Medical Care
The primary goal of treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is to normalize the flow in the sinusoidal vessels and veins by controlling the vasculitis and fibrin deposition.
Defibrotide
Defibrotide (Defitelio) is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties. [32, 33, 34] The US Food and Drug Administration (FDA) has approved defibrotide for the treatment of adult and pediatric patients who have hepatic VOD/SOS with kidney or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).
FDA approval was based on findings of a phase III trial (n = 102) in which survival and complete response rates were significantly higher in patients receiving defibrotide, compared with 32 historical controls. Survival at Day+100 post-HSCT was 38.2% in the defibrotide group and 25% in the control group (estimated difference of 230%; 95.1% confidence interval [CI] 5.2%-40.8%; P= 0.0109). Observed Day+100 complete response (CR) rates were 25.5% for defibrotide and 12.5% in the controls (19% difference using similar methodology; 95.1% CI 3.5-34.6; P= 0.0160). [35]
Other agents
Historically, low-dose tissue plasminogen activator (t-PA) was used to increase fibrin degradation in VOD/SOS. However, it achieved responses in less than one third of patients. [36, 37] In a report of 12 children with VOD/SOS who were treated with t-PA, only one of the five patients with with severe veno-occlusive disease and multiorgan failure survived. [38] t-PA treatment may result in fatal hemorrhage, and its use is not recommended in the presence of multiorgan failure. [37, 39]
Additional approaches have included antithrombin III (ATIII) replacement and ATIII administered in combination with heparin/t-PA. Although the combination of ATIII and heparin/t-PA were the most commonly administered treatment in the United States, no large-scale studies of these treatment approaches and no head-to-head comparison studies were conducted. Therefore, definitive treatment recommendations are not available. Various other anticoagulant strategies have been tried, with mixed results.
Supportive care
Supportive care for patients with VOD/SOS focuses on kidney and pulmonary function, which are commonly compromised. General recommendations are as follows:
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Minimize exposure to agents that may be hepatotoxic (eg, cyclosporine) or nephrotoxic (eg, aminoglycosides).
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Avoid the use of low-dose dopamine because experimental evidence suggests that it may divert splanchnic blood flow.
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Judiciously manage the sodium and water balance.
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Diuretic medication is indicated when symptoms associated with excess extravascular volume are observed.
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Opiate analgesia should be copiously administered, if indicated (ie, right upper quadrant pain).
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When ascites causes respiratory compromise, paracentesis is appropriate. However, it should be performed with caution, and careful attention should be paid to coagulation parameters.
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Kidney and pulmonary failure are managed with hemodialysis, ultrafiltration, and mechanical ventilation, as indicated.
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Patients with severe VOD/SOS and multiorgan failure are at increased risk for infection. Thus, even though engraftment may have occurred, vigilance regarding infection is appropriate, and recognition that febrile responses may be blunted is important.
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Total parenteral nutrition, almost always used during HSCT, is a potential source of additional liver damage and should be modified according to the guidelines in consideration of the hepatic injury.
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Coagulopathy should be corrected.
Consultations
Patients usually require consultation with several specialists because they frequently develop other end-organ dysfunction and multiorgan failure. The following specialists may be consulted:
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Hematologist
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Pulmonologist
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Critical care specialist
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Nephrologist
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Neurologist
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Infectious disease specialist
Prevention
Preventive measures against VOD/SOS have been studied, mostly in small nonrandomized and retrospective studies. Effective prophylaxis with low-dose or low-molecular weight heparin has frequently been reported. [40, 41, 42, 43] However, a large prospective cohort study performed by the European Group for Blood and Marrow Transplantation (EBMT) demonstrated no benefit. [7]
Deferasirox has been studied as a preventive agent in a single series comprising children with high-risk solid tumors who underwent high-dose chemotherapy and autologous HDCT. In the treatment group, deferasirox (25 mg/kg/day) was initiated when serum ferritin levels increased to more than 1000 ng/mL during induction chemotherapy. No VOD/SOS occurred in the 40 HSCTs in the treatment group, compared with 7 cases in the 39 earlier HSCTs used as historical controls. However, kidney dysfunction, including Fanconi syndrome, was a frequently observed adverse effect in patients receiving deferasirox. [44]
Defibrotide may have prophylactic as well as therapeutic benefit. Following the earlier experience at their center with HSCT for children with malignant infantile osteopetrosis, in which 7 of 11 patients developed VOD/SOS (three cases severe, one fatal), Corbacioglu et al initiated defibrotide prophylaxis and reported only one case of moderate VOD in nine subsequent patients. [4] In a prospective international multicenter trial in children at high risk for developing VOD/SOS, 22 (12%) of 180 patients randomly allocated to the defibrotide group had VOD/SOS by 30 days after HSCT, compared with 35 (20%) of 176 controls, suggesting a possible benefit. [45]
Jiang et al reported that prophylaxis with pravastatin and ursodiol (ursodeoxycholic acid) was effective in reducing the incidence of VOD/SOS. In patients at high risk for VOD/SOS, the cumulative incidence of the disorder was 2.2% in patients who received pravastatin/ursodiol prophylaxis, compared with 18.1% and 16.8% in two similar cohorts without prophylaxis (P < 0.0001). [44] However, an earlier prospective randomized trial by Park et al found no difference in efficacy between heparin plus ursodiol and heparin alone for the prevention of hepatic VOD/SOS. [46]
A Cochrane Review concluded that there is low or very low quality evidence that ursodiol may reduce the incidence of hepatic VOD/SOS, all-cause mortality, and mortality due to VOD/SOS in HSCT recipients. The authors also found insufficient evidence to support the use of heparin, low molecular weight heparin, defibrotide, glutamine, fresh frozen plasma, antithrombin III, or prostaglandin E1. [47]
Tables
Criteria |
Mild |
Moderate |
Severe |
Very Severe (Multi-Organ Dysfunction/Failure) |
Time since first clinical manifestations |
> 7 days |
5-7 days |
≤4 days |
Any time |
Bilirubin |
2 to < 3 mg/dL 34 to < 51 μmol/L |
3 to < 5 mg/dL 51 to < 85 μmol/L |
5 to < 8 mg/dL 85 to < 136 μmol/L or doubling of bilirubin within 48 hr |
≥8 mg/dL ≥136 μmol/L |
Transaminases |
≤2 x normal |
> 2 to 5 x normal |
> 5 to 8 x normal |
> 8 x normal |
Weight increase |
< 5% |
5% to < 10% |
5% to < 10% |
≥10% |
Kidney function |
< 1.2 x baseline |
1.2 to < 1.5 x baseline at transplant |
1.5 to < 2 x baseline at transplant |
≥2 x baseline at transplant or other signs of multi-organ dysfunction/failure |
