bluuebunny/crossref_metadata_2025 huggingface dataset:
Qualität der Blutdruckeinstellung in der hausärztlichen Praxis unter Verwendung der 24-Stunden-Langzeitblutdruckmessung – eine retrospektive monozentrische Querschnittsstudie
Authors: Häckel Stefanie , Stein Friederike , Wolf Gunter , Stein Günter , Busch Martin
Published: July 2018

Einleitung Die Diagnostik und Therapie der arteriellen Hypertonie ist eine kontinuierliche Herausforderung in Hausarztpraxen. Ziel dieser Arbeit ist es, die Art und Effektivität der Blutdruckeinstellung bei Patienten mit bekannter arterieller Hypertonie in einer hausärztlichen Praxis unter strikter Verwendung der Office- (OBPM) und ambulanten Langzeit- (ABPM) Blutdruckmessung zu analysieren.

Methoden Retrospektiv wurden 283 Patienten (90 % aller regelmäßig betreuten Hypertoniker) hinsichtlich des Erreichens der Zielblutdruckwerte in ABPM und OBPM der zurückliegenden 1 bis 2 Jahre untersucht. Die Zielwerte entsprachen den geltenden ESH-Empfehlungen (Office-Blutdruck < 140/90 mmHg, 24-h-Mittelwert der ABPM < 130/80 mmHg).

Ergebnisse Der OBPM aller Patienten (Alter: 68 ± 12,7, 48 % Frauen) lag bei 132 ± 11,8/80 ± 4,2 mmHg, der 24-h-ABPM betrug 128 ± 10,7/74 ± 7,9 mmHg. Eine isolierte Praxishypertonie hatten 11,3 %, eine maskierte Hypertonie 21,9 %. Nur 33,9 % wiesen ein physiologisches Dippingverhalten auf (49,1 % Non-Dipper, 13,8 % Reverse-Dipper und 3,2 % Extrem-Dipper). Die Blutdruck-Kontrollrate (Erreichen des Zielblutdruckes) betrug 67,8 % in der OBPM und 57,2 % in der 24-h-ABPM. 23,0 % wurden mit einer Monotherapie, 37,5 % mit Zweifach-Kombination, 19,8 % mittels Dreifach-Kombination und 14,5 % mit > 3 Antihypertensiva behandelt, 83,9 % erhielten RAS-Blocker. Der OBPM-Zielwert wurde bei 75,0 % unter einer Dreifach- und 71,7 % unter einer Zweifach-Kombination erzielt, der 24-h-ABPM-Zielwert zumeist bei Patienten, die nur einer Monotherapie bedurften (66,2 %) oder mittels Zweifachtherapie behandelt wurden (60,4 %), ansonsten < 60 % Zielwerterreichung.

Schlussfolgerung In der untersuchten Hausarztpraxis war die Therapiekontrolle von Patienten mit therapierter arterieller Hypertonie mehrheitlich leitliniengerecht und besser als in der Literatur beschrieben. Die parallele und konsequente Durchführung von OBPM und ABPM sowie die hohe Verschreibungsrate von RAS-Blockern und empfohlenen Kombinationstherapien könnte hierfür der Schlüssel sein.
The B-ADENOMA Study: Bowelscope – Accuracy of Detection using Endocuff Optimisation of Mucosal Abnormalities: Study Protocol for randomised controlled trial
Authors: Ngu Wee , Walls Martin , Bhandari Pradeep , Stokes Clive , Totton Nikki , Hoare Zoe , Bastable Lexi , Rees Colin
Published: July 2018

Background and study aims UK Bowel Cancer Screening flexible sigmoidoscopy (BowelScope) currently offers patients aged 55 a one-off flexible sigmoidoscopy for adenoma clearance to decrease colorectal cancer incidence by interrupting the adenoma-carcinoma sequence. Recent evidence has shown maximum benefit in increasing adenoma detection rate (ADR) using the Endocuff Vision device in the left side of the colon and in screening patients. Currently, ADR is low and shows unacceptable variation in BowelScope. ADR is a quality indicator in screening sigmoidoscopy and higher rates have been shown to reduce colorectal cancer incidence.

Patients and methods This will be a prospective, multicenter, UK-based randomized controlled trial (RCT) comparing ADR in Endocuff-assisted versus standard bowel cancer screening flexible sigmoidoscopy (BowelScope). All patients aged 55 to 61 years invited to BowelScope screening and able to give informed consent will be eligible for recruitment. Exclusion criteria include absolute contraindications to flexible sigmoidoscopy, known or suspected large bowel obstruction or pseudo-obstruction, colonic strictures or polyposis syndromes, known severe diverticular segment, active colitis, inability to give informed consent, anticoagulation precluding polypectomy and pregnancy. Patients will be randomized on the day of procedure to Endocuff-assisted flexible sigmoidoscopy or standard flexible sigmoidoscopy, stratified by age group and sex. Baseline, endoscopy and polyp data were collected as well as nurse and patient assessment of comfort. Polyp histology was collected when available. Patients will be asked to return a comfort questionnaire the following day and were followed up for 14 days for complications.

The study will take place across 12 to 20 hospital trusts across the UK and recruited 3222 patients.

Results The ADENOMA trial will be designed to demonstrate a significant improvement in ADR with maximal effect in the left colon and in fecal occult blood test-positive screening patients. This trial will be the first RCT to look at Endocuff Vision in bowel cancer screening flexible sigmoidoscopy. We will aim to establish whether Endocuff vision improves ADR in this population.

