Successful treatment with recombinant soluble thrombomodulin of two cases of sinusoidal obstructive syndrome/hepatic veno‐occlusive disease after bone marrow transplantation
Authors: Chikako Ohwada, Masahiro Takeuchi, Takeharu Kawaguchi, Shokichi Tsukamoto, Shio Sakai, Yusuke Takeda, Daijiro Abe, Emiko Sakaida, Naomi Shimizu, Koutaro Yokote, Tohru Iseki, Chiaki Nakaseko
Journal: American Journal of Hematology (2011)

Hepatic sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is recognized as one of the most important regimen-related toxicities experienced after hematopoietic stem cell transplantation (SCT). It is a clinical syndrome characterized by painful hepatomegaly, jaundice, ascites, fluid retension, and weight gain [1]. Across 135 studies between 1979 and 2007, the overall incidence was 13.7% in patients undergoing SCT [2], and it usually occurs within the first 3 weeks after high-dose chemotherapy followed by SCT [3]. Severity ranges from mild, reversible disease to a severe syndrome associated with multiorgan failure [4]. Recombinant human soluble thrombomodulin (rTM) is an active, extracellular domain of TM. rTM inactivates coagulation by binding to thrombin and also activates protein C, consequently leading to the inhibition of thrombin formation. A phase III trial has shown that rTM significantly improved disseminated intravascular coagulopathy (DIC) associated with hematological malignancies and infections as compared to unfractionated heparin [5]. Recent studies have shown that rTM also exhibits anti-inflammatory activity by dampening proinflammatory mediators [6]. We here describe two cases of SOS/VOD successfully treated with rTM after bone marrow transplantation (BMT). Clinical courses of two cases with SOS/VOD. BW, body weight; T-Bil, total bilirubin; PT-INR, prothrombin time in international normalized ratio; FDP, fibrin degradation products; WBC, white blood cell; PLT, platelet; Hb, hemoglobin; G-CSF, granulocyte colony stimulating factor; PTF, platelet transfusion; PSL, prednisone; ATIII, antithrombin III; rTM, recombinant human soluble thrombomodulin. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The first case (Figure 1A) is a 55-year-old man who was diagnosed with acute myelogeneous leukemia (French-American-British classification, M1) in September 2008. He received two courses of induction chemotherapy before achieving first complete remission (CR). After three courses of consolidation therapy with high-dose cytarabine, he underwent BMT from Human Leukocyte Antigen (HLA)-matched unrelated donor in April 2009. The conditioning regimen consisted of 12 Gy of total body irradiation (TBI) and high dose cyclophosphamide (60 mg/kg/day for 2 days). The graft-versus-host disease (GVHD) prophylaxis included tacrolimus and short-term methotrexate (MTX). Ursodeoxycholic acid prophylaxis for SOS/VOD was administered from day −14 to day 75 after transplantation. He developed febrile neutropenia on day 6. Administration of broad-spectrum antibiotic was initiated, but his blood culture was negative. On day 13, the patient complained of pain in the right upper quadrant, accompanied by body weight gain, reaching an 11% gain compared with pretransplant baseline, total bilirubin elevation of 2.3 mg/dl, and transfusion-refractory thrombocytopenia. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase were slightly elevated within 2.5 times of normal range. According to McDonald's criteria, the patient was diagnosed as SOS/VOD. At the same time, he also developed DIC, with fibrin degradation products (FDP) elevation, prothrombin time (PT) prolongation, and antithrombin III (ATIII) decrease, which required consecutive administration of ATIII concentrate (1,500 U/day) to maintain ATIII activity at >70%, but no serious bleeding complication was observed. rTM (370 U/kg/day for 10 days) was administered from the same day. At the second day of rTM, pain in the right upper quadrant immediately disappeared and weight gain stopped, which was normalized by day 20 after transplantation. Elevated bilirubin levels and coagulation abnormalities also began to normalize after the initiation of rTM. The patient recovered from DIC on day 22. On day 15, he developed grade II acute GVHD involving the skin (stage 3), along with neutrophil recovery, which was successfully treated by prednisolone (PSL, 2 mg/kg). On day 38, the patient's bone marrow showed CR with 100% donor chimerism, and platelet recovery was complete by day 38. He developed progressive-type extensive chronic GVHD involving the skin, liver, and lungs, 4 months after BMT, which was well controlled by tacrolimus and low-dose PSL. Twenty-four months after transplant, he remains in CR with good performance status. The second case (Figure 1B) is a 27-year-old male who was diagnosed with T-lymphoblastic lymphoma in December 2009. He achieved CR with alternating regimen of hyper-CVAD (Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone) and high-dose MTX plus cytarabine regimen, and underwent BMT from one-locus HLA-mismatched related donor in May 2010. Twelve Gy of TBI and high-dose cyclophosphamide (60 mg/kg/day for 2 days) were given as a conditioning regimen. GVHD prophylaxis consisted of tacrolimus and short-term MTX. The patient received Ursodeoxycholic acid for SOS/VOD prophylaxis from day −14, but he discontinued it due to severe oral mucositis on day 10 after transplantation. He developed transfusion-refractory thrombocytopenia on day 9, and showed weight