AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Along with graft versus host disease (GVHD) and cytomegalovirus (CMV) infection, veno-occlusive disease (VOD) is one of the most frequently encountered serious complications after stem cell transplantation. The reported overall incidence rate of VOD ranges from 5% to more than 60% in children who have undergone stem cell transplantation, and similar rates have been reported in adults.^{1, 2, 3, 4, 5, 6, 7} The causes of VOD are still unclear, but a combination of pretransplant risk factors and transplant-related conditions are believed to trigger a primarily hepatic sinusoidal injury. This can quickly extend to a hepatocytic and panvasculitic disease, which is followed by multiorgan failure that is associated with substantial mortality. The initiating pathophysiological events have prompted the suggestion that this form of liver disease be renamed sinusoidal obstruction syndrome (SOS).  

The risk of VOD in the pediatric population is not limited to a well-defined group of high-risk patients who have undergone transplantation. The disease frequently occurs outside this group. For example, patients treated for solid tumors (eg, neuroblastomas) are at a high risk for developing VOD, especially after treatment with a combination of busulfan and melphalan.

Pathophysiology

The early pathophysiology of VOD remains obscure. The primary injury in VOD is most likely a lesion of the sinusoidal endothelial cells of hepatic venules. The first recognizable histologic changes are characterized by widening of the subendothelial zone, red cell extravasation, fibrin deposition, and expression of factor VIII/von Willebrand factor within venule walls, followed by necrosis of the perivenular hepatocytes. Late histological findings include deposits of extracellular matrix, an increased number of stellate cells, and subsequent sinusoidal fibrosis. This process eventually leads to complete venular obliteration, extensive hepatocellular necrosis, and widespread fibrous tissue replacement of normal liver.

The detritus, which consist of endothelial cells, Kupffer cells, and stellate cells, embolize and obstruct downstream sinusoidal flow, characteristically affecting the centrilobular zone 3. Zone 3 is nearest to the central hepatic venules, according to the distance from the afferent arterial supply. Therefore, it receives the least oxygen supply and is given the term centrilobular.

Occluded hepatic venules were not found during autopsy in 25% of patients with even severe VOD. Because involvement of the hepatic veins does not appear to be essential for the development of clinical signs of VOD, a proposal has been made to change the name of the disease to sinusoidal obstruction syndrome.^{8, 9}

Frequency

United States

Overall, VOD is a rare but significant complication of allogeneic bone marrow transplantation (BMT). Along with GVHD and CMV infection, VOD is one of the most common serious complications after stem cell transplantation and is associated with high posttransplantation morbidity and mortality rates. Precise estimates of frequency are difficult because the incidence of VOD varies depending on the preparative regimen, the type of transplantation, and the underlying disease. Therefore, the reported overall incidence of VOD ranges from 5% to more than 60% in children, and similar rates have been reported in adults.^{1, 2, 3, 4, 5, 6, 7}

International

The worldwide incidence rate of VOD appears to be similar to that in the United States.

Mortality/Morbidity

Severe disease is associated with significant morbidity and a mortality rate of more than 90%.¹⁰ In children, the mortality rate in patients with VOD 100 days posttransplantation is 38.5%, as opposed to 9% in patients who do not have VOD.¹

Early identification of high-risk patients with severe disease is of the utmost importance because of the high mortality rates associated with severe VOD.

The severity of VOD is divided into the following 3 categories:

• Mild disease
  
  
  • No adverse effects from VOD
  • No treatment necessary
  • Self-limiting
• Moderate disease
  
  
  • No adverse effects from VOD
  • Requires treatment (pain medication, diuretics, other supportive care)
• Severe disease
  
  
  • Unresolved signs and symptoms of VOD 100 days after stem cell transplantation
  • Death due to complications directly attributable to VOD

Severe VOD was recently more precisely defined based on the presence of multiorgan failure in addition to VOD. Multiorgan failure is characterized by oxygen requirement (with an oxygen saturation of <90% on room air, ventilator dependence, or both), renal dysfunction (defined as doubling of baseline creatinine levels, dialysis dependence, or both), and/or encephalopathy.¹¹

Race

VOD has no racial predilection.

