Bone Marrow Transplantation, (1998) 21, 947–949 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Case report Hepatic veno-occlusive disease with severe capillary leakage after peripheral stem cell transplantation: treatment with recombinant plasminogen activator and C1-esterase inhibitor concentrate ¨ ¨ ¨ R Heying, W Nurnberger, U Spiekerkotter and U Gobel ¨ Department for Pediatric Hematology and Oncology, Heinrich-Heine-University Medical Center, Dusseldorf, Germany Summary: stitial space.4 CLS is considered to be a systemic, inflam- matory reaction. An activation of the complement system Severe veno-occlusive disease (VOD), characterised by via the classical pathway has been described in CLS after elevated serum bilirubin levels, is a known complication interleukin-2 therapy as well as after BMT.5,8 in the first 3 weeks after peripheral blood stem cell Because the above mentioned treatment of VOD does transplantation (PBSCT). Severe VOD is associated not address the problem of complement activation, further with capillary leakage and multiple organ dysfunction to rt-PA, our patient received C1 esterase inhibitor (C1- and leads to high mortality. We report a 17-year-old INH-C) as the main physiological inhibitor of the classical male, who developed VOD with capillary leakage (CL) pathway of the complement system.5 after allogeneic PBSCT. The patient presented with a VOD is divided into mild, moderate and severe forms maximum serum bilirubin of 25.4 mg/dl, weight gain with respect to severity of jaundice, weight gain, edema (10% of baseline weight), generalized edema, cardio- and ascites.6 The severe form, as characterized by a vascular insufficiency, complement activation, jaundice maximum total bilirubin of 25 mg/dl, is associated with and a decreased AT and protein C functional activity. capillary leakage and a high incidence of multiple organ After VOD and CL were diagnosed the patient was failure.6 Whereas VOD in general is associated with a mor- treated with recombinant human plasminogen activator tality of 45–48%, the mortality with severe VOD is (rt-PA) and C1 esterase-inhibitor concentrate (C1-INH- reported to be as high as 98%.1,6 C). The clinical symptoms resolved and the patient’s We present a patient with severe VOD and associated status stabilized. The patient was in an adequate clinical CL after PBSCT, who showed rapid resolution of clinical state 5 months after transplantation. We noted that the symptoms after treatment with rt-PA and C1-INH concen- combined therapy with rt-PA and C1-INH-C in this trate (C1-INH-C). high-risk situation led to a resolution of VOD with CL. Keywords: veno-occlusive disease; capillary leakage; rt-PA; C1 esterase inhibitor Case report Hepatic VOD is a complication after peripheral blood stem A 17-year-old male patient with acute lymphoblastic leuke- cell transplantation which presents with different degrees of mia (pre-B-ALL) in second remission was referred to the severity. Liver damage caused by obliteration of the hepatic BMT unit of the Department of Pediatric Hematology and ¨ venules by fibrin material and sinusoidal congestion is sug- Oncology, University of Dusseldorf, for PBSCT. 1,2 gested as the pathophysiological cause. Therefore the The preparative regimen prior to PBSCT included hyper- usual therapy for severe VOD is based on the principle fractionated total body irradiation (total dose 12 Gy) com- of anticoagulation with heparin, recombinant plasminogen bined with 1 × 40 mg/kg body weight (BW) etoposide and 2,3 activator (rt-PA) and antithrombin (AT) substitution. 2 × 60 mg/kg BW cyclophosphamide. A condition of vascular hyperpermeability classified as Allogeneic-related stem cells were obtained from the systemic capillary leak syndrome (CLS) is known as asso- HLA-compatible mother. The nucleated cell dose was 1,4 ciated with or isolated from VOD. Hypovolemic shock 9.1 × 108/kg BW (CD34+ cells 6.55 × 106/kg BW). Graft- and organ dysfunction are the clinical consequences of a versus-host disease (GVHD) prophylaxis consisted of CsA fluid and protein shift from the intravascular to the inter- started 1 day before, and intravenous methotrexate (MTX) 15 mg/m2 body surface 1 day after PBSCT. The patient received 50 U/kg BW heparin by continuous Correspondence: Dr R Heying, Department for Pediatric Hematology and Oncology, Heinrich Heine University Medical Center, Moorenstra␤e5, infusion for thrombosis prophylaxis. ¨ D-40225 Dusseldorf, Germany Engraftment was documented 20 days after transplan- Received 15 August 1997; accepted 4 December 1997 tation. rt-PA and C1-INH-C treatment for VOD with CL R Heying et al 948 Clinical/laboratory findings and treatment a 120 bilirubin (mg/dl) weight % of baseline VOD was diagnosed on the basis of increasing jaundice 110 (bilirubin Ͼ2 mg/dl), hepatomegaly and weight gain of 6– 1,7 7% on day 6 after PBSCT. 