 [MCP], CD59, and CFHR1-CFHR5), and platelet activation (eg, DGKE) from 40 adult patients with iTTP. Multiple genetic variations were identified in 12 of 20 genes of interest. More than 80% of patients harbored genetic variants in CFI, CFH, C5, and ADAMTS13; 15% to 55% of patients had variants in C3, INF2, CFHR5, and PLG; and <10% of patients had variants in CD46, C3AR1, DGKE, and THBD. Of these, the variants in C5 are associated with a more favorable renal function, whereas the variants in DGKE are associated with more persistently elevated creatinine levels. These results demonstrate that variants in the genes involved in coagulation, complement, and platelet activation are common in patients with iTTP, which may contribute to phenotypical modulations of or predispose to iTTP resulting from severe ADAMTS13 deficiency.
{"title":"Genetic variants contribute to modulation of renal function in patients with immune thrombotic thrombocytopenic purpura","authors":"Wenjing Cao , Malay K. Basu , Elizabeth Staley , X. Long Zheng","doi":"10.1016/j.bvth.2024.100019","DOIUrl":"10.1016/j.bvth.2024.100019","url":null,"abstract":"<div><h3>Abstract</h3><div>Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13. However, the contribution of genetic variations that may modulate its clinical presentations remains unknown. This study aimed to determine the potential contribution of variants in the genes associated with coagulation, complement activation or regulation, and platelet activation to pathophysiology of iTTP. Multicenter case series, whole-exome sequencing, and bioinformatic approaches were used. We focused on analysis of 20 genes that are involved in regulation of coagulation (eg, <em>ADAMTS13</em>, <em>THBD</em>, <em>MMACHC</em>, <em>INF2</em>, and <em>PLG</em>), complement activation (eg, <em>C3</em>, <em>C3AR1</em>, <em>C5</em>, <em>CFB</em>, <em>CFH</em>, <em>CFI</em>, <em>C4BPA</em>, <em>CD46</em> [<em>MCP</em>], <em>CD59</em>, and <em>CFHR1</em>-<em>CFHR5</em>), and platelet activation (eg, <em>DGKE</em>) from 40 adult patients with iTTP. Multiple genetic variations were identified in 12 of 20 genes of interest. More than 80% of patients harbored genetic variants in <em>CFI</em>, <em>CFH</em>, <em>C5</em>, and <em>ADAMTS13</em>; 15% to 55% of patients had variants in <em>C3</em>, <em>INF2</em>, <em>CFHR5</em>, and <em>PLG</em>; and <10% of patients had variants in <em>CD46</em>, <em>C3AR1</em>, <em>DGKE</em>, and <em>THBD</em>. Of these, the variants in <em>C5</em> are associated with a more favorable renal function, whereas the variants in <em>DGKE</em> are associated with more persistently elevated creatinine levels. These results demonstrate that variants in the genes involved in coagulation, complement, and platelet activation are common in patients with iTTP, which may contribute to phenotypical modulations of or predispose to iTTP resulting from severe ADAMTS13 deficiency.</div></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 4","pages":"Article 100019"},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141709314","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}
Pub Date : 2024-07-16DOI: 10.1016/j.bvth.2024.100018
Amirhossein Mafi ∗ , Matthew Bratkowski ∗ , Jiefei Geng , Alyssa A. Brito , Janani Sridar , Dongjian Hu , Anhdao T. Darcy , Dhaval Nanavati , Nathan J. Brown , Manoj K. Rathinaswamy , Yuliya Kutskova , Dan Eaton , Qi Hao † , Marcia Paddock †
Abstract
Myeloproliferative leukemia protein (MPL), also known as thrombopoietin (TPO) receptor, is a class I cytokine receptor that is expressed on hematopoietic progenitors, promoting growth and differentiation toward the megakaryocyte lineage and is critical for normal platelet production. Mutations in MPL, TPO, or Janus kinase 2 (JAK2) have been implicated in multiple diseases from congenital thrombocytopenias to myeloproliferative neoplasms. The ligand for MPL, TPO, stimulates platelet production by inducing MPL dimerization and results in an active conformation that allows downstream JAK2/STAT5 signaling. Despite the biological importance of this pathway, the molecular signaling mechanism remained unclear. Here, we present a 3.39-Å cryo-electron microscopy structure of the ectodomain of mouse MPL bound to TPO. The structure revealed both low and high affinity sites between MPL and TPO that contain several pathologic mutations. To better understand TPO-driven MPL signaling, we expanded upon this structure by molecular dynamic (MD) simulations to model the full-length human MPL/TPO complex, and showed that MPL D4-D4 domain interactions are functionally relevant in activity assays. To build on our understanding of downstream activation, we added JAK2 to the MPL/TPO complex by MD simulations. This ternary complex illustrates JAK2 dimerization through the pseudokinase domain, illustrates residues important for MPL interactions, and reveals the constitutive activation mechanism of patient mutant V617F. The model also suggests the mechanism of JAK2 tyrosine kinase domain transphosphorylation. Overall, our studies illuminate TPO/MPL/JAK2 signaling mechanisms and provide additional insight into the nature of receptor signaling, which will further benefit human health.
{"title":"Structural basis of MPL activation by thrombopoietin","authors":"Amirhossein Mafi ∗ , Matthew Bratkowski ∗ , Jiefei Geng , Alyssa A. Brito , Janani Sridar , Dongjian Hu , Anhdao T. Darcy , Dhaval Nanavati , Nathan J. Brown , Manoj K. Rathinaswamy , Yuliya Kutskova , Dan Eaton , Qi Hao † , Marcia Paddock †","doi":"10.1016/j.bvth.2024.100018","DOIUrl":"10.1016/j.bvth.2024.100018","url":null,"abstract":"<div><h3>Abstract</h3><p>Myeloproliferative leukemia protein (MPL), also known as thrombopoietin (TPO) receptor, is a class I cytokine receptor that is expressed on hematopoietic progenitors, promoting growth and differentiation toward the megakaryocyte lineage and is critical for normal platelet production. Mutations in MPL, TPO, or Janus kinase 2 (JAK2) have been implicated in multiple diseases from congenital thrombocytopenias to myeloproliferative neoplasms. The ligand for MPL, TPO, stimulates platelet production by inducing MPL dimerization and results in an active conformation that allows downstream JAK2/STAT5 signaling. Despite the biological importance of this pathway, the molecular signaling mechanism remained unclear. Here, we present a 3.39-Å cryo-electron microscopy structure of the ectodomain of mouse MPL bound to TPO. The structure revealed both low and high affinity sites between MPL and TPO that contain several pathologic mutations. To better understand TPO-driven MPL signaling, we expanded upon this structure by molecular dynamic (MD) simulations to model the full-length human MPL/TPO complex, and showed that MPL D4-D4 domain interactions are functionally relevant in activity assays. To build on our understanding of downstream activation, we added JAK2 to the MPL/TPO complex by MD simulations. This ternary complex illustrates JAK2 dimerization through the pseudokinase domain, illustrates residues important for MPL interactions, and reveals the constitutive activation mechanism of patient mutant V617F. The model also suggests the mechanism of JAK2 tyrosine kinase domain transphosphorylation. Overall, our studies illuminate TPO/MPL/JAK2 signaling mechanisms and provide additional insight into the nature of receptor signaling, which will further benefit human health.</p></div>","PeriodicalId":100190,"journal":{"name":"Blood Vessels, Thrombosis & Hemostasis","volume":"1 3","pages":"Article 100018"},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2950327224000184/pdfft?md5=a1683a278ce551192c96b84e0e3238ed&pid=1-s2.0-S2950327224000184-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141706607","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}
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