Journal of Thrombosis and Haemostasis最新文献_第5页

Acquired hemophilia A following SARS-CoV-2 infection and vaccination: clinical summary and insights SARS-CoV-2感染后获得性血友病A和疫苗接种：临床总结和见解。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.030

Alyssa L. Carlson , Jeremy Althouse , Naveed Ahmed , Matthew A. Nazari , Hussam Alkaissi

Background

Acquired hemophilia A (AHA) is a bleeding diathesis caused by antifactor (F)VIII antibodies produced spontaneously or in response to triggers such as infections, autoimmune disorders, and malignancies. Recently, SARS-CoV-2 exposure, through both infection and vaccination, has emerged as a potential trigger.

Objectives

This is the first systematic review to compare cases of AHA following both SARS-CoV-2 infection and vaccination, presented alongside an illustrative case of severe AHA following SARS-CoV-2 infection during the Omicron variant outbreak. This is also the first study to explore the potential for molecular mimicry between SARS-CoV-2 spike protein (S) and human FVIII.

Methods

A systematic review of AHA cases associated with SARS-CoV-2 infection (n = 14) or vaccination (n = 28) was conducted. An in silico analysis was performed to compare surface epitopes between SARS-CoV-2 S and human FVIII.

Results

AHA following SARS-CoV-2 infection or vaccination presented in individuals aged >60 years, with a significantly more rapid onset and potentially milder anti-FVIII response following vaccination. Spontaneous hemorrhagic shock was observed exclusively in AHA following infection. In silico analysis revealed 2 shared surface epitopes between SARS-CoV-2 S and FVIII, one of which is specific to the Omicron variant.

Conclusion

AHA following SARS-CoV-2 exposure is an emerging trend that may become more prominent with newer variants, highlighting the need for improved clinical characterization and earlier intervention. Preliminary evidence of shared surface epitopes between FVIII and SARS-CoV-2 S supports further investigation of molecular mimicry, and the identification of variant-specific epitopes offers insights into possible differences in immunogenicity between variants.

背景：获得性血友病A （AHA）是由抗因子VIII （FVIII）抗体自发产生或响应诸如感染、自身免疫性疾病和恶性肿瘤等触发因素引起的出血。最近，通过感染和疫苗接种暴露于SARS-CoV-2已成为潜在的触发因素。目的：这是第一个比较SARS-CoV-2感染和疫苗接种后AHA病例的系统综述，同时提出了一个在Omicron变体爆发期间SARS-CoV-2感染后的严重AHA病例。这也是首个探索SARS-CoV-2刺突蛋白(S)与人类FVIII之间分子模拟潜力的研究。方法：系统回顾与SARS-CoV-2感染（n=14）或疫苗接种（n=28）相关的AHA病例。用计算机分析比较了sars - cov - 2s和人FVIII病毒的表面表位。结果：60岁以上的个体在SARS-CoV-2感染或接种疫苗后出现AHA，接种疫苗后发病明显更快，抗fviii反应可能更温和。出血性休克只在AHA感染后出现。计算机分析显示，sars - cov - 2s和FVIII之间有两个共享的表面表位，其中一个是特异于Omicron变体的。结论：SARS-CoV-2暴露后的AHA是一种新兴趋势，随着新变体的出现，这种趋势可能会变得更加突出，这突出了改善临床特征和早期干预的必要性。FVIII和sars - cov - 2s之间共享表面表位的初步证据支持进一步研究分子拟态，而变体特异性表位的鉴定有助于了解变体之间可能存在的免疫原性差异。

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引用次数: 0

Shapes and dimensions of blood clots affect the rate and extent of platelet-driven clot contraction and determine the outcomes of thrombosis 血栓的形状和尺寸影响血小板驱动的血栓收缩的速度和程度，并决定血栓形成的结果。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.007

Rafael R. Khismatullin , Alina I. Khabirova , Shakhnoza M. Saliakhutdinova , Rustem I. Litvinov , John W. Weisel

Background

Contraction of blood clots has multiple pathophysiological implications.

