bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond Black–Scholes: A Neural Networks-Based Approach to Options Pricing
Authors: Zapart Christopher A.
Published: July 2003

The paper presents two alternative schemes for pricing European and American call options, both based on artificial neural networks. The first method uses binomial trees linked to an innovative stochastic volatility model. The volatility model is based on wavelets and artificial neural networks. Wavelets provide a convenient signal/noise decomposition of the volatility in the non-linear feature space. Neural networks are used to infer future volatility levels from the wavelets feature space in an iterative manner. The bootstrap method provides the 95% confidence intervals for the options prices. In the second approach neural networks are trained with genetic algorithms in order to reverse-engineer the Black–Scholes formulae. The standard Black–Scholes model provides a starting point for an evolutionary training process, which yields improved options prices. Market options prices as quoted on the Chicago Board Options Exchange are used for performance comparison between the Black–Scholes model and the proposed options pricing schemes. The proposed models produce as good as and often better options prices than the conventional Black–Scholes formulae.
On the Pricing of Credit Spread Options: A Two Factor HW–BK Algorithm
Authors: Garcia Joao B. C. , van Ginderen Helmut , Garcia Reinaldo C.
Published: July 2003

In this article we describe what a credit spread option (CSO) is and show a tree algorithm to price it. The tree algorithm we have opted for is a two factor model composed by a Hull and White (HW) one factor for the interest rate process and a Black-Karazinsky (BK) one factor for the default intensity. As opposed to the tree model of Schonbucher 1999 the intensity process cannot become negative. Having as input the risk free yield curve and market implied default probability curve the model by construction will price correctly the associated defaultable bond. We then use Market data to calibrate the model to price an at the money (ATM) CSO call and then test it to price an out of the money (OTM) Bermudan CSO call on a CDS. Furthermore the discussions in this paper show in practice the difficulties and challenges faced by financial institutions in marking to market those instruments.
Systematic Generation of Parametric Correlation Structures for the LIBOR Market Model
Authors: Schoenmakers John , Coffey Brian
Published: July 2003

We present a conceptual approach of deriving parsimonious correlation structures suitable for implementation in the LIBOR market model. By imposing additional constraints on a known ratio correlation structure, motivated by economically sensible assumptions concerning forward LIBOR correlations, we yield a semi-parametric framework of non-degenerate correlation structures with realistic properties. Within this framework we derive systematically low parametric structures with, in principal, any desired number of parameters. As illustrated, such structures may be used for smoothing a matrix of historically estimated LIBOR return correlations. In combination with a suitably parametrized deterministic LIBOR volatility norm we so obtain a parsimonious multi-factor market model which allows for joint calibration to caps and swaptions. See Schoenmakers [14] for a stable full implied calibration procedure based on the correlation structures developed in this paper.
RELAXATION TIMES IN SYSTEMS WITH ZERO AND NON-ZERO STATIONARY FLOW
Authors: AGUDOV N. V. , SAFONOV A. V.
Published: July 2003

We examine the kinetics of relaxation processes in dynamical models with the fixed number of Brownian particles and with the constant source of the particles. The former evolves to the zero equilibrium distribution, while the latter develops to the stationary state with non-equilibrium distribution and non-zero stationary flow. We show that the relaxation times in the both systems coincide. This is valid for an arbitrary noise intensity and shape of potential profile. In addition we propose to modify the well-known Kramers' approach for the determination of relaxation time. The modified approach is valid for an arbitrary height of potential barriers.
COHERENCE RESONANCE OF THE NOISE-INDUCED MOTION ON THE WAY TO BREAKDOWN OF SYNCHRONIZATION IN CHAOTIC SYSTEMS
Authors: BALANOV A. G. , JANSON N. B. , McCLINTOCK P. V. E.
Published: July 2003

We investigate the way in which noise destroys phase synchronization in chaotic systems. Two cases are considered: where the route to synchronization involves frequency locking; and where it occurs via a suppression of the natural dynamics. We show that, just as in the case of synchronization of periodic oscillations, noise induces a new motion whose coherence depends non-monotonically (resonantly) on the noise intensity.
ENTRAINMENT OF OPTICAL LOW-FREQUENCY FLUCTUATIONS IS ENHANCED BY COUPLING
Authors: BULDÚ J. M. , GARCÍA-OJALVO J. , TORRENT M. C. , VICENTE RAÚL , PÉREZ TONI , MIRASSO CLAUDIO R.
Published: July 2003

The control of the low-frequency fluctuations exhibited by two mutually coupled semiconductor lasers is studied experimentally and numerically. We observe that coupling enhances the response of the system to a weak periodic modulation of the injection current of one of the lasers, leading to a highly efficient entrainment of the synchronized low-frequency power dropouts to the external periodic driving. We compare the quality of the entrainment with the one obtained in a single semiconductor laser with optical feedback, showing the beneficial role of coupling in this pursuit. The experimental observations are satisfactorily reproduced by numerical simulations of a set of coupled delay-differential rate equations.
SYNCHRONIZATION OF STOCHASTIC MOTIONS IN SWARMS OF ACTIVE BROWNIAN PARTICLES WITH GLOBAL COUPLING
Authors: EBELING WERNER
Published: July 2003

