bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison between Endogenous Thrombin Potential (ETP) and INR To Assess Liver Function in Patients with Liver Cirrhosis.
Authors: Schouten Jeoffrey , Gadisseur Alain P. , Franque Sven , Van der Planken Marc , Michielsen Peter , Berneman Zwi N. 
Published: April 2020

Abstract
The decreased hepatic synthesis of coagulation factors is a marker of liver failure and a prognostic indicator of survival in cirrhosis. The aPTT and PT/INR are the conventional coagulation tests to measure the haemostatic capacity of the liver. The INR was developed uniquely for use in patients under oral anticoagulation and may not adequately reflect the coagulation changes in liver cirrhosis. However, prognostic models for liver disease include the INR (MELD). New coagulation assessment tests are obviously needed in liver cirrhosis. Recently a test has become available to routinely measure the endogenous thrombin generation potential (ETP). This more physiological test is currently investigated in several haemostatic disorders but not yet in liver failure.
The aim of the study is to investigate correlations between ETP performed on the BCS® system (both Dade Behring, Marburg, Germany) and liver function tests, and compared with INR. We analysed 112 patients with liver cirrhosis (73 Child A, 21 Child B, 18 Child C) without known pre-existing coagulation abnormalities. In these patients ETP, APTT, PT/INR and S-cholinesterase were measured and an C14-Aminopyrine breathing test was performed.
Both INR and ETP show good correlation with the Child score (P&lt;0.01) as a whole. Looking at the Child score for bilirubin there is a clear correlation with the normalized ETP with 0.84 (CI95 0.81 - 0.88) for Child A, 0.74 (CI95 0.55 - 0.93) for Child B, and 0.67 (CI95 0.60 - 0.75) for Child C (p&lt;0.01). For the presence of ascites there is a correlation with the ETP with 0.86 (CI95 0.82 - 0.89) for Child A, 0.71 (CI95 0.62 - 0.79) for Child B, and 0.69 (CI95 0.59 - 0.80) for Child C (p&lt;0.01). Looking at the albumin level there is a clear correlation with the normalized ETP with 0.83 (CI95 0.79 - 0.86) for Child A patients, 0.72 (CI95 0.57 - 0.88) for Child B, and 0.69 (CI95 0.60 - 0.78) for Child C (p=0.02). In a linear regression model bilirubin (β= −0.319, p&lt;0.01) and ascites (β= −0.233, p=0.06) are the main predictive factor for decreasing thrombin generation. No such clear relationships can be identified for the INR. Both ETP and INR correlate well with S-cholinesterase levels (p&lt;0.01). ETP correlated better with the breathing test than the INR.
These results indicate that the integrity of the coagulation decreases in line with deterioration of other liver functions in patients with liver cirrhosis. The seriousness of this decrease in haemostatic capacity is better demonstrated by the ETP than by the INR (currently part of MELD). In the future the ETP may supersede the INR in prognostic classification systems for hepatic failure.
Trypsin Mediated Activation of Thrombin Activatable Fibrinolytic Inhibitor (Carboxypeptidase U): Potential Clinical Implications.
Authors: Kujawski Michelle , Cunanan Josephine , Hoppensteadt Debra A. , Bick Rodger L. , Fareed Jawed 
Published: April 2020