Objectives

To determine whether the initial shape and dimensions of blood clots affect clot contraction.

Methods

Thrombin-induced clots of various sizes were formed in human blood or platelet-rich plasma in a cylinder, cuboid, or flat chamber. Clot shrinkage was tracked photographically. After complete contraction, the physiologically most relevant cylindrical clots of various initial volumes were analyzed with scanning electron microscopy for composition and spatial nonuniformity with the emphasis on compressed polyhedral erythrocytes (polyhedrocytes).

Results

With the same volumes studied, the final extents of contraction of 0.3-mL whole blood clots were shape-dependent, such that flat was more contracted than cylindrical, which was equal to cuboid. Irrespective of the shape, the smaller clots mainly contracted to a larger extent. Unlike whole blood clots, platelet-rich plasma clots contracted independently of the clot volumes and shapes studied, indicating a key role of erythrocytes. The smaller blood clots contained more erythrocytes, especially polyhedrocytes, due to tight packing and a decrease in the intercellular space. The spatial segregation within the larger clots was less marked than in the smaller clots, reflecting incomplete spatial redistribution of blood clot components typical for robust contraction.

Conclusion

Contraction of blood clots depends on their shape and size. The smaller and larger clots have distinct size-dependent rates and extents of contraction as well as degrees of structural nonuniformity, reflecting different spatial gradients of compressive stresses. These findings are relevant to the variable geometry and size of intravascular blood clots and thrombi.

背景：血凝块的收缩具有多种病理生理意义。目的：探讨血凝块的初始形状和尺寸是否影响血凝块收缩。方法：在人血或富血小板血浆中形成不同大小的凝块，在圆柱体、长方体或扁平腔中形成。用照相法跟踪血块收缩情况。在完全收缩后，用扫描电镜分析不同初始体积的生理上最相关的圆柱形血块的组成和空间不均匀性，重点分析压缩的多面体红细胞（polyhedrocytes）。结果：在研究体积相同的情况下，0.3 ml全血凝块的最终收缩程度与形状有关，扁平比圆柱形收缩更大，圆柱形收缩与长方体收缩相等。无论形状如何，较小的血块主要收缩程度较大。与全血凝块不同，富血小板血浆凝块的收缩与所研究的凝块体积和形状无关，这表明红细胞起着关键作用。较小的血块含有较多的红细胞，尤其是多角细胞，这是由于紧密的填充物和细胞间隙的减少。大血块的空间分离不像小血块那么明显，反映了血凝块成分的空间再分配不完全，这是典型的强劲收缩。结论：血凝块的收缩取决于其形状和大小。较小和较大的凝块具有不同的尺寸依赖性速率和收缩程度以及结构不均匀度，反映了不同的压应力空间梯度。这些发现与血管内血块和血栓的几何形状和大小的变化有关。

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引用次数: 0

Venous ultrasonography and computed tomography venography in diagnosis of peripherally inserted central venous catheter–associated venous thrombosis: complementary strategies for expecting the unexpected? 静脉超声和计算机断层静脉造影在周围静脉导管相关静脉血栓诊断中的应用：预测意外的互补策略？

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.019

Stanislav Henkin , Gregory Piazza

引用次数: 0

Confining thrombus morphospace through targeted inhibition of platelet mechanosensory signaling 通过靶向抑制血小板机械感觉信号来限制血栓形态空间。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.08.013

Pia Larsson , Abigail McGovern , Volga Tarlac , Natasha M. Setiabakti , Louis Parker , Stephen H. Cody , Juan Nunez-Iglesias , Lars Faxälv , Lisa Prahl Wittberg , Justin R. Hamilton , Niklas Boknäs

Background

While current antiplatelets protect against thrombosis, their clinical utility is limited by an elevated risk of bleeding.

Objectives

To understand how structure-function relations in the hemostatic system may be leveraged into improve risk/benefit ratios of antiplatelet therapies.

Methods

We developed a deep learning-based framework to track the activities of large numbers of platelets in vivo, enabling a detailed comparative assessment of the effects of therapeutic interventions on the evolving structural hierarchy of the hemostatic response.