We consider here the dynamics and stochastic theory of swarms of self-propelled particles. Driving is modelled by the Schienbein-Gruler expression for negative friction. Global coupling is introduced by linear forces attracting to the center of mass and to the mean velocity of the swarm. Solutions for the stationary distribution of swarms are given which represent: (i) synchronized translation of the swarm with small fluctuations around its center of mass and, (ii) synchronized rotations around the center of mass which is at rest or slowly moving.
COLLECTIVE MOTION OF BROWNIAN PARTICLES WITH HYDRODYNAMIC INTERACTIONS
Authors: ERDMANN UDO , EBELING WERNER
Published: July 2003

Biological motion and human traffic require energy supply from external sources. We develop here a model for the dynamics of driven entities which includes hydrodynamic interactions in order to adapt the model to the dynamics of swarms moving in dense fluids. Our entities have the ability to use the energy contained in an internal energy depot or an external energy inflow for the acceleration of motion. As a prototype of such entities we study Brownian particles having the ability to take up energy from their environment, to store it in an internal energy depot and to convert internal energy into kinetic energy. The motion of the particles is described by Langevin equations which include a dissipative force term resulting from the driving and equations for the dynamics of the depot. The hydrodynamic interactions are modeled by an Oseen-type tensorial force. It is shown that hydrodynamic interactions lead to the synchronization of the directions of motion leading to several new collective modes of the dynamics, including spontaneous rotations of the swarm.
STATIONARY PROBABILITY DISTRIBUTIONS FOR FITZHUGH-NAGUMO SYSTEMS
Authors: KOSTUR MARCIN , SAILER XAVER , SCHIMANSKY-GEIER LUTZ
Published: July 2003

We study numerically the stationary solutions of the Fokker-Planck equation for the FitzHugh-Nagumo model with additive noise. In the parameter regimes where the deterministic model is excitable we find various sets of maxima, minima, and saddle points of the stationary probability distribution depending on the noise intensity and separation of the time scales between activator and inhibitor.
INTERACTIONS AND SYNCHRONIZATION IN THE CARDIOVASCULAR SYSTEM
Authors: McCLINTOCK PETER V. E. , STEFANOVSKA ANETA
Published: July 2003

There is strong evidence for couplings between the five oscillatory processes that characterize the human blood distribution system. In particular, mutual modulation and/or episodes of synchronization between the oscillations may be observed for a variety of different cardiovascular signals. Such phenomena can reveal information about the nature and strength of the couplings, which in turn reflect the state of the organism in sickness or in health. Earlier work on the inter-oscillator interactions is reviewed briefly, and some recent research on cardio-respiratory synchronization is considered in more detail. It is reported that, for rats, the directionality of the cardiorespiratory coupling reverses under anæsthesia. The interplay between synchronization and modulation is discussed and their coexistence in the cardiorespiratory interaction is illustrated.
NOISE INDUCED PHENOMENA IN LOTKA-VOLTERRA SYSTEMS
Authors: SPAGNOLO B. , FIASCONARO A. , VALENTI D.
Published: July 2003

We study the time evolution of two ecosystems in the presence of external noise and climatic periodical forcing by a generalized Lotka-Volterra (LV) model. In the first ecosystem, composed by two competing species, we find noise induced phenomena such as: (i) quasi deterministic oscillations, (ii) stochastic resonance, (iii) noise delayed extinction and (iv) spatial patterns. In the second ecosystem, composed by three interacting species (one predator and two preys), using a discrete model of the LV equations we find that the time evolution of the spatial patterns is strongly dependent on the initial conditions of the three species.
USING SYNCHRONIZATION TO DETECT CHAOTIC RESPONSE IN EXTERNALLY FORCED DYNAMICAL SYSTEMS
Authors: STEFANSKI ANDRZEJ , KAPITANIAK TOMASZ , SZUMINSKI PRZEMYSLAW
Published: July 2003

In this paper we present a simple way of chaos detection in forced dynamical systems. The method exploits a synchronization phenomenon of a set of identical mechanical systems driven by the same external excitation. The properties of this synchronization allow for easy and fast detection of chaos in dynamical systems in a wide range of system parameters. The presented approach can be successfully applied both for discrete-time and continuous-time systems. Some applications of the method are presented.
NOISE-INDUCED PHASE SYNCHRONIZATION: THEORETICAL AND EXPERIMENTAL RESULTS
Authors: FREUND JAN A. , BARBAY SYLVAIN , LEPRI STEFANO , ZAVATTA ALESSANDRO , GIACOMELLI GIOVANNI
Published: July 2003

