Foam-like compression behavior of fibrin networks

The rheological properties of fibrin networks have been of long-standing interest. As such there is a wealth of studies of their shear and tensile responses, but their compressive behavior remains unexplored. Here, by characterization of the network structure with synchronous measurement of the fibrin storage and loss moduli at increasing degrees of compression, we show that the compressive behavior of fibrin networks is similar to that of cellular solids. A non-linear stress-strain response of fibrin consists of three regimes: 1) an initial linear regime, in which most fibers are straight, 2) a plateau regime, in which more and more fibers buckle and collapse, and 3) a markedly non-linear regime, in which network densification occurs {{by bending of buckled fibers}} and inter-fiber contacts. Importantly, the spatially non-uniform network deformation included formation of a moving "compression front" along the axis of strain, which segregated the fibrin network into compartments with different fiber densities and structure. The Young's modulus of the linear phase depends quadratically on the fibrin volume fraction while that in the densified phase depends cubically on it. The viscoelastic plateau regime corresponds to a mixture of these two phases in which the fractions of the two phases change during compression. We model this regime using a continuum theory of phase transitions and analytically predict the storage and loss moduli which are in good agreement with the experimental data. Our work shows that fibrin networks are a member of a broad class of natural cellular materials which includes cancellous bone, wood and cork

Molecular Mechanisms Of The Effect Of Ultrasound On The Fibrinolysis Of Clots

Background: Ultrasound accelerates tissue-type plasminogen activator (t-PA)–induced fibrinolysis of clots in vitro and in vivo. Objective: To identify mechanisms for the enhancement of t-PA–induced fibrinolysis of clots. Methods: Turbidity is an accurate and convenient method, not previously used, to follow the effects of ultrasound. Deconvolution microscopy was used to determine changes in structure, while fluorescence recovery after photobleaching was used to characterize the kinetics of binding/unbinding and transport. Results: The ultrasound pulse repetition frequency affected clot lysis times, but there were no thermal effects. Ultrasound in the absence of t-PA produced a slight but consistent decrease in turbidity, suggesting a decrease in fibrin diameter due solely to the action of the ultrasound, likely caused by an increase in protofibril tension because of vibration from ultrasound. Changes in fibrin network structure during lysis with ultrasound were visualized in real time by deconvolution microscopy, revealing that the network becomes unstable when 30–40% of the protein in the network was digested, whereas without ultrasound, the fibrin network was digested gradually and retained structural integrity. Fluorescence recovery after photobleaching during lysis revealed that the off-rate of oligomers from digesting fibers was little affected, but the number of binding/unbinding sites was increased. Conclusions: Ultrasound causes a decrease in the diameter of the fibers due to tension as a result of vibration, leading to increased binding sites for plasmin(ogen)/t-PA. The positive feedback of this structural change together with increased mixing/transport of t-PA/plasmin(ogen) is likely to account for the observed enhancement of fibrinolysis by ultrasound

Effects of unidirectional flow shear stresses on the formation, fractal microstructure and rigidity of incipient whole blood clots and fibrin gels

Incipient clot formation in whole blood and fibrin gels was studied by the rheometric techniques of controlled stress parallel superposition (CSPS) and small amplitude oscillatory shear (SAOS). The effects of unidirectional shear stress on incipient clot microstructure, formation kinetics and elasticity are reported in terms of the fractal dimension (df ) of the fibrin network, the gel network formation time (TGP ) and the shear elastic modulus, respectively. The results of this first haemorheological application of CSPS reveal the marked sensitivity of incipient clot microstructure to physiologically relevant levels of shear stress, these being an order of magnitude lower than have previously been studied by SAOS. CSPS tests revealed that exposure of forming clots to increasing levels of shear stress produces a corresponding elevation in df , consistent with the formation of tighter, more compact clot microstructures under unidirectional flow. A corresponding increase in shear elasticity was recorded. The scaling relationship established between shear elasticity and df for fibrin clots and whole blood confirms the fibrin network as the dominant microstructural component of the incipient clot in terms of its response to imposed stress. Supplementary studies of fibrin clot formation by rheometry and microscopy revealed the substantial additional network mass required to increase df and provide evidence to support the hypothesis that microstructural changes in blood clotted under unidirectional shear may be attributed to flow enhanced thrombin generation and activation. CSPS also identified a threshold value of unidirectional shear stress above which no incipient clot formation could be detected. CSPS was shown to be a valuable haemorheological tool for the study of the effects of physiological and pathological levels of shear on clot properties

an interim analysis from the prospective GMMG-MM5 trial

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16

a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24)

Intrinsic honesty and the prevalence of rule violations across societies

Deception is common in nature and humans are no exception. Modern societies have created institutions to control cheating, but many situations remain where only intrinsic honesty keeps people from cheating and violating rules. Psychological, sociological and economic theories suggest causal pathways to explain how the prevalence of rule violations in people’s social environment, such as corruption, tax evasion or political fraud, can compromise individual intrinsic honesty. Here we present cross-societal experiments from 23 countries around the world that demonstrate a robust link between the prevalence of rule violations and intrinsic honesty. We developed an index of the ‘prevalence of rule violations’ (PRV) based on country-level data from the year 2003 of corruption, tax evasion and fraudulent politics. We measured intrinsic honesty in an anonymous die-rolling experiment. We conducted the experiments with 2,568 young participants (students) who, due to their young age in 2003, could not have influenced PRV in 2003. We find individual intrinsic honesty is stronger in the subject pools of low PRV countries than those of high PRV countries. The details of lying patterns support psychological theories of honesty. The results are consistent with theories of the cultural co-evolution of institutions and values, and show that weak institutions and cultural legacies that generate rule violations not only have direct adverse economic consequences, but might also impair individual intrinsic honesty that is crucial for the smooth functioning of society

The Effects of Temperature on Clot Microstructure and Strength in Healthy Volunteers

BACKGROUND: Anesthesia, critical illness, and trauma are known to alter thermoregulation, which can potentially affect coagulation and clinical outcome. This in vitro preclinical study explores the relationship between temperature change and hemostasis using a recently validated viscoelastic technique. We hypothesize that temperature change will cause significant alterations in the microstructural properties of clot. METHODS: We used a novel viscoelastic technique to identify the gel point of the blood. The gel point identifies the transition of the blood from a viscoelastic liquid to a viscoelastic solid state. Furthermore, identification of the gel point provides 3 related biomarkers: the elastic modulus at the gel point, which is a measure of clot elasticity; the time to the gel point (TGP), which is a measure of the time required to form the clot; and the fractal dimension of the clot at the gel point, df, which quantifies the microstructure of the clot. The gel point measurements were performed in vitro on whole blood samples from 136 healthy volunteers over a temperature range of 27°C to 43°C. RESULTS: There was a significant negative correlation between increases in temperature, from 27°C to 43°C, and TGP (r = −0.641, P 37°C. CONCLUSIONS: This study demonstrates that the gel point technique can identify alterations in clot microstructure because of changes in temperature. This was demonstrated in slower-forming clots with less structural complexity as temperature is decreased. We also found that significant changes in clot microstructure occurred when the temperature was ≤32°C

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition