DIAGNOSTIC CRITERIA FOR VOD/SOS

VOD/SOS diagnostic criteria and considerations

Historically, the Baltimore and modified Seattle criteria have been used for diagnosis of VOD/SOS1-3

There are limitations to these criteria1,4,5

  • Criteria do not consider that signs and symptoms of VOD/SOS can occur after the first 21 days post HSCT
  • Criteria do not consider VOD/SOS that presents in the absence of specified signs and symptoms; eg, VOD/SOS without hyperbilirubinemia is not considered in the Baltimore criteria
  • Criteria do not capture recent clinical descriptions of disease
  • Criteria do not include newer imaging capabilities, which may be more sensitive to specific indicators of VOD/SOS

Contemporary criteria detect the confluence of signs and symptoms of VOD/SOS early and accurately4-7

Adult EBMT criteria
Pediatric EBMT criteria
Cairo/Cooke criteria
Summary

EBMT diagnostic criteria for VOD/SOS in adults5

Probable

Clinical

Proven

Two of the following criteria must be present:

  • Bilirubin ≥2 mg/dL
  • Painful hepatomegaly
  • Weight gain >5%
  • Ascites
  • Ultrasound and/or elastography suggestive of VOD/SOS

Bilirubin ≥2 mg/dL and 2 of the following criteria must be present:

  • Painful hepatomegaly
  • Weight gain >5%
  • Ascites

Histologically proven VOD/SOS or hemodynamically proven (HVPG ≥10 mmHg)

No limitation for time of VOD/SOS onset

In the first 21 days after HSCT: classical VOD/SOS

>21 days after HSCT: late onset VOD/SOS

For any patient, these symptoms/signs should not be attributable to others causes.

Contemporary criteria base a diagnosis of VOD/SOS on identifying 2 or more cardinal features4,5

Because presentation of VOD/SOS differs among patients, watch for changes in these values from baseline4,5:

Ascites
Painful hepatomegaly
Bilirubin ≥2 mg/dL
Weight gain >5%
Ultrasound and/or elastography suggestive of VOD/SOS

Watch for transfusion refractory thrombocytopenia as another feature of VOD/SOS.5

Serial ultrasound can help identify VOD/SOS early8

Liver stiffness appears earlier than clinical and biochemical signs8

EBMT adult criteria categorize VOD/SOS as “probable” when 2 or more of the above cardinal features are evident.4,5

Classifying VOD/SOS as probable resulted in diagnosing 5 days earlier9

Immediate treatment after a probable diagnosis may help overcome the poor prognosis of VOD/SOS.9

EBMT diagnostic criteria for VOD/SOS in children, with implementation guidance6,7

THE EMBT CRITERIA FOR CHILDREN DO NOT INCLUDE A LIMITATION FOR TIME OF VOD/SOS ONSET
The presence of 2 or more of the following is required6,a:
Implementation guidance from Mahadeo et al:
  • Unexplained consumptive and transfusion-refractory thrombocytopeniab
  • Defined as a CCI of <5000-7500 following ≥2 sequential ABO-compatible fresh platelet transfusions7
  • Otherwise unexplained weight gain on 3 consecutive days, despite the use of diuretics, or weight gain >5% above baseline value
  • Hepatomegaly above baseline value (best if confirmed by imaging)c
  • Defined as an absolute increase of ≥1 cm in liver length at the midclavicular line; if a baseline measurement is not available, can be defined as >2 SDs above normal for age7
  • Ascites above baseline value (best if confirmed by imaging)c
  • Mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all 3 regions with >1 cm fluid in at least 2 regions). When feasible, baseline ultrasound should be used to identify increased ascites7
  • Rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours
  • Liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of VOD/SOS in children, adolescents, and young adults7
  • Use of a structured radiologic reporting template is recommended when there is clinical concern for VOD/SOS7
THE EMBT CRITERIA FOR CHILDREN DO NOT INCLUDE A LIMITATION FOR TIME OF VOD/SOS ONSET

The presence of 2 or more of the following is required6,a:

  • Unexplained consumptive and transfusion-refractory thrombocytopeniab
Implementation guidance from Mahadeo et al:
  • Defined as a CCI of <5000-7500 following ≥2 sequential ABO-compatible fresh platelet transfusions7
  • Otherwise unexplained weight gain on 3 consecutive days, despite the use of diuretics, or weight gain >5% above baseline value
  • Hepatomegaly above baseline value (best if confirmed by imaging)c
Implementation guidance from Mahadeo et al:
  • Defined as an absolute increase of ≥1 cm in liver length at the midclavicular line; if a baseline measurement is not available, can be defined as >2 SDs above normal for age7
  • Ascites above baseline value (best if confirmed by imaging)c
Implementation guidance from Mahadeo et al:
  • Mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all 3 regions with >1 cm fluid in at least 2 regions). When feasible, baseline ultrasound should be used to identify increased ascites7
  • Rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours
Additional implementation guidance from Mahadeo et al:
  • Liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of VOD/SOS in children, adolescents, and young adults7
  • Use of a structured radiologic reporting template is recommended when there is clinical concern for VOD/SOS7