The beneficial role fluctuations can play in the process of phase synchronization is analyzed in terms of a model with binary input and output signals. Special attention is paid to the relation between noise-induced phase synchronization and the well-known phenomenon of stochastic resonance. Analytic predictions are compared with experimental data from a vertical cavity surface emitting laser. Various measures for aperiodic stochastic resonance, frequency entrainment and stochastic phase synchronization reveal a satisfactory agreement between theory and experiment.
A MODEL OF OSCILLATIONS OF MACROMOLECULE WITH ANOMALOUS QUALITY FACTOR
Authors: CHICHIGINA O. , NETREBKO A. , ROMANOVSKY Yu.
Published: July 2003

The effect of anomalously enhanced quality factor (small damping decrement) is demonstrated and explained by phase dependence of interaction with particles of medium. The dependence of quality factor on the temperature of the medium is described. The most suitable noise intensity is determined. Molecular dynamics simulations qualitatively confirm the results. The size and mass of real bio-molecules, the frequency, amplitude of their oscillations and the temperature of living body are suitable conditions for this effect.
SPECTRAL AND CORRELATION ANALYSIS OF SPIRAL CHAOS
Authors: ANISHCHENKO VADIM S. , VADIVASOVA TATJANA E. , KOPEIKIN ANDREY S. , STRELKOVA GALINA I. , KURTHS JÜRGEN
Published: July 2003

We study numerically the behavior of the autocorrelation function (ACF) and the power spectrum of spiral attractors without and in the presence of noise. It is shown that the ACF decays exponentially and has two different time scales. The rate of the ACF decrease is defined by the amplitude fluctuations on small time intervals, i.e., when τ < τ cor , and by the effective diffusion coefficient of the instantantaneous phase on large time intervals. It is also demonstrated that the ACF in the Poincare map also decreases according to the exponential law exp (- λ+ k), where λ+ is the positive Lyapunov exponent. The obtained results are compared with the theory of fluctuations for the Van der Pol oscillator.
SOCIODYNAMICS — A SYSTEMATIC APPROACH TO MATHEMATICAL MODELLING IN THE SOCIAL SCIENCES
Authors: WEIDLICH WOLFGANG
Published: July 2003

A general concept is presented which allows of setting up mathematical models for stochastic and quasi deterministic dynamic processes in social systems.

The basis of this concept is the master equation for the probability distribution over appropriately chosen personal and material macrovariables of the society. The probabilistic transition rates depend on motivation potentials governing the decisions and actions of the social agents. The transition from the probability distribution to quasi-meanvalues leads to in general nonlinear coupled differential equations for the macrovariables of the chosen social sector. Up to now several models about population dynamics, collective political opinion formation, dynamics of economic processes and the formation of settlements have been published.
FLUCTUATION-INDUCED LOCAL OSCILLATIONS AND FRACTAL PATTERNS IN THE LATTICE LIMIT CYCLE MODEL
Authors: PROVATA A. , TSEKOURAS G. A. , DIAKONOS F. , FRANTZESKAKIS D. , BARAS F. , SHABUNIN A. V. , ASTAKHOV V.
Published: July 2003

The fractal properties of the Lattice Limit Cycle model are explored when the process is realized on a 2-dimensional square lattice support via Monte Carlo Simulations. It is shown that the structure of the steady state presents inhomogeneous fluctuations in the form of domains of identical particles. The various domains compete with one another via their borders which have self-similar, fractal structure. The fractality is more prominent, (fractal dimensions df < 2), when the parameter values are near the critical point where the Hopf bifurcation occurs. As the distance from the Hopf bifurcation increases in the parameter space the system becomes more homogeneous and the fractal dimension tends to the value df = 2.
RENORMALIZATION IN QUASIPERIODICALLY FORCED SYSTEMS
Authors: OSBALDESTIN A. H. , MESTEL B. D.
Published: July 2003

We review our recent rigorous results on renormalization in a variety of quasiperiodically forced systems. Our results include a description of (i) self-similar fluctuations of localized states in the Harper equation, including the renormalization strange set (known as the orchid) in the generalized Harper equation; and (ii) self-similarities in the correlations of strange nonchaotic attractors, barrier billiards, and quantum two-level systems.
Shannon Wavelet Approach to Sub-Band Coding
Authors: Chui Charles K. , Wang Jianzhong
Published: July 2003

It is well known that the Shannon Sampling Theorem allows us to fully recover a continuous-time bandlimited signal from its digital samples, as long as the sampling rate to be chosen is not smaller than the Nyquist frequency. This theory applies to all bandlimited signals, which may or may not occupy the entire frequency band. Hence, it is intuitively convincing that for continuous-time signals, such as those in speech, that do not fully utilize the entire frequency intervals, less digital samples are required for their full recovery. Current techniques in sub-band coding are used for achieving this goal. The objective of this paper is to present a wavelet theory for establishing the mathematical foundation of this sub-band coding approach. A wavelet packet decomposition of the signal provides the optimal sub-band coding bit-rate by using the Shannon wavelet library introduced in this paper.
Image Recognition Based on Nonlinear Wavelet Approximation
Authors: Yang L. H. , Bui T. D. , Suen C. Y.
Published: July 2003

