Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation.

Veno-occlusive disease (VOD) is a major cause of toxic death after autologous bone marrow transplantation (ABMT). We studied the potential role of continuous administration of low-dose heparin for VOD prevention in 234 consecutive patients who underwent ABMT in our institution. The population consisted of 98 patients autografted before October 1984 who did not receive heparin, and a series of 136 patients autografted from October 1984 to March 1989 containing 98 patients included in a randomized trial comparing heparin administration (n = 52) vs no heparin (n = 46), and an additional group of 38 patients who received non-randomized heparin in view of high-risk criteria to develop VOD (n = 31) or other reasons unrelated to VOD (n = 7). Overall, 90 patients (38%) received heparin and 144 (62%) did not. The global incidence of VOD was 13/234 (5-5%). Heparin did not reduce the risk of VOD in all subgroups studied. In particular, in the randomized trial, the incidence of VOD was 2.2% in the group without heparin vs 7-7% in the group receiving heparin. We analyzed in depth the 13 patients who developed VOD and we compared them to a control group of 13 patients pair-matched for age, sex, diagnosis and preparative regimen, who did not develop VOD. We found that abnormal LFT before ABMT predisposed patients to VOD; refractoriness to platelet transfusion was observed in 85% of the patients in the VOD group vs 15% in the control group (p less than 0.05). VOD patients had an increased requirement for red cells and platelet transfusions, a lower recovery (R less than 25%) after the second and third platelet transfusion, and shorter intervals separating the first four platelet transfusions. Further, the platelet reconstitution after ABMT in the VOD group was slower in comparison to the control group (p less than 0.01). Again, in this pair-matched analysis continuous infusion of low-dose heparin did not prevent VOD.     

Hepatic veno-occlusive disease in a patient with lupus anticoagulant after allogeneic bone marrow transplantation

A 37-year-old man with acute myeloblastic leukemia (FAB M2) in first remission underwent a bone marrow transplant (BMT) following conditioning with high-dose cytarabine and total body irradiation. The donor was an HLA-identical brother. Graft rejection occurred and a second BMT was performed from the same donor following conditioning with cyclophosphamide. Engraftment was achieved, but the patient developed severe jaundice and died of respiratory failure on day +46 after the second BMT. Liver biopsy revealed luminal narrowing of the central veins and a diagnosis of hepatic veno-occlusive disease (VOD) was made. The coagulation studies showed a prolonged kaolin clotting time which was not corrected by 1:1 mixture with normal plasma, and the platelet neutralization test was positive. Dilute tissue thromboplastin time and dilute Russell viper venom time were also prolonged. These results fulfilled the criteria for lupus anticoagulant, which may have contributed to VOD in this patient.     

Fatal veno-occlusive disease of the liver following high dose chemotherapy,irradiation and bone marrow transplantation

In two patients fatal veno-occlusive disease of the liver developed after bone marrow transplantation for underlying malignancies. Both had received significant pretransplant chemotherapy, including cystosine arabinoside, and total body irradiation. The diagnosis of veno-occlusive disease should be considered in patients in whom hepatomegaly, ascites and deteriorating liver function tests develop after they have received cancer chemotherapy.     

Serum immunoglobulin levels following allogeneic bone marrow transplantation

Summary In order to study the posttransplant evolution of serum immunoglobulin levels, we measured serum IgG, IgA and IgM levels in 50 recipients of allogeneic bone marrow before transplantation and at different intervals thereafter (days 39, 120, 365 and 730). IgG and IgM levels were depressed for 1 year and IgA levels for 2 years posttransplant. Immunoglobulin deficiency was more severe and prolonged in patients with graft versus-host-disease. Hypogammaglobulinemia may contribute to the frequent infections observed in these patients, especially those with chronic graft-versus-host disease.     