Sex

VOD occurs equally in males and females.

Age

VOD occurs in both children and adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

In children, the following criteria are associated with a significantly increased risk for developing veno-occlusive disease (VOD) and should be identified prior to BMT: 

• Preexisting liver disease (eg, liver fibrosis, hepatitis, abdominal irradiation, pretransplantation transaminitis of unclear origin)

• Second myeloablative hematopoietic stem cell transplantation (HSCT) 
• History of treatment with gemtuzumab ozogamicin (Mylotarg, Wyeth)  
• Allogeneic HSCT for leukemia beyond the second relapse  
• Conditioning with busulfan, melphalan, or both  
• Osteopetrosis (OP)  
• Macrophage-activating syndromes (eg, hemophagocytic lymphohistiocytosis, Griscelli syndrome)

Physical

The clinical symptoms of VOD include weight gain, an increase in abdominal circumference, hepatomegaly, right upper quadrant pain, ascites, and elevated total and direct bilirubin levels. The onset of transfusion-refractory thrombocytopenia with no detectable cause is frequently noted as an early and suggestive sign.

The onset of VOD usually occurs prior to 20 days after HSCT, with a peak 12 days posttransplantation. However, the onset of VOD has been reported even later. In 2 recent pediatric studies, VOD occurred more than 20 days after HSCT (ranging from 21-509 d after HSCT) in 55% of patients and 29% of patients, respectively.^{12, 13}

Typical early symptoms include weight gain and tender hepatomegaly, followed by edema and ascites, which are reflected in the clinical criteria developed by the Seattle and Baltimore groups.^{10, 6} These criteria predict VOD with an accuracy of more than 90% but have a relatively low sensitivity of 56%.¹⁴

• According to the modified Seattle criteria, 2 or more of the following must be present prior to 20 days after stem cell transplantation for a diagnosis of VOD:
  
  
  
  • Bilirubin level of more than 2 mg/dL (34 µmol/L)
    
    
    
  • Hepatomegaly and upper right quadrant pain of liver origin 
    
    
  • Ascites and/or unexplained weight gain of more than 2% above the reference range
    
    
• According to the Baltimore criteria, hyperbilirubinemia (≥2 mg/dL) and 2 or more of the following must be present prior to 21 days after stem cell transplantation:
  
  
  
  • Hepatomegaly (usually painful)
    
    
    
  • Ascites
    
    
  • Weight gain of more than 5% above the reference range

Causes

The principal cause of most cases of VOD is the toxicity of the preparative regimen for BMT. Several recent clinical publications confirmed that administration of busulfan-containing preparative regimens is a significant risk factor for VOD.^{10, 1, 15} Whether the observed toxicity of busulfan is due to a hepatic first-pass effect following oral administration of busulfan is controversial.^{16, 17, 18} However, a recent study comparing orally administered busulfan with intravenously administered busulfan showed decreased incidence of VOD associated with intravenously administered busulfan.¹⁹

In patients who have not undergone transplantation, VOD has occurred after radiation to the liver and after therapy with actinomycin D, which is a known hepatotoxic agent.

VOD in the liver has occurred following liver transplantation.

The end result of inflammation due to the preparative regimen or other causes of vasculitis is a narrowed lumen of the hepatic sinusoids, the venules, and, eventually, the veins.

