Hepatopathy-thrombocytopenia Syndrome (HTS) after Actinomycin-D Therapy: Report of Three Cases and Review of the Literature

Abstract

Hepatopathy-thrombocytopenia syndrome (HTS) is a severe complication very similar to vein occlusive disease (VOD), also known as hepatic sinusoidal obstructive syndrome (SOS), characterized by fever, hepatopathy (hepatomegaly with abnormal liver function tests), ascites, weight gain, jaundice, and thrombocytopenia (platelet count less than 25 × 10(3)/μL). It has been generally observed in patients with Wilms tumor, and is commonly associated to administration of actinomycin D. We report three children with Wilms tumor, with severe HTS/SOS, but had a different outcome, in spite of vigorous supportive therapy.

“Pre‐emptive strike”—the case for early treatment of hepatic sinusoidal obstruction syndrome with defibrotide

“…In one case series of Wilms tumor, isolated severe thrombocytopenia was the most striking earliest sign with a median platelet count of 12 × 10 9 /l (range 4–48 × 10 9 /l) before signs of HSOS became evident . Others have also reported this observation in patients with Wilms tumor and proposed naming it “hepatopathy‐thrombocytopenia syndrome.” The authors concluded that children developing “isolated” thrombocytopenia following actinomycin‐D are “at risk” of developing HSOS, which, given the liver biopsy findings, is unlikely to be related to the immune‐mediated effect of actinomycin‐D . In another study, 12% of patients with ALL had severe persistent thrombocytopenia out of proportion with the degree of neutropenia and thought to be the sentinel clue for 6‐thioguanine induced HSOS .…”

“…Wilms tumor and proposed naming it "hepatopathy-thrombocytopenia syndrome." 1,2 The authors concluded that children developing "isolated" thrombocytopenia following actinomycin-D are "at risk" of developing HSOS, which, given the liver biopsy findings, is unlikely to be related to the immune-mediated effect of actinomycin-D. 19 In another study, 12% of patients with ALL had severe persistent thrombocytopenia out of proportion with the degree of neutropenia and thought to be the sentinel clue for 6-thioguanine induced HSOS. 4 The current understanding of HSOS pathophysiology emphasizes that consumptive thrombocytopenia and refractoriness to platelet transfusions secondary to uncontrolled endothelial/sinusoidal activation is the hallmark of HSOS.…”

“…Hepatic sinusoidal obstruction syndrome (HSOS), also termed veno‐occlusive disease of the liver, is a life‐threatening complication associated with hematopoietic stem cell transplantation (HSCT). However, HSOS is also well described outside the HSCT setting in children with Wilms tumor, rhabdomyosarcoma, medulloblastoma, and acute lymphoblastic leukemia (ALL) treated with conventional chemotherapy containing actinomycin‐D, cyclophosphamide, vincristine, 6‐thioguanine, and radiotherapy . HSOS in children is associated with significant morbidity, and mortality rates range from 7% to 100%.…”

“…However, HSOS is also well described outside the HSCT setting in children with Wilms tumor, rhabdomyosarcoma, medulloblastoma, and acute lymphoblastic leukemia (ALL) treated with conventional chemotherapy containing actinomycin-D, cyclophosphamide, vincristine, 6-thioguanine, and radiotherapy. [1][2][3][4][5][6][7][8][9] HSOS in children is associated with significant morbidity, and mortality rates range from 7% to 100%. The diagnosis of HSOS is based on two sets of guidelines known as the Baltimore and modified Seattle criteria, which have been used for the past three decades in pediatric and adult patients with HSCT (Table 1).…”

Evaluation of Neoadjuvant Chemotherapy Effects on Liver Parenchyma in Resected Pediatric Malignancies

“…In fact, several studies confirm that cisplatin and another alkylating agent such as carboplatin have been rarely associated with the development of veno-occlusive disease in patients who had undergone stem cell transplantation [15]. This is not really true for actinomycin-D that has been associated to veno-occlusive disease and SOS in children [16], and that was administered to our two patients with hepatic sarcoma. But even in those patients, we did not find any CALI.…”