Results

Unlike conventional antiplatelets targeting paracrine signaling, selective pharmaceutical inhibition of platelet mechanosensory signaling via PI3KC2α preserved the initial build-up of thrombi following vascular injury to high-flow mesenteric veins. However, as this burst of hemostatic activity subsided, inhibition of platelet mechanosensory signaling caused localized reductions of platelet intracellular calcium ion levels ([Ca²⁺]_i) in shear-exposed peripheral thrombus subregions, inhibiting the formation of platelet clusters capable of withstanding the drag forces of the blood flow. As a consequence, platelets in these subregions detached, became elongated, and/or slid along the thrombus surface. On a macrostructural level, this selective destabilization prevented sustained physical expansion of thrombi outside the perimeters of vascular injuries while preserving platelet packing density in thrombus subregions close to vascular injuries.

Conclusion

Collectively, our results highlight platelet mechanosensory signaling as a significant driver of sustained platelet population growth after the initial agonist-driven phase of thrombus expansion. We show that pharmaceutical targeting of this pathway enforced the convergence of thrombus growth trajectories toward a rheologically favorable setpoint without compromising the structural integrity of thrombus subregions that are critical for hemostasis.

背景：虽然目前的抗血小板药物可以防止血栓形成，但其临床应用受到出血风险升高的限制。目的：了解止血系统中的结构-功能关系如何被用于提高抗血小板治疗的风险/收益比。方法：我们开发了一个基于深度学习的框架来跟踪体内大量血小板的活动，从而能够详细地比较评估治疗干预对不断变化的止血反应结构层次的影响。结果：与传统的靶向旁分泌信号的抗血小板药物不同，通过PI3KC2α选择性药物抑制血小板机械感觉信号（iPMS）可保留高流量肠系膜静脉血管损伤后血栓的初始形成。然而，随着这种止血活性的爆发消退，iPMS导致剪切暴露的外周血栓亚区血小板[Ca2+]i的局部减少，抑制了能够承受血流阻力的血小板簇的形成。结果，这些亚区中的血小板分离、拉长和/或沿着血栓表面滑动。在宏观结构水平上，这种选择性不稳定阻止了血栓在血管损伤周围外的持续物理扩张，同时保持了血栓亚区靠近血管损伤的血小板堆积密度。结论：总的来说，我们的研究结果强调了血小板机械感觉信号在激动剂驱动的血栓扩张初始阶段后持续血小板数量增长的重要驱动因素。我们表明，药物靶向这一途径强制收敛血栓生长轨迹向一个流变性有利的设定点，而不损害血栓亚区域的结构完整性，这是止血的关键。

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引用次数: 0

Anti-Xa directed low-molecular-weight heparin dosing to reduce the risk of venous thromboembolism in pregnant women with inherited antithrombin deficiency 抗xa定向低分子肝素（LMWH）剂量降低遗传性抗凝血酶缺乏孕妇静脉血栓栓塞的风险

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.07.031

Caroline Dix , Karen Breen , Susan Robinson , Aine McCormick , Beverley J. Hunt

Background

Inherited antithrombin deficiency (ATD) is associated with a high risk of venous thromboembolism (VTE), particularly during risk periods, including pregnancy. Guidelines vary regarding thromboprophylaxis with low-molecular-weight heparin (LMWH). LMWH use in women with inherited ATD is hampered by the fact that antithrombin is the substrate for its anticoagulant effect, and therefore, larger doses of LMWH are needed.

Objectives

Assess the rate of VTE in pregnant women with inherited ATD after our institution changed practice to using anti–Xa-guided LMWH in 2012.

Methods

This was a retrospective single-center cohort study of pregnant women with inherited ATD, followed from positive pregnancy test to 6 weeks postpartum.

