Recombinant human soluble thrombomodulin for the treatment of hepatic sinusoidal obstructive syndrome post allogeneic hematopoietic SCT

Article metrics

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.

Figure 1
figure1

Clinical course of SOS. rTM, recombinant human soluble thrombomodulin.

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.

References

  1. 1

    Bearman SI . The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85: 3005–3020.

  2. 2

    Bearman SI, Lee JL, Baron AE, McDonald GB . Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 1997; 89: 1501–1506.

  3. 3

    Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T . Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy. Haematologica 2006; 91: 795–800.

  4. 4

    Bearman SI, Shen DD, Hinds MS, Hill HA, McDonald GB . A phase I/II study of prostaglandin E1 for the prevention of hepatic venocclusive disease after bone marrow transplantation. Br J Haematol 1993; 84: 724–730.

  5. 5

    Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337–4343.

  6. 6

    Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5: 31–41.

  7. 7

    Ikezoe T, Togitani K, Komatsu N, Isaka M, Yokoyama A . Successful treatment of sinusoidal obstructive syndrome after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Bone Marrow Transplant 2010; 45: 783–785.

  8. 8

    Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H . Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol 1983; 49: 265–275.

  9. 9

    McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

Download references

Author information

Correspondence to N Arima.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading