Platelet packing density is an independent regulator of the hemostatic response to injury

• Published in: Journal of thrombosis and haemostasis 2018-05, Vol.16 (5), p.973-983
• Main Authors: Mirramezani, M., Herbig, B. A., Stalker, T. J., Nettey, L., Cooper, M., Weisel, J. W., Diamond, S. L., Sinno, T., Brass, L. F., Shadden, S. C., Tomaiuolo, M.
• Format: Article
• Language: English
• Subjects: Abdominal Muscles - blood supply; Animals; Arterioles - injuries; Arterioles - pathology; Arterioles - physiopathology; Blood Flow Velocity; Blood Platelets - metabolism; Blood Platelets - pathology; Clot Retraction; Computer Simulation; Contraction; Diffusion; Disease Models, Animal; fluid dynamics; Hemostasis; hemostatic injury; mass transport; Mice, Inbred C57BL; Microcirculation; Models, Biological; Platelet Aggregation; Platelets; Porosity; Scanning electron microscopy; Size distribution; Solutes; Thrombin; Thrombin - metabolism; Thrombosis - blood; Thrombosis - pathology; Thrombosis - physiopathology; Time Factors; Vascular System Injuries - blood; Vascular System Injuries - pathology; Vascular System Injuries - physiopathology
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13986

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. Summary Background 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.