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1.  Relevance of ADAMTS13 to liver transplantation and surgery 
World Journal of Hepatology  2015;7(13):1772-1781.
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) specifically cleaves unusually-large von Willebrand factor (VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, termed thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP). Children with advanced biliary cirrhosis due to congenital biliary atresia sometimes showed pathological features of TMA, with a concomitant decrease of plasma ADAMTS13 activity. Disappearance of their clinical findings of TTP after successful liver transplantation suggested that the liver is a major organ producing plasma ADAMTS13. In situ hybridization analysis showed that ADAMTS13 was produced by hepatic stellate cells. Subsequently, it was found that ADADTS13 was not merely responsible to development of TMA and TTP, but also related to some kinds of liver dysfunction after liver transplantation. Ischemia-reperfusion injury and acute rejection in liver transplant recipients were often associated with marked decrease of ADAMTS13 and concomitant formation of unusually large VWF multimers without findings of TMA/TTP. The similar phenomenon was observed also in patients who underwent hepatectomy for liver tumors. Imbalance between ADAMTS13 and VWF in the hepatic sinusoid might cause liver damage due to microcirculatory disturbance. It can be called as “local TTP like mechanism” which plays a crucial role in liver dysfunction after liver transplantation and surgery.
PMCID: PMC4491906  PMID: 26167250
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13; Thrombocytopenia; Microcirculation; Liver dysfunction; von Willebrand factor; Liver transplantation; Acute rejection; Ischemia-reperfusion injury; Hepatectomy; Liver surgery; Local thrombotic thrombocytopenic purpura like mechanism
2.  A Novel Quantitative Hemolytic Assay Coupled with Restriction Fragment Length Polymorphisms Analysis Enabled Early Diagnosis of Atypical Hemolytic Uremic Syndrome and Identified Unique Predisposing Mutations in Japan 
PLoS ONE  2015;10(5):e0124655.
For thrombotic microangiopathies (TMAs), the diagnosis of atypical hemolytic uremic syndrome (aHUS) is made by ruling out Shiga toxin-producing Escherichia coli (STEC)-associated HUS and ADAMTS13 activity-deficient thrombotic thrombocytopenic purpura (TTP), often using the exclusion criteria for secondary TMAs. Nowadays, assays for ADAMTS13 activity and evaluation for STEC infection can be performed within a few hours. However, a confident diagnosis of aHUS often requires comprehensive gene analysis of the alternative complement activation pathway, which usually takes at least several weeks. However, predisposing genetic abnormalities are only identified in approximately 70% of aHUS. To facilitate the diagnosis of complement-mediated aHUS, we describe a quantitative hemolytic assay using sheep red blood cells (RBCs) and human citrated plasma, spiked with or without a novel inhibitory anti-complement factor H (CFH) monoclonal antibody. Among 45 aHUS patients in Japan, 24% (11/45) had moderate-to-severe (≥50%) hemolysis, whereas the remaining 76% (34/45) patients had mild or no hemolysis (<50%). The former group is largely attributed to CFH-related abnormalities, and the latter group has C3-p.I1157T mutations (16/34), which were identified by restriction fragment length polymorphism (RFLP) analysis. Thus, a quantitative hemolytic assay coupled with RFLP analysis enabled the early diagnosis of complement-mediated aHUS in 60% (27/45) of patients in Japan within a week of presentation. We hypothesize that this novel quantitative hemolytic assay would be more useful in a Caucasian population, who may have a higher proportion of CFH mutations than Japanese patients.
PMCID: PMC4423893  PMID: 25951460
3.  STEC:O111-HUS complicated by acute encephalopathy in a young girl was successfully treated with a set of hemodiafiltration, steroid pulse, and soluble thrombomodulin under plasma exchange 
Clinical Case Reports  2015;3(4):208-212.
Key Clinical Message
We report a 14-year-old girl, who developed shigatoxin-producing E. coli (STEC)-HUS complicated by encephalopathy. She was successfully treated with hemodiafiltration, high-dose methylprednisolone pulse therapy, and soluble recombinant thrombomodulin under plasma exchange. von Willebrand factor multimers analysis provides potential insights into how the administered therapies might facilitate successful treatment of STEC-HUS.