Clinicaltrials.gov Identifier: NCT03072472
Number of polyps detected is a useful indicator of quality of clinical colonoscopy
Authors: Amano Takahiro , Nishida Tsutomu , Shimakoshi Hiromi , Shimoda Akiyoshi , Osugi Naoto , Sugimoto Aya , Takahashi Kei , Mukai Kaori , Nakamatsu Dai , Matsubara Tokuhiro , Yamamoto Masashi , Hayashi Shiro , Nakajima Sachiko , Fukui Koji , Inada Masami
Published: July 2018

Background and study aims Adenoma detection rate (ADR) is a well-known quality indicator (QI) for colonoscopy. It is, however, difficult to evaluate ADR during practice. The aim of this study was to investigate the number of endoscopically detected polyps as a QI for colonoscopy.

Patients and methods This was a retrospective single-center cohort study of 5,190 consecutive patients who underwent colonoscopy from January 2015 to May 2016. Among these patients, we ultimately enrolled 1,937 patients for initial colonoscopy. We evaluated QIs including bowel preparation, cecum intubation time, withdrawal time, number of endoscopically detected polyps, ADR and advanced neoplasia detection rate (ANDR)

Results The mean number of endoscopically detected polyps, ADR and ANDR were 1.5 ± 2.3 (95 % confidence interval (CI)1.4 – 1.6), 38.6 % (95 % CI 36.5-40.8), and 18.3 % (95 % CI 16.6 – 20.1), respectively. ADR and ANDR increased with the number of endoscopically detected polyps, but the correlation reached a plateau at five or more polyps. We divided the patients into three groups based on the number of polyps (1 to 2, 3 to 4, and 5 or more). Logistic regression analysis adjusted by age and sex revealed that presence of a large number of polyps was a strong predictor of advanced neoplasia (odds ratio: 3.1 [95 % CI 2.2 – 4.3] for 3 to 4 polyps and 7.9 [95 % CI 5.4 – 11.8] for 5 or more polyps when using the presence of 1 or 2 polyps as a reference).

Conclusion The number of endoscopically detected polyps can predict risk of advanced neoplasia and may thus be a new QI for colonoscopy.
Enteral stent placement for malignant afferent loop obstruction by the through-the-scope technique using a short-type single-balloon enteroscope
Authors: Sasaki Takashi , Yamada Ikuhiro , Matsuyama Masato , Sasahira Naoki
Published: July 2018

Background and study aims A short-type single-balloon enteroscope with a 3.2-mm working channel makes it possible to insert an enteral stent by the through-the-scope technique in patients with malignant afferent loop obstruction. Here, we report five cases of malignant afferent loop obstruction treated with endoscopic enteral stenting. We also propose a new classification for three types of malignant afferent loop obstruction. Type 1: The obstruction site is located distal to the papilla or the bilioenteric anastomosis. Type 2: The obstruction site is located at the papilla or the bilioenteric anastomosis. Type 3: The obstruction site is located between the bilioenteric and pancreaticoenteric anastomosis. The patients with type 1 and 3 were simply treated by inserting an enteral stent endoscopically. The patient with type 2 was treated with an endoscopic enteral stent for malignant afferent loop obstruction and with percutaneous transhepatic biliary stenting for malignant biliary obstruction. Although double stenting for type 2 remains a difficult endoscopic procedure, the endoscopic approach has become the standard approach for malignant afferent loop obstruction.
Endosonography-guided drainage of loculated malignant ascites using double-pigtail plastic stents
Authors: Köck Reiner , Jürgensen Christian , Fischer-Lampsatis Rupert
Published: July 2018

Background and study aims Endoscopic ultrasound (EUS)-guided drainage is a well-established procedure for peripancreatic fluid collections (PFC) that develop in the context of acute pancreatitis or following pancreatic surgery. Malignant ascites can occur in a loculated form resembling PFC causing a variety of symptoms, with limited treatment options. There is a paucity of data about application of EUS-guided drainage for these kinds of fluid collections. So far, only one report exists describing clinical success in three cases, using fully-covered self-expanding metal stents (FCSEMS). FCSEMS, however, have possible drawbacks, particularly if they have to remain in place for an indeterminate period of time. Herein, we describe EUS-guided drainage of loculated malignant ascites using double-pigtail plastic stents in two patients severely symptomatic from esophagogastric obstruction symptoms. Technical and clinical success was achieved in both cases without clinically significant complications including one case, where ongoing symptom control could be observed after 6 months of follow-up.
Polypectomy techniques among gastroenterologists in Norway – a nationwide survey
Authors: Pedersen Ina , Løberg Magnus , Hoff Geir , Kalager Mette , Bretthauer Michael , Holme Øyvind
Published: July 2018

Background and study aims Incomplete polyp removal has been estimated to cause 27 % of all colorectal cancers detected soon after colonoscopy. There is limited information regarding polypectomy techniques among endoscopists. The article is a nationwide survey of polypectomy techniques among Norwegian endoscopists.

Materials and methods We invited all board-certified gastroenterologists in Norway to complete a web-based questionnaire about their polypectomy technique. Inadequate polypectomy techniques were defined as using biopsy forceps for polyps larger than 3 mm in diameter, using hot biopsy forceps for polypectomy, and using the same electrocautery output irrespective of polyp size and morphology.

Results Twenty-six of 30 Norwegian gastroenterology departments participated in the study. A total of 119 endoscopists received the survey, and 70 (59 %) responded. Mean duration of endoscopy practice was 11.5 years, and 95 % had performed more than 1,000 colonoscopies during their career. Twenty-eight endoscopists (40 %) used one or more inadequate polypectomy techniques: 10 (14.3 %) used biopsy forceps for removal of polyps larger than 3 mm in diameter, five (7.1 %) used hot biopsy for polypectomy, and 17 (24 %) used the same electrocautery output for all polypectomies. Five (7 %) endoscopists reported that they did not remove polyps smaller than 4 mm.

