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

Jansen, Karin A.; Zhmurov, Artem; Vos, Bart E.; Portale, Giuseppe; Hermida‐Merino, Daniel; Litvinov, Rustem I.; Tutwiler, Valerie; Kurniawan, Nicholas A.; Bras, Wim; Weisel, John W.; Barsegov, Valeri; Koenderink, Gijsje H.

doi:10.1039/d0sm00916d

Cited by 16 publications

(8 citation statements)

References 70 publications

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“…In the SRS spectra of sparse networks, we found the ratio was 0.7 ± 0.1 for unstrained fibrin fibers whereas strained fibrin fibers showed an increase in symmetric to asymmetric stretching ratio to 0.9 ± 0.2, which is consistent with our previous study. Combined with previous work showing increased protofibril packing in fibrin fibers using X-ray scattering ( 19 , 21 , 22 ), we surmise that the change in molecular distances between adjacent proto fibrils in fibrin fibers leads to increased steric hindrance for the CH 3 asymmetric vibrational mode, making the lower energy CH 3 symmetric mode more prevalent. Microscopically, the decreased molecular distance in fibers highlights the increased packing of protofibrils into tighter bundles prior to unfolding of coiled coil domains from helices into sheets.…”

Section: Resultssupporting

confidence: 83%

“…The impact of the molecular properties of fibrin, specifically the conformation and molecular structure of fibrin proteins that constitute fibers, on fibrin biology and biochemistry are largely absent from the fibrin structure-function literature. This is despite evidence by many groups ( 8 , 19 , 20 ) showing that fibrin molecular structure changes from a dominant α-helix to a dominant β-sheet structure and that molecular distances in fibrin fibers shrink with increasing deformation ( 21 – 23 ).…”

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confidence: 84%

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Structural control of fibrin bioactivity by mechanical deformation

Kumar

Wang

Hedayati

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Fibrin plays a vital role in biology as the fibrous network that stabilizes blood clots and also through interaction with numerous blood components. While much is known about fibrin mechanics, comparatively little is known about how fibrin’s mechanics influence its biochemistry. We show that structural changes in fibrin under mechanical tension reduces binding of tissue plasminogen activator, an enzyme that initiates lysis. Furthermore, these structural transitions also led to decreased platelet activation through suppressed binding between platelet integrins and fibrin. Our work shows that fibrin possesses an intrinsic mechano-chemical feedback loop that regulates its bioactivity via molecular structural rearrangements.

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Section: Resultssupporting

confidence: 83%

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confidence: 84%

Structural control of fibrin bioactivity by mechanical deformation

Kumar

Wang

Hedayati

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Accordingly, no dependence of Δ τ p is observed for an increased NaCl concentration at constant fibrinogen concentration. Only for very high NaCl concentrations of 120 m m a small decrease of Δ τ p was found, which is accounted for by a very fast fibril formation process leading to very thin fibrin fibrils, too, and the nonlinear dependence of turbidity on fibril diameter, [ 34,35 ] see also the discussion further below.…”

Section: Resultsmentioning

confidence: 99%

Correlation between Fibrin Fibrillation Kinetics and the Resulting Fibrin Network Microstructure

Pietsch

Storm-Johannsen

Schmidt-Thomée

et al. 2022

Adv Healthcare Materials

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Fibrin, the prominent extracellular matrix in early wound tissue, is discussed to influence immune cells and healing. The nature of fibrinogen/fibrin to form fibrillary networks is frequently exploited to engineer microenvironments for cellular analysis. This study focuses on revealing the correlation of fibril formation kinetic and the resulting network microstructure of engineered 3D fibrin networks. Different concentrations of fibrinogen (1–3 mg mL−1), thrombin (0.01–0.15 U mL−1), sodium chloride (40–120 mm), and calcium chloride (1–10 mm) are applied to assess the impact on the fibril growth kinetics by turbidity analysis and on the resulting fibril and pore diameter by laser scanning microscopy. The results highlight a direct influence of the sodium chloride concentration on fibrillation kinetics and reveal a strong correlation between fibrillation kinetics and network microstructure. With the assumption of a first‐order growth kinetic, an increase of the growth constant k (0.015–0.04 min−1) is found to correlate to a decrease in fibril diameter (1–0.65 µm) and pore diameter (11–5 µm). The new findings enable an easy prediction of 3D fibrin network microstructure by the fibril formation kinetic and contribute to an improved engineering of defined scaffolds for tissue engineering and cell culture applications.

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“…These 22.5 nm repeats are also present as a band pattern on fibrin fibers on electron microscopy images 38 . However, only a shortrange and weak lateral (or radial) order of around 13 nm 39 and 18 nm 40 was found, indicating that fibrin fibers have less ordered packing laterally than axially. Turbidimetry and fibrinography are multiwavelength scattering methods optimized to reveal detail about the protein density and protofibril content of fibrin fibers 37,41,42 .…”

Section: Formation Of Protofibrils and Protofibril Packing In Fibrin ...mentioning

confidence: 95%

Why fibrin biomechanical properties matter for hemostasis and thrombosis

Feller

Connell

Ariёns

2022

Journal of Thrombosis and Haemostasis

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One of the key functions of blood coagulation is to produce a fibrin clot to stem bleeding after injury. The protease responsible for fibrin production is thrombin, which has many other functions including the activation of platelets but also the activation of anticoagulant systems (protein C) and inhibition of fibrinolysis (via the thrombin activatable fibrinolysis inhibitor). 1 Fibrin is produced in a matter of minutes by thrombin-mediated cleavage of fibrinogen, a protein with a very high concentration in the blood, second only to albumin and the immunoglobulins. Once converted from highly soluble fibrinogen to fibrin, the protein rapidly generates a network that contains

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

Abstract: The blood clotting protein fibrin has extraordinary elastomeric properties due to its hierarchical structure. SAXS is combined with computational molecular modeling, providing insight in fibrin elasticity and guidelines for designing new polymers.

Cited by 16 publications

References 70 publications

Structural control of fibrin bioactivity by mechanical deformation

Structural control of fibrin bioactivity by mechanical deformation

Correlation between Fibrin Fibrillation Kinetics and the Resulting Fibrin Network Microstructure

Why fibrin biomechanical properties matter for hemostasis and thrombosis

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