Abstract
Thrombin activatable fibrinolytic inhibitor (TAFI) (EC 3.4.17.20) is now known to mediate the fibrinolytic deficit in various pathophysiologic conditions such as thrombotic stroke, acute coronary syndrome and pancreatic disorders. While such serine proteases as plasmin are known to activate TAFI into TAFIa, no information is available on the effect of trypsin (EC 3.4.21.4) on the activation process. Pancreatic diseases including inflammatory conditions, surgical interventions and malignancies are associated with hypercoagulable state and DIC. Fibrinolytic deficit is also commonly observed in these patients. In these conditions, pancreatic enzymes are released into circulation. While the pathogenic role of pancreatic leakage mediator is known the effect of such pancreatic enzymes, as trypsin on the conversion of TAFI to TAFIa has not been addressed. To test the hypothesis that the observed fibrinolytic deficit in pancreatic disorders may be related to the conversion of TAFI to TAFIa by trypsin, the effects of this serine protease were studied on immunopurified human TAFI utilizing proteomic profiling, SDS gel electrophoresis and functional TAFI evaluation employing a specific substrate for TAFIa. Immunopurified human TAFI was incubated with human trypsin at graded concentrations in standardized assays with appropriate controls. The activation of TAFI was monitored by using a TAFIa substrate (Benzoyl-(L)-lysyl-(e-benzyloxycarbonyl)-a-(L)-(2-quanidinoethylthio)-glycine) from Pentapharm Inc. (Basel Switzerland). Thrombin thrombomodulin complex (T-TM) was also used as a positive control for TAFI to TAFIa conversion. The proteomic profile of the cleavage products generated was profiled utilizing surface enhanced laser desorption ionization (SELDI) (Ciphergen, Freemont, CA). Additionally, SDS gel electrophoresis of the cleavage products with appropriate controls were also obtained. Trypsin and TAFI alone did not produce any hydrolysis of the TAFIa substrate. However, when trypsin was added to TAFI it produced a concentration dependent hydrolysis of the substrate, which was comparable to that observed upon the activation of TAFI by T-TM. The proteomic profile of trypsin activated TAFI revealed specific peaks at 45.2, 35.6, 24.4 and 19 kDa. In addition, there were several cleavage products at &lt; 10 kDa molecular weight range, which was not seen with the activation of TAFI by T-TM. Similarly activation products as measured by SDS gel electrophoresis showed differential molecular profiles between trypsin and T-TM. These observations clearly suggest that trypsin is capable of activating TAFI into TAFIa independent of other processes such as the T-TM and plasmin mediated conversions. The observed fibrinolytic deficit in pancreatitus/pancreatic cancer may be due to the leakage of trypsin into circulation.
Extrapolating Mixing Study Results from the STACLOT-LA.
Authors: Dlott Jeffrey S. , Tushek Michael T. , Strother Rachael S. , Gallivan Monica V. 
Published: April 2020

Abstract
The International Society on Thrombosis and Haemostatis (ISTH) has established criteria for the diagnosis of lupus anticoagulants (LA) to include a mixing study to establish the presence of an inhibitor. Up to 30% of LAs are time and temperature dependent inhibitors, therefore only an incubated mixing study will detect this subtype. Global assays (i.e. STACLOT-LA® Diagnostica Stago) incorporate a sensitive screening reagent, a source of normal pooled plasma (npp) for an immediate mixing study, and a step to demonstrate phospholipids dependence. It does not, however, include an incubated mixing study. 493 consecutive STACLOT-LA samples were evaluated based on outcome and compared to the clotting time for Tube 1 (sample + npp + buffer) and Tube 2 (sample + npp + buffer + hexagonal phospholipids). All samples were tested according to manufacture’s instructions with a delta &gt; 8 seconds considered positive. Figure 1 reveals the lack of clear demarcation between negative and positive outcomes. Figure 2 identifies considerable differences between the clotting times of tube 1. Tube 2, while statistically different, has greatly overlapping confidence intervals. From this, it was identified that samples with Tube 1 clotting times between 55–75 seconds represented the population most likely to give borderline confirmatory calculations (CC). Subsequently, 45 samples with this criterion were selected for study, 17 negatives and 28 positives (CC 6.2–9.7). Immediate and 1 hour incubated mixing studies were performed with two reagents - aPTT-A and aPTT-LA® (Diagnostica Stago). The results are given in the table.
Figure 1 Scatter plot of LA Calculation Figure 1. Scatter plot of LA Calculation Figure 2 Figure 2. aPTT-A aPTT-LA Correction Reference Interval NC Reference Interval NC npp + 5 seconds Correction Reference Interval NC Reference Interval NC npp + 5 seconds NC= No correction; npp= Normal pooled plasma time; †2 of 3 LA positive by dRVVT; *1 case is a time dependent inhibitor Positive, (n=28) 22 (78) 6 (21) 13 (46) 23* (82) 5 (18) 14 (50) Negative, (n=17) 14 (82) 0 3† (18) 14 (82) 0 3† (18)
Conclusions: Borderline positive STACLOT-LA results showed an inhibitor pattern only 50% of the time under the most optimal conditions of a LA sensitive aPTT reagent with select interpretative guidelines. Therefore, a borderline or indeterminate range might be a more effective way to communicate these results if the inclination is to avoid a separate mixing study.
Successful Treatment of Intra-Cranial Hemorrhage with Repeated Doses of Activated Recombinant FVII in a Newborn with Severe Factor VII Deficiency.
Authors: Farah Roula , Hamod Dany , Bechara Elie , Melick Nancy , Hage Paul , Giansily-Blaizot Muriel , Sallah Ahmed S. 
Published: April 2020