Results

We identified 32 pregnancies in 17 women, 12 with type 1 and 5 with type 2 inherited ATD. Twenty-two (69%) resulted in a live birth. There were 4 cases of VTE (12.5%): 2 occurred in women prior to referral to our unit on subtherapeutic doses of LMWH; 1 in a nonadherent patient with homozygous AT Budapest; and 1 postpartum VTE in the setting of nonadherence. The median starting dose of LMWH in the whole cohort was 6250 units (96 units/kg), increasing to 16 750 units (247 units/kg) by the end of pregnancy. Antithrombin concentrate was given peripartum in 20 pregnancies. There were 4 postpartum hemorrhages (12.5%), 1 minor and 3 moderate.

Conclusion

In this retrospective cohort study of 32 pregnancies, 12.5% of our cohort had a VTE. However, there was no VTE in those who were adherent and received anti-Xa monitored LMWH with risk-assessed use of peripartum antithrombin concentrate.

背景：遗传性抗凝血酶缺乏症（ATD）与静脉血栓栓塞（VTE）的高风险相关，特别是在包括怀孕在内的危险时期。关于使用低分子肝素（LMWH）预防血栓的指导方针各不相同。由于抗凝血酶是其抗凝作用的底物，因此需要大剂量的低分子肝素，这阻碍了遗传性ATD妇女使用低分子肝素。目的：评估我院于2012年改为使用抗xa引导低分子肝素后，遗传性ATD孕妇静脉血栓栓塞率。患者/方法：回顾性单中心队列研究，对妊娠试验阳性至产后6周的遗传性ATD孕妇进行随访。结果：我们在17名妇女中发现32例妊娠，其中12例为1型，5例为2型遗传性ATD。22例（69%）导致活产。有4例静脉血栓栓塞（12.5%）：2例发生在转介到我们单位之前，低分子肝素的亚治疗剂量；1例纯合子AT布达佩斯非粘附患者；以及产后静脉血栓栓塞。在整个队列中，低分子肝素的中位起始剂量为6250单位（96单位/kg），到妊娠结束时增加到16750单位（247单位/kg）。20例孕妇围产期给予浓缩抗凝血酶。有4例产后出血（12.5%），1例轻微出血，3例中度出血。结论：在32例妊娠的回顾性队列研究中，12.5%的队列发生静脉血栓栓塞。然而，在那些坚持并接受抗xa监测低分子肝素并使用围产期抗凝血酶浓缩物进行风险评估的患者中，没有静脉血栓栓塞。

{"title":"Anti-Xa directed low-molecular-weight heparin dosing to reduce the risk of venous thromboembolism in pregnant women with inherited antithrombin deficiency","authors":"Caroline Dix , Karen Breen , Susan Robinson , Aine McCormick , Beverley J. Hunt","doi":"10.1016/j.jtha.2025.07.031","DOIUrl":"10.1016/j.jtha.2025.07.031","url":null,"abstract":"<div><h3>Background</h3><div>Inherited antithrombin deficiency (ATD) is associated with a high risk of venous thromboembolism (VTE), particularly during risk periods, including pregnancy. Guidelines vary regarding thromboprophylaxis with low-molecular-weight heparin (LMWH). LMWH use in women with inherited ATD is hampered by the fact that antithrombin is the substrate for its anticoagulant effect, and therefore, larger doses of LMWH are needed.</div></div><div><h3>Objectives</h3><div>Assess the rate of VTE in pregnant women with inherited ATD after our institution changed practice to using anti–Xa-guided LMWH in 2012.</div></div><div><h3>Methods</h3><div>This was a retrospective single-center cohort study of pregnant women with inherited ATD, followed from positive pregnancy test to 6 weeks postpartum.</div></div><div><h3>Results</h3><div>We identified 32 pregnancies in 17 women, 12 with type 1 and 5 with type 2 inherited ATD. Twenty-two (69%) resulted in a live birth. There were 4 cases of VTE (12.5%): 2 occurred in women prior to referral to our unit on subtherapeutic doses of LMWH; 1 in a nonadherent patient with homozygous AT Budapest; and 1 postpartum VTE in the setting of nonadherence. The median starting dose of LMWH in the whole cohort was 6250 units (96 units/kg), increasing to 16 750 units (247 units/kg) by the end of pregnancy. Antithrombin concentrate was given peripartum in 20 pregnancies. There were 4 postpartum hemorrhages (12.5%), 1 minor and 3 moderate.</div></div><div><h3>Conclusion</h3><div>In this retrospective cohort study of 32 pregnancies, 12.5% of our cohort had a VTE. However, there was no VTE in those who were adherent and received anti-Xa monitored LMWH with risk-assessed use of peripartum antithrombin concentrate.</div></div>","PeriodicalId":17326,"journal":{"name":"Journal of Thrombosis and Haemostasis","volume":"24 1","pages":"Pages 234-240"},"PeriodicalIF":5.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thrombolytic drugs for ischemic stroke: historical perspective, state of play, and future developments 缺血性脑卒中的溶栓药物：历史观点、现状和未来发展。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.021