These proposed criteria have not been prospectively validated in clinical trials6,7

aWith the exclusion of other potential differential diagnoses.6

b≥1 weight-adjusted platelet substitution/day to maintain institutional transfusion guidelines.6

cSuggested: imaging (US, CT, or MRI) immediately before HSCT to determine baseline value for both hepatomegaly and ascites.6

Cairo/Cooke revised diagnostic criteria for VOD/SOS in children and adults4

ANY 2 OF THE FOLLOWING AFTER HSCTd
OR
ANY 1 OF THE FOLLOWING AFTER HSCTd
  • Elevated bilirubin (≥2 mg/dL) or greater than upper institutional limitse
  • Unexpected weight gain (≥5% compared with baseline weight pre HSCT)
  • Excessive platelet transfusions consistent with refractory thrombocytopenia post HSCT
  • Hepatomegaly for age or increased size over pre HSCT
  • Right upper quadrant pain
  • Ascites confirmed by physical exam and/or imaging studies
  • Reversal of portal venous flow (hepatofugal flow) by Doppler ultrasound
  • Hepatic biopsy consistent with VOD/SOS
  • Unexplained elevated portal venous wedge pressure

    Though it is not recommended, a liver biopsy or direct portal wedge pressure measurements can be used when making a diagnosis of VOD/SOS, if necessary4

ANY 2 OF THE FOLLOWING AFTER HSCTd

  • Elevated bilirubin (≥2 mg/dL) or greater than upper institutional limitse
  • Unexpected weight gain (≥5% compared to baseline weight pre HSCT)
  • Excessive platelet transfusions consistent with refractory thrombocytopenia post HSCT
  • Hepatomegaly for age or increased size over pre HSCT
  • Right upper quadrant pain
  • Ascites confirmed by physical exam and/or imaging studies
  • Reversal of portal venous flow (hepatofugal flow) by Doppler ultrasound
OR

ANY 1 OF THE FOLLOWING AFTER HSCTd

  • Hepatic biopsy consistent with VOD/SOS
  • Unexplained elevated portal venous wedge pressure

    Though it is not recommended, a liver biopsy or direct portal wedge pressure measurements can be used when making a diagnosis of VOD/SOS, if necessary4

These proposed criteria have not been prospectively validated in clinical trials4

dProbably or definitely secondary to VOD/SOS and not other etiologies.4

eIn patients with an already elevated bilirubin prior to HSCT conditioning, this criterion should not be used in the diagnostic criteria.4

More recent criteria detect the confluence of signs and symptoms of VOD/SOS early and accurately

EBMT PEDIATRIC/AYA
(EST. 2018)6

CAIRO/COOKE4

EBMT ADULT
(UPDATED 2023)5

No time constraint to diagnose VOD/SOS

Allows for cases of anicteric VOD/SOS
(bilirubin <2 mg/dL)

Includes refractoriness to excessive platelet transfusions

Includes abdominal ultrasound (hepatomegaly and/or ascites)

Includes Doppler ultrasound imaging (reversal of portal venous flow)

Hemodynamic stability/hepatic wedge pressure

f

Biopsy

f

These proposed criteria have not been prospectively validated in clinical trials4-6

fWhile not recommended, if conducted and diagnostic, this allows for a VOD/SOS diagnosis independent of any other findings.4

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Signs of renal or pulmonary dysfunction

IMPORTANT SAFETY INFORMATION AND INDICATION

Contraindications

Defitelio is contraindicated in the following conditions:

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Warnings and Precautions

Hemorrhage

Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.

Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Please see full Prescribing Information.

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Warnings and Precautions

Hemorrhage

Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.

Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Please see full Prescribing Information.

AYA=adolescent and young adult; CCI=corrected count increment; CT=computed tomography; EBMT=European Society for Blood and Marrow Transplantation; HSCT=hematopoietic stem-cell transplantation; HPVG=hepatic venous pressure gradient; MOA=mechanism of action; MRI=magnetic resonance imaging; SD=standard deviation; SOS=sinusoidal obstruction syndrome; US=ultrasonography; VOD=veno-occlusive disease.

References: 1. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, et al, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176-195. 2. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44(6):778-783. 3. McDonald GB, Sharma P, Matthews DE, et al. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4(1):116-122. 4. Cairo MS, Cooke KR, Lazarus HM, et al. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation. Br J Haematol. 2020;190(6):822-836. 5. Mohty M, Malard F, Abecassis M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016;51(7):906-912. 6. Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2018;53(2):138-145. 7. Mahadeo KM, Bajwa R, Abdel-Azim H, et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network; Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement. Lancet Haematol. 2020;7(1):e61-e72. 8. Colecchia A, Ravaioli F, Sessa M, et al. Liver stiffness measurement allows early diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome in adult patients who undergo hematopoietic stem cell transplantation: results from a monocentric prospective study. Biol Blood Marrow Transplant. 2019;25(5):995-1003. 9. Ichikawa H, Yakushijin K, Kurata K, et al. Utility of the refined EBMT diagnostic and severity criteria 2023 for sinusoidal obstruction syndrome/veno-occlusive disease. Bone Marrow Transplant. 2024;59(4):518-525.