2. Your Patient:
• 14 month old boy with SCID, day 19 s/p haplo-
identical matched donor peripheral stem cell
transplant, emergently transferred from
inpatient unit after developing progressively
worsening respiratory distress over a 2 day
period.
3. Your Patient:
• Upon arrival to PICU patient was placed on
BiPAP for increased work of breathing.
• PE demonstrated a tired-appearing fussy child
w/ mild scleral icterus, tachypnia with sub-
costal retractions and large distended abdomen
w/ tenderness to palpation and hepatomegaly.
4. Your Patient:
• Laboratory evaluation demonstrates AST of 324
U/L, ALT of 236 U/L, Total Bilirubin of 4.6 mg/dL,
Direct Bilirubin 3.9 mg/dL, Albumin 2.1 U/L
• X-ray of chest and abdomen demonstrated a large
right sided pleural effusion, requiring chest tube
placement which significantly improved his
respiratory distress
• US of the abdomen demonstrated hepatomegaly and
ascites
5. Differential Diagnosis
• Hyperacute graft-vs-host disease (GVHD)
• Cholestasis of sepsis
• Medication side effect
• Biliary obstruction
• Fungal abscess
• and….
Johnson and Savani 2012
6. Hepatic Veno-Occlusive Disease:
Overview
• Epidemiology
• Clinical Presentation
• Risk Factors for VOD
• Pathophysiology of VOD
• Prevention of VOD
• Treatment of VOD
• Prognosis
7. Hepatic Veno-Occlusive Disease (VOD)
AKA: Sinusoidal Obstruction Syndrome
• A well recognized complication and leading
cause of mortality in hematopoietic stem cell
transplant (HSCT) resulting from severe hepato-
cellular necrosis and hepatic vascular congestion
8. Epidemiology
• Mean incidence of VOD is 14% (0-62.3%) in
patients undergoing SCT
• Incidence of VOD is highest in children
• VOD occurs within the first 30 days after SCT
Cesaro et al, 2005 and
Coppell et al, 2010
10. Clinical Signs of VOD
• Laboratory Evidence:
▫ Elevated aminotransferases
▫ Hyperbilirubinemia (conjugated)
▫ Prolonged PT
▫ Signs of decreased synthetic function (low albumin).
11. Clinical Signs of VOD
• Criteria established for diagnosis of VOD w/o
need for liver biopsy
Coppell et al., 2010
Original Seattle Criteria Baltimore Criteria
Presence before day 30
post-SCT of 2+ of the
following:
Bilirubin ≥ 2mg/dL before
day 21 post-SCT and at least
2 of the following:
1. Bilirubin ≥ 2mg/dL 1. Hepatomegaly
2. Hepatomegaly, right
upper quadrant pain
2. Ascites
3. Ascites with or without
unexplained weight gain of
> 2% over baseline
3. Weight gain > 5% over
basline
Modified
Seattle criteria
require
presence of the
clinical
symptoms of
VOD before
day 20 post-
SCT
12. • Mild: Patients requiring no medications for
pain control or diuresis for fluid overload.
Eventually patients have resolution of all signs
and symptoms and complete normalization of
lab abnormalities.
Clinical Gradation of VOD
13. Clinical Gradation of VOD
• Moderate: Patient requiring sodium restriction
and diuresis to minimize fluid overload and/or
medication to alleviate pain. Eventually patients
have complete resolution of all signs and
symptoms of hepatic disease.
14. Clinical Gradation of VOD
• Severe: 15-27% of VOD cases
▫ Patient demonstrate adverse effects from liver
disease including severe pain, fluid overload
leading to respiratory compromise, hepato-renal
syndrome etc. In these patients all abnormal
symptoms, signs and laboratory values do not
resolve before day 1o0 post-HSCT.
15. Risk Factors for VOD
• Allogeneic SCT vs. Autologous SCT
• Conditioning chemotherapy prior to SCT
• Conditioning total body irradiation (TBI) prior
to SCT
• Use of Busulfan in conditioning regimen
• Use of HLA-mismatched donors
• Pre-existing liver disease
16. Risk Factors for VOD: Other Settings
• High dose radiation to the liver
• Radio-embolization of liver tumors and after
liver transplant
• Pyrrolizidine alkaloids from herbal sources
(bush tea)
24. Prevention of VOD
• Careful screening for pre-existing risk factors:
▫ Obesity
▫ Younger age at SCT
▫ Elevated LFTs
▫ h/o viral hepatitis
▫ h/o of previous VOD
▫ h/o of abdominal irradiation
Johnson and Savani 2012
25. • In 1992 Attal et al. demonstrated that
continuous heparin infusion from day -8 to day
+30 s/p SCT resulted in reduction of VOD from
13.7% in control group to 2.5% in the study
group
Prevention of VOD: Heparin
26. Prevention of VOD: Heparin
• Other studies supported use of heparin and
LMWH for VOD ppx, although not all outcomes
have been as robust as the initial studies
• In 2002 Park et al. demonstrated that heparin
ppx was not improved with addition of ursodiol
• No study has yet to look at ursodiol vs. ursodiol
+ heparin
Rosenthal et al., Or et al. and Imran et al.
