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Rtpa) for the Treatment of Hepatic Veno-Occlusive Disease (VOD

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Rtpa) for the Treatment of Hepatic Veno-Occlusive Disease (VOD Bone Marrow Transplantation, (1999) 23, 803–807 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD) S Kulkarni1, M Rodriguez2, A Lafuente2, P Mateos2, J Mehta1, S Singhal1, R Saso3, D Tait4, JG Treleaven3 and RL Powles1 Departments of 1Medical Oncology, 3Haematology and 4Radiotherapy, Royal Marsden NHS Trust, Sutton, Surrey, UK; and 2Haematology Department, Hospital La Paz, Madrid, Spain Summary: clinical syndrome characterized by hyperbilirubinemia, hepatomegaly and fluid retention,2,3 and results from dam- Seventeen patients who developed hepatic veno-occlus- age to structures in zone 3 of the liver acinus.4 In patients ive disease (VOD) following hematopoietic stem cell who have undergone hematopoietic stem cell transplan- transplantation were treated with recombinant tissue tation, chemoradiotherapy-induced endothelial cell damage plasminogen activator (rtPA) with or without heparin. is likely to be responsible for the pathogenesis of vessel rtPA was started a median of 13 days post transplant obstruction.5 (range 4–35). All patients received rtPA at a dose of 10 Treatment of established VOD has primarily been sup- mg/day as a starting dose, and 12 patients also received portive and any specific measures have resulted in little heparin (1500 U bolus; then 100 U/kg/day as a continu- impact on outcome. Based on the available evidence for ous i.v. infusion). The median number of days of rtPA involvement of hemostatic mechanisms and cytokines in therapy was 2.5 (1–12). The median total serum biliru- the pathogenesis of VOD,6–8 anti-thrombotic and anti-cyto- bin level was 116 mmol/l (range 63–194) at the begin- kine agents have been assessed for their role in treatment. ning of treatment. Six patients showed a response to Recombinant tissue plasminogen activator (rtPA) is a rtPA treatment (29%). It was observed that by day 2 thrombolytic agent which has a high specificity for fibrin- of rtPA therapy, bilirubin levels in responders showed bound plasminogen, and significant clot specificity.9 It has a downwards trend as compared to those in non- been used for the treatment of severe hepatic VOD with responders. In all except one patient this response was variable success.10–12 Here, we report our experience of observed after two doses of rtPA. Seven out of the 11 rtPA used to treat hepatic VOD. non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of Materials and methods onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of Patients commencing treatment. No patient experienced severe The prospectively maintained database at the Royal hemorrhagic complications during therapy. Four Marsden Hospital identified 17 patients with hepatic VOD responders survived for more than 100 days compared treated with rtPA, between May 1995 and May 1998. Nine to none of the non-responders. Probability of survival fulfilled the Seattle criteria for VOD1,2 and eight more also was 33% at day 100. It is difficult to unequivocally fulfilled the Baltimore criteria.3 Tables 1 and 2 summarize establish the role of rtPA in the treatment of VOD. The patient characteristics. Sixteen patients had received pre- importance of bilirubin levels on days 2 or 3 of therapy vious chemotherapy, four previous radiotherapy, and two in predicting outcome should be established, as should interferon. Eight patients had a previous history of hepatic the optimum dose of rtPA and optimum duration of dysfunction, and five had abnormal liver function at trans- therapy. plant. All 17 patients had normal renal function pre-trans- Keywords: hepatic veno-occlusive disease; recombinant plant. Patients with active bleeding or neurological prob- tissue plasminogen activator; hematopoietic stem cell trans- lems were not treated with rtPA in spite of having a clinical plantation diagnosis of VOD. All patients underwent baseline coagu- lation studies together with blood counts, liver and renal function tests. All parameters were monitored daily. An attempt was made to undertake liver ultrasound examin- Hepatic veno-occlusive disease (VOD) is one of the com- ations as soon as hepatic VOD was suspected. Invasive mon early complications following hematopoietic stem cell diagnostic procedures were not performed. transplantation1 with a potentially fatal outcome. It is a Conditioning regimen and GVHD prophylaxis Correspondence: Dr S Kulkarni, Dept. Medical Oncology, Royal Marsden NHS Trust, Downs Road, Sutton SM2 5PT, UK Conditioning regimens used are shown in Table 1. Total Received 20 August 1998; accepted 17 November 1998 body irradiation (TBI) was used in 11 