Conclusion A substantial number of Norwegian endoscopists use inadequate polypectomy techniques. Improved training and certification of endoscopists is warranted.
Mirizzi’s syndrome in Roux-en-Y bypass patient successfully treated with cholangioscopically-guided laser lithotripsy via percutaneous gastrostomy
Authors: Hammoudi Nassim , Brieau Bertrand , Barret Maximilien , Bordacahar Benoit , Leblanc Sarah , Coriat Romain , Chaussade Stanislas , Prat Frédéric
Published: July 2018

Obesity and bariatric surgery are major risk factors in gallstone disease. In patients with a past history of Roux-en-Y gastric bypass, Mirizzi’s syndrome is a challenging endoscopic situation because of the modified anatomy. Here we report the first case of a patient with a Roux-en-Y gastric bypass treated by intracorporeal lithotripsy with a digital single-operator cholangioscope following an endoscopic retrograde cholangiopancreatography (ERCP) using a percutaneous gastrostomy access.
Use of over-the-scope-clip (OTSC) improves outcomes of high-risk adverse outcome (HR-AO) non-variceal upper gastrointestinal bleeding (NVUGIB)
Authors: Asokkumar Ravishankar , Soetikno Roy , Sanchez-Yague Andres , Kim Wei Lim , Salazar Ennaliza , Ngu Jing
Published: July 2018

Background and study aims Endoscopic treatment of non-variceal upper gastrointestinal bleeding (NVUGIB) with high-risk adverse outcome (HR-AO) features has a high risk of failure. We studied the safety and efficacy of over-the-scope clips (OTSC) to treat these lesions.

Patients and methods We included patients who were treated using OTSC for NVUGIB from January 2015 to October 2017. We studied rebleeding and mortality rates and used the Rockall data and our institution’s prior data for comparison. We used descriptive and chi-square statistics.

Results We studied 18 patients with 19 bleeding lesions: 9 (47 %) duodenal ulcers, 4 (21 %) Dieulafoy’s lesion, 3 (16 %) gastric ulcer, and 3 (16 %) bleeding after gastric biopsy, gastric polypectomy and endoscopic ultrasound-guided fine-needle aspiration of peri-gastric mass. We applied OTSC as the first-line treatment in 10 (53 %) and as the second-line treatment in 9 (47 %) bleeding lesions. Continued bleeding after OTSC occurred in six patients, but we treated it successfully and achieved complete hemostasis in all patients. We found OTSC use significantly decreased (0 % vs. 53 %, P < 0.01) and reduced (0 % vs. 24 %, P = 0.08) the rebleeding rate in our high-risk (RS ≥ 8) and intermediate-risk (RS = 4 – 7) Rockall score patients as compared to the rates reported by the Rockall study, respectively. When compared to our institution’s prior study, we found a decrease in the rebleeding rate with OTSC (0 % vs. 21 %, P = 0.06) in our intermediate-to-high risk Rockall score patients (RS ≥ 4). There was no difference in mortality rates as compared to both control studies.

Conclusion Use of OTSC is safe, efficacious and appears superior to standard treatment for HR-AO NVUGIB. OTSC should be considered as first-line treatment for HR-AO bleeding.
„Medikamentös ausbehandelte Fluktuationen“ trotz „optimierter peroraler/transdermaler Therapie“ bei Morbus Parkinson: Versuch einer pragmatischen Definition
Authors: Ebersbach Georg , Poewe Werner
Published: July 2018

Im Verlauf der Behandlung des idiopathischen Parkinson-Syndroms (IPS) kann es dazu kommen, dass L-Dopa-induzierte motorische Komplikationen (Wirkfluktuationen und Dyskinesien) nicht mehr suffizient durch Anpassung der oralen oder transdermalen Medikation beherrschbar sind. Diese Situation wird unter anderem mit dem Begriff „medikamentös ausbehandelte Fluktuationen“ (MAF) umschrieben und bildet den Ausgangspunkt für eskalierende Therapieentscheidungen mit teilweise weitreichender Bedeutung für die Alltagsabläufe, Lebensqualität und Zukunftsperspektiven der betroffenen Patienten und für ihr Umfeld. Nationale und internationale Leitlinien empfehlen, zu diesem Zeitpunkt die (Differenzial-)Indikation für eine der derzeit etablierten eskalierten Therapien mittels tiefer Hirnstimulation (THS), kontinuierlicher subkutaner Apomorphin-Infusion (APO) oder intrajejunaler Infusion von Levodopa-Gel (IJLG) zu prüfen.

Obwohl die Termini „medikamentös ausbehandelte“ bzw. „refraktäre“ Fluktuationen/Dyskinesien intuitiv genauso verständlich erscheinen wie der eng damit verbundene Begriff der „optimierten Medikation“, handelt es sich letztlich um Konstrukte, die in Leitlinien nicht konkret definiert und daher einer subjektiven individuellen Beurteilung anheimgestellt werden. Weil die Feststellung von „MAF“ weitreichende therapeutische Konsequenzen hat, wird in diesem Artikel ein pragmatischer Algorithmus für die Optimierung der Medikation bei Fluktuationen und Dyskinesien vorgestellt, der zur Operationalisierung des Begriffs der MAF beitragen soll. Außerdem soll die Frage diskutiert werden, ob und unter welchen Umständen bei der Indikationsstellung zur THS oder anderen Eskalationstherapien auf eine vorangehende Optimierung der oralen/transdermalen Medikation verzichtet werden kann.