Coronary artery disease following bone marrow transplantation

A 19-year-old woman died suddenly 30 months after allogeneic bone marrow transplantation for refractory leukemia. On postmortem examination severe coronary artery disease and acute myocardial infarction were found. The patient had previously been given chemotherapy including daunorubicin for treatment of her leukemia. She received high dose cyclophosphamide and total body irradiation (1260 cGy) for her transplant. Diffuse chronic graft-versus-host disease, mainly affecting skin, subsequently developed, and was resistant to various therapies. The possible association of coronary artery disease and allogeneic bone marrow transplantation is discussed.     

Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation

Severe veno-occlusive disease (VOD) of the liver is a leading cause of mortality after bone marrow transplantation (BMT). Vascular and parenchymal injuries account for acute portal hypertension and liver failure is frequently present. We describe the results of transjugular intrahepatic portosystemic shunt (TIPS) for the management of VOD after BMT. TIPS was performed in 10 patients with histologically proven severe VOD. Portal hypertension was controlled by TIPS in all patients (mean hepatic venous pressure gradient before, 20 +/- 11 vs 6 +/- 5 mm Hg after TIPS, P < 0.01) without technical complications. Five patients with rapidly worsening VOD died within 10 days of TIPS without any improvement. The five remaining patients with less advanced disease showed improvement in various clinical and biological parameters. Four patients subsequently died. The lone survivor continues to do well with resolution of VOD 6 months after TIPS. TIPS can be performed safely and controls portal hypertension in VOD after BMT. Arguments from the present series and from eight previously reported cases favour earlier application of TIPS to obtain improved overall survival. Bone Marrow Transplantation (2000) 25, 987-992.     

Orthotopic liver transplantation for graft-versus-host disease following bone marrow transplantation

Chronic graft-vs.-host disease occurs in 30%-50% of long-term survivors of allogeneic bone marrow grafts, and may eventuate in cirrhosis. In this study, a young woman, originally diagnosed as having acute myelogenous leukemia, underwent successful bone marrow transplantation but later developed graft-vs.-host disease-induced cirrhosis and recurrent variceal hemorrhage. She underwent successful orthotopic liver transplant. Her postoperative course was uncomplicated, with no evidence of rejection or recurrence of graft-vs.-host disease. As bone marrow transplantation is more widely used and survival improves, the number of patients with graft-vs.-host disease or venoocclusive disease resulting in cirrhosis is likely to increase. Hepatic transplantation should be considered for bone marrow transplant patients who develop end-stage liver disease.     

Plasma levels of D-dimer and circulating endothelial adhesion molecules in veno-occlusive disease of the liver following allogeneic bone marrow transplantation

Abstract: Veno-occlusive disease (VOD) of the liver is a frequent and life-threatening complication of BMT. Recently, successful treatment by t-PA has been reported but has been compromised by fatal bleeding events. Therefore, t-PA application should be restricted to patients with severe VOD. However, moderate and severe forms of VOD are difficult to distinguish in early stages. We analyzed plasma levels of cross-linked fibrin degradation products (D-dimer) and soluble endothelial adhesion molecules such as sE-selectin, sVCAM-1 and sICAM-1 in 10 consecutive patients undergoing allogeneic BMT to evaluate their use in identifying severe forms of VOD. During the observation period, 4 episodes of VOD occurred, 2 of which were fatal due to early onset of multiorgan failure. Concentrations of D-dimer generally increased after transplantation. However, there was an additional significant increase in D-dimer levels during severe VOD. Thus, D-dimer levels above 1000 μg/1 were only found in 2 cases with severe VOD and fatal outcome. When compared with bilirubin concentrations substantial increases of D-dimers appeared earlier during the course of severe VOD. In contrast, VOD episodes were not accompanied by significant increases in sE-selectin, sVCAM-1 and sICAM-1 levels. It is concluded that measurement of D-dimer concentrations may aid accuracy to the early diagnosis of severe VOD.     

