Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease

Abstract

Venoocclusive disease (VOD) is the most frequent cause of early nonrelapse mortality among patients receiving high-dose chemoradiotherapy and hematopoietic stem cell transplantation. Endothelial injury of sinusoids and hepatic veins following chemotherapy is considered the initial event in the development of VOD. Activation of the coagulation cascade and inflammatory processes following endothelial injury results in a hypercoagulable state and a localized consumption of the natural anticoagulants, antithrombin III, protein C and protein S. The resultant coagulopathy can lead to multiorgan dysfunction and death. The objective was to retrospectively study the largest series of patients that has received antithrombin III for the treatment of VOD following hematopoietic stem cell transplantation. A total of 48 patients were diagnosed with VOD post hematopoietic stem cell transplantation (median age, 39 years; range, 1-69 years); 38 of the 48 received a nonradiation-based conditioning regimen and 21 of 48 received a transplant from an unrelated donor. Treatment was primarily directed at early intervention rather than prophylactic therapy to correct the antithrombin III deficiency associated with VOD. We attempted to achieve antithrombin III levels greater than 120%. There was no significant treatment-related morbidity. The overall 100-day mortality for the treatment cohort was 17%, with 10% for the mild/moderate group and 39% for the severe group, respectively. In conclusion, the encouraging results of this study suggest that this antithrombin III treatment should be further considered in patients with severe VOD.

BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation

“…Anti‐thrombin has been investigated in a number of small studies as levels of anti‐thrombin are low in patients with VOD and anti‐thrombin has a protective effect on the vascular endothelium (Morris et al , ; Mertens et al , ). Peres et al () reported a retrospective review of 48 patients with VOD who received early treatment with anti‐thrombin. The overall 100‐d mortality was 17% (10% in the mild/moderate group, 39% in the severe group).…”

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

“…One such agent, antithrombin III, was examined in a retrospective review of 48 patients (adults and children) who received the agent as treatment of VOD following SCT, yielding an overall 100-day mortality of 17%. The fatality rates in patients who developed mild/moderate and severe VOD were 9 and 38%, respectively [77]. A prospective study was then performed to compare the incidence of VOD in 71 children undergoing SCT who did not receive any specific VOD prophylaxis or therapy, with 91 children who received antithrombin III prophylaxis [68].…”

Hepatic Veno-Occlusive Disease

“…Previously, fibrinolytic treatment was the preferred approach, with or without anticoagulants, but the use of this therapy in pediatric patients has been described in few cases; [78,79] although recombinant human tissue plasminogen activator (rh-tPA) seems to be an effective therapy for established VOD at a dosage of 0.2 mg m 2 day as an intravenous infusion over 4 hours, further studies are necessary to determine its safety and optimal dosing regimen. Use of ATIII and activated C protein could be a treatment option for VOD; [81,82] ATIII treatment should be further considered in patients with severe VOD, but studies in pediatric series are lacking. Consequently, such a treatment modality is appropriate only in the initial phase of the disease, and is limited by hematologic risk.…”