PMCID: PMC4405303  PMID: 25914810
Encephalopathy; Escherichia coli O111; hemolytic uremic syndrome; plasma exchange; recombinant soluble thrombomodulin; von Willebrand factor
4.  A Unique Case Involving a Female Patient with Upshaw-Schulman Syndrome: Low Titers of Antibodies against ADAMTS13 prior to Pregnancy Disappeared after Successful Delivery 
Upshaw-Schulman syndrome (USS) is usually suspected based on severe deficiency of ADAMTS13 activity without ADAMTS13 antibody, but the definitive diagnosis is made by ADAMTS13 gene analysis. We present a unique case of USS with low titers of ADAMTS13 antibodies before pregnancy. Interestingly, titers of ADAMTS13 antibodies decreased to almost undetectable levels after delivery.
Case Report
In patient LL4, the diagnosis of USS was confirmed at age 27 by ADAMTS13 gene analysis. She became pregnant at age 30. During the pregnancy, she received regular fresh frozen plasma (FFP) infusion. Plasma von Willebrand factor levels increase as pregnancy progresses. To prevent platelet thrombi, much more ADAMTS13 supplementation is necessary during late gestation in patients with USS. Therefore, we shortened the interval between and increased the volume of FFP infusions as pregnancy progressed. At 39 weeks, she delivered a healthy baby girl. Before pregnancy, she had low titers of both neutralizing and binding anti-ADAMTS13 antibodies. Despite frequent FFP infusions, titers of the antibodies did not increase, but rather decreased to almost undetectable levels during pregnancy.
Both the neutralizing and binding antibodies against ADAMTS13 decreased to almost undetectable levels after delivery in this patient, which can be caused by an immunological reset.
PMCID: PMC4404895  PMID: 25960717
Upshaw-Schulman syndrome; Pregnancy; ADAMTS13 antibody; ADAMTS13 gene mutation; Fresh frozen plasma
5.  Candidate gene analysis using genomic quantitative PCR: identification of ADAMTS13 large deletions in two patients with Upshaw-Schulman syndrome 
Direct sequencing is a popular method to discover mutations in candidate genes responsible for hereditary diseases. A certain type of mutation, however, can be missed by the method. Here, we report a comprehensive genomic quantitative polymerase chain reaction (qPCR) to complement the weakness of direct sequencing. Upshaw-Schulman syndrome (USS) is a recessively inherited disease associated with severe deficiency of plasma ADAMTS13 activity. We previously analyzed ADAMTS13 in 47 USS patients using direct sequencing, and 44 of them had either homozygous or compound heterozygous mutations. Then, we sought to reveal more extensive defects of ADAMTS13 in the remaining three patients. We quantified copy numbers of each ADAMTS13 exon in the patients by using genomic qPCR. Each primer pair was designed to contain at least one of the two primers used in direct sequencing, to avoid missing any exonic deletions. The qPCR demonstrated heterozygous loss of exons 7 and 8 in one patient and exon 27 in the other, and further analysis revealed c.746_987+373del1782 and c.3751_3892+587del729, respectively. Genomic qPCR provides an effective method for identifying extensive defects of the target genes.
PMCID: PMC4049364  PMID: 24936513
ADAMTS13; genetic analysis; hereditary disease; mutation; quantitative PCR; thrombotic thrombocytopenic purpura; Upshaw-Schulman syndrome
7.  Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR) 
Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
9.  Long term follow up of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) on hemodialysis for 19 years: a case report 
BMC Nephrology  2013;14:156.
Thrombotic thrombocytopenic purpura (TTP) is frequently associated with renal abnormalities, but there have been few reports about renal abnormalities in patients with hereditary TTP. In particular, little is known about the long-term prognosis of patients with childhood-onset congenital TTP.
Case presentation
We report a Japanese patient with congenital TTP (Upshaw–Schulman syndrome) who was followed for 19 years after initiation of hemodialysis when he was 22 years old. At the age of 6 years, the first episode of purpura, thrombocytopenia, and proteinuria occurred without any precipitating cause. He underwent living-related donor kidney transplantation from his mother, but the graft failed after 5 months due to recurrence of TTP. Even after resection of the transplanted kidney and resumption of regular hemodialysis, TTP became refractory to infusion of fresh frozen plasma (FFP). Therefore, splenectomy was performed and his disease remained in remission for 10 years. However, TTP recurred at the age of 39 years. Plasma activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) was less than 3%, while ADAMTS13 inhibitor was not detected (< 0.5 Bethesda units/mL). The patient died suddenly after hemodialysis at the age of 41 years. Subsequent genetic analysis of this patient and his parents revealed two different heterozygous mutations of ADAMTS13, including a missense mutation in exon 26 (c.T3650C causing p.I1217T) inherited from his father and a missense mutation in exon 21 (c.G2723A causing p.C908Y) inherited from his mother. The former mutation has not been detected before in Japan, while the latter mutation is common in Japan. A retrospective review showed that serum C3 levels were consistently low while C4 levels were normal during follow-up, and C3 decreased much further during each episode of TTP.