Bamlaku Enawgaw Walie , Christoph E. Hagemeyer , Rong Xu , Be’eri Niego

Thrombolytic agents are serine proteases or related enzymes that facilitate blood clot breakdown via a process called thrombolysis. They work either indirectly, via activation of plasminogen into plasmin—a potent fibrin-degrading enzyme—or by direct dissolution of fibrin within clots. Numerous clinical trials investigating thrombolytic candidates for major thrombotic conditions, such as heart attack and acute ischaemic stroke (AIS), have led to the development of several potential therapies. However, while some drugs show clinical benefits, most still possess substantial limitations, especially for the treatment of AIS. Recombinant tissue-type plasminogen activator (rt-PA; alteplase) was the only clot-busting medication officially approved by the Food and Drug Administration for AIS from 1996 until 2024, until the recent approval of its mutated version, tenecteplase (2025). However, the use of rt-PA is significantly limited by its short plasma half-life, and both rt-PA and tenecteplase possess reduced efficacy against platelet-rich thrombi and a narrow, guideline-recommended therapeutic window up to 4.5 hours from stroke onset, primarily due to a diminished risk-benefit profile beyond this time point. While recent thrombectomy techniques offer ground-breaking ways for the removal of large clots, a pressing need remains to improve pharmacological thrombolysis. Novel strategies, including the fusion of clot-busting enzymes with thrombus-targeting antibodies and nanotechnology-based delivery systems, are being tested for their ability to increase the precision and safety of thrombolytic therapy. This review will articulate the historical milestones in thrombolysis, discuss key thrombolytic agents and their generational derivatives, and explore innovative approaches to advance this life-saving therapy for AIS.

溶栓剂是丝氨酸蛋白酶或相关酶，通过称为溶栓的过程促进血凝块分解。它们要么通过将纤溶酶原活化成纤溶酶（一种有效的纤维蛋白降解酶）间接起作用，要么直接溶解凝块内的纤维蛋白。许多临床试验研究了主要血栓性疾病（如心脏病发作和急性缺血性卒中（AIS））的溶栓候选药物，导致了几种潜在治疗方法的发展。然而，虽然一些药物显示出临床益处，但大多数药物仍然具有很大的局限性，特别是在治疗AIS方面。从1996年到2024年，重组组织型纤溶酶原激活剂（rt-PA; alteplase）是FDA正式批准的唯一用于AIS的凝块破坏药物，直到最近批准了其突变版本tenecteplase （TNK; 2025）。然而，rt-PA的使用受到其血浆半衰期短的显著限制，并且rt-PA和TNK对富血小板血栓的疗效降低，并且指南推荐的治疗窗口较窄，最长可达中风发作后4.5小时，主要是由于超过该时间点风险-收益谱降低。虽然最近的取栓技术为清除大凝块提供了突破性的方法，但迫切需要改进药物溶栓。新的策略，包括凝块破坏酶与血栓靶向抗体和基于纳米技术的递送系统的融合，正在测试它们提高溶栓治疗的准确性和安全性的能力。本综述将阐述溶栓的历史里程碑，讨论关键的溶栓药物及其世代衍生品，并探索创新方法来推进这种挽救生命的治疗方法。

