bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparin-induced Thrombocytopenia – Pathogenesis and Treatment
Authors: Greinacher A. 
Published: March 2018

SummaryHeparin-induced thrombocytopenia (HIT) is now recognized as the most frequent immune-mediated adverse drug reaction. During the last decade, fundamental aspects of the pathogenesis of HIT have been resolved. The understanding of some the mechanisms underlying the development of new, paradox thromboembolic complications in HIT led to the concept that thrombin generation plays a key-role in clinically manifest HIT. Consequently new therapeutic concepts imply the use of drugs with either indirect of direct anti-thrombin activity such as donaparoid-sodium and the recombinant hirudin lepirudin. During the last years results of first prospective studies assessing various treatment regimens in HIT became available. Although data of randomized trials are still missing some treatment recommendations can already be drawn from these studies. This review summarizes key aspects of the pathogenesis of HIT and provides an overview of current treatment strategies.
Treatment of Carotid Artery Stenosis by Elective Stent Placement Instead of Carotid Endarterectomy in Patients with Severe Coronary Artery Disease
Authors: Krämer Jochen , Vogel Peter , Friedrich Ingrid , Michael Gross C. , Uhlich Frank , Tamaschke Christian , Dietz Rainer , Waigand Jürgen 
Published: March 2018

SummaryPatients with concomitant cardiac and cerebrovascular disease undergoing revascularization procedures are at high risk of both, cardiac and cerebrovascular complications. The purpose of our study was to evaluate the feasibility of prior elective carotid artery stenting as an alternative treatment procedure to carotid endarterectomy (CEA) in patients with concomitant coronary artery disease (CAD), who clearly needed coronary revascularization. We offered extracranial internal carotid stenting to 85 patients with 89 significant carotid stenoses. Out of these, 19 patients were symptomatic. The quantitative mean reduction in diameter was 77 ± 11%. Stent implantation was successful in 88 lesions. Two disabling major and 3 reversible minor strokes occurred periprocedurally. Three patients showed asymptomatic restenosis and stent deformation was detected in 2 patients. Based on this experience, carotid stenting in high risk patients with severe coronary artery disease is feasible and safe and might be indicated as an alternative procedure for combined surgery.
Impact of Apolipoprotein(a) Isoform Size Heterogeneity on the Lysine Binding Function of Lipoprotein(a) in Early Onset Coronary Artery Disease
Authors: Simó Josep , Vilella Elisabet , Ribas Montserrat , Pujana Miguel , Sundaram Indirana , Hammel Jeffrey , Hoover-Plow Jane , Joven Jorge 
Published: March 2018

SummaryElevated plasma Lp(a) is an independent risk factor for cardiovascular disease. Unique to Lp(a) is the apoprotein, apo(a) which can vary from 250 to 800 kDa in molecular weight. Small isoforms are also associated with the risk of cardiovascular disease. The purpose of this study was to examine the association of Lp(a) concentration, apo(a) size, and Lp(a) lysine-binding site(s) (LBS) function in patients with early onset heart disease, and age-matched controls. Mean values of Lp(a) were significantly higher in the patients than for the age-matched group. The smallest molecular weight isoform for each subject had significantly fewer kringles for the patients than the age-matched controls. There was a significant correlation between LBS activity and kringle number in the single-banded phenotypes of the patients, but not the controls. LBS activity was significantly higher in patients with small isoforms (≤18 kringles) compared to controls. The odds ratio for coronary artery disease for high LBS activity and high Lp(a) concentration was 4.4 (p = 0.002) and for high LBS activity and small isoforms was 10.1 (p = 0.002). In the patients, Lp(a) concentration was higher, apo(a) size was smaller, and LBS activity higher in the small isoforms compared to the controls. This study suggests an association of high LBS activity in small isoforms of Lp(a) with disease in humans.
Genetic Predisposition to Bleeding during Oral Anticoagulant Therapy: Evidence for Common Founder Mutations (FIXVal-10 and FIXThr-10) and an Independent CpG Hotspot Mutation (FIXThr-10)
Authors: Kriz K. , Wuillemin W. A. , Maly F. E. , von Felten A. , Siegemund A. , Keeling D. M. , Baker P. , Chu K. , Konkle B. A. , Lämmle B. , Albert T. , Oldenburg J. ,   the Study Group on Hereditary Warfarin Sensitivity
Published: March 2018

