Anticoagulants and the Propagation Phase of Thrombin Generation

The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may provoke fewer bleeding episodes. More generally, the study shows that computational modeling of the response of core elements of the coagulation proteome to a physiologically relevant tissue factor stimulus may improve the monitoring of a broad range of anticoagulants

The neuropathology of autism: where do we stand?

The neurobiology and neuropathology of the autism spectrum disorders (ASD) remain poorly defined. Brain imaging studies suggest that the deficits in social cognition, language, communication and stereotypical patterns of behaviour that are manifest in individuals with ASD, are related to functional disturbance and 'disconnectivity', affecting multiple brain regions. These impairments are considered to arise as a consequence of abnormal pre- and postnatal development of a distributed neural network. Examination of the brain post mortem continues to provide fundamental information concerning the cellular and subcellular alterations that take place in the brain of autistic individuals. Neuropathological observations that have emerged over the past decade also point towards early pre- and postnatal developmental abnormalities that involve multiple regions of the brain, including the cerebral cortex, cortical white matter, amygdala, brainstem and cerebellum. However, the neuropathology of autism is yet to be clearly defined, and there are several areas that remain open to further investigation. In this respect, more concerted efforts are required to examine the various aspects of cellular pathology affecting the brain in autism. This paper briefly highlights four key areas that warrant further evaluation