Thrombophilia and direct thrombin inhibitor lepirudin clinical and monitoring aspects

Thrombophilia (TF) predisposes both to venous and arterial thrombosis at a young age. TF may also impact the thrombosis or stenosis of hemodialysis (HD) vascular access in patients with end-stage renal disease (ESRD). When involved in severe thrombosis TF may associate with inappropriate response to anticoagulation. Lepirudin, a potent direct thrombin inhibitor (DTI), indicated for heparin-induced thrombocytopenia-related thrombosis, could offer a treatment alternative in TF. Monitoring of narrow-ranged lepirudin demands new insights also in laboratory. The above issues constitute the targets in this thesis. We evaluated the prevalence of TF in patients with ESRD and its impact upon thrombosis- or stenosis-free survival of the vascular access. Altogether 237 ESRD patients were prospectively screened for TF and thrombogenic risk factors prior to HD access surgery in 2002-2004 (mean follow-up of 3.6 years). TF was evident in 43 (18%) of the ESRD patients, more often in males (23 vs. 9%, p=0.009). Known gene mutations of FV Leiden and FII G20210A occurred in 4%. Vascular access sufficiently matured in 226 (95%). The 1-year thrombosis- and stenosis-free access survival was 72%. Female gender (hazards ratio, HR, 2.5; 95% CI 1.6-3.9) and TF (HR 1.9, 95% CI 1.1-3.3) were independent risk factors for the shortened thrombosis- and stenosis-free survival. Additionally, TF or thrombogenic background was found in relatively young patients having severe thrombosis either in hepatic veins (Budd-Chiari syndrome, BCS, one patient) or inoperable critical limb ischemia (CLI, six patients). Lepirudin was evaluated in an off-label setting in the severe thrombosis after inefficacious traditional anticoagulation without other treatment options except severe invasive procedures, such as lower extremity amputation. Lepirudin treatments were repeatedly monitored clinically and with laboratory assessments (e.g. activated partial thromboplastin time, APTT). Our preliminary studies with lepirudin in thrombotic calamities appeared safe, and no bleeds occurred. An effective DTI lepirudin calmed thrombosis as all patients gradually recovered. Only one limb amputation was performed 3 years later during the follow-up (mean 4 years). Furthermore, we aimed to overcome the limitations of APTT and confounding effects of warfarin (INR of 1.5-3.9) and lupus anticoagulant (LA). Lepirudin responses were assessed in vitro by five specific laboratory methods. Ecarin chromogenic assay (ECA) or anti-Factor IIa (anti-FIIa) correlated precisely (r=0.99) with each other and with spiked lepirudin in all plasma pools: normal, warfarin, and LA-containing plasma. In contrast, in the presence of warfarin and LA both APTT and prothrombinase-induced clotting time (PiCT®) were limited by non-linear and imprecise dose responses. As a global coagulation test APTT is useful in parallel to the precise chromogenic methods ECA or Anti-FIIa in challenging clinical situations. Lepirudin treatment requires multidisciplinary approach to ensure appropriate patient selection, interpretation of laboratory monitoring, and treatment safety. TF seemed to be associated with complicated thrombotic events, in venous (BCS), arterial (CLI), and vascular access systems. TF screening should be aimed to patients with repeated access complications or prior unprovoked thromboembolic events. Lepirudin inhibits free and clot-bound thrombin which heparin fails to inhibit. Lepirudin seems to offer a potent and safe option for treatment of severe thrombosis. Multi-centered randomized trials are necessary to assess the possible management of complicated thrombotic events with DTIs like lepirudin and seek prevention options against access complications.

Aspects of Inflationary Models at Low Energy Scales

Cosmological inflation is the dominant paradigm in explaining the origin of structure in the universe. According to the inflationary scenario, there has been a period of nearly exponential expansion in the very early universe, long before the nucleosynthesis. Inflation is commonly considered as a consequence of some scalar field or fields whose energy density starts to dominate the universe. The inflationary expansion converts the quantum fluctuations of the fields into classical perturbations on superhorizon scales and these primordial perturbations are the seeds of the structure in the universe. Moreover, inflation also naturally explains the high degree of homogeneity and spatial flatness of the early universe. The real challenge of the inflationary cosmology lies in trying to establish a connection between the fields driving inflation and theories of particle physics. In this thesis we concentrate on inflationary models at scales well below the Planck scale. The low scale allows us to seek for candidates for the inflationary matter within extensions of the Standard Model but typically also implies fine-tuning problems. We discuss a low scale model where inflation is driven by a flat direction of the Minimally Supersymmetric Standard Model. The relation between the potential along the flat direction and the underlying supergravity model is studied. The low inflationary scale requires an extremely flat potential but we find that in this particular model the associated fine-tuning problems can be solved in a rather natural fashion in a class of supergravity models. For this class of models, the flatness is a consequence of the structure of the supergravity model and is insensitive to the vacuum expectation values of the fields that break supersymmetry. Another low scale model considered in the thesis is the curvaton scenario where the primordial perturbations originate from quantum fluctuations of a curvaton field, which is different from the fields driving inflation. The curvaton gives a negligible contribution to the total energy density during inflation but its perturbations become significant in the post-inflationary epoch. The separation between the fields driving inflation and the fields giving rise to primordial perturbations opens up new possibilities to lower the inflationary scale without introducing fine-tuning problems. The curvaton model typically gives rise to relatively large level of non-gaussian features in the statistics of primordial perturbations. We find that the level of non-gaussian effects is heavily dependent on the form of the curvaton potential. Future observations that provide more accurate information of the non-gaussian statistics can therefore place constraining bounds on the curvaton interactions.

Control aspects in proportionality Markov manpower systems

In this paper, the control aspects of a hierarchical organization under the influence of "proportionality" policies are analyzed. Proportionality policies are those that restrict the recruitment to every level of the hierarchy (except the bottom most level or base level) to be in strict proportion to the promotions into that level. Both long term and short term control analysis have been discussed. In long term control the specific roles of the parameters of the system with regard to control of the shape and size of the system have been analyzed and yield suitable control strategies. In short term control, the attainability of a target or goal structure within a specific time from a given initial structure has been analyzed and yields the required recruitment strategies. The theoretical analyses have been illustrated with computational examples and also with real world data.

Optimal Resource Partitioning in a Military Conflict based on Lanchester Attrition Models

This paper develops a model for military conflicts where the defending forces have to determine an optimal partitioning of available resources to counter attacks from an adversary in two different fronts. The Lanchester attrition model is used to develop the dynamical equations governing the variation in force strength. Three different allocation schemes - Time-Zero-Allocation (TZA), Allocate-Assess-Reallocate (AAR), and Continuous Constant Allocation (CCA) - are considered and the optimal solutions are obtained in each case. Numerical examples are given to support the analytical results.

Optimal Resource Partitioning in a Military Conflict based on Lanchester Attrition Models

This paper develops a model for military conflicts where the defending forces have to determine an optimal partitioning of available resources to counter attacks from an adversary in two different fronts. The Lanchester attrition model is used to develop the dynamical equations governing the variation in force strength. Three different allocation schemes - Time-Zero-Allocation (TZA), Allocate-Assess-Reallocate (AAR), and Continuous Constant Allocation (CCA) - are considered and the optimal solutions are obtained in each case. Numerical examples are given to support the analytical results.

Control aspects in proportionality Markov manpower systems

In this paper, the control aspects of a hierarchical organization under the influence of "proportionality" policies are analyzed. Proportionality policies are those that restrict the recruitment to every level of the hierarchy (except the bottom most level or base level) to be in strict proportion to the promotions into that level. Both long term and short term control analysis have been discussed. In long term control the specific roles of the parameters of the system with regard to control of the shape and size of the system have been analyzed and yield suitable control strategies. In short term control, the attainability of a target or goal structure within a specific time from a given initial structure has been analyzed and yields the required recruitment strategies. The theoretical analyses have been illustrated with computational examples and also with real world data. The control of such proportionality systems is then compared with that of the general systems (which do not follow such policies) with some significant conclusions. The control relations of such proportionality systems are found to be simpler and more practically feasible than those of general Markov systems, which do not have such restrictions. Such proportionality systems thus not only retain and match the flexibility of general Markov systems but also have the added advantage of simpler and more practically feasible controls. The proportionality policies hence act as an alternative and more practicably feasible means of control. (C) 2004 Elsevier Inc. All rights reserved.

Aspects of tautomerism. Part II. Reactions of the pseudo-acid chloride of o-benzoylbenzoic acid with nucleophiles

Reactions of fourteen nucleophiles with the pseudo-acid chloride of o-benzoylbenzoic acid in two solvents have been studied. The nucleophiles that react primarily at the tetrahedral carbon atom to give pseudo derivatives, are weaker than those that react at the carbonyl carbon atom causing opening of the lactone ring. An explanation for this phenomenon is advanced.