Evaluation of procollagen-III peptide as a marker for veno-occlusive disease after bone marrow transplantation

 Procollagen-III peptide (PIIIP) has been suggested as a marker for hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). Using the RIA-gnost PIIIP assay, we examined frozen plasma samples from three groups of patients. The groups included (A) four patients with clinically proven VOD, (B) nine patients with remarkably uneventful post-BMT courses, and (C) patients with either early complications other than VOD or pulmonary fibrosis in their later course. In group A, PIIIP levels increased parallel to the clinical course, with maximum values of 2.7–5.5 units/ml. In group B, values did not exceed 1.4 units/ml. In group C, higher values were occasionally observed. In one patient with early relapse of a lymphoma PIIIP peaks correlated with episodes of fever and graft versus host disease (GVHD). In another patient mild VOD seems possible retrospectively. The highest levels (>15 units/ml) occurred in one patient with ileus. Several patients with interstitial pneumonia (IP), adult respiratory distress syndrome (ARDS), or lung fibrosis showed increases in PIIIP levels corresponding to the clinical course; most of these events occurred later than day 30 after BMT. One patient with severe GVHD of the liver showed a maximum of only 1.4 units/ml. PIIIP elevation correlated with clinical VOD and may help to differentiate it from hepatic GVHD. In the presence of other complications (pulmonary, gastrointestinal), some caution in interpreting the results may be advisable. Received: 21 September 1995 / Accepted: 20 March 1996     

Disseminated Fusarium infections in patients following bone marrow transplantation

Intensive immunosuppressive therapy and broad spectrum antibiotics predispose cancer patients to opportunistic fungal infections. Fusarium has rarely been reported as a pathogen in immunocompromised patients, but is almost uniformly fatal. Only six cases of disseminated Fusarium infection have been described in patients following bone marrow transplantation (BMT). We report here two additional cases. Fusarium infection initially presented with pyomyositis in one patient and with embolic skin lesions in another following T cell-depleted BMT. Both patients died with active Fusarium infection despite an extensive course of amphotericin B, rifampicin and granulocyte transfusions. From this experience and from a review of the literature, Fusarium infections appear to be increasing in prevalence as significant pathogens in immunocompromised hosts and are resistant to many conventional forms of therapy.     

Serum levels of cytokines after bone marrow transplantation: increased IL-8 levels during severe veno-occlusive disease of the liver

Abstract: We investigated the cytokine profile and peak levels of interleukin (IL) -6, IL-8, IL-10 and tumour necrosis factor (TNF) -α levels in 42 patients after allogeneic bone marrow transplantation (BMT). Eleven of them developed veno-occlusive disease (VOD) of the liver. Fourteen patients had moderate-to-severe acute graft-versus-host disease (aGvHD), 10 isolated bacteraemia and 7 had no major complication. Those who developed severe VOD (n = 6) showed a short, very high IL-8 peak (median: 6632 pg/ml, range: 5546 – 10,000 vs. 280 pg/ml, 0 – 2042 in controls, p < 0.01) 1 – 4 d after diagnosis of the liver disease. Five of these patients had high peak levels of IL-6. Five patients with mild VOD showed a lower increase in the cytokines tested. Bilirubin levels, at day of IL-8 peak, did not differ statistically between mild and severe VOD. The highest levels of IL-10 were found in those with aGvHD. IL-8 levels were also increased, but not to the same extent as in patients with severe VOD (p = 0.01 vs. VOD). In patients with bacteraemia, very high levels of IL-6 were seen. In patients without major complications, the levels of cytokines were low. In conclusion, high levels of IL-8 occurred in severe VOD of the liver, which may be of value to determine prognosis.     

Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.     