• The first result is bidirectional flow, followed by reversal of flow in the veins observed using Doppler ultrasonography.
• Obstruction of the hepatic and portal outflow causes engorgement of the liver and centrilobular necrosis in centrilobular zone 3. This also results in increased levels of bilirubin, γ-glutamyltransferase (GGT), and alkaline phosphatase.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The most prevalent differential diagnoses include sepsis-related cholestasis (cholangitis lenta), drug toxicity (ie, cyclosporine, fluconazole, itraconazole, trimethoprim), and hepatic GVHD. Other differential diagnoses include fungal infiltration; viral hepatitis, including CMV infection; total parenteral nutrition–related cholestasis; persistent tumor infiltration into the liver; and neutropenic colitis. Differentiating between capillary leak syndrome (CLS) and veno-occlusive disease (VOD) is often difficult but is very important because CLS promptly responds to treatment with steroids.

Differential diagnosis of VOD include the following:

• Sepsis-related cholestasis (cholangitis lenta) 
   
• Drug-induced cholestatic and hepatotoxicity (ie, cyclosporine, fluconazole, itraconazole, trimethoprim, methotrexate)  
• Fungal infiltration
  
• Viral hepatitis, including CMV infection
  
• Chemical hepatitis
  
• Total parenteral nutrition–related cholestasis
  
• Persistent tumor infiltration into the liver
  
• CLS
  
• Neutropenic colitis
• Pancreatic ascites
  
• Chylous ascites
  
• Right heart failure
  
• Constrictive pericarditis
  
• Multiorgan system failure
• Hepatic outlet obstruction

• Jaundice and hepatic injury with transaminitis are common and unspecific changes that occur after HSCT. Most of these changes are not associated with hepatomegaly and fluid retention. 
• GVHD cannot be present without T cells and can be excluded based on cell engraftment. 
• Transaminases levels are not elevated early in the course of VOD because it is primarily a sinusoidal disease, rather than a hepatocytic disease, and the elevated levels reflect disease progress. 
• Early in the disease progression, transaminitis is associated with primary hepatocytic toxicity (eg, drug toxicity, viral disease). 
• Unlike CLS, VOD is not initially associated with generalized edema and pericardial or pleural effusion.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• One of the major challenges in the diagnosis of veno-occlusive disease (VOD) 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 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.
• Relevant laboratory findings include hyperbilirubinemia, parameters of cholestasis (alkaline phosphatase and GGT), thrombocytopenia, and abnormal coagulation parameters (especially elevated plasminogen activator inhibitor-1 [PAI-1] levels), as well as decreased antithrombin III (ATIII), protein C, and protein S levels.
  
  
  • Documentation of increased total and direct bilirubin levels assists in the identification of cholestatic disease. 
  • GGT, alkaline phosphatase, and transaminase levels should be measured to rule out other causes of hepatic inflammation.
  • A CBC count and differential should be obtained to assess engraftment total lymphocyte count, as well as transfusion-refractory thrombocytopenia.
  • Coagulation parameters should include prothrombin and activated partial thromboplastin times, fibrinogen levels, fibrin split product levels, D-dimer levels, ATIII levels, protein C levels, and protein S levels to rule out disseminated intravascular coagulation (DIC) and to assess specific VOD-related coagulation factors. 
  • PAI-1 levels are often abnormally elevated, and ATIII levels are decreased in patients with hepatic VOD; thus, measurement of these factors may be helpful as sensitive markers of VOD.¹⁵ Recent reports suggest that PAI-1 may also be an essential factor in the pathogenesis of VOD.²⁰
• Parameters of infection and/or inflammation (eg, C-reactive protein levels) should be obtained to help assess the infectious risk and rule out sepsis.
• Despite the vasculitic basis for this disease, obtaining sedimentation rates is not particularly helpful because they may be nonspecifically elevated in any patient who has undergone transplantation.
• A decrease in the anticoagulant protein 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.
• Baseline chemistries, including BUN, creatinine, and serum albumin and total protein levels, may reveal other end-organ dysfunction and may delineate the severity of the CLS in the patient.

