Laboratory Studies
One of the major challenges in the diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is the lack of sensitive laboratory and imaging studies that can accurately assist in diagnosis, which is very important with regard to the prompt start of appropriate treatment. Early diagnosis and subsequent timely treatment significantly affect the risks of morbidity and mortality. However, current diagnostic tools lack the necessary sensitivity.
The laboratory workup of a patient with possible VOD/SOS has several objectives. The first goal, of course, is to confirm the diagnosis, the second goal is to look for a detectable discrete cause, and the third goal is to establish the function of the liver and other end organs.
Indicated laboratory studies include the following:
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A complete blood cell count and differential – To assess engraftment total lymphocyte count, as well as transfusion-refractory thrombocytopenia
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Total and direct bilirubin levels – Hyperbilirubinemia assists in the identification of cholestatic disease.
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Liver function studies, including alkaline phosphatase and γ-glutamyltransferase ( GGT) – These can help rule out other causes of hepatic inflammation.
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Kidney function studies – Blood urea nitrogen (BUN), serum creatinine, and albumin and total protein levels may reveal other end-organ dysfunction and may delineate the severity of the capillary leak syndrome (CLS) in the patient.
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C-reactive protein level – Helps assess the infectious risk and rule out sepsis. However, despite the vasculitic basis for this disease, obtaining an erythrocyte sedimentation rate (ESR) is not particularly helpful because the ESR may be nonspecifically elevated in any patient who has undergone transplantation.
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Coagulation studies – To rule out disseminated intravascular coagulation (DIC) and to assess specific VOD/SOS–related coagulation factors
Coagulation studies should include the following:
Patients with hepatic VOD/SOS often have abnormally elevated PAI-1 levels and decreased ATIII levels. [13] PAI-1 may also be an essential factor in the pathogenesis of the disorder. [29]
A decrease in protein C and S levels after transplantation may be a harbinger of early end-organ damage, particularly in patients with preexisting conditions (eg, low anticoagulant protein levels prior to transplantation). Weekly measurements of these anticoagulants during the first 2 weeks after transplantation may allow for early detection of VOD/SOS.
Laboratory results comprise most of the criteria in a severity grading system for suspected VOD/SOS in adults that was created by the European Society for Blood and Marrow Transplantation. [20] See the table below.
Table. European Society for Blood and Marrow Transplantation Severity Grading for Suspected VOD/SOS in Adults (Open Table in a new window)
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 |
Multiorgan failure in VOD/SOS is characterized by one or more of the following [30] :
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Oxygen requirement (oxygen saturation of < 90% on room air, ventilator dependence, or both)
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Kidney dysfunction (doubling of baseline creatinine levels, dialysis dependence, or both)
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Encephalopathy
Jiang et al reported that a biomarker-based VOD/SOS risk calculator, the Endothelial Activation and Stress Index (EASIX), performed well in comparison with the Center for International Blood and Marrow Transplant Research clinical risk calculator (see Presentation/History and Physical Examination). EASIX is calculated by multiplying lactate dehydrogenase (in U/L) by serum creatinine (in mg/dL) and dividing the product by the platelet count (109 cells/L). EASIX assessed on the day of allogeneic HSCT was significantly associated with VOD/SOS incidence (P< 0.0001), overall survival, and non-relapse mortality. The median EASIX was significantly higher in patients who subsequently developed VOD/SOS than in those who did not (8.64 versus 2.28, respectively, in the validation cohort). [31]
Imaging Studies
Imaging studies should be used to assess the following:
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Size of liver and spleen
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Free abdominal fluid
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Thickening of the gallbladder wall
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Diameter of the portal vein and liver veins
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Portal venous flow
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Hepatic venous flow
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Loss of the respiration-dependent flow modulation
The imaging study of choice is abdominal Doppler ultrasonography, which reveals direction of flow in the veins. Reversal of flow in the portal and hepatic veins is the diagnostic ultrasonography finding. Other ultrasonography findings include ascites and hepatomegaly. In addition, other hepatic pathology may be detected (eg, gallbladder thickening, gallstones, lymphadenopathy).
Although ultrasonography is a powerful tool for confirming diagnosis, typical findings often do not manifest until late in the course or are not always apparent. Thus, ultrasonography should not be relied on to rule out the diagnosis of veno-occlusive disease in the face of other evidence that would support it.
Histologic Findings
See the list below:
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Histologic findings include hepatic engorgement and zone 3 inflammation. Occasionally, zone 2 may also be involved.
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Injury to endothelial cells and the terminal hepatic venule is common.
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For more information, see Pathophysiology.
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 |
