Hepatic sinusoidal obstructive syndrome (SOS) is one of the most life-threatening non-hematological complications following myeloablative conditioning regimens for allogeneic hematopoietic SCT (allo-HSCT). SOS may present clinically with rapid and unexplained weight gain, ascites, painful hepatomegaly and jaundice.1 Injury to sinusoidal endothelial cells and hepatocytes by high-dose chemotherapy has been implicated in the pathogenesis of SOS. A number of markers of endothelial injury, including plasma thrombomodulin, tissue factor pathway inhibitor, soluble tissue factor and plasminogen activator inhibitor-1 is reported to be upregulated in patients with SOS. Standard treatment for SOS is supportive management in Japan. Clinical trials using anticoagulants or thrombolytics as treatment options for SOS have not been satisfactory.2, 3, 4 Defibrotide (DF) has been shown to be effective as prophylaxis and in the treatment of SOS,5 but it is not yet available for routine clinical practice in Japan.
Thrombomodulin is a thrombin receptor on the endothelial cell surface that has an important role in regulating intravascular coagulation. Recombinant human soluble thrombomodulin (rTM) inactivates intravascular coagulation by binding to thrombin. A recent phase-III trial comparing the efficacy and safety of rTM with those of low-dose unfractionated heparin showed that rTM significantly improved clinical outcomes in disseminated intravascular coagulopathy (DIC) associated with hematological malignancies or infection.6 A recent report indicates a favorable therapeutic potential of rTM in the management of SOS complicated by DIC;7 however, the efficacy of rTM for the treatment of SOS devoid of DIC remains to be elucidated.
We report here a case of a 53-year-old woman with SOS in the absence of DIC following allo-HSCT, successfully treated with rTM.
In September 2010, the patient with AML underwent allo-HSCT from a one-locus HLA-A mismatched unrelated donor immediately after second hematological remission following high-dose re-induction chemotherapy. The conditioning regimen used was i.v. infusion of BU (16 mg/kg) and CY (120 mg/kg). GVHD prophylaxis included tacrolimus and MTX. The patient started to receive ursodeoxycholic acid before transplantation (day −14) and continuous infusion of 5000 units/day of low molecular weight heparin (LMWH) from post-transplant day 1 (PTD 1) for SOS prophylaxis. On PTD 10, the patient developed jaundice (bilirubin 2.3 mg/dL) without increasing aspartate transaminase, alanine transaminase or alkaline phosphatase levels and peaked on PTD 15 (bilirubin 10.0 mg/dL) (Figure 1). During that time, there was significant weight gain, reaching a increase 7.6% from baseline on PTD 15, and she complained of tenderness in the right upper quadrant, leading us to suspect SOS. On PTD 13, the coagulation profile revealed a platelet count of 3.6 × 1010/L, PT 84%, aPTT 43.0 seconds (normal range 26.1–35.6), fibrinogen 656 mg/dL (normal range 150–450), FDP 6.4 ug/mL (< 5.0), D-dimer 1.5 μg/mL. At that time, the patient's condition did not satisfy the Japanese Ministry of Health and Welfare (JMHW) criteria for DIC.8 From PTD 12, the patient received continuous infusion of prostaglandin E1 (500 μg/day) and antithrombin concentrate (1500 units/day) in addition to continuous infusion of LMWH, but which failed to decrease bilirubin level or ameliorate the right upper quadrant pain, although the liver remained non-palpable clinically and there was no ascites on abdominal ultrasound. On the basis of the modified Seattle Criteria,9 a definitive diagnosis of SOS was carried out. Because a recent report indicates a favorable outcome of rTM in the management of SOS,7 use of rTM (380 U/kg/day for 14 days) was initiated on PTD 15 with informed consent. Total bilirubin level decreased to 6.0 mg/dL the day after starting rTM and had normalized by PTD 30. Her weight began to decrease rapidly and had normalized by PTD 28 (Figure 1). Granulocyte engraftment occurred on PTD 21; however, the increased level of bilirubin and body weight gain occurred from PTD 10. There was no urticaria, non-cardiac pulmonary edema or renal dysfunction. Accordingly, it is improbable that the patient had engraftment syndrome, which may have clinical features similar to SOS.
Thrombomodulin has a central role in the regulation of intravascular coagulation. rTM is composed of the active, extracellular domain of thrombomodulin, and inactivates intravascular coagulation by binding to thrombin. In addition, the thrombin–rTM complex activates protein C, which in the presence of protein S inactivates factors VIIIa and Va, thereby inhibiting further thrombin formation.6 DF increases plasma tissue plasminogen activator activity and decreases plasminogen activator inhibitor-1 activity. In addition, DF mobilizes tissue factor pathway inhibitor, which inhibits Factor Xa and thrombin, from endothelial cells. Similarly, rTM decreases levels of plasminogen activator inhibitor-1 (ref. 6) and inhibits VIIIa, Va and thrombin, thus may function in a similar manner as DF in the treatment of SOS.
In the aforementioned case, the patient did not meet criteria for DIC throughout her entire clinical course and showed rapid increase of bilirubin, which is a characteristic feature of SOS. In contrast, two previously reported cases of SOS successfully treated with rTM were complicated by DIC without hyperbilirubinemia.7 Thus, this is the first SOS case with hyperbilirubinemia successfully treated with rTM in the absence of DIC. In conclusion, our case indicates that rTM may be a potent new treatment strategy or alternative to DF for patients with SOS.
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The authors declare no conflict of interest.
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Nakamura, D., Yoshimitsu, M., Kawada, H. et al. Recombinant human soluble thrombomodulin for the treatment of hepatic sinusoidal obstructive syndrome post allogeneic hematopoietic SCT. Bone Marrow Transplant 47, 463–464 (2012) doi:10.1038/bmt.2011.103
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