Background: Hepatic veno-occlusive disease (VOD) is a devastating regimen-related toxicity after hematopoietic stem cell transplantation (HSCT). There is no safe and proven therapy for established VOD, and focus has been on its prevention. Previous studies have shown that ATIII level is markedly decreased in patients with VOD. We conducted a prospective, randomized trial to compare heparin plus ATIII versus heparin alone in HSCT recipients.

Methods: A clinical diagnosis of hepatic VOD was defined as satisfying two of the following criteria: bilirubin > 2.0 mg/dl, unexplained weight gain of > 2% from baseline, and hepatomegaly. The levels of PAI-1, TFG-β and TNF-α were measured at weekly basis for correlative analysis. Patients were randomized to receive or not receive prophylactic ATIII 1000U twice daily from day 1 until day +14 post-HSCT plus heparin 5U/kg/hr from day 1 until day +21 or discharge after HSCT.

Results: Thirty patients were enrolled for the study. Fourteen patients received heparin + ATIII and 16 patients received heparin alone for VOD prophylaxis during HSCT. There were 9 AML, 6 NHL, 4 ALL, 3 CML, 2 ABL, 2 MM, 1 MDS, 1 HD, 1 AA and 1 SLL patient. Of the 30 patients enrolled, 13 patients received sibling allogeneic HSCT, 13 autologous, 3 unrelated allogeneic and 1 cord blood HSCT. VOD occurred in 4 patients (25%) in the heparin alone group and none in the heparin + ATIII group (0%, P = 0.044). The incidence of bleeding complication was higher in the heparin alone group (4/16, 25%) than the heparin + ATIII group (1/14, 7%) without statistical significance (P = 0.190). The mean baseline level of PAI-1 was slightly higher in the heparin + ATIII group (30.9 ± 31.0 ng/ml) when compared to the heparin group (18.9 ± 13.0 ng/ml, P = 0.062). The PAI-1 level decreased markedly in the heparin + ATIII group (23.0 ±10.1 ng/ml) by the third week following VOD prophylaxis therapy (heparin group; PAI level 40.3 ± 40 ng/ml, P = 0.010). The mean baseline levels of TGF-β and TNF-α did not differ significantly between the two groups. There was no VOD-related death.

Conclusions: Although it was a preliminary analysis, the combination of ATIII and heparin for VOD prophylaxis in HSCT recipients seems to be more effective than heparin alone without increasing the hemorrhagic complication.

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