Abstract
Factor VII deficiency is a rare inherited bleeding disorder. Intracranial hemorrhage can occur in approximately 1 to 10% of the cases. We report the case of a one month old girl from Lebanon who presented with vomiting, abnormal cry, lethargy and partial seizures. She was diagnosed prenatally with severe factor VII deficiency after detection of a splice-site mutation in exon 2 of the FVII gene (IVS2+1 G→C) that was described previously in her sister who died at the age of 4 months from severe intracranial hemorrhage. The parents are first degree cousins and are both heterozygous. She has a healthy heterozygous two year old sister.
An emergency head CT Scan showed intra ventricular and right hemispheric intra parenchymal hemorrhage, peri-hemorrhage edema and minimal midline shift. The patient was placed immediately on mechanical ventilation and anti-epileptics and activated recombinant factor VII (rFVIIa, NovoSeven) was administered intra-venously at 60 ug/kg for the first dose then 30 ug/kg/dose every 4 to 6 hours for 10 days then once a day for 5 days. She was treated conservatively with no surgery. Stabilization of the hematoma was observed with gradual improvement of her neurological condition. Communicating hydrocephalus developed later and a ventriculo-peritoneal shunt was placed on day 16 post-hemorrhage. Subsequently, she received weekly infusions of rFVIIa at 30 ug/kg/dose for 4 weeks after this episode and showed no bleeding symptoms. Follow-up two months later showed axial hypotonia and a mild left sided spasticity. Auditory evoked potentials were normal. However, afte prophylactic rFVIIa was dicontinued, the patient developed sub-arachnoid hemorrhage and was placed again on weekly prophylactic infusions of rFVIIa at 30 ug/kg/dose. The patient tolerated the infusions very well. No side-effects were observed.
Conclusion: rFVIIa is safe and effective in Factor VII deficient newborns with intracranial hemorrhage. Rapid treatment at the onset of hemorrhage is critical to reduce mortality and improve the outcome. Prophylactic factor VII infusions can be proposed in this setting to minimize the risk of subsequent bleeding episodes. The ideal dosing and schedule for treatment and/or prophylaxis will have to be defined. Despite the short half-life of rFVIIa, weekly infusions in our experience seemed safe and effective in reducing the incidence of further bleeding episodes.
Reduction of Anti-FIX Inhibitor Titers in a Hemophilia B Patient with Continuous Use of FEIBA.
Authors: Watanabe Hiroyoshi , Watanabe Tsutomu , Onishi Toshihiro , Okamura Kazumi , Kagami Shoji , Yamada Tadashi , Kawano Yoshifumi 
Published: April 2020

Abstract
Background: Inhibitor formation is a severe complication of hemophilia B associated with poor response to factor replacement and uncontrolled bleeding, although an inhibitor formation in hemophilia B is a rare event compared to hemophilia A. Currently, immune tolerance is the only proven method for inhibitor eradication. However, immune tolerance induction in patients with hemophilia B is a rare occurrence. We report a case of a hemophilia B patient who had a reduction of inhibitor titer during continual use of FEIBA.
Case report: Patient is an 11-year-old boy with severe FIX deficiency and high titer inhibitor (historical peak: 65 BU/mL) since age 3 years. Since inhibitor formation, the patient had received FEIBA or FVIIa on demand. FVIIa became therapeutically not effective in 1999 October, and bleeding frequency increased as he developed a target joint. In 1999 November, 2002 February, and 2004 September, he received high dose of FIX concentrate for neutralization of inhibitor and then cyclophosphamide for 8 weeks. We achieved only a transient effect in reducing the inhibitor titer. The inhibiter titer fluctuated between 20 and 60 BU/mL. Since 2005 January, subsequently, he had received FEIBA 1,000–2,000 IU per dose (30–50 units/kg) on demand. He needed FEIBA twice or thrice a week, and continued to receive this dose till now. The inhibitor titer was gradually getting lower after a transient rise up to 39 BU/mL on 2005 February. On 2006 February, the inhibitor titer became below 1.0 BU/mL, and finally undetectable on 2006 March, despite the longevity of the inhibitor (8 years). Factor IX recovery was normalized, and bleeding frequency dramatically decreased. Elimination of the inhibitor by the continued administration of FEIBA was observed. Anaphylactic reaction and the development of nephrotic syndrome were not seen.
Conclusion: The continuing use of FEIBA safely and effectively might decrease the inhibitor titer and the frequency of bleeding episodes in hemophilia B patients. This case may provide us the optimization of the FEIBA dose, and duration of treatment for inducing tolerance by using FEIBA.
Hepatocellular Carcinoma in Patients with Hemophilia and Chronic Hepatitis C Infection.
Authors: von Auer Charis , Heinsdorf Sandra , Krause Manuela , Miesbach Wolfgang , Scharrer Inge 
Published: April 2020