SummaryThe recent discovery of five patients with coumarin sensitive FIX-variants due to a missense mutation in the FIX propeptide, either Ala-10Val or Ala-10Thr, has highlighted a novel type of genetic predisposition to bleeding during oral anticoagulant therapy (OAT). In the present study, we report six additional patients with such FIX variants. Haplotype analysis of FIX polymorphisms revealed a founder effect in the five German and Swiss patients with the Val-10 variant. Also, four Thr-10 variants detected in Germany, Switzerland and Great Britain derived from a common founder. Two Thr-10 variants from USA showed an independent de novo origin at a CpG dinucleotide that in general represents a mutation hotspot. These findings implicate the existence of additional subjects with corresponding variants in the populations of various countries. Even though the rare occurrence of these variants does not justify a general aPTT screening during OAT, it is recommended to monitor each bleeding event during OAT in males in order to exclude a genetic predisposition to bleeding by means of the following testing strategy: a) aPTT-testing in each bleeding complication of male patients during OAT, b) if aPTT is disproportionately prolonged, determination of FIX:C, and c) if FIX:C is disproportionately decreased as compared to FII:C, FVII:C and FX:C, sequencing of exon 2 of the FIX gene. This strategy will provide a cost-effective and safe procedure to identify patients that carry the FIX variants. Moreover, such a strategy accumulates data about the prevalence of these FIX mutations in a given population.
Elevated Plasma Levels of Crosslinked Fibrinogen Gamma-chain Dimer Indicate Cancer-related Fibrin Deposition and Fibrinolysis
Authors: Steinkellner Werner , Holzmann Klaus , Gsur Andrea , Grimm Rudolf , Ensinger Christian , Obrist Peter , Sauermann Georg , Gerner Christopher 
Published: March 2018

SummaryCancer-related fibrin deposition and fibrinolysis were investigated by two-dimensional gel electrophoresis of human solid tumor and effusion specimen in addition to plasma samples. Fibrinogen gamma-chain dimer indicating fibrin deposition and plasmin-generated fibrinogen beta-chain fragments were identified in various solid tumor types by amino acid sequencing, mass spectrometry analysis and Western blotting. In tumor-associated effusions, these techniques allowed to observe plasmin-generated fragments of fibrinogen alpha, beta and gamma-chains in addition to elevated levels of acute-phase proteins. Similar observations were made in case of inflammation-associated effusions. No fibrin degradation product was observed in plasma samples, however, high amounts of fibrinogen gamma-chain dimer crosslinked by transglutaminase were detected in plasma from tumor patients, but not in plasma from controls and patients suffering acute infections and/or inflammations. This finding demonstrated that high transglutaminase activity may be associated with cancer. The presented data indicate that the amount of crosslinked fibrinogen gamma-chain dimer in plasma may correlate with tumor-associated fibrin deposition. The tumor-biological relevance of this potential marker protein is discussed.
Antiplatelet and Antithrombotic Activity of SL65.0472, a Mixed 5-HT1B/5-HT2A Receptor Antagonist
Authors: Lorrain Janine , Lochot Sylvette , Delahaye Monique , Lalé Alain , Savi Pierre , Lechaire Irène , Ferrari Patrice , Bernat André , Schaeffer Paul , Janiak Philippe , Duval Nicole , Grosset Alain , Herbert Jean-Marc , O’Connor Stephen , Berry Christopher 
Published: March 2018

SummaryThe antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-dihydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 μM 5-HT + threshold concentrations of ADP (0.5-1 M) or collagen (0.3 g/ml) with mean IC50 values of 49 ± 13 and 48 ± 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p. o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p. o. SL65.0472 (30 μg/kg i. v.) virtually abolished coronary cyclic flow variations (7.2 ± 1.0/h to 0.6 ± 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 ± 0.8 ml/ min to 31.8 ± 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p. o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.
Effect of Ca2+ Chelation on the Platelet Inhibitory Ability of the GPIIb/IIIa Antagonists Abciximab, Eptifibatide and Tirofiban
Authors: Marciniak Stanley , Jordan Robert , Mascelli Mary 
Published: March 2018