27. Prevention of VOD: Ursodeoxycholic
Acid (UA)
• Natural component of bile (<5%)
• Hydrophilic bile acid which, by changing the
total composition of bile, reduces retained bile
acid within the hepatic biliary tree, thereby
reducing its hepato-toxicity
• Also attenuates the pro-inflammatory
environment by reducing expression of pro-
inflammatory cytokines
Johnson and Savani 2012
28. • In 2006 Tay et al. undertook a systemic review
of the literature re: UA ppx in prevention of VOD
▫ UA ppx was associated w/ reduced incidence of
VOD in patients undergoing allogeneic SCT (RR
0.34; 95% CI 0.17-0.66)
▫ UA ppx was associated w/ reduced transplant-
related mortality (death within first 100 days s/p
SCT) (RR 0.36; 95% CI 0.35-0.95)
Prevention of VOD: Ursodeoxycholic
Acid (UA)
29. • UA ppx did not change overall survival in
patients undergoing allogeneic SCT
• UA ppx is started two weeks prior to SCT and
continued through the high risk period after SCT
Prevention of VOD: Ursodeoxycholic
Acid (UA)
30. • UA ppx can sometimes be problematic in the
pediatric population, because most patients have
difficulty taking PO meds at some point post-
SCT as mucositis sets in from pre-conditioning
Prevention of VOD: Ursodeoxycholic
Acid (UA)
31. Prevention of VOD: Prostaglandin E1
• PGE1 induces vasodialtion, inhibits platelet
aggregation and activates the fibrinolytic system.
• Conflicting evidence exists for the use of PGE1,
which is also shown to be highly toxic.
• New preparations using lipid microspheres
containing PGE1 are being studied and appear to
have some efficacy for VOD ppx in pediatric
SCT.
Lee et al., 2010
32. Prevention of VOD: Defibrotide
• Defibrotide is a porcine derived mixture of single
stranded oligonucleotide swith anti-
inflammatory, pro-fibrinolytic and
anti0thrombotic actions without significant
systemic anticoagulation effects.
• Defibrotide has protective effects on activated
endothelial cells.
33. • In 2012 Corbacioglu et al. published a phase III
clinical trial examining the use of defibrotide
prophylaxis in pediatric patients at risk for VOD
• Patients were randomized to prophylaxis with
defibrotide or no VOD prophylaxis
• Patients began prophylaxis w/ their pre-
conditioning regimen and completed
prophylaxis 30 days s/p SCT
Prevention of VOD: Defibrotide
34. • All patients who developed VOD were treated
with defibrotide until complete recovery or
death
Prevention of VOD: Defibrotide
35. Prevention of VOD: Defibrotide
• Defibrotide reduced VOD rate from 20% in control
group to 12% in treatment group (p = 0.0488)
• In patients undergoing allogeneic SCT the severity
of VOD was reduced with defibrotide ppx (p =
0.0062 at 30 days and p = 0.0034 at 100 days)
• Defibrotide therapy did not improve morbidity or
mortality in patients who did develop VOD
36. Treatment of VOD
• Mild Disease: No specific treatment required
• Moderate Disease: Sodium restriction, diuresis
and pain control
• Severe Disease: Above + supportive care
managing symptoms including ascites, renal
insufficiency, cardiac failure, bleeding and confusion
37. Defibrotide in Treatment of VOD
• Initially evaluated in 1998 by Richardson et al.,
in a retrospective study of VOD patients who
received defibrotide on a compassionate use
basis.