100 Ascites, another criterion of VOD, was not seen. Jaun- dice continued to increase after diagnosis and the patient 90 complained of upper right abdominal pain with a liver pal- 20 pable 5 cm below the costal margin. An ultrasound investigation on day +13 confirmed an 10 increased liver size of 19 cm in the anterior axillary line, mg/dl-% of baseline weight 0 an increase of 5 cm over the baseline value. Pleural or peri- 4 6 8 10 12 14 16 18 20 22 cardial effusion and ascites were not seen. Also, flow in Days after transplant the hepatic veins was normal. b VOD became more severe with an associated CL on day AT substitution +13. The patient developed generalized edema and cardio- vascular insufficiency with a mean arterial pressure of 43– rt-PA 51 mmHg. The patient was tachycardic with a heart rate of 130–145/min. A weight gain of 8% over baseline was seen. C1-INH-C Also, bilirubin levels increased significantly after day 46 8 10 12 1416182022 +12 (Figure 1a). The value was 13.4 mg/dl on day +13 and Days after transplant reached a maximum level of 25.4 mg/dl on day +17 with c 120 a direct bilirubin ranging from 11.2 to 21.0 mg/dl. Because of the severe VOD, informed consent was taken 110 for therapy. The patient was treated with rt-PA for 4 days 100 between days +13 and +16. The starting dose was 1 × 0.4 mg/kg BW and 1 × 0.8 mg/kg BW were administrated on 90 80 the following 3 days (Figure 1b). Heparin was continued C5a [µ g/l) with 50 U/kg BW except on days +14 and +15, when the 2.5 g/l % 2.0 AT [%] patient received 100 U/kg BW heparin. µ Cardiovascular function stabilized on day +13 after the 1.5 first dose of rt-PA and 1000 ml human albumin 5%. 1.0 + 0.5 On day 14 the weight gain exceeded 10% over baseline 0.0 (no difference in total fluid intake) and did not respond to 4 6 8 10 12 14 16 18 20 22 diuretics (6.5 mg/kg × day furosemide). Days after transplant Because of complement activation, as confirmed by Figure 1 Parameters of VOD and capillary leakage. (a) Bilirubin levels increasing C5a levels from 0.94 ␮g/l on day +13 to 2.5 and body weight between days 5 and 21 after PBSCT (VOD diagnosed ␮g/l on day +14, C1-INH-C therapy started on day +14 on day +6). (b) Therapy of VOD; antithrombin (AT) was substituted con- (C1-INH levels were not measured). C1-INH-C was given tinuously, C1-INH-C and rt-PA were given as bolus injections. (c)AT × (normal range 70–120%) and C5a (normal range 0.1–0.75 ␮g/l) levels at an initial dose of 60 U/kg BW followed by 8 30 U/kg during treatment. AT and C5a values normalized after treatment with rt- BW and 3 × 15 U/kg BW C1-INH-C every 12 h until day PA and C1-INH-C. The patient’s body weight returned to baseline. +19. After two doses of C1-INH-C we observed a negative fluid balance of 530 ml over 24 h, mean blood pressures between 65 and 80 mmHg and a heart rate of 120–130/min. Discussion Although AT was substituted from day +11 to +19 with 20–30 U/kg BW, the values for AT decreased from 115% VOD is a known complication after bone marrow trans- baseline level to a minimum of 82% on day +14. The values plantation. However, the underlying pathophysiological for protein C were also low with a minimum level of 20% mechanisms are not fully understood which is why there is on day +14 (Figure 1c). no well established treatment regimen.1,3,7 Low-dose hep- With combined therapy with rt-PA and C1-INH-C the arin, prostaglandin E, pentoxifylline, AT substitution and – clinical and laboratory findings improved slowly until day probably most promisingly – rt-PA therapy have been used +18. The patient’s body weight returned to baseline on day to date.2,3 +18, and bilirubin values decreased after day +17 reaching The rationale of rt-PA therapy is based on its fibrinolytic normal values (Ͻ2 mg/dl) on day +40. The AT level activity, which is supposed to unblock the hepatic post- (106%) returned to normal on day +16, the C5a level (0.94 sinusoidal obstruction – a major finding in VOD.1,7 The role ␮g/l) on day +19 and the protein C level (76%) on day +21. of AT substitution still remains unclear, although clinical Figures 1a–c show the parameters of VOD and CL from improvement was seen and the risk of unwanted bleeding the onset of the complications to the clinical resolution.