This paper presents a novel approach to recognize images based on nonlinear wavelet approximation. The mathematical theory on nonlinear wavelet approximation is introduced, which shows that nonlinear approximation contains much more information of the original image than linear approximation. Based on this theory, a scheme to obtain the basic information of images with less data is provided. Experiments on face recognition produce effective matching rates.
Optimal Wavelet Filters for Medical Image Compression
Authors: Low Yin Fen , Besar Rosli
Published: July 2003

Recently, the wavelet transform has emerged as a cutting edge technology, within the field of image compression research. The basis functions of the wavelet transform are known as wavelets. There are a variety of different wavelet functions to suit the needs of different applications. Among the most popular wavelets are Haar, Daubechies, Coiflet and Biorthogonal, etc. The best wavelets (functions) for medical image compression are widely unknown. The purpose of this paper is to examine and compare the difference in impact and quality of a set of wavelet functions (wavelets) to image quality for implementation in a digitized still medical image compression with different modalities. We used two approaches to the measurement of medical image quality: objectively, using peak signal to noise ratio (PSNR) and subjectively, using perceived image quality. Finally, we defined an optimal wavelet filter for each modality of medical image.
Lighting-Effects Classification in Facial Images Using Wavelet Packets Transform
Authors: Kouzani A. Z. , Ong S. H.
Published: July 2003

Faces often produce inconsistent features under different lighting conditions. Classifying lighting effects within a face image is therefore the first crucial step of building a lighting invariant face recognition system. This paper presents a hybrid system to classify face images based on the lighting effects present in the image. The theories of multivariate discriminant analysis and wavelet packets transform are utilised to develop the proposed system. An extensive set of face images of different poses, illuminated from different angles, are used to train the system. The performance of the proposed system is evaluated by conducting experiments on different test sets and by comparing its results against those of some existing counterparts.
Content-Based Image Retrieval Technique Using Wavelet-Based Shift and Brightness Invariant Edge Feature
Authors: Kubo Masaaki , Aghbari Zaher , Makinouchi Akifumi , Oh Kun-Seok
Published: July 2003

This paper proposes a technique for indexing, clustering and retrieving images based on their edge features. In this technique, images are decomposed into several frequency bands using the Haar wavelet transform. From the one-level decomposition sub-bands an edge image is formed. Next, the higher order autocorrelation function is applied on the edge image to extract the edge features. These higher order autocorrelation features are normalized to generate a compact feature vector, which is invariant to shift, image size and gray level. Then, these feature vectors are clustered by a self-organizing map (SOM) based on their edge feature similarity. The performed experiments show the high precision of this technique in clustering and retrieving images in a large image database environment.
Prediction Based on a Multiscale Decomposition
Authors: Renaud Olivier , Starck Jean-Luc , Murtagh Fionn
Published: July 2003

A wavelet-based forecasting method for time series is introduced. It is based on a multiple resolution decomposition of the signal, using the redundant "à trous" wavelet transform which has the advantage of being shift-invariant.

The result is a decomposition of the signal into a range of frequency scales. The prediction is based on a small number of coefficients on each of these scales. In its simplest form it is a linear prediction based on a wavelet transform of the signal. This method uses sparse modelling, but can be based on coefficients that are summaries or characteristics of large parts of the signal. The lower level of the decomposition can capture the long-range dependencies with only a few coefficients, while the higher levels capture the usual short-term dependencies.

We show the convergence of the method towards the optimal prediction in the autoregressive case. The method works well, as shown in simulation studies, and studies involving financial data.
What Makes Product Development Market Oriented? Towards a Conceptual Framework
Authors: Kok Robert A. W. , Hillebrand Bas , Biemans Wim G.
Published: July 2003

While there is quite some literature on the relationship between market orientation and product development, it is still unclear what market-oriented product development really is. In this article the authors present a conceptual framework detailing the elements of market-oriented product development and the relationships between these elements. More specifically, market-oriented product development is conceptualised as a combination of specific capabilities and market information processing activities. These capabilities encapsulate the values and norms, knowledge and skills, technical and managerial knowledge systems, which enable learning about markets through information processing behaviour in product development and improve this market learning behaviour. As such it is argued that market-oriented product development may be regarded as an organisational learning capability.
The Complex Relations Between Communities of Practice and the Implementation of Technological Innovations
Authors: Hislop Donald
Published: July 2003

