Hepatic Sinusoidal Obstruction Syndrome in the Era of Defibrotide

Special Article - Hematopoietic Stem Cell Transplantation

Ann Hematol Oncol. 2017; 4(1): 1131.

Hepatic Sinusoidal Obstruction Syndrome in the Era of Defibrotide

Ozkan MC¹, Sahin F², Besisik SK³ and Saydam G²*

¹Department of Hematology, Inonu University Medical School, Turkey

²Department of Hematology, Ege University Medical School, Turkey

³Department of Hematology, Istanbul University, Turkey

*Corresponding author: Guray Saydam, Department of Hematology, Ege University Medical School, Turkey

Received: December 18, 2016; Accepted: February 06, 2017; Published: February 09, 2017


Background: Hepatic sinusoidal obstruction syndrome (SOS) termed as hepatic veno-oclusive disease previously (VOD), is a toxic injury of liver sinusoids resulting obliterative venulitis of the terminal hepatic venules. In hematopoietic stem cell transplantation (HSCT) setting, SOS appears at a rate of 10 to 60% and severe SOS with hepatic failure causes considerable mortality.

Case Report: A 40-year-old male with myelodysplastic syndrome was underwent HSCT from matched unreleated donor in active disease status. Hepatic SOS was diagnosed on 21th day of HSCT with epigastric pain and abdominal distension. The patient was successfully treated with defibrotide and steroids.

Conclusion: Defibrotide, a novel agent in SOS, has been shown to improve the clinical outcome and survival in patients with severe VOD. Avoiding from major risk factors is primary method of preventing from SOS. Patients identified as being at higher risk for SOS and the risk could not be decreased, should be considered for DF prophylaxis.

Keywords: Defibrotide; Sinusoidal obstruction syndrome; Veno-occlusive disease


Hepatic sinusoidal obstruction syndrome (SOS) is an obliterative venulitis of the terminal hepatic venules, previously termed as hepatic veno-occlusive disease (VOD). The first report as obliterative endophlebitis was attributed to syphilis, whereas many years later it was reported in Jamaican drinkers of bush tea [1,2]. Currently, SOS is encountered mainly as a result of cytoreductive therapy prior to hematopoietic stem cell transplantation (HSCT), following oxaliplatin-containing adjuvant or neoadjuvant chemotherapy for colorectal carcinoma metastatic to the liver and treated by partial hepatectomy, in patients taking pyrrolizidine alkaloidcontaining herbal remedies, and in other particular settings such as liver transplantation, high dose radiation therapy to the liver (usually exceeding 30 Gy) without cytoreductive chemotherapy, and radioembolization of liver tumors [3-8].

Hepatic SOS may occur at any age. Toxic injury to liver sinusoids causes sloughing of endothelial cells which embolise to hepatic venules and cause eventual fibrosis of the venules. This results in hepatic congestion and post sinusoidal portal hypertension [9]. The incidence of hepatic SOS ranges from 3 to 54% in the largest series which are published mostly before some prophylactic measures where the disease was documented as a potentially life-threatening complication observed after HSCT [10].

Case Presentation

A 40-year-old male with myelodysplastic syndrome (MDS) as classified refractory anemia with excess blasts type II received induction chemotherapy with standard doses of idarubicin and cytarabine, followed by consolidation treatment with high dose cytarabine. While he has proved to be not having a matched unrelated donor (MUD), intensificated chemotherapy was with autologous HSCT. The patient had a relapse after 15 months and was treated by reinduction with azacytidine of five cycles and refereed to Bone Marrow Transplant Center. He underwent HSCT from MUD in active disease status as MDS RAEB-II. The conditioning regimen was busulfan and cyclophosphamide in standard doses with defibrotide (DF) prophylaxis at a dose 25 mg/kg/day (intravenously every 6 h in a 2-h administration) and urso-deoxycolic acid. The patient experienced epigastric pain on 21th days after HSCT. On examination, he had right upper quadrant tenderness and abdominal distension. Bilirubin (direct biluribin; 2.36 mg/dl) and gamma glutamyle transferase levels were mild increased, and transaminases were elevated by less than two-fold. Abdominal ultrasound at the time revealed diffuse thickening of the gallbladder wall and sludge and minimal ascite. Hepatic and portal veins were patent on ultrasound. Leucocyte engraftment was established but he was still thrombocytopenic and needed frequent thrombocyte transfusions. Hepatic SOS was diagnosed clinically. The patient was then treated with fluid restriction and sprinolactone. The dose of defibrotide was increased to 40 mg/kg/day and methylprednisolone was started with a goal maintaining for at least 3 weeks and continue until the patient’s symptoms resolve. In 3 days all symptoms/signs were resolved.

Clinical presentation and diagnosis

Hepatic SOS’ diagnosis based mainly on symptoms. Blood test results that suggest liver dysfunction are directing. The HSCT teams in Seattle and Baltimore described two different sets of clinical criteria (Table 1) [11,12]. Both of them preclude late appearing SOS. Ultrasound findings, such as hepatomegaly, ascites, gall bladder wall thickening (>6-8 mm) are nonspecific. Doppler ultrasonography suggesting attenuated or reversed hepatic venous flow (portal vein dilatation, portal venous pulsatility, hepatofugal portal venous flow) and elevated hepatic artery resistive index (>0.8), may help in the differential diagnosis [13,14]. Occasionally, invasive tests are necessary. These tests include liver biopsy or measurement of blood pressure in the hepatic veins and portal vein (hepatic venous gradient pressure; HVGP) which is measured through the jugular vein. A HVGP =10 mmHg in a patient without previous liver disease is seen almost exclusively in SOS [15].