Neben einer methodischen Analyse der vorhandenen therapeutischen Optionen bedeutet die individuelle Festlegung, ab welchem Zeitpunkt Komplikationen der oral-medikamentösen Therapie als nicht mehr tolerabel betrachtet werden, immer auch eine Berücksichtigung der Präferenzen und Bedenken des einzelnen Patienten. Eine pragmatische Definition von MAF ersetzt daher nicht eine individualisierte Entscheidungsfindung für eine eskalierte Therapie im Sinne eines „shared informed decision making“, sondern soll dem Behandler therapeutische Grundregeln für diesen Prozess an die Hand geben.
Des-Gamma-Carboxyprothrombin (PIVKA II) and Plasma Vitamin K1 in Newborns and Their Mothers
Authors: von Kries R , Shearer M J , Widdershoven J , Motohara K , Umbach G , Göbel U
Published: July 2018

Assessments of the vitamin K status in newborns and their mothers by means of des-γ-carboxy-prothrombin (PIVKA II) measurement have given equivocal results. Part of the variability could be attributed to differences in sensitivity (i.e. the ability to detect small concentrations) and validity (i.e. ability to detect vitamin K deficiency) of the methods applied. None of these methods have yet been validated with respect to plasma vitamin K1. In 22 healthy mother/infant pairs PIVKA II was determined using three different assays including ratio Xa/ecarin (Xa/ec), crossed immunoelectrophoresis (CIE), and an ELISA with a monoclonal antibody (MAB). The results were compared with conventional clotting tests and plasma vitamin K1. The following results were obtained:

Cord blood: Clotting tests within age-related normal ranges; PIVKA II detection rates: 0/22 (Xa/ec), 1/22 (CIE), 4/22 (MAB); plasma vitamin K1: undetectable in 20/22.

Mothers: Clotting tests all within normal range; PIVKA II detection rates: 1/22 (Xa/ec), 0/22 (CIE), 5/22 (MAB); plasma vitamin K1 (pg/ml) for all mothers (median; range): 186; 55–833; for PIVKA II positive mothers: 213; 59–699.

PIVKA II detectability in newborns and mothers was not correlated. The results show an increase in sensitivity for PIVKA II detection in the order of MAB ≫CIE >Xa/ec. Due to the very low plasma vitamin K1 at birth, no correlation was possible between cord PIVKA II detectability and plasma vitamin K1. However, in mothers at term PIVKA II MAB appears to be unrelated to the vitamin K status.
Serum Osteocalcin as a Marker for Vitamin K-Status in Pregnant Women and Their Newborn Babies
Authors: Jie Kon-Siong G , Hamulyák Karly , Gijsbers Birgit L M G , Roumen Frans J M E , Vermeer Cees
Published: July 2018

Osteocalcin (bone Gla-protein) is a vitamin K-dependent protein synthesized by osteoblasts. Its hydroxylapatite binding capacity (HBC) is generally used to estimate the Gla-content of circulating osteocalcin. Here we have used the HBC of serum osteocalcin as a marker for the vitamin K-status in pregnant women and their offspring. For all cases investigated the HBC values in the cord samples were substantially lower than in the corresponding maternal ones. Babies from mothers who had been treated with vitamin K during the last 6 weeks prior to delivery, had significantly higher HBC values than those from a placebo group. The results presented in this paper are indicative for a generally occurring vitamin K deficiency in newborns. At delivery the HBC in untreated women was low as well. In both the placebo- and the vitamin K-group a good correlation was found between the HBC values in paired samples from mother and child. Whether the maternal HBC value may be used as a prenatal marker for estimating the fetal vitamin K-status remains to be seen.
Multicentric Evaluation of a New Assay for Prothrombin Fragment F1+2 Determination
Authors: Bruhn H D , Conard J , Mannucci M , Monteagudo J , Pelzer H , Reverter J C , Samama M , Tripodi A , Wagner C
Published: July 2018

A multicenter study of a recently developed ELISA for the determination of prothrombin fragment Fl+2 was performed in order to evaluate analytical and clinical aspects.

Mean intra-assay and inter-assay reproducibility were found to be 11.0 and 12.6%, respectively. The measuring range covered by the calibration curve reaches from 0.04 to 10.0 nM/1 Fl+2. Testing 133 healthy subjects a reference range of 0.37 to 1.11 nM/1 Fl+2 (2.5–97.5 percentile) with a median of 0.66 nM/1 F1+2 was calculated. Minor difficulties with blood sampling (venous occlusion for 2 min) did not affect Fl+2 plasma concentrations.

Significantly increased F1+2 levels were measured in patients with leukemia (p <0.0001), severe liver disease (p <0.005) and after myocardial infarction (p <0.01). Elevated F1+2 concentration before the beginning of heparin therapy (1.25 nM/1) decreased to 0.77 nM/1 (p <0.0001) after 1 day of therapy. For patients in the stable phase of oral anticoagulant therapy decreasing Fl+2 concentrations were measured with increasing INR. Fl+2 levels were already significantly reduced in patients with INR <2.0 (0.56 nM/1; p = 0.0005). Thus Fl+2 determination may be helpful in identifying activation processes as well as in monitoring anticoagulant therapy.
Collaborative Study of a Proposed International Standard for Plasma Fibrinogen Measurement
Authors: Gaffney Patrick J , Wong M Y
Published: July 2018

There is increased interest in the relationship between plasma fibrinogen levels and the incidence of coronary artery disease. The National Institute for Biological Standards and Control (UK) has completed a study to establish an International Standard for plasma fibrinogen. This study was conducted using a recommended assay procedure to measure the clottable material present in the proposed lyophilised Standard (coded 89/644). Twenty-two laboratories from nine countries took part in the study and analysis of the data allowed the calibration of 89/644 at 2.4 mg/ml clottable protein. Agreement with this figure was established in two laboratories using three or more different assays for plasma fibrinogen. Degradation studies of the proposed plasma fibrinogen Standard suggested that no loss of clottable protein was observed when the lyophilised material was stored at 20° C for 1 year.