patients, total lymph- rtPA for the treatment of hepatic VOD S Kulkarni et al 804 Table 1 Patient characteristics rtPA was started at a median of 13 days post hematopo- etic rescue (range: 4–35). The mean total dose was 25 mg Number of patients 17 (range 10–120 mg), and the median total days of adminis- Age median (range) years 36 (21–58) tration was 2.5 days (range 1–12 days). At the start of Diagnosis AML 6 thrombolytic therapy, the median total serum bilirubin was ALL 3 116 mmol/l (range 63–194), and the median serum creatin- Myeloma 3 ine was 155 mmol/l (range 59–551). Median weight gain CML 2 at the time of starting rtPA was 4.4% (range: 1.6-13%) over NHL 2 the baseline. Hodgkin’s 1 Type of transplant The INR was maintained between 1.0 and 1.4 while Matched sibling allograft 12 patients were receiving heparin. Heparin was discontinued Mismatched allograft 1 if the INR rose above this level, or if the APTT was more Matched unrelated allograft 3 than 1.5 times the upper level of the institutional normal. Autologous 1 ϫ Conditioning regimen The median platelet count at the start of therapy was 15 9 Melphalan/TBI 9 10 /l (range 3–51). BuCy2 4 Melphalan/Cyclo/TBI 1 BuCy2/TLI 1 Results VP-16/TBI 1 Melphalan 1 GVHD prophylaxis Of the 17 patients with a clinical diagnosis of hepatic VOD Cyclosporin A Methotrexate 14 who received rtPA, 12 also received heparin with the rtPA Cyclosporin A alone 2 for 10 days. All patients had jaundice, 12 had unexplained None (autograft) 1 Previous liver dysfunction 11 weight gain, 12 had hepatomegaly and eight had ascites. Median bilirubin levels (range) 39 ␮mol/l (34–80) The median total serum bilirubin level at diagnosis of Median creatinine levels (range) 78 ␮mol/l (50–198) VOD was 48 mmol/l (range 34–80). Six patients had abnor- Median platelet count (range) 21 ϫ 109/l (6–202) mal serum creatinine levels (defined as doubling of the pre- conditioning serum creatinine) at diagnosis of VOD (median 86 mmol/l; range 48–198). The median weight Table 2 Biochemical parameters at the start of rtPA treatment gain at diagnosis of VOD was 3.5% (range 0.3%-10.4%) from baseline. Parameter Median (range) Serum bilirubin 116 ␮mol/l (63–194) Efficacy of treatment Serum creatinine 155 ␮mol/l (59–551) Platelet count 15 ϫ 109/l (3–51) Four of 17 patients experienced prompt decreases in their Percent weight gain 4.4% (1.6–13%) over baseline serum bilirubin levels, and in one the bilirubin stabilized. Time to start rtPA 13 days (4–35) The mean decrease in total serum bilirubin was 36.7% (range: 16–53%), and 56.6% (range 33–67%) at 48 and 96 h after commencement of rtPA (Figure 1). After 10 days oid irradiation (TLI) and chemotherapy in one patient, and of rtPA treatment, the mean decrease in serum bilirubin five received chemotherapy only conditioning. for these five patients was 72% (range 65–80%).These five Fourteen allograft patients received a combination of patients had also received heparin from the time of starting short-course methotrexate (MTX) and cyclosporin A rtPA. One additional patient had a prompt reduction in his (CsA). Two patients received CsA alone. Eight patients weight gain and his bilirubin levels decreased over 8 days developed acute graft-versus-host disease (GVHD) and were treated with additional methylprednisolone. 250 Thrombolytic treatment 200 Thrombolytic treatment is described in Table 3. Patients either received rtPA alone or with heparin. 150 Series 1 Table 3 Thrombolytic therapy Series 2 100 Drug Dose Number of Duration Mean bilirubin patients (range) 50 rt PA 10 mg/day i.v. 17 1–12 days 0 bolus 12345678910111213141516171819 Heparin 1500 U i.v. bolus 12 10 days Day then 100 U/kg/h as CI Figure 1 Daily mean bilirubin levels of responders and non-responders. By day 2 bilirubin levels are decreasing in responders as compared to CI ϭ continuous infusion. non-responders. rtPA for the treatment of hepatic VOD S Kulkarni et al 805 and eventually normalized. Eleven of 17 patients had no Discussion response to thrombolytic therapy and experienced a pro- gressive increase in bilirubinemia. Twelve patients died The pathogenesis of VOD is complex. Several laboratory early post-transplant due to hepatic and multiorgan failure. and clinical criteria indicate that, at some stage, blood clot- The mean total serum bilirubin was 159 mmol/l (range ting and inflammation result in hepatic damage.6,13,14 150–194 mmol/l) at the start of therapy in the five patients Deficiency of protein C, factor VII and antithrombin III has who responded. The mean total serum bilirubin level was been observed in some patients with VOD7,15 but it is not 102 mmol/l (range 63–165 mmol/l) at the start of therapy clear whether these agents are involved in the pathogenesis in the non-responders.
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