Imaging Studies

• The diagnostic imaging study of choice is abdominal Doppler ultrasonography. Ultrasonography of the liver reveals engorgement, and the Doppler reveals direction of flow in the veins.
• Other hepatic pathology may be detected (eg, gallbladder thickening, gallstones, lymphadenopathy).
• Ultrasonography is a powerful tool for confirming diagnosis, but typical findings often manifest late in the course or are not always apparent. Thus, ultrasonography should not be relied on to rule out the diagnosis of VOD in the face of other evidence that would support it.
• The diagnostic ultrasonography finding is a reversal of flow in the portal and hepatic veins. Other findings include ascites and hepatomegaly.
• Imaging studies should be used to assess the following:
  
  
  • Size of liver and spleen
  • Free abdominal fluid
  • Thickening of the gallbladder wall
  • Diameter of the portal vein and liver veins
  • Portal venous flow
  • Hepatic venous flow
  • Loss of the respiration dependent flow modulation

Histologic Findings

Histologic findings include hepatic engorgement and zone 3 inflammation. Occasionally, zone 2 may also be involved. Injury to endothelial cells and the terminal hepatic venule is common. For more information, see Pathophysiology.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No specific treatment modality for veno-occlusive disease (VOD) that could serve as a reference or criterion standard has been established. Studies on the use of many drugs to treat VOD are limited to case reports and small series.

The primary goal of treatment is to normalize the flow in the sinusoidal vessels and veins by controlling the vasculitis and fibrin deposition. 

• Low-dose tissue plasminogen activator (t-PA) has been used to increase fibrin degradation. However, it achieved responses in less than one third of patients^{21, 22} A recent pediatric series reported on 12 children with VOD, including 5 with multiorgan failure who were treated with t-PA.²³ The survival rate in the 5 patients with severe VOD treated with t-PA was only 20%. t-PA may be associated with fatal hemorrhage, and its use is not recommended in the presence of multiorgan failure. ^{22, 24} 
  
   
• Additional approaches have included ATIII replacement and ATIII administered in combination with heparin/t-PA. Although the combination of ATIII and heparin/t-PA has become the most commonly administered treatment in the United States, as of August 2000, no large-scale studies of these treatment approaches and no head-to-head comparison studies have been conducted. Therefore, definitive treatment recommendations are not available. 
  
  
• Various other anticoagulant strategies have been tried, with mixed results.
  
  
• One of the most promising experimental drugs currently available for the treatment of VOD is defibrotide. It is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties. 
  
  
  
  • In preclinical studies, defibrotide exerted a protective effect on injured microvasculature.^{25, 26, 27, 28, 29}
    
     
  • Encouraging responses were observed in early retrospective clinical trials of defibrotide, mostly in adult patients who fulfilled criteria for severe VOD based on the presence of multiorgan failure. The initial study by Richardson et al showed a resolution of severe VOD in 8 of 19 patients, with 6 of 8 surviving past day 100. ¹¹
    
    
  • In a similar high-risk population, a complete response was shown in 36% of study participants after a median duration of treatment with defibrotide for 18 days³⁰
    
    
    
  • A single-arm cohort study and a prospective randomized trial that mostly consisted of adult patients with severe VOD showed efficacy of defibrotide in the treatment of patients with severe VOD.³¹³²
    
    
  • In a recent pediatric study, preemptive treatment with defibrotide within 24 hours of clinical diagnosis was associated with a significantly superior outcome¹³

Supportive care

The availability of defibrotide is limited to clinical studies and compassionate use because it is currently not licensed by the US Food and Drug Administration. Supportive care currently remains the mainstay of treatment because of the paucity of established and effective treatment modalities. This care includes support of renal and pulmonary function, which are commonly compromised in patients with VOD.

General recommendations are as follows:

• Minimize exposure to potential hepatotoxic (ie, cyclosporine) and nephrotoxic agents (ie, aminoglycosides).
  
  
• Avoid the use of low-dose dopamine because experimental evidence suggests that it may divert splanchnic blood flow.
  
  
• Judiciously manage the sodium and water balance.
  
  
• Diuretic medication is indicated when symptoms associated with excess extravascular volume are observed.
  