The Fibrinogen Sub-Committee of the ISTH (Amsterdam, The Netherlands, June 1991) supported the establishment of 89/644 as an International Standard. This collaborative study will be presented to the Expert Committee on Biological Standardisation of the World Health Organisation at their 1992 session. In the meantime 89/644 will be distributed as the proposed International Standard for plasma fibrinogen measurement containing 2.4 mg/ ml clottable protein.
Mutations in Severe, Type III von Willebrand’s Disease in the Dutch Population: Candidate Missense and Nonsense Mutations Associated with Reduced Levels of von Willebrand Factor Messenger RNA
Authors: Eikenboom Jeroen C J , Ploos van Amstel Hans K , Reitsma Pieter H , Briët Ernest
Published: July 2018

The von Willebrand factor (vWF) genes of nine unrelated, severe, type III von Willebrand’s disease (vWD) patients (six of Dutch origin) and four unrelated Dutch type I vWD patients were screened for mutations in exons that contain CGA codons (Arg), which are liable to mutation to TGA stop codons. The nine exons of the vWF gene (3, 8, 9, 10, 28, 31, 32, 43 and 45) that contain all the CGA codons (11 in total) of the vWF cDNA were amplified by the polymerase chain reaction and screened for mutations by single-strand conformation polymorphism analysis, restriction enzyme – and/or nucleotide sequence analysis. Three of the severe vWD patients were found to be heterozygous for a nonsense mutation: CGA Arg 2535 → TGA Stop. Three other severe vWD patients were homozygous for a single nucleotide substitution, AAC Asn 2546 → TAC Tyr. The transcription of these mutated alleles was tested by cDNA dependent amplification of platelet RNA. The level of transcription product was strongly reduced for either mutant allele.
A Specific Immunologic Assay for Functional Plasminogen Activator Inhibitor 1 in Plasma – Standardized Measurements of the Inhibitor and Related Parameters in Patients with Venous Thromboembolic Disease
Authors: Philips Malou , Juul Anne-Grethe , Selmer Johan , Lind Bent , Thorsen Sixtus
Published: July 2018

A new assay for functional plasminogen activator inhibitor 1 (PAI-1) in plasma was developed. The assay is based on the quantitative conversion of PAI-1 to urokinase-type plasminogen activator (u-PA)-PAI-l complex the concentration of which is then determined by an ELISA employing monoclonal anti-PAI-1 as catching antibody and monoclonal anti-u-PA as detecting antibody. The assay exhibits high sensitivity, specificity, accuracy, and precision. The level of functional PAI-1, tissue-type plasminogen activator (t-PA) activity and t-PA-PAI-1 complex was measured in normal subjects and in patients with venous thromboembolism in a silent phase. Blood collection procedures and calibration of the respective assays were rigorously standardized. It was found that the patients had a decreased fibrinolytic capacity. This could be ascribed to high plasma levels of PAI-1. The release of t-PA during venous occlusion of an arm for 10 min expressed as the increase in t-PA + t-PA-PAI-1 complex exhibited great variation and no significant difference could be demonstrated between the patients with a thrombotic tendency and the normal subjects.
Comparative Arterial Antithrombotic Activity of Clopidogrel and Acetyl Salicylic Acid in the Pig
Authors: Samama Ch M , Bonnin Ph , Bonneau M , Pignaud G , Mazoyer E , Bailliart O , Maffrand J P , Viars P , Caen J P , Drouet L O
Published: July 2018

We investigated the comparative antithrombotic properties of clopidogrel, an analogue of ticlopidine, and aspirin, using the Folts' model on femoral arteries in 22 pigs. On each animal, clopidogrel or aspirin were used to treat the thrombotic process on the left femoral artery and to prevent this process on the right femoral artery. Sequentially: an injury and stenosis were carried out on the left femoral artery; the thrombotic process was monitored with a Doppler during a 30-min observation period for cyclic flow reductions or permanent cessation of flow; after the first cyclic flow reduction occurred, clopidogrel (5 mg kg-1) or aspirin (2.5, 5, 100 mg kg-1) were injected intravenously; if cyclic flow reductions were abolished, epinephrine (0.4 µg kg-1 min-1) was injected to try to restore cyclic flow reductions and/or permanent cessation of flow; then injury and stenosis were applied on the right femoral artery. Before and after injection of clopidogrel or aspirin, ear immersion bleeding times and ex-vivo platelet aggregation were performed. Clopidogrel (n = 7) abolished cyclic flow reductions in all animals and epinephrine did not restore any cyclic flow reduction. On the right femoral artery, cyclic flow reductions were efficiently prevented, even for two injuries. Basal bleeding time (5 min 28) was lengthened (>15 min, 30 min after clopidogrel and remained prolonged even after 24 h). ADP-induced platelet aggregation was inhibited (more than 78%). Comparatively, aspirin had a moderate and no dose-dependent effect. Aspirin 2.5 mg kg-1 (n = 6) abolished cyclic flow reductions in 2 animals, CFR reoccurred spontaneously in one animal and epinephrine restored it in a second animal. Aspirin 5 mg kg-1 (n = 6) abolished cyclic flow reductions in only 3 animals and epinephrine always restored it. Aspirin 100 mg kg-1 (n = 3) was unable to abolish cyclic flow reductions. On the right femoral artery, aspirin did not significantly prevent cyclic flow reductions which occurred in all animals after one (n = 14) or two injuries (n = 1), except for one animal. Basal bleeding time was lengthened but it shortened rapidly, reaching its basal value after 24 h. ADP-induced aggregation was not significantly inhibited, whereas arachidonic acid induced aggregation was always inhibited. Clopidogrel appears as a more potent antithrombotic drug than aspirin in this model, in treating and preventing spontaneous or epinephrine-induced cyclic flow reductions and lengthening bleeding time.
Structure, Kinetics, and Function of Human and Rhesus Plasma Prekallikreins Are Similar
Authors: Veloso Dulce , Smith Joseph I , Denny Stephen , Cosgriff Thomas M
Published: July 2018