Abstract
Hepatitis C virus (HCV) infection is often observed in hemophilic patients who were treated with non-virus inactivated clotting factor concentrates prior to the mid 1980s. HCV infected patients exhibit an increased risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Hemophilia cohort studies until 2004 suggest a prevalence of HCC development of 0,1–0,2% in HCV infected hemophilic patients. During the last two years we observed a rapid increase in HCC development in our hemophilia treatment center. In the current study we analyzed our data to investigate the impact of chronic HCV infection in hemophilic patients today. We treated 90 hemophiliacs with chronic HCV hepatitis. Seven of these patients (6,3%) developed a HCC between 2002 and 2005, six of them only between 2004 and 2005. Five patients had severe hemophilia A, one mild hemophilia A, one severe hemophilia B, two of them had co-infections (HIV and HIV+HBV). Three had HCV genotype 1b, three 3a and one unknown. Four had been treated with interferon alpha/peginterferon alone or in combination with ribavirin, only one achieved a virologic response. Two patients refused treatment of HCV infection, one patient was not treated due to HIV co-infection. Their age at HCC diagnosis ranged from 40 to 73 years (median 60), time-course between estimated HCV infection and HCC development ranged between 11 and 35 years (median 22). All patients had developed liver cirrhosis: two Child-Pugh A, one Child-Pugh B and four Child-Pugh C. Six patients were asymptomatic; only one patient had jaundice when HCC was detected. All were regularly checked at least once a year with routine screening of AFP level and ultrasound (US) scans. Three patients had normal, four elevated AFP levels (&gt;15ng/ml), three had US scans without pathological finding when HCC was detected. All had consistently or intermittently elevated serum ALT levels during the last five years before diagnosis. HCC was diagnosed either by elevated AFP levels plus US identification (2) or plus MRT (2), by MRT plus check of arterial hypervascularisation (1) plus liver biopsy (1). One patient was only diagnosed after liver transplantation for chronic liver disease. Orthotopic liver transplantation was done in one patient, transcatheter arterial chemoembolization (TACE) in three, two patients have died of liver failure. Our data show that at present HCC is an increasingly frequent cause of mortality in hemophilic patients with chronic HCV infection. The detection of six HCC in only 15 months is striking. Especially nowadays a close follow up on hemophilic patients with chronic HCV infection seems to be mandatory. This should result in earlier detection and consequently more easily treatable tumors and longer survival of our patients.
Liver Transplantation for Prothrombin Deficiency Causing Life-Threatening Bleeds.
Authors: Dower Nancy A. , McClure Wilma , Akabutu John J. 
Published: April 2020

