Determination of ADAMTS13 and Its Clinical Significance for ADAMTS13 Supplementation Therapy to Improve the Survival of Patients with Decompensated Liver Cirrhosis

The liver plays a central role in hemostasis by synthesizing clotting factors, coagulation inhibitors, and fibrinolytic proteins. Liver cirrhosis (LC), therefore, impacts on both primary and secondary hemostatic mechanisms. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate cells, and specifically cleaves unusually large von Willebrand factor multimers (UL-VWFM). Deficiency of ADAMTS13 results in accumulation of UL-VWFM, which induces platelet clumping or thrombi under high shear stress, followed by sinusoidal microcirculatory disturbances and subsequent progression of liver injuries, eventually leading to multiorgan failure. The marked imbalance between decreased ADAMTS13 activity (ADAMTS13 : AC) and increased production of UL-VWFM indicating a high-risk state of platelet microthrombi formation was closely related to functional liver capacity, hepatic encephalopathy, hepatorenal syndrome, and intractable ascites in advanced LC. Some end-stage LC patients with extremely low ADAMTS13 : AC and its IgG inhibitor may reflect conditions similar to thrombotic thrombocytopenic purpura (TTP) or may reflect “subclinical TTP.” Hence, cirrhotic patients with severe to moderate deficiency of ADAMTS13 : AC may be candidates for FFP infusion as a source of ADAMTS13 or for recombinant ADAMTS13 supplementation. Such treatments may improve the survival of patients with decompensated LC

Oxaliplatinによる肝類洞障害は肝臓内にvon Willebrand因子が血小板血栓を形成することにより発症する

Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation.博士（医学）・乙第1373号・平成28年3月15日Copyright: © 2015 Nishigori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Salvage living donor liver transplantation after percutaneous transluminal angioplasty for recurrent Budd-Chiari syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>Budd-Chiari syndrome is a very rare pathological entity that ultimately leads to liver failure. Several therapeutic modalities, including percutaneous transluminal angioplasty, have been attempted to save the life of patients with Budd-Chiari syndrome. Few reports have described a salvage living donor liver transplantation performed after percutaneous transluminal angioplasty in a patient with acute Budd-Chiari syndrome.</p> <p>Case presentation</p> <p>A 26-year-old Japanese man developed severe progressive manifestations, such as massive ascites and hematemesis due to rupture of esophageal varices. After making several investigations, we diagnosed the case as Budd-Chiari syndrome. We first performed percutaneous transluminal angioplasty to dilate a short-segment stenosis of his inferior vena cava. The first percutaneous transluminal angioplasty greatly improved the clinical manifestations. However, after a year, re-stenosis was detected, and a second percutaneous transluminal angioplasty failed to open the severe stricture of his inferior vena cava. Since our patient had manifestations of acute liver failure, we decided to perform salvage living donor liver transplantation from his brother. The transplantation was successfully performed and all clinical manifestations were remarkably alleviated.</p> <p>Conclusion</p> <p>In cases of recurrent Budd-Chiari syndrome, the blocked hepatic venous outflow is not always relieved, even with invasive therapies. We have to take into account the possibility of adopting alternative salvage therapies if the first therapeutic modalities fail. When invasive therapy such as percutaneous transluminal angioplasty fails, liver transplantation should be considered as an alternative option.</p

INDUCTION OF SMALL BOWEL TRANSPLANTATION TOLERANCE BY DONOR-SPECIFIC BONE MARROW TRANSPLANTATION

Immune response after allogeneic small bowel transplantation is more vigorous compared to other organ transplantations. It is often difficult to control small bowel allograft rejection with conventional immunosuppressive therapy. While many experimental studies showed organ transplantation tolerance, there have been few reports of tolerance in allogeneic small bowel transplantation. Induction of bone marrow chimerism is a potent strategy of tolerance induction. We tried to induce tolerance in SBT using donor-specific bone marrow transplantation (BMT) with cyclophosphamide (CYP) and tacrolimus. BN and LEW rats were used as donors and recipients. LEW recipients received BMT from BN donors after injection of CYP. The recipients were further treated with 0.3 mg/kg/day tacrolimus on days 0-6 (n=5). Establishment of bone marrow chimerism in BMT recipients was evaluated by flowcytometry of peripheral blood mononuclear cells. These recipients received small bowel transplantation from BN donors on day 100 after BMT. All of these recipients accepted BN small bowel allografts indefinitely (＞100 days), while untreated LEW controls rejected BN grafts within 8 days (n=6). Histologic signs of chronic rejection were not observed in small bowel allografts in these recipients. In conclusion, donor-specific BMT with a single dose of CYP and a short course of tacrolimus in the early phase successfully induced small bowel transplant tolerance across MHC-barriers. This strategy may lead to technical innovation of immuno- suppressive treatment in clinical small bowel transplantation