To determine if rhesus monkeys (Macaca mulatta) could serve as a model for studying the role of the contact system in the pathophysiology of human infections, we compared structural, kinetic, and functional characteristics of plasma prekallikrein and its activation products in rhesus and humans. Three prekallikrein variants (85-, 89- and 93-kDa) were revealed in rhesus plasma as compared with the two variants (85- and 88-kDa) in human plasma by immunoblotting with the monoclonal antibody MAb 13G11. The prekallikrein concentration in rhesus plasma was 1.5-fold that in human plasma as determined by computerized immunoblot analyses (CIBA) and amidolytic activity. The electrophoretic mobility of prekallikrein from plasma of both species increased after deglycosylation. Inhibition of prekallikrein activation by MAb 13G11 was 55% (rhesus plasma) and 76% (human plasma), with similar inhibition curves. Immunoblots of activated rhesus plasma showed prekallikrein, complexes of kallikrein with C1 inhibitor, α2-macroglobulin and ~60-kDa inhibitor(s) (viz. antithrombin III), and 45-kDa fragments, like those in activated human plasma. Concentrations and molecular masses of factor XII and high molecular weight kininogen were similar in rhesus and human plasma. The activated partial thromboplastin time (APTT) and prothrombin time were 20.1 ± 1.6 and 9.7 ± 0.3 s for rhesus and 32.0 ±5.6 and 12 ± 0.5 s for human plasma. Human and rhesus APTTs were similar when prekallikrein concentrations in human and rhesus plasma became alike by adding human purified prekallikrein. We conclude that the contact systems of rhesus and humans are similar in many respects and that rhesus should be a useful model to study the role of the contact system in the pathophysiology of human infectious diseases.
The Influence of Glycosylation on the Catalytic and Fibrinolytic Properties of Pro-Urokinase
Authors: Lenich Catherine , Pannell Ralph , Henkin Jack , Gurewich Victor
Published: July 2018

We previously found that human pro-UK expressed in Escherichia coli is more active in fibrinolysis than recombinant human pro-UK obtained from mammalian cell culture media. To determine whether this difference is related to the lack of glycosylation of the E. coli product, we compared the activity of E. coli-derived pro-UK [(-)pro-UK] with that of a glycosylated pro-UK [(+)pro-UK] and of a mutant of pro-UK missing the glycosylation site at Asn-302 [(-) (302) pro-UK]. The latter two pro-UKs were obtained by expression of the human gene in a mammalian cell. The nonglycosylated pro-UKs were activated by plasmin more efficiently (≈2-fold) and were more active in clot lysis (1.5-fold) than the (+)pro-UK. Similarly, the nonglycosylated two-chain derivatives (UKs) were more active against plasminogen and were more rapidly inactivated by plasma inhibitors than the (+)UK.

These findings indicate that glycosylation at Asn-302 influences the activity of pro-UK/UK and could be the major factor responsible for the enhanced activity of E. coli-derived pro-UK.
Adrenergic Stimulation of Regional Plasminogen Activator Release in Rabbits
Authors: Chandler W L , Loo S C , Mornin D
Published: July 2018

The purpose of this study was to determine whether different regions of the rabbit vascular system show variations in the rate of plasminogen activator (PA) secretion. To start, we evaluated the time course, dose response and adrenergic specificity of PA release. Infusion of 1 µg/kg of epinephrine stimulated a 116 ± 60% (SD) increase in PA activity that peaked 30 to 60 s after epinephrine administration. Infusion of 1 µg/kg of norepinephrine, isoproterenol and phenylephrine had no effect on PA activity. Pretreatment with phentolamine, an alpha adrenergic antagonist, blocked the release of PA by epinephrine while pretreatment with the beta blocker propranolol had no effect. This suggests that PA release in the rabbit was mediated by some form of alpha receptor.

Significant arterio-venous differences in basal PA activity were found across the pulmonary and splanchnic vascular beds but not the lower extremity/pelvic bed. After stimulation with epinephrine, PA activity increased 46% across the splanchnic bed while no change was seen across the lower extremity/pelvic bed. We conclude that several vascular beds contribute to circulating PA activity in the rabbit, and that these beds secrete PA at different rates under both basal and stimulated conditions.
Human Platelets Exposed to Mechanical Stresses Express a Potent Lipoxygenase Product
Authors: Margalit Alon , Livne Avinoam A
Published: July 2018

Human platelets exposed to hypotonicity undergo regulatory volume decrease (RVD), controlled by a potent, yet labile, lipoxygenase product (LP). LP is synthesized and excreted during RVD affecting selectively K+ permeability. LP is assayed by its capacity to reconstitute RVD when lipoxygenase is blocked. Centrifugation for preparing washed platelets (1,550 × g, 10 min) is sufficient to express LP activity, with declining potency in repeated centrifugations, indicating that it is not readily replenish-able. When platelet suspension flows in a vinyl tubing (1 mm i.d.), at physiological velocity, controlled at 90–254 cm/s, LP formation increases as a function of velocity but declines as result of increasing the tubing length. Stirring the platelets in an aggregometer cuvette for 30 s, yields no LP unless the stirring is intermittent. No associated platelet lysis or aggregation are observed following the mechanical stress applications. These results demonstrate that although mechanical stresses result in LP production, the mode of its application plays a major role. These results may indicate that LP is synthesized under pathological conditions and could be of relevance to platelets behavior related to arterial stenosis.
Effect of Platelet Encapsulated lloprost on Platelet Aggregation and Adhesion to Collagen and Injured Blood Vessels In Vitro
Authors: El-Gamal B A B , Pfliegler G , Crawford N
Published: July 2018

