Ginsberg, A. G. | Search bioRxiv

bioRxiv2026

Modeling the Role of Platelet-Released Polyphosphates in Tissue-Factor-Initiated Coagulation under Flow

BackgroundActivated platelets release polyphosphate (polyP), a linear polymer of inorganic phosphate residues, from dense granules. Experiments performed under no-flow conditions show that polyP alters the kinetics of tissue factor (TF) pathway reactions, accelerating FXI activation by thrombin and FV activation by FXa and thrombin, and may impact inhibition by tissue factor pathway inhibitor (TFPI). How polyP influences this pathway in conjunction with platelet deposition under flow remains understudied. ObjectivesTo investigate how polyP-mediated acceleration of FV and FXI activation modulates thrombin generation under flow in TF-initiated coagulation. MethodsWe extended a previously validated mathematical model of platelet deposition and coagulation under flow to examine polyP-mediated effects following a small vascular injury during intravascular clotting. Simulations varied the surface density of TF exposed, wall shear rate, and plasma TFPI concentration. ResultsPolyP shifts the threshold TF density for a thrombin burst to lower TF densities. For TF densities above this threshold, polyP shortens the lag time to thrombin generation in a TF- and shear-rate-dependent manner. Although no explicit effect of polyP on TFPI function was included in the model, thrombin generation was much less sensitive to TFPI concentration with polyP, in a TF-dependent manner. Relative contributions of accelerations of FV and FXI activations depend on incompletely known enhancements by polyP. ConclusionsThe experimentally observed influence of polyP on TFPI function depends on TF density and may arise indirectly from accelerated FV and FXI activation, with the dominant effect arising through accelerated thrombin-mediated conversion of FV to FVa.

systems biology↗

bioRxiv2024

Mechanisms for dysregulation of excitatory-inhibitory balance underlying allodynia in dorsal horn neural subcircuits

Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common type of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord. In this work, we analyze biophysically-motivated subcircuit structures that represent common motifs in neural circuits in layers I-II of the dorsal horn. These circuits are hypothesized to be part of the neural pathways that mediate two different types of allodynia: static and dynamic. We use neural firing rate models to describe the activity of populations of excitatory and inhibitory interneurons within each subcircuit. By accounting for experimentally-observed responses under healthy conditions, we specify model parameters defining populations of subcircuits that yield typical behavior under normal conditions. Then, we implement a sensitivity analysis approach to identify the mechanisms most likely to cause allodynia-producing dysregulation of the subcircuits E-I signaling. We find that disruption of E-I balance generally occurs either due to downregulation of inhibitory signaling so that excitatory neurons are "released" from inhibitory control, or due to upregulation of excitatory neuron responses so that excitatory neurons "escape" their inhibitory control. Which of these mechanisms is most likely to occur, the subcircuit components involved in the mechanism, and the proportion of subcircuits exhibiting the mechanism can vary depending on the subcircuit structure. These results suggest specific hypotheses about diverse mechanisms that may be most likely responsible for allodynia, thus offering predictions for the high interindividual variability observed in allodynia and identifying targets for further experimental studies on the underlying mechanisms of this chronic pain condition. Author summaryWhile chronic pain affects roughly 20% of the US adult population [1], symptoms and presentations of the condition are highly variable across individuals and its causes remain largely unknown. A prevailing hypothesis for the cause of a type of chronic pain called allodynia is that the balance between excitatory and inhibitory signaling pathways between neuron populations in the spinal cord dorsal horn may be disrupted. To help better understand neural mechanisms underlying allodynia, we analyze biologically-motivated mathematical models of subcircuits of neuron populations that are part of the pain processing signaling pathway in the dorsal horn of the spinal cord. We use a novel sensitivity analysis approach to identify mechanisms of subcircuit dysregulation that may contribute to two different types of allodynia. The model results identify specific subcircuit components that are most likely to contribute to each type of allodynia. These mechanisms suggest targets for further experimental study, as well as for pharmacological intervention for better pain treatments.

neuroscience↗