gain from day 12. His weight showed a 14% increase compared with the pretransplant baseline on day 15. Simultaneously, the total bilirubin level was elevated to 1.8 mg/dl, with massive abdominal effusion and pain in the right upper quadrant. The hepatic ultrasonography showed retrograde flow in the right hepatic vein. In addition, the patient developed DIC with elevated FDP level and PT prolongation without hemorrhagic complications. Laboratory data revealed slightly elevated levels of AST, ALT, and lactate dehydrogenase, within 2.5 times of normal range. The diagnosis of SOS/VOD was made by McDonald's criteria on day 15, and rTM (370 U/kg/day for 11 days) was administered from that day. The right upper quadrant pain improved immediately after the initiation of rTM. On day 25, the body weight normalized to the baseline level and hepatic ultrasonography showed anterograde flow in the hepatic veins. Elevated bilirubin level and coagulation abnormalities were normalized by day 28. Platelet and neutrophil recovery was complete by day 25, and on day 28 the bone marrow showed 100% donor chimerism. CT and positron emission tomography scanning at day 46 showed no evidence of residual tumor. The patient developed grade II acute GVHD involving skin (stage 1) and intestine from day 21, which was well controlled by low dose steroid administration. After 11 months post-transplant, the patient remains in CR with complete donor chimerism and good performance status. The etiology of SOS/VOD is not yet fully understood, but it is thought to involve sinusoidal endothelial cell injury due to cytotoxic chemotherapy and irradiation. Several markers of endothelial injury, such as plasminogen activator inhibitor-1, tissue plasminogen activator, and protein C have been found to be elevated in patients with SOS/VOD, along with markers that indicate activation of the coagulation system, such as thrombin–antithrombin complexes and prothrombin fragment 1+2 [3, 7]. Recently, defibrotide, a single strand polydeoxiribonucleotides, has been shown to be effective in the treatment of SOS/VOD. In a phase II trial, defibrotide showed 100-day survival rate of 35–79% [8-10]. ATIII concentrate has also been reported to be effective, but its efficacy as a single agent against SOS/VOD has not been confirmed [11]. rTM was originally developed as an anticoagulation agent, but it has been recently reported to possess anti-inflammatory potential by binding and decreasing the activity of high-mobility group-B1 protein (HMGB1) [12, 13]. HMGB1 is a nuclear architectural chromatin-binding protein released by necrotic cells and has recently identified as a mediator of endotoxin-induced lethality [14]. Its accumulation in the systemic circulation triggers activation of proiflammatory signaling pathways, such as elaboration of reactive oxygen intermediates and nuclear factor-kappa B (NF-κB) activation [6]. It has been shown that plasma HMGB1 levels are increased in patients with DIC [15]. These findings led us to hypothesize that severe damage to the sinusoidal endothelial cells in the transplant recipient might lead to increased systemic circulation of HMGB1, thereby amplifying host inflammatory response and consequently promoting SOS/VOD. rTM could play a protective role by inhibiting such amplification of the host systemic inflammatory response. Recently, published case reports have claimed that rTM is not only effective for SOS/VOD [16] but also for transplantation-associated microangiopathy (TAM) [17]. Both SOS/VOD and TAM are severe post-transplant complications due to endothelial damage induced by chemotherapy and irradiation, further supporting the hypothesis that rTM has a protective activity against endothelial damage. rTM has also been reported to neutralize lipopolysaccaride [18], a constituent of Gram-negative bacteria, that play a key role in Gram-negative bacterial sepsis. As in case 1, presented above, post-transplant SOS/VOD are usually accompanied by severe infections, so it is reasonable to expect rTM to be effective in such a situation. However, one must be aware that the anticoagulant potential of rTM might enhance the bleeding tendency in patients with severe endothelial damage, transfusion-refractory thrombocytopenia, and coagulation abnormalities, which are the manifestations usually recorded in patients with SOS/VOD [19]. Therefore, rTM should be indicated in patients who do not possess critical bleeding complications, and sufficient supportive care and close observation must be given to prevent these. On the other hand, the decision to initiate rTM should be made promptly, before organ damage becomes irreversible. Both of our patients showed rapidly developing manifestations of SOS/VOD, without any signs of bleeding complications. We consider they were the best candidates for rTM administration. Our experiences show that rTM may serve as an effective treatment option in severe post-transplantation complications induced by endothelial damage. Further prospective studies are required to determine its efficacy, safety, and optimal patient selection. Chikako Ohwada*, Masahiro Takeuchi*, Takeharu Kawaguchi* , Shokichi Tsukamoto*, Shio Sakai*, Yusuke Takeda*, Daijiro Abe*, Emiko Sakaida*, Naomi Shimizu* , Koutaro Yokote , Tohru Iseki* , Chiaki Nakaseko*, * Department of Hematology, Chiba University Hospital, Chiba, Japan, Department of Blood Transfusion, Chiba University Hospital, Chiba, Japan, Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.