A novel approach to site-directed delivery of drugs in vivo using blood platelets as carrier vehicles is being investigated. In this context some initial studies are reported on the effect of platelet encapsulated anti-platelet drugs on platelet aggregation and adhesion to fibrillar collagen and injured arteries in vitro. The stable prostacyclin analogue lloprost has been encapsulated within human and pig platelets by high voltage electroporation (Hughes and Crawford 1989 and 1990). After resealing the platelets, the packaged drug has a negligible effect upon platelet adhesion to a surface of fibrillar collagen or to damaged aorta (stripped to the tunica media to simulate deep injury). The rate of platelet recruitment to the collagen shows no dose dependency with respect to intracellular lloprost concentrations. After high lloprost loading, as few as 2% drug loaded platelets in a mixture with control (sham encapsulated) platelets, inhibit agonist-induced platelet aggregation >50%. The prior deposition of a “lawn” of Iloprost-loaded platelets onto fibrillar collagen or damaged aorta has a substantial inhibitory effect (50–70%) upon the secondary recruitment of normal platelets compared with recruitment to a “lawn” of normal platelets. This inhibition of secondary recruitment occurs even in the presence of a platelet activator. If reduction of platelet recruitment to a vessel wall lesion results in a decrease in the local concentration of platelet granule-derived smooth muscle cell chemotactic and proliferative factors, this site-directed drug delivery may well have application for the prevention of restenosis following balloon angioplasty procedures.
Relationships between Haemostatic Factors and Capillary Morphology in Human Diabetic Neuropathy
Authors: Ford Isobel , Malik Rayaz A , Newrick Paul G , Preston F Eric , Ward John D , Greaves Michael
Published: July 2018

We have examined haemostatic factors in 15 diabetic patients with peripheral neuropathy and 10 diabetic patients without clinical complications. Plasma and blood viscosity, fibrinogen, factor VIIIc, von Willebrand factor activity, spontaneous platelet aggregation and fibrinolytic activity were not significantly different between diabetic patients without clinical complications and diabetic patients with peripheral neuropathy. Platelet aggregation was enhanced in diabetic patients with neuropathy compared with those without complications. In the 15 patients with neuropathy and 3 without complications, who underwent biopsy of sural nerve, skin and muscle, associations were found between haemostatic variables and measures of nerve capillary pathology, notably: plasma fibrinogen and nerve capillary basement membrane thickness (r = 0.70, p <0.001); thromboxane B2 production and nerve capillary basement membrane thickness (r = –0.61, p <0.01); plasma fibrinolytic activity and endoneurial capillary lumen size (r = 0.60, p <0.01) and endothelial cell outer perimeter (r = 0.65, p <0.01). The main associations of skin and muscle capillary abnormalities were with measures of in vitro platelet aggregation, and the correlations found with nerve capillary measurements were not echoed in the overlying muscle and skin. The results are supportive of the involvement of haemostatic abnormalities in the pathogenesis of diabetic neuropathy.
Tissue Factor Localization in Non-Human Primate Cerebral Tissue
Authors: del Zoppo Gregory J , Yu Jian-Qing , Copeland Brian R , Thomas Winston S , Schneiderman Jacob , Morrissey James H
Published: July 2018

Tissue factor (TF), the principal procoagulant of human brain, resides in specific regions of the non-human primate central nervous system. Immunohistochemical studies employing murine anti-human TF monoclonal antibodies (MoAbs) detected TF antigen in the cortex, basal ganglia, cerebellum, and cervical spinal cord in three normal baboon subjects. Although significantly less prominent than human cortical gray matter, a distinct partition of TF in gray matter >white matter was noted. The gray matter predilection of TF was confirmed in primate temporal and parietal lobe cortex by both sandwich ELISA and one-stage coagulation assay. Variation in the relative quantity of TF antigen was observed by ELISA among the three subjects studied. Procoagulant activity followed the pattern of TF antigen (cortical gray matter >basal ganglia ≥cerebellum >cortical white matter), and was 96.5–98.5% inhibitable by a function inhibiting anti-human TF MoAb combination. TF antigen was associated with the microvasculature of all cerebral tissues studied, and spared capillaries most selectively in the cerebral cortex, basal ganglia, and cerebellum. These findings suggest a highly specific ordering of TF antigen and related procoagulant activity in the central nervous system of the baboon, confined primarily to gray matter parenchyma, and to the non-capillary microvasculature.
Inhibition of Platelet Adhesion to Fibrin(ogen) in Flowing Whole Blood by Arg-Gly-Asp and Fibrinogen γ-Chain Carboxy Terminal Peptides
Authors: Hantgan Roy R , Endenburg Silvia C , Cavero I , Marguerie Gérard , Uzan André , Sixma Jan J , de Groot Philip G
Published: July 2018

We have employed synthetic peptides with sequences corresponding to the integrin receptor-recognition regions of fibrinogen as inhibitors of platelet aggregation and adhesion to fibrinogen-and fibrin-coated surfaces in flowing whole blood, using a rectangular perfusion chamber at wall shear rates of 300 s–1 and 1,300 s–1. D-RGDW caused substantial inhibition of platelet aggregation and adhesion to fibrinogen and fibrin at both shear rates, although it was least effective at blocking platelet adhesion to fibrin at 300 s–1. RGDS was a weaker inhibitor, and produced a biphasic dose-response curve; SDRG was inactive. HHLGGAK-QAGDV partially inhibited platelet aggregation and adhesion to fibrin(ogen) at both shear rates. These results support the identification of an RGD-specific receptor, most likely the platelet integrin glycoprotein IIb: III a, as the primary receptor responsible for platelet: fibrin(ogen) adhesive interactions under flow conditions, and indicate that platelet adhesion to surface bound fibrin(ogen) is stabilized by multivalent receptor-ligand contacts.
Protein S Tokushima: An Abnormal Protein S Found in a Japanese Family with Thrombosis
Authors: Shigekiyo T , Uno Y , Kawauchi S , Saito S , Hondo H , Nishioka J , Hayashi T , Suzuki K
Published: July 2018