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引用次数: 0

Concizumab use in toddlers with hemophilia B and inhibitors real-world data from an international collaboration 康珠单抗用于血友病B患儿和抑制剂的国际合作的真实世界数据。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.038

Sarina Levy-Mendelovich , Judith Timmermans , Beatrice Nolan , Sabina Heine , Federica Achini-Gutzwiller , Allison P. Wheeler , Gili Kenet

Background

Hemophilia B (HB) with inhibitors presents a treatment challenge, particularly in young children who may also experience allergic reactions to factor (F)IX. Concizumab, an antitissue factor pathway inhibitor monoclonal antibody, is a novel subcutaneous prophylactic agent recently approved for patients aged ≥12 years. However, data on its use in young children remain limited.

Objectives

To assess the safety, efficacy, and dosing of prophylactic concizumab in children under 6 years old with severe HB and inhibitors using data from compassionate or off-label use in Europe, Israel, and the United States.

Methods

This international retrospective cohort study included 5 children aged 0 to 6 years with severe HB (FIX <1%) and inhibitors (Bethesda units >0.6) who were treated with concizumab for at least 12 weeks. Clinical, genetic, laboratory, and thrombin generation data were collected and analyzed. Exclusion criteria included coagulopathies and enrollment in industry-sponsored trials.

Results

All patients experienced allergic reactions to FIX and developed inhibitors at a median age of 15 months. Concizumab prophylaxis began at a median age of 21 months. Annualized bleeding rates after concizumab therapy ranged from 0 to 4, with only 2 patients experiencing spontaneous bleeds, both resolving after dose adjustments. No thrombotic events occurred. Thrombin generation improved significantly posttreatment, and FIX inhibitor levels declined without additional FIX exposure or immune tolerance induction.

Conclusion

Concizumab appears safe and effective in young children with severe HB and inhibitors. It offers a promising, factor-free prophylactic strategy.

背景：血友病B （HB）与抑制剂提出了一个治疗挑战，特别是在幼儿谁也可能经历因子IX过敏反应（FIX）。Concizumab是一种抗tfpi单克隆抗体，是最近批准用于年龄≥12岁患者的新型皮下预防药物。然而，关于其在幼儿中的使用的数据仍然有限。目的：利用欧洲、以色列和美国同情用药或标签外用药的数据，评估6岁以下严重HB患儿预防性concizumab的安全性、有效性和剂量。患者/方法：这项国际回顾性队列研究包括5名0-6岁患有严重HB （FIX 0.6）的儿童，他们接受了concizumab治疗至少12周。收集并分析临床、遗传、实验室和凝血酶生成数据。排除标准包括凝血病变和行业赞助试验的入组。结果：所有患者在中位年龄15个月时出现FIX过敏反应并产生抑制剂。康珠单抗预防开始的中位年龄为21个月。康珠单抗治疗后的年化出血率从0到4不等，只有两名患者出现自发性出血，均在剂量调整后消退。未发生血栓事件。治疗后凝血酶生成显著改善，FIX抑制剂水平下降，无需额外的FIX暴露或免疫耐受诱导。结论：Concizumab对患有严重HB和抑制剂的幼儿安全有效。它提供了一种有希望的、无因素的预防策略。

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引用次数: 0

Defective lymphangiogenesis and iron removal after hemarthrosis in factor VIII-deficient mice are rectified with therapeutic factor VIII administration—implications for joint health 治疗性给药FVIII纠正了FVIII缺陷小鼠关节血肿后淋巴生成缺陷和铁去除-对关节健康的影响。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.08.016

Bilgimol Chumappumkal Joseph , Juan Andres De Pablo-Moreno , Nicca Falah , Mia Lora Cacho , Annette von Drygalski

Background

Maladaptive lymphangiogenesis after hemarthrosis in factor(F)VIII-deficient (knockout [KO]) mice facilitates synovial iron accumulation.