▫ 19 patients with severe VOD identified
▫ 42% (8 patients) had complete resolution of VOD
6 patients survived longer than 100 days post-
diagnosis
No significant bleeding seen
38. • Phase III, historically-controlled clinical trial
published in 2009
▫ 102 patients with VOD (diagnosed by Baltimore
criteria) with multiple organ failure (renal/lung) by
day 28 post-SCT
Patients received 6.25mg/kg every 6h for at least 21 days
Placebo arm was composed of historic controls
▫ Complete remission (resolution of MOF and Bili <
2mg/dL) achieved in 24% of Defibrotide group vs. 9%
in historic controls
▫ 100 day mortality of 62% in Defibrotide group vs. 75%
in control group
Defibrotide in Treatment of VOD
39. • Meta-analysis by Richardson et al., (2010)
combining results of Phase II and Phase III trials
demonstrated:
▫ 133 patients treated with defibrotide
▫ 29% achieved complete remission by day 100
compared to 9% in the historic controls
▫ 100 day mortality was 60% in defibrotide group
versus 75% in the historic control group
▫ Hemorrhage incidence (61% vs. 72%) and GvHD
incidence (6% vs. 25%) were lower in the
defibrotide group compared with historic controls
Defibrotide in Treatment of VOD
40. Prognosis
• Overall VOD mortality: 6.9% of all VOD patients
• Severe Disease mortality: > 50%,
• Mortality highest in patients who develop multi-
organ failure
Lee et al., 2010
41. Summary
• VOD is a common problem post-SCT (~14%)
• Results from hepatic endothelial injury -> sinusoidal
congestion -> venular congestion -> hepato-cellular injury
• Patients present with weight gain, pain and jaundice
• Prevention w/ heparin, ursodiol, PGE1 or defibrotide can lead
to reduced risk of VOD post-SCT
• Severe disease requires aggressive multi-organ supportive
care and is associated with high mortality rates
• Defibrotide is a promising new intervention that can decrease
both the morbidity and mortality associated with severe VOD
42. References
1. Attal M, Huguet F, Rubie H, Huynh A., et al. Prevention of hepatic veno-occlusive disease after bone marrow transplantation by
continuous infusion of low-dose heparin: A prospective, randomized trial. Blood 1992 79;2834-2840
2. Cesaro S, Pillon M, Talenti E et al. A prospective survey on incidence , risk factors and therapy of hepatic veno-occlusive disease in
children after hematopoietic stem cell transplantation. Haematologica 2005 90:1396-1404
3. Coppell JA, Rachardson PG, Soiffer R, Martin PL, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence,
clinical course, and outcome. Biol Blood Marrow Transplant. 2010 16: 157-168
4. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in pediatric
hemopoietic stem0cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 379:1301-09
5. Imran H, Tleyjeh IM, Zirakzadeh A, Rodriguez V, Khan SP. Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive
disease in patients undergoing hematopoietic stem cell transplantation: A systemic review and meta-analysis. Bone Marrow
Transplant 2006 37:677-686
6. Johnson DB and Savani BN. How can we reduce hepatic veno-cclusive disease-related deaths after allogeneic stem cell transplantation?
Experimental hematology 2012 40;513-517
7. Lee SH, Yoo KH, Sung KW, Koo HH et al. Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation:
incidence, risk factors and outcome. Bone Marrow Transplantation 2010 45:1287-1293
8. Or R, Nagler A, Shpilberg O et al. Low molecular weight heparin for the prevention of veno-occlusive disease of the liver in bone
marrow transplantation patients. Transplantation 1996 61;1067-1071
9. Park SH, Lee MH, Lee H, et al. A randomized trial of heparin plus ursodiol vs. heparin alone to prevent hepatic veno-occlusive disease
after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2004 10:635-644
10. Richardson P, Tomblyn M, Kernan N, Brochstein JA, Mineishi S, Termuhlrn A et al. Defibrotide in the treatment of severe hepatic
veno-occlusive disease with multi-organ failure following stem cell transplantation:results of phase 3 study utilizing a historic control.
2009 Blood 114:abstract 654
11. Richardson PG, Steinbach G, Kernan N, Guinan EC, Chen AR, Martin PL et al. Meta-analysis of defibrotide in the treatment of severe
hepatic veno-occlusive disease with multiorgan failure with comparison to a historic control. 2010 Blood 116:abstract 3481
12. Rosenthal J, Sender L, Secola R et al. Phase II trial of heparin prophylaxis for veno-occlusive disease of the liver in bone marrow
transplantation. Bone Marrow Transplant 1996 18: 185-191
13. Rubbia-Brandt, L. Sinusoidal Obstruction Syndrome. Clin Liver Dis . 2010 14: 651-668
14. Tay J, Tinmouth A, Fergusson D, Huebsch L and Allan DS. Systemic review of controlled clinical trials on the use of ursodeoxycholic
acid for the prevention of hepatic veno-occlusive disease in hematopoietic stem cell transplantation. Biol Blood Marrow transplant.
2007 13: 206-217
Notes de l'éditeur
Both have high sensitivity for VOD, Baltimore criteria identifies more severe cases earlier
40-60% of patients develop moderate disease
Patients often require ICU level care and have multiple organ involvement
Actigalll
PGE1 studies emerging from Korea where mostly Heparin and PGE1 are used