  
• Opiate analgesia should be copiously administered, if indicated (ie, right upper quadrant pain).
  
  
• When ascites cause respiratory compromise, paracentesis is appropriate. However, it should be performed with caution, and careful attention should be paid to coagulation parameters.
  
  
• Renal and pulmonary failure are managed with hemodialysis, ultrafiltration, and mechanical ventilation, as indicated.
  
  
• Patients with severe VOD 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.
  
  
• 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.
  
  
• 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:

Pulmonologist

Critical care specialist

Nephrologist

Neurologist

Infectious disease specialist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In the United States, defibrotide is currently an investigational drug associated with the most promising results for treating veno-occlusive disease (VOD). It elicits antithrombotic and fibrinolytic properties and may increase prostaglandin E2 and prostacyclin levels, alter platelet activity, and increase tissue plasminogen activator function while decreasing tissue plasminogen activator inhibitor activity. See Medical Care.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

The lack of sensitive and specific diagnostic tools warrants prophylactic intervention. Several preventive measures have been studied, mostly in small nonrandomized and retrospective studies. Effective prophylaxis with low-dose or low-molecular weight heparin has frequently been reported.^{33, 34, 35, 36} However, a large prospective cohort study performed by the European Group for Blood and Marrow Transplantation (EBMT) demonstrated no benefit.⁷

The efficacy of prostaglandin E1 (PGE1) was investigated, but a prospective trial showed no convincing evidence beyond confirming the known considerable toxicities. ^{37, 38, 36, 33} Ursodeoxycholic acid was of no benefit in a prospective randomized trial.³⁹ ATIII was also studied only in small series or in combination with DF.^{40, 41} Additionally, none of these drugs demonstrated superior therapeutic efficacy.

Defibrotide is an effective therapeutic modality that is becoming available. Defibrotide was assessed in a recent retrospective study of 45 children with veno-occlusive disease (VOD¹³ The study showed that, in the subgroup of 22 patients with severe disease, younger age and early start of defibrotide administration was associated with a significantly superior outcome. In a subgroup of patients who underwent transplantation for malignant infantile osteopetrosis, the incidence rate of VOD exceeded 60%. Because of this high incidence of VOD, defibrotide prophylaxis was initiated in 9 consecutive patients who underwent transplantation⁴ In this group, only one patient (11.1%) was diagnosed with moderate VOD.

A prospective randomized international multicenter trial that intends to conclude if prophylactic defibrotide is superior to therapeutic defibrotide in children at high risk for developing VOD during stem cell transplantation is currently being conducted in Europe (NIH Trial Number: NCT00272948).

Transfer

• A transplantation-trained physician with experience with this disease should administer primary care for patients at a center with an active hemostasis laboratory.

Deterrence/Prevention

• Post-BMT VOD may be reduced with pretransplantation screening of both patients and donors.

Complications

• Commonly observed complications include the following:
  
  

  • Hepatic failure: Some degree of hepatic dysfunction is observed in all cases of post-BMT hepatic VOD; however, in rare severe cases, overt liver failure may be observed.
    

  • Renal failure: This may be secondary to hepatorenal syndrome, as well as direct injury by the vasculopathy. In patients who have undergone transplantation, numerous frequently used nephrotoxic drugs (eg, vancomycin, amphotericin B, cyclosporine) can result in preexisting renal dysfunction and loss of renal function reserve. Separating the effects of the drugs from the effects of VOD may be difficult.

