Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7). CONCLUSIONS: Anti-spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP

Shrinking Weibel‐Palade bodies prevents high platelet recruitment in assays using thrombotic thrombocytopenic purpura plasma

Background: Thrombotic thrombocytopenic purpura (TTP), caused by a genetic or autoimmune-driven lack of ADAMTS-13 activity, leads to high levels of the ultra-large von Willebrand factor (VWF) multimers produced by endothelial cells, causing excess platelet recruitment into forming thrombi, often with mortal consequences. Treatments include plasma infusion or replacement to restore ADAMTS-13 activity, or prevention of platelet recruitment to VWF. // Objectives: We tested a different approach, exploiting the unique cell biology of the endothelium. Upon activation, the VWF released by exocytosis of Weibel-Palade bodies (WPBs), transiently anchored to the cell surface, unfurls as strings into flowing plasma, recruiting platelets. Using plasma from patients with TTP increases platelet recruitment to the surface of cultured endothelial cells under flow. WPBs are uniquely plastic, and shortening WPBs dramatically reduces VWF string lengths and the recruitment of platelets. We wished to test whether the TTP plasma-driven increase in platelet recruitment would be countered by reducing formation of the longest WPBs that release longer strings. // Methods: Endothelial cells grown in flow chambers were treated with fluvastatin, one of 37 drugs shown to shorten WPBs, then activated under flow in the presence of platelets and plasma of either controls or patients with TTP. // Result: We found that the dramatic increase in platelet recruitment caused by TTP plasma is entirely countered by treatment with fluvastatin, shortening the WPBs. // Conclusions: This potential approach of ameliorating the endothelial contribution to thrombotic risk by intervening far upstream of hemostasis might prove a useful adjunct to more conventional and direct therapies

Effect of laser surface treatment on the corrosion and fatigue performance of aa5456-h116 alloys

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Current-oscillator correlation and Fano factor spectrum of quantum shuttle with finite bias voltage and temperature

A general master equation is derived to describe an electromechanical single-dot transistor in the Coulomb blockade regime. In the equation, Fermi distribution functions in the two leads are taken into account, which allows one to study the system as a function of bias voltage and temperature of the leads. Furthermore, we treat the coherent interaction mechanism between electron tunneling events and the dynamics of excited vibrational modes. Stationary solutions of the equation are numerically calculated. We show current through the oscillating island at low temperature appears step like characteristics as a function of the bias voltage and the steps depend on mean phonon number of the oscillator. At higher temperatures the current steps would disappear and this event is accompanied by the emergence of thermal noise of the charge transfer. When the system is mainly in the ground state, zero frequency Fano factor of current manifests sub-Poissonian noise and when the system is partially driven into its excited states it exhibits super-Poissonian noise. The difference in the current noise would almost be removed for the situation in which the dissipation rate of the oscillator is much larger than the bare tunneling rates of electrons.Comment: 14 pages, 8 figure

Entanglement and teleportation via chaotic system

The dynamics of entangled state interacting with a single cavity mode is investigated in the presence of a random parameter. We have shown that degree of entanglement decays with time and rate of decay is defined by features of random parameter. Quantum teleportation through dissipative channal and teleportation fidelity as a function of damping rates has been studied. The sensitivity of the fidelity with respect to random parameter is discussed. We have evaluated the time interval during which one can perform the quantum teleportation and send the information with reasonable fidelity, for a given values of correlation length of random parameter.Comment: Accepted in Physica

Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura

Background Severe deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease. Objectives To investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy. Patients/Methods Anti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes. Results At presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance. Conclusion These data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP

Entanglement generation in double-Λ\Lambda system

In this paper, we study the generation of entanglement in a double-$\Lambda$ system. Employing standard method of laser theory, we deduce the dynamic evolution equation of the two-mode field. We analyze the available entanglement criterion for double-$\Lambda$ system and the condition of entanglement existence. Our results show that under proper parameters, the two-mode field can entangled and amlified

Integral Relaxation Time of Single-Domain Ferromagnetic Particles

The integral relaxation time \tau_{int} of thermoactivating noninteracting single-domain ferromagnetic particles is calculated analytically in the geometry with a magnetic field H applied parallel to the easy axis. It is shown that the drastic deviation of \tau_{int}^{-1} from the lowest eigenvalue of the Fokker-Planck equation \Lambda_1 at low temperatures, starting from some critical value of H, is the consequence of the depletion of the upper potential well. In these conditions the integral relaxation time consists of two competing contributions corresponding to the overbarrier and intrawell relaxation processes.Comment: 8 pages, 3 figure

Probing the nanoscale phase separation in binary photovoltaic blends of poly(3-hexylthiophene) and methanofullerene by energy transfer

The generation of charge carriers in organic photovoltaic devices requires exciton diffusion to an interface of electron donor and acceptor materials, where charge separation occurs. We report a time resolved study of fluorescence quenching in films of poly(3-hexylthiophene) containing a range of fractions of the electron acceptor [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). We show that energy transfer from P3HT to PCBM helps to bring excitons to the interface, where they dissociate into charge carriers. Fluorescence quenching in blends with ≤50 wt% of PCBM is controlled by exciton diffusion in P3HT. This allows us to estimate the average size of PCBM domains to be about 9 nm in the 1:1 blend. The implications for polymer solar cells are discussed

Absorbing state phase transition with competing quantum and classical fluctuations

Stochastic processes with absorbing states feature examples of non-equilibrium universal phenomena. While the classical regime has been thoroughly investigated in the past, relatively little is known about the behavior of these non-equilibrium systems in the presence of quantum fluctuations. Here we theoretically address such a scenario in an open quantum spin model which in its classical limit undergoes a directed percolation phase transition. By mapping the problem to a non-equilibrium field theory, we show that the introduction of quantum fluctuations stemming from coherent, rather than statistical, spin-flips alters the nature of the transition such that it becomes first-order. In the intermediate regime, where classical and quantum dynamics compete on equal terms, we highlight the presence of a bicritical point with universal features different from the directed percolation class in low dimension. We finally propose how this physics could be explored within gases of interacting atoms excited to Rydberg states