The syndrome of hepatic veno-occlusive disease after marrow transplantation

The clinical syndrome of VOD is a frequent cause of nonrelapse mortality among patients receiving high-dose cytoreductive regimens. Patients likely to develop VOD have existing liver dysfunction, evidence of infection before conditioning, tend to receive more intensive preparative regimens, and often receive marrow from alternative donors. Therapeutic drug monitoring of busulfan and pharmacokinetic dose adjustments appear to be useful in reducing the incidence of VOD in patients receiving this agent. Data are contradictory as regards whether pharmacologic prophylaxis is effective. Patients who will develop severe VOD are characterized by a rapid increase in serum bilirubin as well as weight. Supportive management of these patients should attempt to preserve respiratory as well as renal function, sometimes a very difficult task. Treatment with recombinant tissue plasminogen activator has promise. However, given its potential for toxicity, a prospective randomized trial should be performed. Hopefully, as more data regarding the molecular and cellular mechanisms of this illness are elucidated, more thoughtful prevention strategies will be developed. This will be necessary, particularly as newer, more intensive preparative regimens are being developed, as access to alternative donors increases, and as more diseases will be treated with this approach.     

TIPS for veno-occlusive disease following stem cell transplantation

Hepatic veno-occlusive disease (VOD) is a complication of allogeneic blood stem cell transplantation (SCT). Duplex ultrasound has been proposed to predict the outcome of VOD. We report here the case of a 39-year-old female patient with VOD following allogeneic SCT for AML. Repeated Doppler ultrasound examinations did not indicate a high-risk profile. However, the patient's condition deteriorated and was refractory to medical therapy. Transjugular intrahepatic portosystemic shunting (TIPS) was performed 19 days after transplantation and VOD resolved subsequently. VOD often has an unpredictable course. Transjugular intrahepatic portosystemic shunts may prove beneficial for patients with refractory disease.     

Long-term follow-up following bone marrow transplantation for Hunter disease

Bone marrow transplantation (BMT) was performed in 10 patients with Hunter disease (mucopolysaccharidosis type II, iduronate-2-sulphatase deficiency). The donor was an HLA-identical sibling in 2 cases, an HLA-nonidentical relative in 6 cases, a volunteer unrelated donor in 1 case, and details were not available in 1 case. Only three patients have survived for more than 7 years post BMT; however, this high mortality probably resulted from poor donor selection. In two, there has been a steady progression of physical disability and mental handicap. One patient has maintained normal intellectual development, with only mild physical disability. It is possible that BMT may be useful in selected patients with MPS II.     

Changes in autoimmune thyroid disease following allogeneic bone marrow transplantation

Autoimmune diseases can be transmitted and eliminated by bone marrow transplantation (BMT). There have been several cases of autoimmune thyroid disease (AITD) occurring after BMT, but AITD remission has been rarely reported. We present four cases in which the remission or transfer of AITD occurred after an allogeneic BMT. Two patients with severe aplastic anemia (SAA) showed evidence of remission of Hashimoto's thyroiditis which they had before allogeneic BMT. One patient with SAA, which developed during treatment with propylthiouracil for Graves' disease, underwent allogeneic BMT and showed evidence of Graves' disease remission following BMT. In one patient, new AITD occurred after an allogeneic BMT from an HLA-matched sibling who already had AITD. These cases support the evidence that the immune system is newly reconstituted after BMT, and severe autoimmune disease can be an indication for BMT. To fully understand the real changes in autoimmune status after BMT, long-term prospective studies are necessary.     

Hepatic veno-occlusive disease following hematopoietic stem cell transplantation

The clinical syndrome of hepatic veno-occlusive disease (VOD) is one of the most common and serious complications following hematopoietic stem cell transplantation (SCT). High-dose chemotherapy or chemoradiation therapy in the context of autologous and allogeneic SCT can profoundly injure sinusoidal endothelium and hepatocytes within zone 3 of the liver acinus, producing the clinical syndrome of hepatomegaly and/or right upper quadrant pain with jaundice and fluid retention, typically manifest as weight gain. The incidence is variable and ranges from 10 to 60%. Mild to moderate disease is characterized by eventual complete resolution. In contrast, severe disease frequently results in multiorgan failure and death. The purpose of this review is to discuss the pathophysiology and clinical features of VOD, and the current status and future directions of research for both prevention and treatment.