Objectives

To investigate the effect of FVIII treatment on lymphangiogenesis, iron clearance, and joint health after hemarthrosis.

Methods

Two days after knee injury/bleed (subpatellar needle puncture) FVIII-KO mice were separated into 3 groups receiving (1) intravenous saline, (2) recombinant human FVIII for 2 days, or (3) murine (m)FcFVIII for 14 days. FVIII activity levels were measured repeatedly (peak/trough) for 14 days. Joint tissues were processed at 2 and 4 weeks postbleed for Prussian blue staining (iron), CD68 (macrophage), αSMA (vascular remodeling), and LYVE1 (lymphangiogenesis) immunohistochemistry, and Safranin-O-Green staining (cartilage health).

Results

Joint injury caused profound hemarthrosis. Mice treated with mFcFVIII maintained stable FVIII activity levels for 14 days (troughs 29%-38%). Pronounced synovial iron accumulation colocalizing with macrophages, along with severely impaired lymphangiogenesis and joint health parameters, were present in saline-treated mice at 2 and 4 weeks when compared with baseline. Short-term recombinant human FVIII administration resulted in partially impaired lymphangiogenesis and iron clearance with delayed recovery of joint health parameters. In contrast, mice treated with mFcFVIII experienced rapid iron clearance alongside normal lymphangiogenesis, associated with fast and effective normalization of joint health parameters, particularly with respect to cartilage health.

Conclusion

Prolonged FVIII availability in the “mild hemophilia range” (± Fc-mediated effects) after hemarthrosis seem critical for lymphangiogenesis, rapid iron removal, and joint repair, including glycosaminoglycan-dependent cartilage restoration. Intensified courses of FVIII treatment in patients may therefore be beneficial for postbleed management.

背景：因子(F)VIII缺乏症（KO）小鼠关节血肿后的不适应淋巴管生成促进滑膜铁积聚。目的：探讨FVIII治疗对血肿后淋巴管生成、铁清除和关节健康的影响。方法：膝关节损伤/出血（髌骨下针穿刺）2 d后，将FVIII- ko小鼠分为3组，分别给予(1)静脉注射生理盐水，(2)重组人（rh）FVIII 2 d,(3)小鼠(m)FcFVIII 14 d。连续14天反复测定FVIII活性水平（峰/谷）。在出血后2周和4周对关节组织进行普鲁士蓝染色（铁）、CD68（巨噬细胞）、αSMA（血管重塑）、LYVE1（淋巴管生成）和红花素- o -绿（组织学、软骨健康）。结果：关节损伤引起深度关节积血。经mFcFVIII处理的小鼠在14天内保持稳定的FVIII活性水平（波幅为29-38%）。与基线相比，盐水处理小鼠在2周和4周时出现了明显的滑膜铁积累与巨噬细胞共定位，以及严重受损的淋巴管生成和关节健康参数。短期给药导致部分淋巴管生成和铁清除受损，关节健康参数恢复延迟。相比之下，用mFcFVIII治疗的小鼠在正常淋巴管生成的同时经历了快速的铁清除，与关节健康参数的快速有效正常化有关，特别是在软骨健康方面。结论：关节血肿后，延长FVIII在“轻度血友病范围”（+/- fc介导作用）的可用性似乎对淋巴管生成、快速铁清除和关节修复（包括糖胺聚糖依赖性软骨修复）至关重要。因此，患者强化FVIII治疗可能有利于出血后的处理。

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引用次数: 0

Macrophage Plg-RKT expression promotes diet-induced obesity and metabolic dysfunction-associated steatotic liver disease 巨噬细胞Plg-RKT表达促进饮食诱导的肥胖和代谢功能障碍相关的脂肪变性肝病。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.020

Lindsey A. Miles , Hongdong Bai , Sagarika Chakrabarty , Nagyung Baik , Yuqing Zhang , Robert J. Parmer , Fahumiya Samad

Background

Plg-R_KT is a transmembrane plasminogen receptor that enhances the activation of plasminogen to plasmin and localizes proteolytic activity of plasmin on the cell surface.

