Biology subjects

Weisel, J. W.

Publications and source records attributed to Weisel, J. W..

4 recordsLinked to original sources

bioRxiv2025

Shapes and Dimensions of Blood Clots Affect the Rate and Extent of Platelet-Driven Clot Contraction and Will Determine the Outcomes of Thrombosis

BackgroundContraction (retraction, shrinkage) of hemostatic blood clots and obstructive thrombi is an important pathophysiological process. To mimic thrombi of various locations, we sought to determine whether the initial shape and dimensions of blood clots affect the rate and extent of clot contraction. MethodsThrombin-induced clots were formed in 0.3-5.7 ml samples of citrated human blood or platelet-rich plasma in a cylinder, cuboid, or flat chamber. The clots were allowed to contract at 37{degrees}C for 60 minutes with shrinkage tracked photographically. Following complete contraction, the physiologically most relevant cylindrical clots of various initial volumes (0.5 ml or 1.5 ml) were analyzed with scanning electron microscopy for composition and spatial non-uniformity with the emphasis on compressed polyhedral erythrocytes (polyhedrocytes). ResultsWith the same volumes studied, the rates and final extents of contraction of whole blood clots were shape-dependent in the following order: flat > cuboid = cylindrical. Irrespective of the shape, the initially smaller clots always contracted to a larger extent. Unlike clots in whole blood, the platelet-rich plasma clots contracted almost independently of the clot volumes and shapes studied, indicating a key role of erythrocytes. The smaller blood clots with a higher extent of contraction contained more relative volume fraction of erythrocytes, especially compressed polyhedrocytes, due to tight packing and a decrease in the intercellular space. Unlike the smaller clots, the larger clots were not clearly segregated into distinct layers, reflecting incomplete spatial redistribution of blood clot components typical for contraction. ConclusionsContraction of blood clots depends on their shape and size. The smaller and larger clots have distinct size-dependent rates and extents of contraction as well as degrees of structural non-uniformity, reflecting different spatial gradients of compressive stresses. The physiological relevance of these findings is related to the variable geometry and size of intravascular blood clots and thrombi.

cell biology↗

bioRxiv2024

Hormone-induced thrombosis is mediated through non-canonical fibrin(ogen) aggregation and a novel estrogen target in zebrafish

Venous thrombosis is a well-known complication of estrogen exposure, with nearly every woman at risk across her lifetime through contraception, pregnancy, or hormone therapy. Although estrogens alter expression of coagulation factors, the mechanisms that mediate estrogen-induced thrombosis are poorly understood, partially due to the absence of an animal model. Identification of these mediators is central to understanding of hormone-induced pathophysiology, could ascertain patients at higher risk for thrombosis, and pinpoint future therapeutic targets. The zebrafish is characterized by external development, high fecundity, optical transparency, and hemostasis is highly conserved with humans. Through a transgenic line that generates GFP-tagged fibrinogen, we show rapid onset of thrombosis after exposure to various estrogens, but not progestins or testosterone. Thrombi are localized to the venous system with evidence for clot contraction. Thrombosis is only partially impeded by anticoagulants, occurs in the absence of factor VII, factor X, and prothrombin, but is dependent on tissue factor and fibrin(ogen). Finally, targeting of all known estrogen receptors does not eliminate thrombosis. The inability to completely inhibit thrombosis through genetic/pharmacologic anticoagulation or estrogen receptor disruption suggests mechanisms different from canonical coagulation/thrombosis. These studies suggest that estrogen-induced thrombosis is a unique entity distinct from other forms of venous thrombosis.

pathology↗

bioRxiv2020

Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling

Fibrin is the major extracellular component of blood clots and a proteinaceous hydrogel used as a versatile biomaterial. Fibrin forms branched networks of polymeric fibers, built of laterally associated double-stranded protofibrils. This multiscale hierarchical structure is crucial for the extraordinary mechanical resilience of blood clots. Yet, the structural basis of clot mechanical properties remains largely unclear due, in part, to the unresolved molecular packing structure of fibrin fibers. Here we quantitatively assess the packing structure of fibrin fibers by combining Small Angle X-ray Scattering (SAXS) measurements of fibrin networks reconstituted under a wide range of conditions with computational molecular modeling of fibrin oligomers. The number, positions, and intensities of the Bragg peaks observed in the SAXS experiments were reproduced computationally based on the all-atom molecular structure of reconstructed fibrin protofibrils. Specifically, the model correctly predicts the intensities of the reflections of the 22.5 nm axial repeat, corresponding to the half-staggered longitudinal arrangement of fibrin molecules. In addition, the SAXS measurements showed that protofibrils within fibrin fibers have a partially ordered lateral arrangement with a characteristic transverse repeat distance of 13 nm, irrespective of the fiber thickness. These findings provide fundamental insights into the molecular structure of fibrin clots that underlies their biological and physical properties.

biophysics↗

bioRxiv2019

Revealing the molecular origins of fibrin’s elastomeric properties by in situ X-ray scattering

Fibrin is an elastomeric protein forming highly extensible fiber networks that provide the scaffold of blood clots. Here we reveal the molecular mechanisms that explain the large extensibility of fibrin networks by performing in situ small angle X-ray scattering measurements while applying a shear deformation. We simultaneously measure shear-induced alignment of the fibers and changes in their axially ordered molecular packing structure. We show that fibrin networks exhibit distinct structural responses that set in consecutively as the shear strain is increased. They exhibit an entropic response at small strains (<5%), followed by progressive fiber alignment (>25% strain) and finally changes in the fiber packing structure at high strain (>100%). Stretching reduces the fiber packing order and slightly increases the axial periodicity, indicative of molecular unfolding. However, the axial periodicity changes only by 0.7%, much less than the 80% length increase of the fibers, indicating that fiber elongation mainly stems from uncoiling of the natively disordered C-peptide linkers that laterally bond the molecules. Upon removal of the load, the network structure returns to the original isotropic state, but the fiber structure becomes more ordered and adopts a smaller packing periodicity compared to the original state. We conclude that the hierarchical packing structure of fibrin fibers, with built-in disorder, makes the fibers extensible and allows for mechanical annealing. Our results provide a basis for interpreting the molecular basis of haemostatic and thrombotic disorders associated with clotting and provide inspiration to design resilient bio-mimicking materials.

biophysics↗