PROGNOSTIC SIGNIFICANCE OF p21 AND p53 EXPRESSION IN HEPATOCELLULAR CARCINOMA

The cyclin-dependent kinase inhibitor p21Waf1/Cip1(p21), which can be transcriptionally activated by p53-dependent and -independent manners, functions to block cell cycle progression. In this study, we analyzed the expression of p21, p53 and proliferating cell nuclear antigen (PCNA) in 85 patients with hepatocellular carcinoma (HCC) by inmiunohistochemistry, and examined whether expression of these proteins was related to prognosis in patients with HCC. In HCC, p21 positive tumors significantly showed high PCNA LI and small size, compared with p21 negative tumors. No relationship between p21 and p53 expression was detected. A multivariate Cox model analysis revealed p21, p53 expression and PCNA LI as independent prognostic factors (p=0.0059, p=0.0004, and p=0.0165, respectively). Furthermore, p21 expression significantly correlated with low recurrence rate in the p53 negative cases (p=0.020) and related to a good outcome in the high PCNA LI cases (p=0.056). Accordingly, the analysis of p21, p53 and PCNA could play an important role in early detection of intrahepatic recurrence and might contribute to improvement of the prognostic characterization

VWF multimer analysis in patients with CALI who were not treated with bevacizumab.

<p>VWF multimer analysis was performed in 4 representative patients out of 6 patients with CALI not treated with bevacizumab. These patients developed CALI during month 3 or 4. UL-VWFMs were found before and during CALI in all patients. Decreased levels of H-VWFMs were found in Patient 4 at months 0 and 1, and in Patient 17 at month 2. VWF von Willebrand factor, CALI chemotherapy-associated liver injury, UL-VWFMs unusually-large VWF multimers, H-VWFM high molecular weight VWF multimers, AST aspartate transaminase, T-Bil total bilirubin, VWF:Ag VWF antigen, VWF:CB VWF collagen binding activity.</p

VWF multimer analysis in patients without CALI who were not treated with bevacizumab.

<p>Results of VWF multimer analysis in 4 representative patients out of 11 patients without CALI not treated with bevacizumab are shown. UL-VWFMs were found in Patients 10, 14, and 15, who did not develop CALI. In Patient 10, decreased levels of H-VWFMs were observed during months 1 and 4. VWF von Willebrand factor, CALI chemotherapy-associated liver injury, UL-VWFMs unusually-large VWF multimers, H-VWFM high molecular weight VWF multimers, AST aspartate transaminase, T-Bil total bilirubin, VWF:Ag VWF antigen, VWF:CB VWF collagen binding activity.</p

Comparison of platelet count, VWF:Ag, ADAMTS13:AC, AST, and T-Bil between patients treated with and not treated with bevacizumab.

<p>(A) Platelet counts decreased until months 3 as the number of chemotherapy cycles increased in both patients who received and did not receive bevacizumab. However, platelet counts in patients not treated with bevacizumab decreased much less in patients who received bevacizumab in months 5. (B) Plasma levels of VWF:Ag increased as the number of chemotherapy cycles increased in patients not treated with bevacizumab, but did not change in patients treated with bevacizumab. (C) Plasma levels of ADAMTS13:AC were unchanged in both groups. (D) Serum AST levels increased as the number of chemotherapy cycles in patients who did not receive bevacizumab, but they were unchanged in patients with bevacizumab. (E) Plasma levels of T-Bil did not change significantly in either group. VWF:Ag von Willebrand factor antigen, ADAMTS13:AC ADAMTS13 activity, AST Aspartate transaminase, T-Bil total bilirubin.</p