Role of plasminogen activator inhibitor-1 (PAI-1) levels in the diagnosis of BMT-associated hepatic veno-occlusive disease and monitoring of subsequent therapy with defibrotide (DF).
Hepatic veno-occlusive disease (VOD) is a common and potentially fatal complication of high dose chemotherapy with allogeneic/autologous stem cell transplant (SCT). The diagnosis and treatment of hepatic VOD is controversial. Clinical features are non-specific and may be mimicked by a number of other conditions causing hyperbilirubinaemia post-transplantation. Plasminogen activator inhibitor-1 (PAI-1) has been proposed as a specific marker of VOD [1]. Defibrotide (DF) is a polydeoxyribonucleotide, which has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anti-coagulation. Recent evidence [2,3] suggests that use of DF in patients with severe VOD results in a promising response rate without attributable significant toxicity. Between January 1998 and July 1999, PAI-1 levels were measured serially in 16 patients undergoing SCT who had subsequently developed hyperbilirubinaemia. Diagnosis of VOD was made by established clinical criteria [4,5]. At the time of diagnosis, PAI-1 levels (mean+/-SD) were significantly elevated in patients with VOD (90.7+/-47 ng/ml, n=7) when compared with patients with jaundice from other causes post transplantation (12.1+/-6.4 ng/ml, n=9). Five of the patients with VOD received treatment with DF. Four out of five patients showed an initial response to DF (significant fall in bilirubin and improvement in other signs/symptoms) with one of these patients having a complete response (bilirubin < 2.0 mg/dl and full resolution of signs/symptoms and end-organ toxicity). Following treatment with DF, a corresponding fall in PAI-1 levels was noted in those responding, with non-responders maintaining raised levels.


CONCLUSIONS
Raised PAI-1 levels post stem cell transplant are specific for VOD and a subsequent decrease in levels following treatment with DF may be associated with response to treatment.
Departments of Medical Oncology and Haematology, Christie Hospital, Wilmslow Rd, Manchester, UK.
M
M
Kaleelrahman
J D
JD
Eaton
D
D
Leeming
K
K
Bowyer
D
D
Taberner
J
J
Chang
J H
JH
Scarffe
R
R
Chopra
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects; D015415:Biomarkers; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006504:Hepatic Veno-Occlusive Disease / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000009:adverse effects; D014182:Transplantation, Autologous / Q000009:adverse effects; D014184:Transplantation, Homologous / Q000009:adverse effects; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D015415:Biomarkers; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D011089:Polydeoxyribonucleotides; C036901:defibrotide