Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome

Ikezoe, Takayuki; Takeuchi, Asako; Taniguchi, Ayuko; Togitani, Kazuto; Yokoyama, Akihito

doi:10.1038/bmt.2010.158

Cited by 31 publications

(26 citation statements)

References 7 publications

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“…38 Recombinant human soluble thrombomodulin has also been shown to ameliorate the vascular leak manifestations of ES. 39 As more biomarkers of GVHD are identified, 40 it may be possible to better determine how to distinguish ES from GVHD and whether they are are different or identical processes. …”

Section: Engraftment Syndromementioning

confidence: 99%

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Spitzer

2015

Bone Marrow Transplant

112

128

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Engraftment syndrome (ES) after hematopoietic cell transplantation (HCT) is increasingly diagnosed. Common features include fever, pulmonary vascular leak, rash and organ dysfunction. Different diagnostic criteria likely account for the wide (7-90%) range of reported incidences. ES typically occurs within 4 days of granulocyte recovery although a recently described seemingly similar syndrome occurs 41 week before granulocyte recovery after umbilical cord blood cell transplants. Although the clinical manifestations of ES may be identical to those of acute GVHD, ES also has been well described in patients without acute GVHD. The data are conflicting as to whether ES is associated with a higher nonrelapse mortality and worse survival after HCT. The pathophysiology of ES is unclear, but endothelial injury and activated granulocytes in the setting of proinflammatory cytokines may be important. ES typically is self-limited, but, like acute GVHD, responds to corticosteroids. Because ES and acute GVHD may have overlapping features and response to therapy, these disease processes may often not be distinct events. Moreover, features of ES may overlap with those of drug-and radiation-induced toxicities and infection. Further research to better characterize the clinical spectrum and etiology of ES and to determine its relationship to GVHD is needed.

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Section: Engraftment Syndromementioning

confidence: 99%

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Spitzer

2015

Bone Marrow Transplant

112

128

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“…The patho-etiology of DS remains to be fully elucidated, but the insults to the respiratory and vascular endothelium caused by cytokines released by differentiated myeloid cells are considered to be involved in the development of this potentially lethal syndrome [89]. rTM may counteract DS, as rTM successfully alleviated capillary leakage in individuals with engraftment syndrome and sinusoidal obstruction syndrome that developed after hematopoietic stem cell transplantation [35,36].…”

Section: Possible Action Of Rtm In Apl Cellsmentioning

confidence: 99%

“…In addition, the thrombin-rTM complex activates protein C to produce activated protein C (APC), which inactivates factors VIIIa and Va in the presence of protein S, further inhibiting thrombin formation [29]. The use of rTM for the treatment of DIC was approved in Japan in 2008, and is effective for the management of DIC complicated by a variety of underlying diseases [30][31][32][33][34][35][36]. rTM possesses anti-inflammatory and cytoprotective effects [37][38][39], and the use of rTM significantly improved survival of mechanically ventilated patients with severe sepsis when compared with control patients who did not receive rTM [30].…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Ikezoe

2013

Int J Hematol

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Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhagerelated death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

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“…Thereafter, the efficacy of rTM has been supported by a numerous reports, particularly in treatment of sepsisinduced DIC [3][4][5][6]. It was also shown in case reports that rTM was effective in microangiopathy of bone marrow transplantation [7,8] and capillary leak of engraftment syndrome [9].…”

Section: Introductionmentioning

confidence: 63%

Recombinant Human Soluble Thrombomodulin is Effective for Severe Childhood EBV-HLH

2016

J Hematol Thromb

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Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease, presenting with T cell-induced dysregulated cytokine production, systemic inflammation, and frequently intractable coagulopathy. We have administered recombinant human soluble recombinant thrombomodulin (rTM) for four cases of severe childhood Epstein-Barr virus-associated HLH (EBV-HLH) in combination with anti-inflammatory therapy and had good clinical outcomes. To evaluate its efficacy, we retrospectively compared to the former six cases without rTM administration. The patients were admitted between May 2003 and July 2014. The median age at diagnosis was 8.2 years (range, 1.6-16 years). All patients except for two cases without rTM who received only steroid, were treated with steroid, cyclosporine A (CSP) and/or etoposide based on HLH-94 or HLH-2004. All patients receiving rTM were induced in remission. However, two patients without rTM administration died of disease progression. The values of FDP, D-dimer, serum ferritin, and bilirubin improved better in patients with rTM. In some cases without rTM, serum bilirubin increased even though D-dimer, FDP, and ferritin were decreased. Although further clinical experience is required, rTM may be effective as an adjuvant therapy for resolution of severe EBV-HLH.

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Recombinant human soluble thrombomodulin counteracts capillary leakage associated with engraftment syndrome

Cited by 31 publications

References 7 publications

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Engraftment syndrome: double-edged sword of hematopoietic cell transplants

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Recombinant Human Soluble Thrombomodulin is Effective for Severe Childhood EBV-HLH

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