Veno-occlusive Hepatic Disease (Sinusoidal Obstruction Syndrome)

Updated: Apr 24, 2021

Author: James L Harper, MD; Chief Editor: Jennifer Reikes Willert, MD

Overview

Practice Essentials

Along with graft versus host disease (GVHD) and cytomegalovirus (CMV) infection, hepatic veno-occlusive disease (VOD) is one of the most frequently encountered serious complications after hematopoietic stem cell transplantation (HSCT). The reported overall incidence rate of VOD ranges from 5% to more than 60% in children who have undergone HSCT, 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, followed by multiorgan failure that is associated with substantial mortality. The initiating pathophysiological events have prompted the use of the term sinusoidal obstruction syndrome (SOS), which is often used together with the older descriptor (ie, VOD/SOS).

The risk of VOD/SOS 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, Wilms tumor, neuroblastomas, and rhabdomyosarcomas[8, 9] ) are at risk for it. VOD/SOS has also been described in a patient with Burkitt lymphoma.[10]

Early identification of high-risk patients with severe disease is of the utmost importance because of the high mortality rates associated with severe cases. The onset of VOD/SOS usually occurs within the first 20 days after HSCT, with a peak 12 days posttransplantation. However, late-onset cases occur. Clinical and laboratory manifestations of VOD/SOS include the following:

Weight gain
Increase in abdominal circumference
Hepatomegaly
Right upper quadrant pain
Ascites
Hyperbilirubinemia
Thrombocytopenia

Imaging studies can be valuable for assessing the liver. Reversal of flow in the portal and hepatic veins is the diagnostic finding on Doppler ultrasonography. See Presentation, DDx/Diagnostic Considerations, and Workup.

Defibrotide is approved for the treatment of adult and pediatric patients who have hepatic VOD/SOS with kidney or pulmonary dysfunction. Supportive care is also important. See Treatment and Medication.

Pathophysiology

The pathophysiology of sinusoidal obstructive syndrome remains obscure. The primary injury in veno-occlusive disease 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 veno-occlusive disease. Because involvement of the hepatic veins does not appear to be essential for the development of clinical signs of veno-occlusive disease, the term sinusoidal obstruction syndrome is increasingly used.[11, 12]

Numerous studies have demonstrated associations with various hemostatic derangements, such as antithrombin deficiency, protein C deficiency, ADAMTS 13 enzyme deficiency, and elevations of plasminogen activator inhibitor; however, no conclusive evidence of a thrombotic origin to the liver damage has been demonstrated.[13, 14]

Epidemiology

Frequency

Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is a rare but significant complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is associated with high posttransplantation morbidity and mortality rates. Precise estimates of frequency are difficult because the incidence varies depending on the preparative regimen, the type of transplantation, and the underlying disease. The reported overall incidence of VOD/SOS ranges from 5% to more than 60% in children, and similar rates have been reported in adults.[1, 2, 3, 4, 5, 6, 7]

A retrospective study by the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party suggested that VOD/SOS may be underdiagnosed as a major cause of multi-organ failure in patients receiving HSCT for acute leukemia. Review of EBMT registry data from 202 allogeneic HSCT patients reported to have died of multi-organ failure identified 70 patients (35%) for whom VOD/SOS could be considered a trigger for the multi-organ failure and of those, 48 (69%) were previously undiagnosed as having VOD/SOS. Most of the missed diagnoses were in late cases that developed beyond 21 days post-HSCT.[15]

VOD/SOS has no racial predilection, occurs equally in males and females, and occurs in both children and adults.

Mortality/Morbidity

Severe disease is associated with significant morbidity and a mortality rate of more than 90%.[16] In children, the mortality rate in patients with veno-occlusive disease 100 days posttransplantation is 38.5%, as opposed to 9% in patients who do not have veno-occlusive disease.[1]

Presentation

History and Physical Examination

Clinical risk factors for the development of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) include the following[17] :

Younger age
Positive hepatitis B/C serology
Lower Karnofsky performance scale score
Use of sirolimus, disease
Myeloablative conditioning regimens, especially busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring

In addition, disease and disease status at transplant influence risk (eg, risk is low with acute lymphoblastic leukemia in first complete remission, high with refractory or relapsed non-Hodgkin lymphoma).[17] A Center for International Blood and Marrow Transplant Research (CIBMTR) risk calculator, which uses the above clinical risk factors, is available online.

