Early coagulation disorder after allogeneic stem cell transplantation is a strong prognostic factor for transplantation-related mortality, and intervention with recombinant human thrombomodulin improves the outcome: a single-center experience

Thrombotic microangiopathy (TMA) and veno-occlusive disease (VOD) are well-known transplantation-related complications induced by coagulation disorder [1–4]. The mortality rates are more than 60–70 % in patients with a severe condition [5]. Basically, patients with SCT are inevitably exposed to mucosal and endothelial damages by conditioning regimens such as irradiation and anticancer drugs, leukocytopenia complicated with infections, hypercytokinemia in an allogeneic immune reaction, and endothelial damages induced by a calcineurin inhibitor [6–8], which altogether lead to an increased susceptibility to a systemic coagulation disorder. Inflammation and coagulation are well known to be closely related and coagulation disorder aggravates graft-versus-host disease (GVHD) and vice versa. This multifactorial and systemic pathology is unique and different in various aspects from coagulation disorder observed in severe infection or malignancy. Recently, defibrotide (DF), a polydisperse oligonucleotide mixture, has been reported to be an effective therapeutic and prophylactic agent for VOD [9, 10]. However, specific strategies for management of coagulopathy in SCT are still not well exploited and remain to be established. Recombinant human thrombomodulin (rhTM) is a newly developed drug, which works not only as an anticoagulant through its interaction with protein C, but also as an anti-inflammatory agent via its interaction with high-mobility group 1 (HMG1) protein and protease-activated receptor 1 (PAR1) [11–13]. In clinical practice, rhTM has shown marked effectiveness in coagulopathy occurring in severe infection, systemic inflammatory response syndrome (SIRS), and malignancy [14–17]. Early coagulopathy in SCT, including TMA and VOD, is considered as an important and central systemic pathology of transplantation-associated complication, which must be controlled in the initial stage. To examine this issue, we retrospectively analyzed the cases of 60 patients who underwent SCT from the coagulopathy point of view and found that coagulopathy was a most significant prognostic factor of early transplantation-related mortality (TRM). We have used rhTM for the first time to prevent the progression of coagulopathy according to our tentative scoring system, which is used to predict the severity of coagulation disorder in SCT. Although the effect was observed in a limited number of patients, rhTM may be effective and safe in the management of coagulopathy observed in the early phase of SCT. Patients and methods Tentative scoring system To evaluate the prognosis of coagulation disorder in SCT, we made an institutional tentative scoring system. We extracted GVHD (grade 3 and more), impairment of renal function, hyper-bilirubinemia, intestinal bleeding, and severe thrombocytopenia as important factors that were closely related with transplantation-related mortality by multivariate analysis of SCT cases performed in our institute. On the basis of these factors, we made a scoring system through discussion that is assessed by daily simple examination (presented in Japanese at the 52nd Annual Meeting of Japanese Pediatric Hematology Association in Osaka, Japan, 2010). This scoring system consists of 5 clinical points: stem cell donor, GVHD and/or sign related to GVHD, increased platelet consumption, abnormal coagulation data, and laboratory data or clinical symptoms that suggest renal impairment, liver dysfunction, or intestinal ischemia. This score is calculated from simple, routine laboratory data and clinical symptoms, and easily evaluated on a daily basis. Patients were evaluated daily until 30 days after SCT, and those with a total score of 7 or more were determined to be ‘‘score positive’’. The precise scoring system is described in Table 1. D-Dimer was measured by using latex-immune-aggregation kit (Mitsubishi Chemical Medicine; Tokyo, Japan) and normal value was below 1 lg/ml. TRM (transplantation-related mortality) within 1 year after SCT is designated as early transplantation-associated death. All of the score-positive patients were qualified as having DIC according to the diagnostic criteria for DIC established by the Japanese Association of Acute Medicine [18]. Patients We retrospectively examined 60 pediatric patients who received