The paper analyses the implementation of IT based innovations through a communities of practice lens. It is suggested that such a framework can add fresh insights to the dynamics of innovation processes. The paper makes an empirical and theoretical contribution to the innovation literature by both examining case study evidence from a number of technological innovation projects, and reflecting on the relationship between innovation processes and communities of practice. It is concluded that this relationship is not unidirectional. Not only did the communities of practice influence the innovation processes, for example through shaping important knowledge sharing processes, but the innovations also impinged on organizational communities of practice in important ways. The paper also proposes ways in which the analytical utility of the community of practice concept can be improved, for example by taking greater account of potential negative effects that communities of practice can have for innovation processes.
Determinants of Co-Workers' Innovative Behaviour: An Investigation into Knowledge Intensive Services
Authors: de Jong Jeroen P. J. , Kemp Ron
Published: July 2003

Innovation researchers increasingly pay attention to service industries, resulting in a large amount of literature on success factors in new service development. However, the role of individual co-workers in innovation is still underexposed.

This paper investigated the drivers of innovative behaviour of individual co-workers, which is considered to be a major determinant of incremental innovation. From the literature seven constructs were derived that are often discussed as drivers of innovation, but have not been tested as determinants of individual co-workers' innovative behaviour. Survey data were collected from 360 persons working in knowledge-intensive service firms. Based on a regression analysis, it appeared that perceptions of job challenge, autonomy, strategic attention and external contacts are positively related to innovative behaviour of individual co-workers. Also, operating in a market where firms compete on differentiation had a positive impact. On the other hand, a firm climate supportive to innovation and a high variation in demand did not affect innovative behaviour in a direct manner.
The Impact of Publishing and Patenting Activities on New Product Development and Firm Performance: The Case of the US Pharmaceutical Industry
Authors: Steven McMillan G. , Mauri Alfredo , Halmilton Robert D.
Published: July 2003

This paper studies the role of publishing and patenting activities as predictors of new product development for a sample of companies in the U.S. pharmaceutical industry. The research also examines the relation between new product development and firm performance. Hypotheses are developed based on the well-established absorptive capacity literature. The results show that publishing scientific articles and stock of patents are both significant predictors of the number of new molecular entities (NMEs) for which a firm receives approval. In addition, the degree to which a firm builds on its own technology (measured as self-citations in its patents) also predicts NMEs, but the regression coefficient had an unexpected negative sign. Finally, the performance results confirm that the approval of NMEs is significantly associated with the market-to-book ratio of a firm. The managerial implications of these findings and study limitations are also discussed.
Technology Strategies in the Knowledge Economy: The Licensing Activity of Himont
Authors: Cesaroni Fabrizio
Published: July 2003

The exchange of technologies and technological knowledge — through joint-ventures, partnerships, licensing, cross-licensing, R&D contracts — and the upsurge of markets for technology are main features of the "knowledge-based" economy. Accordingly, companies are gradually changing their aptitude towards technology trading and exchange. This paper discusses the extent of technology licensing in chemicals, and considers the licensing strategies adopted by large chemical companies. Specifically, by analysing the case of Himont — widely involved in licensing its process technology — this paper explores the motivations for technology licensing, the managerial solutions that Himont adopted for licensing its technology, and the implications of this strategy in terms of antitrust policy. One of the main results emerging from the analysis is the role of external technology suppliers. By increasing the potential competition in the downstream product market, they create incentives for incumbent firms to license-out their technologies, and earn additional profits in the market for technology.
Total characters and Chebyshev polynomials
Authors: Poimenidou Eirini , Wolfe Homer
Published: July 2003

The total character τ of a finite group G is defined as the sum of all the irreducible characters of G. K. W. Johnson asks when it is possible to express τ as a polynomial with integer coefficients in a single irreducible character. In this paper, we give a complete answer to Johnson′s question for all
finite dihedral groups. In particular, we show that, when such a polynomial exists, it is unique and it is the sum of certain Chebyshev polynomials of the first kind in any faithful irreducible character of the dihedral group G.
Some characterizations of specially multiplicative functions
Authors: Haukkanen Pentti
Published: July 2003

A multiplicative function f is said to be specially multiplicative if there is a completely multiplicative function
fA such that f(m)f(n) = ∑d|(m,n)f(mn/d2)fA(d) for all m and n. For example, the divisor functions and Ramanujan′s τ‐function are specially multiplicative functions. Some characterizations of specially multiplicative functions are given in the literature. In this paper, we provide
some further characterizations of specially multiplicative functions.
Endothelial cell function alteration after Junin virus infection
Authors: Gomez Ricardo Martin , Pozner Roberto Gabriel , Lazzari Maria Angela , D’Atri Lina Paola , Negrotto Soledad , Chudzinski-Tavassi Ana Marisa , Berría María Isabel , Schattner Mirta
Published: July 2003

Hematologic involvement is the main feature of Argentine hemorrhagic fever (AHF), an endemo-epidemic disease caused by Junin virus (JV). Since endothelial dysfunction could play a role in AHF-altered hemostasis, we studied human umbilical vein endothelial cell (HUVEC) infection with a virulent (JVv) and a non-virulent (JVa) JV strain. Cells were infected by the two JV variants with no detectable apoptosis or cytopathic effect. Both viral variants up-regulated ICAM-1 and VCAM-1 levels, while von Willebrand factor (VWF) production was decreased. Prostacyclin (PGI2) release and decay accelerating factor (DAF) expression were greater in JVv- than in JVa-infected or control cells. Furthermore, nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) expression was only raised in JVv-infected supernatants. Significant NO and PGI2 values were also detected in AHF patient sera.