Congenital TTP was diagnosed from the clinical, biochemical, and genetic findings. Infusion of FFP controlled each thrombotic episode, but the effect was limited and of short duration. Review of the complement profile in this patient suggested that a persistently low serum C3 level might be associated with refractory TTP and a worse renal prognosis.
PMCID: PMC3729817  PMID: 23870247
Congenital thrombotic thrombocytopenic purpura; ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13); Chronic hemodialysis; Complement activation; C3; Alternative pathway
10.  Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008) 
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
11.  Acquired Idiopathic ADAMTS13 Activity Deficient Thrombotic Thrombocytopenic Purpura in a Population from Japan 
PLoS ONE  2012;7(3):e33029.
Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.
PMCID: PMC3299727  PMID: 22427934
12.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
PMCID: PMC3167088  PMID: 17868804
13.  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.
PMCID: PMC3170842  PMID: 21994870
14.  Cerebral Sinus and Venous Thrombosis Associated with von Willebrand Factor, Independently of Factor VIII 
Background and purpose
Previous studies have linked procoagulant factor VIII (F VIII) to an increased risk of venous thrombosis, whereas the relation between plasma von Willebrand factor (VWF) and venous thrombosis remains poorly understood. Elevated VWF levels are frequently found in patients with cerebral sinus and venous thrombosis (CSVT), always in association with high F VIII levels. We describe a patient with CSVT accompanied by elevated VWF levels without high F VIII levels.
Case description
A 23-year-old healthy man who had headache noticed difficulty in moving the right hand. On the following day, he lost consciousness and had partial seizures of the right hand. After regaining consciousness, weakness of the right extremities developed. The cranial angiogram confirmed occlusion of the superior sagittal sinus. The levels of VWF and F VIII were 238% and 101.9 IU/dl, respectively. We performed balloon percutaneous transluminal angioplasty and mechanical thrombectomy, leading to successful recanalization of the intracranial sinuses. VWF levels were decreased along with radiographic improvement, independently of F VIII.
VWF may contribute to CSVT and that inhibition of VWF activity potentially has a role in the future treatment of pathological conditions related to venous thrombosis.
PMCID: PMC3785342  PMID: 24179341
von Willebrand factor; venous thrombosis; cerebral sinus; procoagulant factor VIII; rheolytic thrombectomy; venous infarction
15.  Nepmucin, a novel HEV sialomucin, mediates L-selectin–dependent lymphocyte rolling and promotes lymphocyte adhesion under flow 
The Journal of Experimental Medicine  2006;203(6):1603-1614.
Lymphocyte trafficking to lymph nodes (LNs) is initiated by the interaction between lymphocyte L-selectin and certain sialomucins, collectively termed peripheral node addressin (PNAd), carrying specific carbohydrates expressed by LN high endothelial venules (HEVs). Here, we identified a novel HEV-associated sialomucin, nepmucin (mucin not expressed in Peyer's patches [PPs]), that is expressed in LN HEVs but not detectable in PP HEVs at the protein level. Unlike conventional sialomucins, nepmucin contains a single V-type immunoglobulin (Ig) domain and a mucin-like domain. Using materials affinity-purified from LN lysates with soluble L-selectin, we found that two higher molecular weight species of nepmucin (75 and 95 kD) were decorated with oligosaccharides that bind L-selectin as well as an HEV-specific MECA-79 monoclonal antibody. Electron microscopic analysis showed that nepmucin accumulates in the extended luminal microvillus processes of LN HEVs. Upon appropriate glycosylation, nepmucin supported lymphocyte rolling via its mucin-like domain under physiological flow conditions. Furthermore, unlike most other sialomucins, nepmucin bound lymphocytes via its Ig domain, apparently independently of lymphocyte function–associated antigen 1 and very late antigen 4, and promoted shear-resistant lymphocyte binding in combination with intercellular adhesion molecule 1. Collectively, these results suggest that nepmucin may serve as a dual-functioning PNAd in LN HEVs, mediating both lymphocyte rolling and binding via different functional domains.
PMCID: PMC2118321  PMID: 16754720

Results 1-15 (15)