An abnormal protein S (PS) was found in a Japanese family with a high incidence of thrombosis. The proband is a woman who was born in Tokushima Prefecture. She had superior sagittal sinus thrombosis, thrombophlebitis of the left leg, and thrombosis of the placenta. She had a normal plasma level of free PS antigen but decreased PS activity. Her mother and aunt also had thrombophlebitis of the leg, and together with four other family members also showed a normal level but decreased activity of PS. This suggests that hereditary dysfunction of PS is inherited in this family as an autosomal dominant trait. The proband’s PS appears to have a slightly higher molecular weight than normal PS both in the intact and modified form, suggesting that it has a molecular defect on the carboxyl-terminal side of the thrombin-sensitive site. This abnormal PS with apparently unique characteristics was named PS Tokushima.
Replacement Therapy with a Purified Protein C Concentrate during Initiation of Oral Anticoagulation in Severe Protein C Congenital Deficiency
Authors: De Stefano V , Mastrangelo S , Schwarz H P , Pola P , Flore R , Bizzi B , Leone G
Published: July 2018

The case of an adult patient with moderately severe protein C deficiency (antigen 16%, activity 12%) is reported. Both parents had protein C levels compatible with heterozygous deficiency. Unlike other reported cases of severe protein C deficiency in adults, the onset of thrombotic symptoms occurred at 1 month of age; however, a symptom-free period until age 17 followed. Replacement therapy with a monoclonal antibody purified protein C concentrate was carried out during the initiation of oral anticoagulation after a course of i.v. heparin for deep vein thrombosis. The administration of the concentrate allowed maintenance of protein C above 50% until a stable therapeutic anticoagulation level could be obtained. This was reached within a short time, thus allowing safe administration of a loading dose of warfarin. We conclude that this approach to the prevention of skin necrosis seems more rapid and safer than previous schedules of oral anticoagulation in protein C-deficient patients.
Positive Association Between Self-Reported Fatty Food Consumption and Factor VII Coagulant Activity, a Risk Factor for Coronary Heart Disease, in 4246 Middle-Aged Men
Authors: Connelly J B , Roderick P J , Cooper J A , Meade T W , Miller G J
Published: July 2018

Raised levels of factor VII coagulant activity (VIIC) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIC. We explored this further in 4,246 men aged 45–69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month.

In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIC was 7.8% of standard (95% CI 5.1–10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIC, serum cholesterol and BMI. Thus, the VIIC difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level.

This study adds to the evidence that dietary fat intake influences VIIC and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.
Features of Thrombi and Diagnostic Accuracy of Impedance Plethysmography in Symptomatic and Asymptomatic Deep Vein Thrombosis
Authors: Agnelli Giancarlo , Cosmi Benilde , Radicchia Stefano , Veschi Franca , Boschetti Enrico , Lupattelli Luciano , Rinonapoli Emanuele , Nenci Giuseppe G
Published: July 2018

Impedance plethysmography (IPG) has high sensitivity and specificity in patients with symptomatic deep vein thrombosis (DVT) while it fails to detect asymptomatic DVT. The aim of this study was to determine whether the features of thrombi such as location, size and occlusiveness could explain the different accuracy of IPG in symptomatic and asymptomatic DVT patients. One-hundred and seventeen consecutive outpatients with a clinical suspicion of DVT and 246 consecutive patients undergoing hip surgery were admitted to the study. In symptomatic patients IPG was performed on the day of referral, followed by venography, while in asymptomatic patients IPG was performed as a surveillance programme, followed by bilateral venography.

A venography proved DVT was observed in 37% of the symptomatic patients and 34% of the asymptomatic limbs. A significantly higher proportion of proximal DVTs was found in symptomatic patients than in asymptomatic patients (78% vs 46%; p = 0.001). The mean Marder score, taken as an index of thrombus size, was significantly higher in symptomatic patients than in asymptomatic patients (19.0 vs 9.6; p = 0.0001). A significantly higher proportion of occlusive DVTs was observed in symptomatic than in asymptomatic patients (69% vs 36%; p = 0.001).

We conclude that the unsatisfactory diagnostic accuracy of IPG in asymptomatic DVT is due to the high prevalence of distal, small and non occlusive thrombi. Such thrombi are unlikely to cause a critical obstruction of the venous outflow and therefore to produce a positive IPG.
Characterization of Monocyte-Associated Factor V
Authors: Kappelmayer Janos , Kunapuli Satya P , Wyshock Edward G , Colman Robert W
Published: July 2018

We demonstrate that in addition to possessing binding sites for intact factor V (FV), unstimulated peripheral blood monocytes also express activated factor V (FVa) on their surfaces. FVa was identified on the monocyte surface by monoclonal antibody B38 recognizing FVa light chain and by human oligoclonal antibodies H1 (to FVa light chain) and H2 (to FVa heavy chain) using immunofluorescence microscopy and flow cytometry. On Western blots, partially cleaved FV could be identified as a 220 kDa band in lysates of monocytes. In addition to surface expression of FVa, monocytes also contain intracellular FV as detected only after permeabilization by Triton X-100 by monoclonal antibody B10 directed specifically to the Cl domain not present in FVa. We sought to determine whether the presence of FV in peripheral blood monocytes is a result of de novo synthesis.

Using in situ hybridization, no FV mRNA could be detected in monocytes, while in parallel control studies, factor V mRNA was detectable in Hep G2 cells and CD18 mRNA in monocytes. In addition, using reverse transcriptase and the polymerase chain reaction, no FV mRNA was detected in mononuclear cells or in U937 cells, but mRNA for factor V was present in Hep G2 cells using the same techniques. These data suggest that FV is present in human monocytes, presumably acquired by binding of plasma FV, and that the presence of this critical coagulation factor is not due to de novo synthesis.