Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation

Inoue, Y.; Matsunawa, Manabu; Sano, Fumiaki; Miura, Ikuo

doi:10.1159/000492105

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…However, TBI and CY can mobilize HMGB1 to the PB, and increased levels of HMGB1 correlate with increased PAI-1 after allo-HSCT, inducing transplantation-associated coagulopathy (TAC) conditions such as veno-occlusive disease (VOD) [154]. Recombinant human soluble thrombomodulin (rhTM) is used to treat disseminated intravascular coagulation (DIC) caused by aGVHD and significantly decreases HMGB1 [155]. Extracorporeal photopheresis (ECP) depends on infusion of UVA-irradiated and 8 methoxy-psoralen (PUVA)-treated leukocytes and is an effective treatment measure for GVHD.…”

Section: The Potential Clinical Applications Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.

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Section: The Potential Clinical Applications Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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“…Therefore, traditional anticoagulation therapies such as heparin or antithrombin III may not have the expected effect. The current study by Inoue et al [6] probes further into the therapeutic role of rhTM in DIC after aHSCT. The authors propose that rhTM is effective against both DIC and systemic inflammatory complications after aHSCT.…”

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confidence: 90%

“…In this issue of Acta Haematologica , Inoue et al [6] have evaluated the efficacy of rhTM in treating DIC complicating aHSCT. They divided DIC patients into 2 groups, treated with or without rhTM.…”

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Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation

Nomura¹

2018

Acta Haematol

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“…TM converts thrombin to the anticoagulant form to reduce blood coagulation and inhibits inflammation in blood vessels [22][23][24][25][26] . Recently, recombinant TM has been developed and can potentially be used to treat patients with inflammatory and thrombotic diseases 27,28 .…”

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confidence: 99%

PPARα activation directly upregulates thrombomodulin in the diabetic retina

Shiono

Sasaki

Sekine

et al. 2020

Sci Rep

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Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferatoractivated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM. Diabetic retinopathy (DR) is the main cause of blindness among working-age adults, and the worldwide prevalence is approximately 35% in patients with diabetes 1. DR is characterized by the combination of increased vessel permeability and progressive vascular occlusion. However, the molecular mechanisms underlying the pathways associated with DR have not been fully elucidated. Several biochemical mechanisms have been proposed to modulate the pathogenesis of DR through effects on cellular metabolism, signaling, and growth factors 2. Implicated pathways include the accumulation of sorbitol and advanced glycation end-products, oxidative stress, protein kinase C activation, and upregulation of the renin-angiotensin system and vascular endothelial growth factor (VEGF). Among them, VEGF strongly promotes angiogenesis, a key mediator of the progression of DR. Inhibition of VEGF (e.g., anti-VEGF therapies) was shown to be effective in the management of DR in numerous studies 3-7. However, some DR patients respond poorly or incompletely to anti-VEGF therapy. Accordingly, there is still substantial unmet medical need in patients with DR. Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates lipid metabolism 8. PPARα is highly expressed in the liver and is also expressed in the retina 9. Recently, two large, prospective clinical trials have demonstrated that fenofibrate, a canonical synthetic PPARα agonist, has protective effects against DR in type 2 diabetes patients. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study reported that fenofibrate therapy significantly reduced the cumulative need for laser therapy for DR 10. The Action Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study of combination simvastatin and fenofibrate demonstrated a greater reduction in the progression of proliferative DR in type 2 diabetes patients compar...

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Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 9 publications

References 22 publications

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation

PPARα activation directly upregulates thrombomodulin in the diabetic retina

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