Summary
Objective. Enhanced GPIIb/IIIa binding and inhibition of platelet aggregation of eptifibatide by the reduction of ionized plasma calcium concentrations have been reported. The present study compared the importance of Ca2+ chelation on the in vitro platelet inhibitory profiles of the GPIIb/IIIa antagonists abciximab, eptifibatide and tirofiban. Methods and Results. Turbidimetric platelet aggregation dose response curves of the various GPIIb/IIIa antagonists were performed using platelet rich plasma (PRP) anticoagulated with either trisodium citrate, or the non-chelating anticoagulant, PPACK. The concentrations of antagonist that resulted in 50% inhibition of TRAP-induced (10 M) platelet aggregation (IC50) were measured in the presence of either citrate or PPACK. In addition, the influence of Ca2+ chelation on the binding properties (relative affinity, on- and off-rates) of abciximab for the GPIIb/IIIa receptor on platelets was measured. For all three agonists, the IC50 concentrations were lower for platelets treated with citrate than PPACK, but the degree of difference varied among the agents. The mean TRAP IC50 values for citrate and PPACK were 88.2 ± 12.2 nM and 126.1 ± 28.4 nM for abciximab (1.4 fold enhancement; p = 0.0007), 75.9 ± 13.3 nM and 142.6 ± 32.6 nM for tirofiban (1.9-fold enhancement; p = 0.001), and 260.2 ± 62.5 nM and 810.3 ± 182.5 nM for eptifibatide (3.1-fold enhancement; p = 0.001). A similar shift in effective inhibitor concentrations for abciximab was observed with ADP (10 M). The relative affinities (EC50), on- and off-rates of abciximab for the platelet GPIIb/IIIa receptor in the presence of trisodium citrate and PPACK were equivalent. Conclusions. These data confirm previous observations that Ca2+ chelation afforded by citrate decreases the effective inhibitor concentrations of GPIIb/IIIa antagonists, as assessed by turbidimetric platelet aggregation. However, the extent of decrease was less for abciximab and tirofiban, compared to eptifibatide.
The Subendothelium of the HMEC-1 Cell Line Supports Thrombus Formation in the Absence of von Willebrand Factor and Collagen Types I, III and VI
Authors: Bonnefoy Arnaud , Harsfalvi Jolan , Pfliegler George , Fauvel-Lafève Françoise , Legrand Chantal 
Published: March 2018

SummaryThe macromolecular composition of the extracellular matrix (ECM) produced by the human microvascular endothelial cell line (HMEC-1) was determined by ELISA and its thrombogenicity was studied in blood perfusion assays. Results were compared with those obtained with the ECM produced by human umbilical vein endothelial cells (HUVEC). The HMEC-1’s ECM contains collagen type IV, fibronectin, laminin and thrombospondin, but no detectable levels of collagen types I, III and VI, or von Willebrand factor (vWF), whereas all these components were found in the ECM synthesized by HUVEC. HMEC-1’s ECM was perfused with low-molecular-weight heparin-anticoagulated blood at two wall shear rates (650/s and 2600/s), representative of moderate and high arterial wall shear rates, in parallel plate flow chambers for 5 min. This resulted in the formation of large platelet aggregates, compared to essentially a monolayer of adherent platelets on HUVEC’s ECM. Interestingly, large thrombi were formed at 2600/s when HMEC-1’s ECM was perfused with the blood of a patient with severe type III von Willebrand disease lacking both plasma and platelet vWF, indicating that vWF was not absolutely required for thrombus formation on this matrix. Thrombin generated on the HMEC-1’s ECM contributed importantly to the large platelet thrombi formed, shown by performing blood perfusion experiments in the presence of thrombin inhibitors. Our results indicate that 1) platelet adhesion and aggregate formation on a subendothelium may occur at a high shear rate (2600/s) without the participation of collagen types I, III and VI, and vWF; and 2) the HMEC-1 cell line may prove useful for in vitro studies of the thrombogenic properties of microvascular subendothelium which in most cases does not contain fibrillar collagens and vWF.
P-Selectin Antagonism Causes Dose-dependent Venous Thrombosis Inhibition
Authors: Schaub Robert , Wrobleski Shirley , Londy Frank , Fex Beverly , Chapman Amy , Greenfield Lazar , Wakefield Thomas , Myers Daniel 
Published: March 2018

SummaryInhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 μg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p < 0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extra-vasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.
Pulmonary Fibrosis Is Increased in Mice Carrying the Factor V Leiden Mutation following Bleomycin Injury
Authors: Xu Zuojun , Westrick Randal , Shen YueChun , Eitzman Daniel 
Published: March 2018

SummaryIncreased fibrin deposition following inflammatory lung injury has been proposed to facilitate the development of pulmonary fibrosis. Therefore, factors predisposing to thrombosis may affect the fibrotic response to injury. Activated protein C (aPC) resistance due to the factor V Leiden mutation (FνL) is a common genetic risk factor for vascular thrombosis. To examine the relationship between aPC resistance and the development of pulmonary fibrosis, lung inflammation was induced by bleomycin in mice carrying the FvL mutation. Three weeks following the instillation of 0.0375 U of bleomycin, the lungs of mice homozygous and heterozygous for FvL contained significantly more hydroxyproline (35 ± 4 and 36 ± 7 ug hydroxyproline/ mg total protein, respectively) than wild-type mice (26 ± 6 ug/mg protein, p <0.01 for both comparisons). These data demonstrate a strong relationship between aPC resistance and the pulmonary fibrosis that occurs following inflammatory lung injury.
The Glycoprotein Ib-IX-V Complex in Platelet Adhesion and Signaling
Authors: Andrews Robert , Shen Yang , Gardiner Elizabeth , Dong Jing-fei , López José , Berndt Michael 
Published: March 2018