Initial signs and symptoms of VOD/SOS include the following:

Weight gain
Increase in abdominal circumference
Hepatomegaly
Right upper quadrant pain
Ascites

A bleeding tendency may be noted. Transfusion-refractory thrombocytopenia with no detectable cause is as an early and suggestive sign of VOD/SOS.

The onset of VOD/SOS usually occurs within the first 20 days after HSCT, with a peak 12 days posttransplantation. However, late-onset cases have been reported. In 2 pediatric studies, VOD/SOS occurred more than 20 days after HSCT (ranging from 21-509 d after HSCT) in 55% of patients in one study and 29% of patients in another study.[18, 19]

Clinical manifestations comprise part of the diagnostic criteria for VOD/SOS. Hyperbilirubinemia and imaging studies are also used for diagnosis. See DDx/Diagnostic Considerations and Workup.

Causes

Risk factors for veno-occlusive disease include those related to the transplant, those related to the patient and disease, and those related to the liver.

Transplant-related factors include the following:

Unrelated or HLA-mismatched donor
Non–T-cell-depleted transplant
Myeloablative-conditioning regimen
Oral or high-dose busulfan-based regimen
High-dose total-body irradiation (TBI)–based regimen
Second HSCT

Patient- and disease-related factors include the following:

Older age
Karnofsky score below 90%
Metabolic syndrome
Female receiving norethindrone
Advanced disease (beyond second complete remission [CR] or relapse/refractory)
Thalassemia
Genetic factors (GSTM1 polymorphism, C282Y allele, MTHFR 677CC/1298CC haplotype)

Factors related to the liver include the following[20] :

Transaminase levels > 2.5 upper limit of normal (ULN)
Serum bilirubin > 1.5 ULN
Cirrhosis
Active viral hepatitis
Abdominal or hepatic irradiation
Previous use of gemtuzumab ozogamicin (withdrawn from US market in June, 2010) or inotuzumab ozogamicin
Hepatotoxic drugs
Iron overload

The principal cause of most cases of veno-occlusive disease is the toxicity of the preparative regimen for HSCT. Several clinical publications have confirmed that administration of busulfan-containing preparative regimens is a significant risk factor for veno-occlusive disease.[16, 1, 13] Whether the observed toxicity of busulfan is due to a hepatic first-pass effect following oral administration of busulfan is controversial.[21, 22, 23] However, a study comparing orally administered busulfan with intravenously administered busulfan showed a lower incidence of veno-occlusive disease associated with intravenously administered busulfan.[24]

In a study by Nagler et al of 257 adult acute myeloid leukemia patients whose conditioning regimen for HSCT included intravenous busulfan, the factors associated with the occurrence of SOS were human leukocyte antigen (HLA)-mismatched donor HSCT and transplantation during non-remission. The authors concluded that the outcomes of HSCT using intravenous busulfan are encouraging since SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant.[25]

Single-nucleotide polymorphisms of the donor may also be a factor in the onset of VOD/SOS in children receiving allogeneic HSCT.[26]

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

DDx

Diagnostic Considerations

Two conflicting definitions of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), the Seattle criteria and the Baltimore criteria, have been in use since the 1980s. These criteria predict VOD/SOS with an accuracy of more than 90% but have a relatively low sensitivity of 56%.[27]

According to the modified Seattle criteria, 2 or more of the following must be present prior to 20 days after hematopoietic stem cell transplantation (HSCT) for a diagnosis of VOD/SOS:

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 HSCT:

Hepatomegaly (usually painful)
Ascites
Weight gain of more than 5% above the reference range

More recently, the European Society for Blood and Marrow Transplantation (EBMT) has proposed new diagnostic criteria for VOD/SOS, with separate criteria for pediatric and adult patients.[20, 28] For hepatic VOD/SOS in children, the EBMT includes no limitation for time of onset after HSCT.[28] Diagnosis requires the presence of two or more of the following:

Unexplained consumptive and transfusion-refractory thrombocytopenia
Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain > 5% above baseline value
Hepatomegaly above baseline value
Ascites above baseline value
Rising bilirubin from a baseline value on 3 consecutive days or bilirubin increase of ≥2 mg/dL within 72 h

The EBMT advises that hepatomegaly and ascites values are best confirmed by imaging. To determine baseline imaging values, the EBMT recommends performing ultrasonography, computed tomography, or magnetic resonance imaging immediately before HSCT.