These data demonstrate that endothelial cell responses are triggered subsequently by JV infection, suggesting that such alterations play a major role in the pathogenesis of AHF and perhaps in other viral-induced hemorrhagic diseases.
Two novel mutations in the human coagulation factor VII promoter
Authors: Kavlie Anita , Hiltunen Leena , Rasi Vesa , Prydz Hans
Published: July 2003

The factor VII genes of five unrelated Finnish female patients, F1-F5, with moderate bleeding tendency, were screened for mutations using single strand conformational polymorphisms and DNA sequencing. Heterozygous shifts were detected in exons 5 and 8 for patient F1, and sequencing confirmed the presence of the silent dimorphism H115H, the polymorphism R353Q and the mutation A294V. The patient F1 was also heterozygous for a novel –59T/G transversion mutation in the Hepatocyte nuclear factor 4-binding site. The remaining four patients carried a –32A/C transversion mutation located in a footprint (–51 to –32) covering the major transcription initiation start site (–51). There was also a consensus sequence match to an initiator response-like binding element covering –51. Two patients were homozygous and two heterozygous for this mutation. Plasma FVII:Ag and FVII:C levels were reduced in parallel. A strong reduction in binding affinity of a specific nuclear protein to the –32C-containing oligonucleotide was found by electrophoretic mobility shift assays on nuclear extracts from HepG2 cells. EDTA caused no reduced binding. A minimal promoter (–191 to +15) containing the wild-type sequence or the –32A/C or –59T/G mutations was cloned in front of the firefly luciferase reporter gene and transiently transfected into Hep3B cells. Reduced activities [23.0 ± 3.1% (–32C), 55.4 ± 6.3% (–59G), 100% (wild-type construct)] were found for the mutated promoters. Southwestern blotting and UV crosslinking analysis showed binding of three proteins (20, 20 and 50 kDa) to the putative initiator response element. The –32A/C mutant oligonucleotide bound two proteins.
Prothrombin and β2-glycoprotein I frequently contribute to antiphospholipid antibody interactions with phospholipids and the generation of abnormal waveform profiles in coagulation assays
Authors: Su Zuowei , Izumi Tomonori , Ortel Thomas L.
Published: July 2003

Transmittance waveforms are generated during clot formation on photo-optical coagulation analyzers. We previously showed that 61.5% of patients with antiphospholipid antibodies (APLA) exhibited a negative deflection in the pre-coagulation phase of the prothrombin time (PT slope 1). The current studies investigated the ‘molecular basis’ of this abnormal parameter. We found that the negative PT slope 1 is IgG-mediated and is not dependent on the presence of fibrinogen or thrombin activity. We also found that IgG from most of the patients required a specific thromboplastin and the presence of prothrombin or β2-glycoprotein I (β2GPI) to produce an abnormal IgG waveform assay. In addition, the abnormal IgG waveform required cofactor binding to phospholipids when β2GPI was the cofactor, and annexin V could partially block this interaction. In conclusion, these results showed that the interactions of IgG with phospholipids via β2GPI or prothrombin constitute the core mechanisms of the abnormal waveforms.
Fixed-dose, body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis
Authors: Koppenhagen Klaus , Tolle Alexander , Kemkes-Matthes Bettina , Gräve Michael , Patek Frantisek , Drexler Michael , Siemens Hans-Joachim G. , Harenberg Job , Weidinger Gottfried , Brom Joachim , Haas Sylvia , Riess Hanno
Published: July 2003

Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up.

In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH.

The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50,50-80 and >80 kg as followed:0,3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and
4.2% for UFH. Overall mortality was 1.9 % in the Certoparin group and 2.7 % in the UFH group.

Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.
A prospective and randomized comparison of the safety and effects of therapeutic levels of enoxaparin versus unfractionated heparin in chronically anticoagulated patients undergoing elective cardiac catheterization
Authors: Hammerstingl Christoph , Schmidt Harald , der Recke Giso von , Paar Wilhelm Dieter , Lüderitz Berndt , Omran Heyder
Published: July 2003