Abstract
We report here the first case of living-related liver transplantation to correct a severe bleeding diathesis. A Caucasian infant was diagnosed at 11 weeks old with prothrombin deficiency after a spontaneous subdural hemorrhage. Even though he had a Factor II activity level of 0.08, he had severe clinical complications including umbilical bleeding, hemorrhagic shock after circumcision and bleeding per rectum.
Prophylactic treatment with prothrombin complex concentrate prevented further bleeding episodes. Unfortunately, he developed clots of the superior vena cava and of the inferior vena cava in the context of central venous catheters. On-demand therapy via peripheral IV was followed for almost a year.
He then had severe subdural and intraparenchymal hemorrhages. His clinical course did not correlate with measured Factor II activity. Investigations looking for other coagulation disorders were negative.
He underwent a living-related liver transplant from his father in order to correct the bleeding diathesis. After transplant his Factor II level rose to 0.51. He required a second liver transplant (cadaveric) and died from tranplant related complications within a month.
Management decisions must reflect the clinical severity of bleeding and not the activity level in rare bleeding disorders where no treatment guidelines exist.
Combination of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) for Relapsed Multiple Myeloma: Results of a Phase I/II Clinical Trial.
Authors: Palumbo Antonio , Ambrosini Maria Teresa , Benevolo Giulia , Pregno Patrizia , Pescosta Norbert , Callea Vincenzo , Cangialosi Clotilde , Caravita Tommaso , Morabito Fortunato , Musto Pellegrino , Bringhen Sara , Gay Francesca , Rus Cecilia , Boccadoro Mario 
Published: April 2020

Abstract
BACKGROUND: In newly diagnosed patients, the addition of thalidomide or bortezomib (Velcade™) to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter, open-label, non randomized, phase I/II trial, the safety/efficacy profile of the 4 drug combination, bortezomib (Velcade™), melphalan, prednisone, and thalidomide (VMPT) was evaluated in patients with relapsed/refractory myeloma.
METHODS: Bortezomib was administered by IV bolus on days 1, 4, 15, 22 at three dose levels: in the first cohort (10 patients) at 1.0 mg/m2; in the second cohort (10 patients) at 1.3 mg/m2and in the third cohort (10 patients) at 1.6 mg/m2. Oral melphalan was administered at 6 mg/m2 on days 1–5, oral prednisone at 60 mg/m2 on days 1–5. Thalidomide was delivered at 50 mg on days 1–35. Each course was repeated every 35 days for a total of 6 courses.
RESULTS: Thirty patients, median age 66 years (range 38–79), with relapsed or refractory myeloma were enrolled. Fourteen patients received VMPT as second line of therapy, 16 as third line. Twenty patients received prior autologous transplant, 10 conventional chemotherapy and 9 thalidomide-based regimens. After a median of 6 courses, 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good partial response (VGPR). Among patients who received VMPT as second line treatment, the PR rate was 79%, and the immunofixation negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 non-hematological adverse events included: infections (5 patients), fatigue (1), vasculitis (1) and peripheral neuropathy (2); no grade 4 toxicities were recorded.
CONCLUSIONS: Initial results showed that VMPT is an effective salvage therapy with a high proportion of responses. Toxicities were manageable. The incidence of neurotoxicities was unexpectedly low.
Digital Analysis of Vascularity in Hemophilic Synovitis.
Authors: Lin Jonathan , Hakobyan Narine , Valentino Leonard A. 
Published: April 2020

Abstract
Hemophilia is a genetic disorder caused by a deficiency of blood coagulation factor VIII or IX. The most serious symptom is bleeding into joints, which over time leads to a proliferative, inflammatory disorder known as hemophilic synovitis. In time, the synovitis develops into hemophilic arthropathy, a form of incapacitating arthritis. While this sequence of events is well documented, the components responsible for the development of hemophilic synovitis are largely unknown. Recent evidence suggests that there is a relation between synovitis and vessel formation. Investigation of this cause-and-effect relationship necessitates a quantitative means of analyzing synovial and vessel hyperplasia. The goal of this experiment is to determine the utility of digital analysis of vessel formation by comparison to visual “hot-spot” scoring (Valentino and Hakobyan 2006, in press). Digital scores were expressed as percentages by dividing the number of vessel pixels in the densest area (“hot-spot”) by the total pixels in the field or separating the entire joint into 10 regions then averaging the percentages from each (“ten field”). Twenty-two histological sections from mouse joints with hemophilic synovitis were scored by visual and digital methods (Fig 1). The correlation of the two “hot-spot” methods (visual and digital) was good (r2=0.81). Next, the relationship of digital “hot-spot” and “ten field” analysis is shown in Fig.2. These data support the use of digital image analysis for evaluation of vessel formation and will allow for rapid examination of multiple samples.
Figure 1: Hot Spot Scoring Figure 1:. Hot Spot Scoring Figure 2: Digital Scoring Figure 2:. Digital Scoring