Tissue plasminogen activator (tPA) as therapy for hepatotoxicity following bone marrow transplantation

Abstract

Summary:The treatment of established veno-occlusive disease (VOD) of the liver with tissue plasminogen activator (tPA) has been disappointing. In attempts to improve upon these results we identified a subgroup of patients with consistently elevated bilirubin levels who did not meet conventional criteria for VOD (Susp VOD) but who had a significant risk of later developing clinical VOD. In January 1994 we began to treat patients who developed Susp VOD with tPA rather than waiting until they developed clinical VOD. We now report on the results of the first 37 patients who ultimately developed clinical VOD and received tPA therapy prior to Susp VOD, or at the time they had established VOD. Significant bleeding complications occurred in 13 (35%) patients but resolved with discontinuation of therapy in all but one. We found that patients treated early in the course of hepatotoxicity prior to the development of overt VOD had a significantly higher response rate and 100 day survival than patients treated at the time of established VOD. Given the poor results seen in treating late VOD, we suggest that early treatment with tPA may improve the outcome in patients who develop signs of hepatotoxicity following marrow transplantation. Keywords: tissue plasminogen activator; hepatotoxicity; bone marrow transplant Hepatic veno-occlusive disease (VOD) is a frequent and serious complication of bone marrow transplantation (BMT). Published reports indicate an incidence of 5-50%, and a mortality as high as 15% depending on the clinical series and the definition used.1-4 Clinically, VOD has been defined as hyperbilirubinemia within the first 4 weeks following BMT, with associated findings of ascites, unexplained weight gain, hepatomegaly or right upper quadrant pain. VOD is characterized histologically, by necrosis of zone 3 hepatocytes and deposition of fibrin and factor VIII in hepatic venules. These findings suggest a role of the coagulation system in the pathophysiology of VOD. sparse, and treatment options are limited. Despite the paucity of data, early experience with tissue plasminogen activator (tPA) is encouraging. Presently, tPA represents the most promising therapy for the treatment of hepatotoxicity following BMT. [6][7][8][9] Based on the promising initial reports of Bearman et al, 9 we began to treat patients with established VOD with tPA in April 1993. Our early experience in treating patients with advanced VOD using tPA was unfavorable, as in the larger trial recently reported by Bearman and colleagues.10 Others had suggested that successful treatment required early therapy.11 Thus in January 1994 we began to treat patients when they developed persistent unexplained hyperbilirubinemia (suspected VOD) without additional clinical evidence of VOD. To investigate whether earlier treatment may influence the course of hepatotoxicity, we examined only those patients who developed clinical VOD, and compared the results for those who received tPA prior to or after developing clinical VOD. Methods Patient selection and hepato...

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure

“…Two clinical studies of moderate size assessing tPA and heparin treatment for VOD/SOS (n = 42 and n = 37) [38,39], and one trial of tPA with and without heparin (n = 56) [39] have reported response to tPA (resolution or improvement of VOD/ SOS symptoms) in approximately 23-52% of DRug EvaluatiOn Richardson, Grupp, Pagliuca, Krishnan, Ho & Corbacioglu future science group patients, although this was accompanied by significant bleeding in 24-35% [38][39][40]. The joint BCSH/BSBMT guideline does not recommend use of tPA for treatment of VOD/SOS due to the associated risk of bleeding [21]; guidelines from the European School of Haematology (ESH)-EBMT note that while tPA may be effective in some patients, it is contraindicated in those with MOF, hemorrhage or severe hypertension [33].…”

Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment

“…The authors concluded that patients who met two McDonald criteria only had a better outcome as their liver damage was less severe and potentially more reversible with treatment. Other studies 11,12,13 have also suggested that the success of thrombolytic therapy for HVOD depends on early treatment, especially before MOF develops. Bearman et al 12 showed that MOF before the start of thrombolytic therapy was an important adverse prognostic factor and that the need for supplemental oxygen, dialysis or mechanical ventilation before start of treatment were associated with lack of response to rtPA treatment.…”

Avoiding hepatic veno-occlusive disease: what do we know and where are we going?

“…While recombinant tissue plasminogen activator (rh-tPA) has been used in many patients, only two series have included substantial numbers of patients. 37,38 We reported that 29% of patients responded and that 24% developed life-threatening hemorrhage. In Scriber's series, 38 most patients began treatment when they were suspected to be developing VOD rather than after established criteria were met.…”

“…37,38 We reported that 29% of patients responded and that 24% developed life-threatening hemorrhage. In Scriber's series, 38 most patients began treatment when they were suspected to be developing VOD rather than after established criteria were met. Of 24 patients who were treated without having met criteria for VOD, 67% responded.…”