• Pulmonary failure
• Neurologic compromise
• Increased risk of infectious complications due to peritoneal drainage and transfer of an immunodeficient patient to intensive care with no laminar air flow units
• Severe consumptive coagulopathy with an increased risk for thrombosis and bleeding

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant. Jul 2003;32(1):79-87. [Medline].
2. Reiss U, Cowan M, McMillan A, Horn B. Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol. Dec 2002;24(9):746-50. [Medline].
3. 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. Oct 2005;90(10):1396-404. [Medline].
4. Corbacioglu S, Honig M, Lahr G, et al. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transplant. Oct 2006;38(8):547-53. [Medline].
5. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. Jun 2003;17(2):63-70. [Medline].
6. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. Dec 1987;44(6):778-83. [Medline].
7. Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood. Nov 15 1998;92(10):3599-604. [Medline].
8. Shulman HM, Gown AM, Nugent DJ. Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol. Jun 1987;127(3):549-58. [Medline].
9. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. Feb 2002;22(1):27-42. [Medline].
10. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. Feb 15 1993;118(4):255-67. [Medline].
11. Richardson PG, Elias AD, Krishnan A, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. Aug 1 1998;92(3):737-44. [Medline].
12. Hasegawa S, Horibe K, Kawabe T, et al. Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplant. Dec 1998;22(12):1191-7. [Medline].
13. Corbacioglu S, Greil J, Peters C, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant. Jan 2004;33(2):189-95. [Medline].
14. Carreras E, Granena A, Navasa M, et al. On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease. Ann Hematol. Feb 1993;66(2):77-80. [Medline].
15. Pihusch M, Wegner H, Goehring P, et al. Diagnosis of hepatic veno-occlusive disease by plasminogen activator inhibitor-1 plasma antigen levels: a prospective analysis in 350 allogeneic hematopoietic stem cell recipients. Transplantation. Nov 27 2005;80(10):1376-82. [Medline].
16. Yeager AM, Wagner JE Jr, Graham ML, et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood. Nov 1 1992;80(9):2425-8. [Medline].
17. Dix SP, Wingard JR, Mullins RE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. Feb 1996;17(2):225-30. [Medline].
18. Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. Apr 15 1997;89(8):3055-60. [Medline].
19. Lee JH, Choi SJ, Lee JH. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. May 2005;84(5):321-30. [Medline].
20. Smith LH, Dixon JD, Stringham JR, et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood. Jan 1 2006;107(1):132-4. [Medline].
21. Kulkarni S, Rodriguez M, Lafuente A, et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant. Apr 1999;23(8):803-7. [Medline].
22. Bearman SI, Lee JL, Baron AE, McDonald GB. Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood. Mar 1 1997;89(5):1501-6. [Medline].
23. Bajwa RP, Cant AJ, Abinun M, et al. Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment. Bone Marrow Transplant. Apr 2003;31(7):591-7. [Medline].
24. Baglin TP, Harper P, Marcus RE. Veno-occlusive disease of the liver complicating ABMT successfully treated with recombinant tissue plasminogen activator (rt-PA). Bone Marrow Transplant. Jun 1990;5(6):439-41. [Medline].
25. Falanga A, Marchetti M, Vignoli A, et al. Defibrotide (DF) modulates tissue factor expression by microvascular endothelial cells. Blood. 1999;94:146a.
26. Falanga A, Marchetti M, Vignoli A, et al. Impact of defibrotide on the fibrinolytic and procoagulant properties of endothelial cells from macro- and micro-vessles. Blood. 2000;96:53a.
27. Falanga A, Vignoli A, Marchetti M, Barbui T. Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells. Leukemia. Aug 2003;17(8):1636-42. [Medline].
28. Eissner G, Multhoff G, Gerbitz A, et al. Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood. Jul 1 2002;100(1):334-40. [Medline].
29. Palmer KJ, Goa KL. Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs. Feb 1993;45(2):259-94. [Medline].
30. Chopra R, Eaton JD, Grassi A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol. Dec 2000;111(4):1122-9. [Medline].
31. Richardson PG, Soiffer R, Antin JH, et al. Defibrotide (DF) appears effective and safe in a Phase II, randomized study of patients with severe veno-occlusive disease (VOD) and multisystem organ failure (MOF) post stem cell transplantation (SCT). Blood. 2002;100:112a.
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Article Last Updated: Jul 16, 2007