Dataset Information

Interrelationships between structure and function during the hemostatic response to injury.

ABSTRACT: Extensive studies have detailed the molecular regulation of individual components of the hemostatic system, including platelets, coagulation factors, and regulatory proteins. Questions remain, however, about how these elements are integrated at the systems level within a rapidly changing physical environment. To answer some of these questions, we developed a puncture injury model in mouse jugular veins that combines high-resolution, multimodal imaging with functional readouts in vivo. The results reveal striking spatial regulation of platelet activation and fibrin formation that could not be inferred from studies performed ex vivo. As in the microcirculation, where previous studies have been performed, gradients of platelet activation are readily apparent, as is an asymmetrical distribution of fibrin deposition and thrombin activity. Both are oriented from the outer to the inner surface of the damaged vessel wall, with a greater extent of platelet activation and fibrin accumulation on the outside than the inside. Further, we show that the importance of P2Y₁₂ signaling in establishing a competent hemostatic plug is related to the size of the injury, thus limiting its contribution to hemostasis to specific physiologic contexts. Taken together, these studies offer insights into the organization of hemostatic plugs, provide a detailed understanding of the adverse bleeding associated with a widely prescribed class of antiplatelet agents, and highlight differences between hemostasis and thrombosis that may suggest alternative therapeutic approaches.

SUBMITTER: Tomaiuolo M

PROVIDER: S-EPMC6369752 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Interrelationships between structure and function during the hemostatic response to injury.

Tomaiuolo Maurizio M Matzko Chelsea N CN Poventud-Fuentes Izmarie I Weisel John W JW Brass Lawrence F LF Stalker Timothy J TJ

Proceedings of the National Academy of Sciences of the United States of America 20190123 6

Extensive studies have detailed the molecular regulation of individual components of the hemostatic system, including platelets, coagulation factors, and regulatory proteins. Questions remain, however, about how these elements are integrated at the systems level within a rapidly changing physical environment. To answer some of these questions, we developed a puncture injury model in mouse jugular veins that combines high-resolution, multimodal imaging with functional readouts in vivo. The result ...[more]

PMID: 30674670

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Project description:BackgroundPregnancy leads to several skin changes, but evidence about structural and functional skin changes is scarce. Findings on skin structure and function in children in their first year reveal rapid skin maturation, but evidence indicates that in particular, water holding and transport mechanisms are different from adults. Important questions include whether maternal cutaneous properties predict infant skin condition, and if so, how. This is especially relevant for the skin's microbiome because it closely interacts with the host and is assumed to play a role in many skin diseases. Therefore, the study objective is to explore characteristics of skin and hair of pregnant women and their newborns during pregnancy and in the first six months after delivery and their associations.MethodsThe study has an observational longitudinal design. We are recruiting pregnant females between 18 and 45 years using advertisement campaigns in waiting areas of gynecologists and hospital's outpatient services. A final sample size of n = 100 women is the target. We perform noninvasive, standardized skin, hair, and skin microbiome measurements. We establish the baseline visit during pregnancy until at the latest four weeks before delivery. We schedule follow-up visits four weeks and six months after birth for mothers and their newborns. We will calculate descriptive statistical methods using frequencies and associations over time depending on scale levels of the measurements. Discussion. The majority of previous studies that have investigated infants' skin microbiome and its associations used cross-sectional designs and focused on selected characteristics in small samples. In our longitudinal study, we will characterize a broad range of individual and environmental characteristics of mothers and their newborns to evaluate interrelationships with skin parameters and their changes over time. Considering the combination of these multiple variables and levels will allow for a deeper understanding of the complex interrelationship of the newborn's skin maturation. This trial is registered with ClinicalTrials.gov (Identifier: NCT04759924).

Project description:Essentials Platelet packing density in a hemostatic plug limits molecular movement to diffusion. A diffusion-dependent steep thrombin gradient forms radiating outwards from the injury site. Clot retraction affects the steepness of the gradient by increasing platelet packing density. Together, these effects promote hemostatic plug core formation and inhibit unnecessary growth.SummaryBackground Hemostasis studies performed in vivo have shown that hemostatic plugs formed after penetrating injuries are characterized by a core of highly activated, densely packed platelets near the injury site, covered by a shell of less activated and loosely packed platelets. Thrombin production occurs near the injury site, further activating platelets and starting the process of platelet mass retraction. Tightening of interplatelet gaps may then prevent the escape and exchange of solutes. Objectives To reconstruct the hemostatic plug macro- and micro-architecture and examine how platelet mass contraction regulates solute transport and solute concentration in the gaps between platelets. Methods Our approach consisted of three parts. First, platelet aggregates formed in vitro under flow were analyzed using scanning electron microscopy to extract data on porosity and gap size distribution. Second, a three-dimensional (3-D) model was constructed with features matching the platelet aggregates formed in vitro. Finally, the 3-D model was integrated with volume and morphology measurements of hemostatic plugs formed in vivo to determine how solutes move within the platelet plug microenvironment. Results The results show that the hemostatic mass is characterized by extremely narrow gaps, porosity values even smaller than previously estimated and stagnant plasma velocity. Importantly, the concentration of a chemical species released within the platelet mass increases as the gaps between platelets shrink. Conclusions Platelet mass retraction provides a physical mechanism to establish steep chemical concentration gradients that determine the extent of platelet activation and account for the core-and-shell architecture observed in vivo.

Dataset Information

Interrelationships between structure and function during the hemostatic response to injury.

Publications

Interrelationships between structure and function during the hemostatic response to injury.

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