Infusions of Fresh Frozen Plasma to the Patients with a High-Risk Group for Hepatic VOD Associated with Stem Cell Transplantation Reduce Its Occurrence.
Authors: Matsumoto Masanori , Kawa Keisei , Yagi Hieo , Park Yong-Dong , Takeshima Yasuhiro , Kosaka Yoshiyuki , Hara Hiroshi , Kai Shunro , Yamamoto Masuji , Kanemaru Akihisa , Fukuhara Shirou , Hino Masayuki , Sako Masahiko , Hiraoka Akira , Ogawa Hiroyasu , Hara Junichi , Fujimura Yoshihiro 
Published: October 2019

Abstract
Backgrounds/Aims: Hepatic veno-occlusive disease (VOD) is a life-threatening complication associated with allogenic stem cell transplantation (SCT). Although some risk factors including the intensified conditioning regimen, the second SCT, and liver dysfunction have been implicated on the pathogenesis of VOD, its etiology remains undetermined. Plasma von Willebrand factor (VWF) is produced in vascular endothelial cells (ECs) as unusually-large VWF multimers (UL-VWFMs) and released into circulation, where UL-VWFMs are cleaved into the small multimers with a specific metalloprotease ADAMTS13. Thus, the elevated level of plasma VWF, together with UL-VWFMs, has been thought in part to be a reflection of vascular EC injuries. Previously, we reported that plasma ADAMTS13 activity significantly decreased in patients with VOD during the first 4 weeks after SCT, compared with those without VOD (BMT2002, 29:789). Since ADAMTS13 down-sizes UL-VWFM by its proteolytic cleavage and reduces its thrombogenicity, we have here performed multicentric, prospective randomized study as to whether the infusion of fresh frozen plasma (FFP), a source of ADAMTS13, can prevent the occurrence of VOD in high-risk group patients with SCT.
Methods: The study was conducted at 10 hospitals between April 2001 and March 2003. Patients for allogenic SCT were enrolled to participate in the study, if they were high-risk for VOD abovementioned. Forty-three patients enrolled in this study were randomly divided into two groups: 23 patients with FFP infusion and 20 patients without. FFP was infused twice a week during conditioning regimen and until day 28 after SCT. The amount of FFP infused depends on body weight as follows; 1 unit (=80 ml) for patients under 10 kg, 2 units for 10–20 kg, 3 units for 20–30 kg, 4 units for 30–40 kg, and 5 units for over 40 kg. Plasma ADAMTS13 activity was measured by a novel monoclonal antibody-based highly sensitive ELISA (Transfusion2006, 46:1444).
Results: Three patients with hepatic VOD occurred within 20 patients who did not receive the FFP infusion, but none were observed in 23 patients who received the FFP infusion. We analyzed both the groups with special references to plasma levels of VWF and ADAMTS13. A significant difference was found in plasma levels of VWF:Ag, where the patients received FFP infusion had the lower values at day 0, day 7, and day 28, than those without receiving FFP infusion. However, no clear difference of plasma levels of ADAMTS13 activity was observed in both the groups. Most interestingly, however, a heightened degradation of VWFM (a total lack of the high ~ intermediate molecular size multimers) was found in patients with VOD who did not receive FFP infusion, but this finding was not seen in those without VOD who received FFP infusion.
Conclusions: FFP infusion apparently reduces plasma levels of VWF:Ag, together with the disappearance of UL-VWFMs, and thereby prevents the occurrence of VOD. On the other hand, in the patients with hepatic VOD, prior to the disease progression the high~intermediate multimers including UL-VWFMs were already consumed, by which platelet aggregation/thrombi might occur, as evidenced by VWFM analysis.