Successful treatment of refractory acute GVHD complicated by severe intestinal transplant-associated thrombotic microangiopathy using recombinant thrombomodulin

Inoue, Y.; Kosugi, Shigeki; Miura, Ikuo; Hatta, Yoshihiro; Jin, Tao

doi:10.1016/j.thromres.2010.12.023

Cited by 16 publications

(9 citation statements)

References 8 publications

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“…There have also been reports of benefit for patients with thrombotic microangiopathies associated with thrombotic thrombocytopenic purpura (49), systemic lupus erythematosus (50), and transplantrelated graft-versus-host disease (51). Further study will demonstrate whether soluble TM can protect against HUS.…”

Section: Discussionmentioning

confidence: 96%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TMwt/wt) and mice that lack the lectin-like domain of TM (TMLeD/LeD), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TMLeD/LeD mice exhibited more severe thrombocytopenia and renal dysfunction than TMwt/wt mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TMLeD/LeD than in TMwt/wt mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TMLeD/LeD mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TMLeD/LeD mice with HUS had a higher mortality rate than TMwt/wt mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.

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Section: Discussionmentioning

confidence: 96%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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“…7 In the few available case reports, rTM was successfully administered for DIC with acute myelogenous leukemia in a child, capillary leakage associated with engraftment syndrome, sinusoidal obstructive syndrome, and thrombotic microangiopathy after hematopoietic stem cell transplantation. [12][13][14] Therefore, the indication of rTM administration for coagulation abnormalities has gradually expanded, and it is essential to identify the indications and contraindications of coagulation abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Clinical Features and Outcomes of 35 Disseminated Intravascular Coagulation Cases Treated with Recombinant Human Soluble Thrombomodulin at a Single Institution

Kawano

Yoshida

Ono

et al. 2011

J Clin Exp Hematopathol

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Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome.

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“…76 Other potential therapies Other therapies that in theory may be beneficial for TA-TMA include recombinant thrombomodulin, VEGF, erythropoietin, TNF-α inhibitors, prostacyclin analog and bosentan. 77,78 A number of new complement-inhibiting agents are being extensively studied, with potential to revolutionize the therapy of TMA in transplant recipients in near future. Their mechanisms of action are illustrated in (Figure 5).…”

Section: No Donorsmentioning

confidence: 99%

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

Khosla

Yeh

Spitzer

et al. 2017

Bone Marrow Transplant

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Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) remains a difficult complication to address due to its high mortality rate, lack of standard diagnostic criteria and limited therapeutic options. Underscoring this challenge is the complex pathophysiology involved and multiple contributing factors that converge on a final pathway involving widespread endothelial injury and complement activation. In addressing our current understanding of TA-TMA, we highlight the risk factors leading to endothelial damage and a pathophysiological cascade that ensues. We have also compared the different definition criteria and biomarkers that can enable early intervention in TA-TMA patients. Current first-line management includes discontinuation or alteration of the immunosuppressive regimen, treatment of co-existing infectious and GVHD, aggressive hypertension control and supportive therapy. We discuss current pharmacological therapies, including newer agents that target the complement cascade and nitric oxide pathways.

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Successful treatment of refractory acute GVHD complicated by severe intestinal transplant-associated thrombotic microangiopathy using recombinant thrombomodulin

Cited by 16 publications

References 8 publications

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Clinical Features and Outcomes of 35 Disseminated Intravascular Coagulation Cases Treated with Recombinant Human Soluble Thrombomodulin at a Single Institution

Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies

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