For VOD/SOS in adult patients, the EBMT proposed separate criteria for classical and late-onset cases. For classical VOD/SOS in the first 21 days after HSCT, the criteria are bilirubin ≥2 mg/dL and two of the following:

Painful hepatomegaly
Weight gain > 5%
Ascites

For late-onset VOD/SOS in adults developing beyond 21 days after HSCT, the EBMT diagnostic criteria are as follows[20] :

Presence of the classical VOD/SOS criteria or
Histologically proven SOS/VOD or
Two or more of the following: Bilirubin ≥2 mg/dL (34 μmol/L), painful hepatomegaly, weight gain > 5%, ascites and
Hemodynamic and/or ultrasonographic evidence of VOD/SOS

Differential Diagnoses

Antithrombin III Deficiency
Budd-Chiari Syndrome
Cholestasis
Gastrointestinal Bleeding: Surgical Perspective
Heart Failure, Congestive
Hematopoietic Stem Cell Transplantation (HSCT)
Hospital-Acquired Infections
Hypoprothrombinemia
Long-Term Effects of Bone Marrow Transplantation
Oncologic Emergencies
Pediatric Aspergillosis
Pediatric Biliary Atresia
Pediatric Cholecystitis
Pediatric Cytomegalovirus Infection
Pediatric Enteroviral Infections
Pediatric Gallstones (Cholelithiasis)
Pediatric Gastroenteritis
Pediatric Graft Versus Host Disease
Pediatric Hepatitis A
Pediatric Hepatitis B
Pediatric Hepatitis C
Pediatric Hepatorenal Syndrome
Pediatric Mononucleosis and Epstein-Barr Virus Infection
Pediatric Sepsis
Pediatric Surgery for Ascites
Pediatric Thromboembolism
Vasculitis and Thrombophlebitis

Workup

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:

A complete blood cell count and differential – To assess engraftment total lymphocyte count, as well as transfusion-refractory thrombocytopenia
Total and direct bilirubin levels – Hyperbilirubinemia assists in the identification of cholestatic disease.
Liver function studies, including alkaline phosphatase and γ-glutamyltransferase ( GGT) – These can help rule out other causes of hepatic inflammation.
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.
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.
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] :

Oxygen requirement (oxygen saturation of < 90% on room air, ventilator dependence, or both)
Kidney dysfunction (doubling of baseline creatinine levels, dialysis dependence, or both)
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:

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

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:

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

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:

Minimize exposure to agents that may be hepatotoxic (eg, cyclosporine) or nephrotoxic (eg, 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 causes respiratory compromise, paracentesis is appropriate. However, it should be performed with caution, and careful attention should be paid to coagulation parameters.
Kidney and pulmonary failure are managed with hemodialysis, ultrafiltration, and mechanical ventilation, as indicated.
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.
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:

Hematologist
Pulmonologist
Critical care specialist
Nephrologist
Neurologist
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]

Medication

Medication Summary

In the United States, defibrotide is the only FDA-approved drug showing significant results for treating veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) compared with historical controls. The mechanism of action has not been fully elucidated, but defibrotide is thought to enhance the enzymatic activity of plasmin to hydrolyze fibrin clots. 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.

Antifibrinolytic/Antithrombotic Agent

Class Summary

Defibrotide is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties.

Defibrotide (Defitelio)

The mechanism of action has not been fully elucidated. It enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide increased tissue plasminogen activator (t-PA) and thrombomodulin expression and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis. It protects ECs from damage caused by chemotherapy, TNF-alpha, serum starvation, and perfusion.

It is indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT).

Follow-up

Complications

Commonly observed complications include the following:

Hepatic failure: Some degree of hepatic dysfunction is observed in all cases of post-HSCT hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS); however, in rare severe cases, overt liver failure may be observed.
Kidney 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/SOS 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

Author

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Selim Corbacioglu, MD Professor of Pediatrics, Chair of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital Regensburg, University of Regensburg, Germany

Selim Corbacioglu, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, European Hematology Association, European Society for Blood and Marrow Transplantation

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, Children's Oncology Group, American Society of Clinical Oncology, International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Chief Editor

Jennifer Reikes Willert, MD Associate Clinical Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Section of Stem Cell Transplantation, Stanford University Medical Center, Lucile Packard Children's Hospital

Jennifer Reikes Willert, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group

Disclosure: Nothing to disclose.

Additional Contributors

Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

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