Consecutive patients with atrial fibrillation and/or prosthetic heart valves, receiving chronic anticoagulation with phenprocoumon and scheduled to undergo cardiac catheterization, were randomized to subcutaneous enoxaparin twice daily (n = 32) or intravenous UFH (n = 36). Cardiac catheterization was performed at an international normalized ratio <1.5. Activated partial thromboplastin times and levels of anti-Factor Xa activity were measured daily. The time until effective anticoagulation (primary endpoint) was significantly shorter for enoxaparin than for UFH (1.1 ± 0.4 days versus 3.7 ± 2.5 days, p <0.0001). The percentage of days of effective anticoagulation was significantly higher in the enoxaparin group than in the UFH group (93.3 ± 9.5% versus 53.7 ± 26.6%, p <0.0001). In conclusion, enoxaparin achieves therapeutic levels of anticoagulation more rapidly and consistently than UFH in chronically anticoagulated patients with prosthetic heart valves and/or atrial fibrillation undergoing cardiac catheterization.
Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon
Authors: Gadisseur Alain A. P. , Pasterkamp Edwin , van der Meer Felix J. M. , Mimi Breukink-Engbers W. G. , Geven-Boere Lya M. , Meegen Erik van , Vries-Goldschmeding Hanneke de , Antheunissen-Anneveld Irma , van’t Hoff Annelies R. , Harderman Derk , Smink Margriet , Rosendaal Frits R. , Fihn Stephan D.
Published: July 2003

Variability in the control of oral anticoagulant therapy has been associated with a heightened risk of complications. We compared control of anticoagulation between two commonly used coumarins, phenprocoumon and acenocoumarol, and among anticoagulation clinics.

All qualifying patients were managed at six regional anticoagulation clinics in the Netherlands.

This retrospective cohort study compiled data during a three-year period from a computerised dosing and management system. Anticoagulation control was expressed as the percent of time within the therapeutic range and stability expressed as the time-weighted variance in the international normalised ratio (INR). Data were available for 22,178 patients of whom 72% were treated with acenocoumarol. INRs of patients who received phenprocoumon were within the therapeutic range 50% of the time compared with 43% for acenocoumarol (OR 1.32,95% CI 1.24-1.41). Moreover, patients on phenprocoumon required 15% fewer monitoring visits and had more stable INR values. These observations were consistent for all six clinics. There were also sizable differences between the clinics with respect to control and stability of anticoagulation that were stable from year-to-year and were unrelated to the drug used.

With its longer half-life of three to five days, phenprocoumon produces more stable anticoagulation than acenocoumarol and should generally be the drug of choice when these are the available choices. The differences observed among clinics suggest that certain clinics employ policies and practices resulting in better control of anticoagulation.
Circulating t-PA antigen predicts major adverse coronary events in patients with stable coronary artery disease – a 13-year follow-up
Authors: Niessner Alexander , Graf Senta , Nikfardjam Mariam , Speidl Walter S. , Huber-Beckmann Renate , Zorn Gerlinde , Wojta Johann , Huber Kurt
Published: July 2003

Thrombus formation after rupture of an atherosclerotic plaque plays a crucial role in coronary artery disease (CAD). A decreased endogenous fibrinolytic system and prothrombotic factors are supposed to influence coronary thrombosis. It was our aim to investigate the predictive value of tissue plasmino-gen activator (t-PA) antigen, von Willebrand Factor, Lipoprotein (a) and anti-cardiolipin antibodies for major adverse coronary events in patients with stable CAD in a prospective cohort study of more than 10 years.

We observed 141 patients with angiographically proven CAD for a median follow-up period of 13 years. t-PA antigen was the only marker predicting coronary events (logistic regression, p = 0.044) with a poor prognosis for patients in the 5th quintile with an odds ratio of 7.3 (compared to the 1st quintile). The odds ratio even increased to 10.0 for coronary events associated with the “natural course” of CAD excluding events due to restenosis. t-PA antigen had a slightly higher prognostic power (ROC curve; AUC = 0.69) than fasting glucose (AUC = 0.68) and cholesterol (AUC = 0.67). Triglycerides influenced plasma levels of t-PA antigen (regression, p < 0.001). The predictive value of t-PA antigen remained significant after adjustment for inflammation (logistic regression, p = 0.013) and extent of CAD (p = 0.045) but disappeared adjusting for insulin resistance (p = 0.12).

In conclusion t-PA antigen predicted coronary events during a very long-term follow-up with a comparable prognostic power to established cardiovascular risk factors. Markers of insulin resistance influenced t-PA antigen and its predictive value.

Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September 2002.
Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia
Authors: Andrew Maureen , Hanna Kim , Abshire Thomas , Halton Jacqueline , Wu John , Anderson Ron , Cherrick Irene , Desai Sunil , Mahoney Donald , McCusker Patricia , Chait Peter , Abdolell Mohamed , Veber Gabrielle de , Mikulis David , Mitchell Lesley
Published: July 2003

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP.

Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.
Myocardial infarction under the age of 36: prevalence of thrombophilic disorders
Authors: Belesi Chrusula I. , Manioudaki Helen S. , Chatziioakimidis Vassilis K. , Fakitsa Vassiliki C. , Sinos Loukas E. , Laoutaris Nikolaos P. , Apostolou Thomas S. , Rallidis Loukianos S.
Published: July 2003

It has been suggested that thrombotic tendency increases the risk of myocardial infarction (MI). To investigate the association between the risk of MI at a young age and genetic thrombogenic disorders (G20210A mutation in the prothrombin gene, G1691A mutation in the factor V gene and deficiencies of protein C, protein S and antithrombin III) we conducted a case-control study among 70 survivors of MI who had experienced the event before the age of 36 and 260 healthy subjects. The G20210A mutation in the prothrombin gene was found more often in young patients with MI than among controls (11.4 versus 3.1%). The odds ratio (OR) for MI for carriers versus non-carriers was 4 (95% confidence interval [CI], 1.5 to 11.3). The adjusted OR for major cardiovascular risk factors (smoking, hypecholesterolaemia, diabetes mellitus, hypertension and obesity) was 4.3 (95% CI,1.3 to 14). The simultaneous presence of both G20210A mutation in the prothrombin gene and smoking further increased the risk of MI compared with nonsmokers and non-carriers (OR, 58; 95% CI, 11.4-294). The G1691A mutation in factor V gene was not associated with an increased relative risk for MI (OR, 0.87; 95% CI, 0.26 to 2.5). Finally, there was no significant difference in the prevalence of deficiencies of protein C, protein S and antithrombin III between cases and controls. In conclusion, our data indicate that the G20210A mutation in the prothrombin gene was the only genetic prothrombotic risk factor associated with the risk of developing MI under the age of 36 years.
Replacement therapy with plasma-derived factor VIII concentrates induces skew in T-cell receptor usage and clonal expansion of CD8+ T-cell in HIV-seronegative hemophilia patients
Authors: Matsutani Takaji , Sakurai Yoshihiko , Yoshioka Takeshi , Tsuruta Yuji , Suzuki Ryuji , Yoshioka Akira , Shima Midori
Published: July 2003

Replacement therapy with factor VIII (FVIII) products causes immune abnormalities in human immunodeficiency virus (HIV)-seronegative hemophilia patients. However, the question remains why an absolute increase in the number of CD8+ T-cells and diminished proliferation responses of lymphocytes to antigen stimulation in vitro occurs in HIV-seronegative hemophilia patients.

To examine whether the FVIII products induce skewing of T-cell receptor (TCR) repertoires, TCR variable region α-chain and β–chain repertoires were analyzed for peripheral blood mononuclear cells (PBMCs) from 15 hemophilia patients treated with heated and/or non-heated plasma-derived FVIII concentrates and 10 age-matched healthy adults. Also, T-cell clonality was compared between these groups using complementarity-determining region 3 (CDR3) size spectratyping. The skewing of TCR repertoires was significantly greater for hemophilia patients than healthy controls. The extent of T-cell clonality was greater for hemophilia patients than the controls, indicating that clonal T-cells frequently expanded in hemophilia patients. The skew in TCR usage and clonal expansion were primarily observed in patients treated with non-heated plasma-derived products.

The spectratyping and sequencing of CDR3 regions revealed that the clonal expansion of T-cells was observed for CD8+ T-cells, but not CD4+ T-cells.

These results suggest that extensive expansion of CD8+ T-cells is induced by some viruses other than HIV present in FVIII preparations, and the resulting accumulation of CD8+ T-cells is responsible for changes in peripheral T-cell population in HIV-seronegative hemophilia patients.
Intracellular activation of the fibrinolytic cascade in the Quebec Platelet Disorder
Authors: Sheth Prameet M. , Kahr Walter H. A. , Haq Anwar M. , Veljkovic Dragoslava Kika , Rivard Georges E. , Hayward Catherine P. M.
Published: July 2003

The Quebec Platelet Disorder (QPD) is an unusual bleeding disorder associated with increased platelet stores of urokinase-type plasminogen activator (u-PA) and proteolysis of platelet α–granule proteins. The increased u-PA and proteolyzed plasmino-gen in QPD platelets led us to investigate possible contributions of intracellular plasmin generation to QPD α-granule proteolysis. ELISA indicated there were normal amounts of plasminogen and plasmin-α2-antiplasmin (PAP) complexes in QPD plasmas. Like normal platelets, QPD platelets contained only a small proportion of the blood plasminogen, however, they contained an increased amount of PAP complexes compared to normal platelets (P < 0.005). The quantities of plasminogen stored in platelets were important to induce QPD-like proteolysis of normal α-granule proteins by two chain u-PA (tcu-PA) in vitro. Moreover, adding supplemental plasminogen to QPD, but not to control, platelet lysates, triggered further α-granule protein proteolysis to forms that comigrated with plasmin degraded proteins. These data suggest the generation of increased but limiting amounts of plasmin within platelets is involved in producing the unique phenotypic changes to α-granule proteins in QPD platelets. The QPD is the only known bleeding disorder associated with chronic, intracellular activation of the fibrinolytic cascade.