IntroductionThrombosis can result in unstable angina, acute myocardial infarction, or stroke, all major causes of death in the Western world. Circulating platelets become adherent and form an occlusive thrombus, either by exposure to sclerotic lesions following plaque rupture or in response to pathological shear stress in obstructed coronary arteries. This process parallels normal haemostasis, where platelets adhere to the subendothelium at sites of vascular injury, become activated, and recruit additional platelets to the developing thrombus. At high shear, thrombus formation is initiated by a specific platelet membrane adhesion receptor, the glycoprotein (GP) Ib-IX-V complex, which binds the adhesive glycoprotein, von Willebrand factor (vWF), in the vessel wall or plasma. Recent evidence also suggests that platelet adhesion to endothelial cells and leukocytes may be involved in atherogenesis, thrombosis, and inflammation. Preliminary findings indicate that GP Ib-IX-V specifically recognizes P-selectin, a member of the selectin superfamily, an interaction that may, at least partially, regulate platelet-endothelial cell adhesion. This review focuses on recent advances in understanding structure-activity relationships of GP Ib-IX-V.
The Role of Genetics in Inhibitor Formation
Authors: Gill Joan Cox 
Published: March 2018

IntroductionTreatment of hemorrhages in patients with inherited severe hemophilia A is dependent on transfusion replacement therapy with either plasma-derived or recombinant factor VIII concentrates.1 Hemorrhages become very difficult to treat after inhibitors develop, resulting in significant decreases in qualityof- life and life expectancy.2-6 Strategies to treat hemorrhages in the face of an inhibitor include the use of “bypass” therapy with activated and nonactivated prothrombin complex concentrates, high-dose factor VIII, porcine factor VIII, and recombinant factor VIIa. None of these is as effective as treatment of the noninhibitor patient with factor VIII.2,6 Therefore, several strategies to induce tolerance to factor VIII administration have been attempted, including administration of daily high-dose intravenous infusions of factor VIII concentrate alone, or in combination with, immune-modulating therapy.2,6 These strategies are extraordinarily difficult and expensive and are frequently unsuccessful, particularly when the inhibitor is well established. Thus, the ability to predict which patients are at risk for inhibitor development and to identify factors that predispose to inhibitor development would allow investigation of therapies targeted to prevent the establishment of the inhibitor response or to provide the ability to initiate early and, thus, more effective, immune tolerance induction for those at risk.
Recombinant Clotting Factors in the Treatment of Hemophilia
Authors: Lee Christine 
Published: March 2018

IntroductionThe field of hemophilia has always been one of rapid change with improvements in clinical practice rapidly following the advances in basic science and clinical research. The major achievements of the last decade have reflected the application of molecular biology, and this has been particularly true for the development of recombinant clotting factors. The interest in developing recombinant factors VIII and IX was driven by the desire for a “safe” clotting factor following the terrible epidemics of transfusion-transmitted disease in the 1970s and 1980s.Although the goals for treatment for hemophilia, as stated by the World Federation of Hemophilia, are “to minimize disability and prolong life, to facilitate general social and physical wellbeing, and to help each patient achieve full potential, while causing no harm,”1 the cost of recombinant clotting factors are comparatively high. As a result, in many instances, the provision has been rationed, even though such therapy is considered state-of-the-art treatment for all patients requiring replacement therapy.
In Vivo Gene Delivery by Lentiviral Vectors
Authors: Naldini Luigi 
Published: March 2018

IntroductionSuccessful gene therapy requires the efficient delivery and sustained expression of a therapeutic gene into the tissues of a human body. Most of the candidate tissues for therapeutic gene transfer are made of quiescent cells, such as from the brain, liver, and muscle. Thus, the optimal vector should infect nondividing cells, become stably associated with the genome of target cells, and support a high, steady-state level of transcription.1,2 Like all vectors derived from retroviruses, lentiviral vectors integrate into the chromatin of target cells and do not transfer any viral genes. Both of these features are important for achieving sustained expression of the transgene. Moreover, lentiviral vectors infect nondividing cells, a feature sharply distinguishing them from simple or onco-retroviral vectors.3 Upon infection, retroviruses deliver a nucleoprotein complex that reverse transcribes the viral RNA and integrates the newly made DNA into the chromatin. The nucleoprotein complexes of onco-retroviruses are excluded by the nucleus, and they reach the chromatin only when the nuclear membrane is fragmented during mitosis. This explains the dependence of a productive onco-retroviral infection on cell division occurring shortly after viral entry.4,5 In contrast, the nucleoprotein complexes of lentiviruses contain nuclear localization signals that mediate their active transport through the nucleopores during interphase. This explains the capacity of lentiviruses to infect macrophages, a nondividing cell type.6-9