Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation

Abstract

Summary:Hepatic veno-occlusive disease (VOD) is a life-threatening complication after stem cell transplantation (SCT), characterized by thrombus formation in hepatic venules leading to a symptom triad of hyperbilirubinemia, hepatomegaly, and ascites. Multifactorial defects in the hemostatic system may contribute to its pathogenesis, but its remains to be investigated. Unusually large VWF multimers (UL-VWFMs), produced in and released from vascular endothelial cells, are most biologically active in the interaction with platelets under a high shear stress. UL-VWFMs are cleaved and degraded into smaller VWFMs by a specific liver producing plasma protease, termed VWF-cleaving protease (VWF-CPase), which has recently been identified as a metalloprotease solely produced in liver, termed ADAMTS13. Herein, we studied the correlation between plasma VWF-CPase activity and UL-VWFMs in 21 patients who received SCT, seven patients with VOD and 14 patients without VOD. In non-VOD patients, activities (mean ؎ 1s.d.) of VWF-CPase were 78 ؎ 17% of the control before the conditioning regimen, 76 ؎ 18% on day 0, 64 ؎ 19% on day 7, 57 ؎ 23% on day 14, 68 ؎ 13% on day 21 and 79 ؎ 19% on day 28 after SCT. The respective values in VOD patients were 32 ؎ 19%, 27 ؎ 15%, 18 ؎ 11%, 22 ؎ 18%, 26 ؎ 22% and 12 ؎ 4%. Thus, VWF-CPase activity was significantly reduced in VOD patients, even before the conditioning regimen, and such a difference was not found in other laboratory tests. However, despite such a clear difference, UL-VWFMs were present in plasmas of both patient groups, together with the increase of VWF antigen and ristocetin cofactor activity. These results indicate that the measurement of this enzyme activity is extremely useful in predicting the occurrence of VOD prior to a demonstration of its direct involvement in its pathogenesis.

The role of the endothelium in the short-term complications of hematopoietic SCT

“…sE-selectin and sVCAM-1 specifically increased in patients with extensive chronic GVHD, and sVCAM-1 increased in patients with TAM. Park et al 25 evidenced significantly reduced VWF-cleaving protease activity in patients with VOD, even before conditioning. Luzzato et al 26 also demonstrated an increase in VWF, TM and sE-selectin after HSCT in a paediatric population.…”

Crucial Role of ADAMTS13 Related to Endotoxemia and Subsequent Cytokinemia in the Progression of Alcoholic Hepatitis

“…Some diseases were shown to be TTP itself, but others did not show any apparent clinical features of TTP, even in the presence of markedly decreased ADAMTS13:AC and increased UL-VWFM that correlate with TTP. Such TTP-like states, but not DIC, may indicate "subclinical TTP" as seen in advanced LC (Uemura et al, 2008a and SAH patients (Matsuyama et al, 2007;Uemura et al, 2005b;Uemura et al, 2008b), or "local TTP" as shown in patients with hepatic VOD after SCT Park et al, 2002) and patients with adverse events after living-donor liver transplantation (Ko et al, 2006). One would be unable to detect such TTP-like phenomena without the determination of ADAMTS13:AC, because the interaction of ADAMTS13 and UL-VWFM is the initial step in hemostasis, and their abnormalities do occur even in the absence of apparent imbalance in other conventional hemostatic factors.…”

“…Furthermore, in SAH patients mild to severe hepatic venoocclusive disease (VOD) was frequently observed (Goodman & Ishak, 1982;Kishi et al, 2000). After stem cell transplantation (SCT), plasma ADAMTS13:AC was significantly lower in patients with hepatic VOD than those without (Park et al, 2002). Prophylactic infusion of fresh frozen plasma (FFP) as a source of ADAMTS13 may be useful in preventing the development of hepatic VOD after SCT , indicating a causative role of increased VWF production relative to decreased ADAMTS13:AC.…”

“…Since HSCs were shown to be the major producing cells of ADAMTS13 in the liver (Uemura et al, 2005a), much attention has been paid to the potential role of ADAMTS13 in the pathophysiology of liver diseases associated with sinusoidal and/or systemic microcirculatory disturbances (Feys et al, 2007;Ishikawa et al, 2010;Ko et al, 2006;Kobayashi et al, 2009;Lisman et al, 2006;Matsuyama et al, 2007;Okano et al, 2010;Park et al, 2002;Pereboom et al, 2009;Uemura et al, 2005b;Uemura et al, 2008a;Uemura et al, 2008b;Uemura et al, 2010;Yagita et al, 2005). ADAMTS13:AC is significantly decreased in patients with hepatic veno-occlusive disease (VOD) Park et al, 2002), AH (Ishikawa et al,2010;Matsuyama et al, 2007;Uemura et al, 2005b, Uemura et al, 2008b, LC (Feys et al, 2007;Uemura et al, 2008a), and patients undergoing living-donor related liver transplantation (Ko et al, 2006;Kobayashi et al,2009;Pereboom et al, 2009) and partial hepatectomy (Okano et al,2010). Furthermore, hepatitis C virus (HCV)-related LC patient with ADAMTS13 inhibitor (ADAMTS13:INH) typically develops TTP (Yagita et al, 2005).…”

Demonstration of reversed flow in segmental branches of the portal vein with hand-held color Doppler ultrasonography after hematopoietic stem cell transplantation

“…Alterations in hemostatic parameters such as plasminogen activator inhibitor type-1 (PAI-1), protein C, factor VII, antithrombin, von Willebrand Factor cleaving protease seen in VOD are not specific. [14][15][16][17] In previous studies using duplex sonography, the hepatic artery resistive index (RI) value and amplitude of pulsatility in hepatic veins were reported to be significantly helpful for diagnosis of VOD. 18,19 However, in a later study, these findings resulted in being of no value in the diagnosis of VOD.…”