Prophylactic fresh frozen plasma may prevent development of hepatic VOD after stem cell transplantation via ADAMTS13-mediated restoration of von Willebrand factor plasma levels

Abstract

We initially conducted a multicenter, randomized trial (n ¼ 43), and subsequently a questionnaire study (n ¼ 209) of participating hospitals, to evaluate whether infused fresh frozen plasma (FFP) could prevent the occurrence of hepatic veno-occlusive disease (VOD) after stem cell transplantation (SCT). Forty-three patients were divided into two groups: 23 receiving FFP infusions and 20 not receiving it. VOD developed in three patients not receiving FFP. Plasma von Willebrand factor (VWF) antigen levels were lower at days 0, 7 and 28 after SCT in patients receiving FFP than in those not receiving it, whereas plasma ADAMTS13 activity (ADAMTS13:AC) did not differ between them. Plasma VWF multimer (VWFM) was demonstrated to be defective in the highBintermediate VWFM during the early post-SCT phase, but there was a significant increase in high VWFM just before VOD onset. This suggests that a relative enzyme-tosubstrate (ADAMTS13/high-VWFM) imbalance is involved in the pathogenesis of VOD. To strengthen this hypothesis, the incidence of VOD was apparently lower in patients receiving FFP infusions than in those not receiving it (0/23 vs 3/20) in the randomized trial. Further, the results combined with the subsequent questionnaire study (0/36 vs 11/173) clearly showed the incidence to be statistically significant (0/59 vs 14/193, P ¼ 0.033).

Pivotal role of ADAMTS13 function in liver diseases

“…Furthermore, in the group without prophylactic FFP infusion, high and/or intermediate molecular weight VWFM was also lacking in the early stage and even in the later stage after SCT. In contrast, in the group with FFP infusion, no apparent changes in VWFM patterns were found throughout SCT [65]. It remains unclear why such a phenomenon occurred, but one possible explanation may be the SEC injury caused by intensive chemotherapy and/or total body irradiation in the setting of SCT.…”

“…Interestingly, in VOD patients, VWFM corresponding to high and intermediate molecular weight, which is usually seen in normal plasma, were lacking at preconditioning or the early period after SCT, and thereafter gradually appeared [65]. Furthermore, in the group without prophylactic FFP infusion, high and/or intermediate molecular weight VWFM was also lacking in the early stage and even in the later stage after SCT.…”

“…A multicenter, prospective, randomized controlled study revealed that prophylactic fresh frozen plasma (FFP) infusion as a source of ADAMTS13 may be instrumental in preventing the development of hepatic VOD after SCT [65]. In two typical cases with hepatic VOD, plasma levels of VWF:AG progressively increased and ADAMTS13:AC gradually decreased from preconditioning or the early period after the SCT to the later period at the occurrence of hepatic VOD [65].…”

Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor

“…This may lead to changes in patient management since plasma exchange using enzyme-containing plasma preparations such as FFP may restore the capacity to cleave ULVWF in the circulation, as shown in patients with high risk developing veno-occlusive disease. 13 This therapeutic approach also needs to be tested for sepsis in controlled prospective studies.…”

Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure

“…The detection limit of the activity was 0.5%; normal value was 99±22% (mean ± standard deviation). Plasma UL-VWFM was analyzed by 0.9% SDS-agarose gel electrophoresis using 1 µl sample aliquots (16). High-molecular-weight bands undetected in normal plasma were defined as UL-VWFM (17).…”