Objectives

We investigated the role of Plg-R_KT in high-fat diet (HFD)-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods

Mice deficient in Plg-R_KT in macrophages (mPlg-R_KT^−/−) or hepatocytes (hPlg-R_KT^−/−) and control mice (Plg-R_KT^flox/flox) were fed a HFD to determine the cell-specific role of this receptor in obesity and MASLD. Glucose homeostasis, hepatic lipogenesis, fatty acid oxidation pathways, adipose macrophage phenotypes, and inflammation were analyzed. RNA sequencing analysis of liver was performed to identify differentially expressed genes and functional pathways impacted by the loss of myeloid Plg-R_KT.

Results

Plg-R_KT levels were significantly elevated in the liver of HFD-fed mice with MASLD. HFD-fed mPlg-R_KT^−/− mice were protected from obesity, MASLD, and liver dysfunction. mPlg-R_KT^−/− mice exhibited reduced liver fat, lower plasma alanine aminotransferase levels, and improved glucose homeostasis. In contrast, HFD-fed hPlg-R_KT^−/− mice were not protected from obesity and MASLD. Mechanistically, mPlg-R_KT deficiency reduced hepatic Akt activation, lowered fatty acid synthase expression, and activated the PPARα fatty acid oxidation pathway. In adipose tissue, mPlg-R_KT deficiency shifted macrophage polarization from proinflammatory M1-like to anti-inflammatory M2-like, enhancing insulin sensitivity, decreasing lipolysis, and lowering plasma free fatty acids available for liver uptake. RNA sequencing revealed significant gene expression changes in lipid metabolism, fibrosis, and inflammation.

Conclusion

These findings underscore the critical role of macrophage Plg-R_KT signaling in the pathogenesis of obesity and MASLD.

背景：Plg-RKT是一种跨膜的纤溶酶原受体，它可以增强纤溶酶原对纤溶酶的激活，并使纤溶酶的蛋白水解活性定位在细胞表面。方法：在巨噬细胞（mPlg-RKT-/-）或肝细胞（hPlg-RKT-/-）和对照小鼠（Plg-RKTflox/flox）中缺乏Plg-RKT的小鼠喂食HFD，以确定该受体在肥胖和MASLD中的细胞特异性作用。分析了葡萄糖稳态、肝脏脂肪生成、脂肪酸氧化途径、脂肪巨噬细胞表型和炎症。对肝脏进行RNA-seq分析，以鉴定受髓系Plg-RKT缺失影响的差异表达基因（DEGs）和功能途径。结果：hfd喂养的MASLD小鼠肝脏中Plg-RKT水平显著升高。hfd喂养的mPlg-RKT-/-小鼠可避免肥胖、MASLD和肝功能障碍。mPlg-RKT-/-小鼠表现出肝脏脂肪减少，血浆丙氨酸转氨酶（ALT）水平降低，葡萄糖稳态改善。相比之下，hfd喂养的hPlg-RKT-/-小鼠没有受到肥胖和MASLD的保护。机制上，mPlg-RKT缺乏可降低肝脏Akt活化，降低脂肪酸合成酶（FAS）表达，激活PPARα脂肪酸氧化途径。在脂肪组织中，mPlg-RKT缺乏将巨噬细胞极化从促炎m1样转变为抗炎m2样，增强胰岛素敏感性，减少脂肪分解，降低可用于肝脏摄取的血浆游离脂肪酸。RNA-seq显示在脂质代谢、纤维化和炎症中显著的基因表达变化。结论：这些发现强调了巨噬细胞Plg-RKT信号在肥胖和MASLD发病机制中的关键作用。

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引用次数: 0

A closer look at the GPIbM assay: unraveling unexpected discrepancies in von Willebrand factor activity testing GPIbM检测的进一步研究：揭示VWF活性检测中意想不到的差异。

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis

Pub Date : 2026-01-01 DOI: 10.1016/j.jtha.2025.09.025

Emily Helm , Daniel E. Sabath , Theingi Tun , Maryam Asif

引用次数: 0