The Ultrastructure of Fibrinogen Caracas II Molecules, Fibers, and Clots

Woodhead, John L.; Nagaswami, Chandrasekaran; Matsuda, Michio; Arocha-Piñango, Carmen Luisa; Weisel, John W.

doi:10.1074/jbc.271.9.4946

Cited by 65 publications

(11 citation statements)

References 46 publications

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“…The mutation is described as a unique N-glycosylated Asn substitution for a Ser at position 434 of the mutant Aa chain that disrupts folding of the carboxyl-terminal region of the Aa chain back upon the central region of the molecule, disrupting its opportunity to participate in lateral aggregation events [40]. Woodhead and Weisel et al, used electron microscopy of individual molecules to find that most of the alpha C domains of fibrinogen Caracas II fail to interact with each other or with the central domain [41]. Caracas II fibrin was made up of thinner fibers that were less-ordered than normal fibers.…”

Section: Discussionmentioning

confidence: 99%

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

White

Wang

et al. 2016

Free Radical Biology and Medicine

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Victims of trauma often develop impaired blood clot formation (coagulopathy) that contributes to bleeding and mortality. Fibrin polymerization is one critical component of clot formation that can be impacted by post-translational oxidative modifications of fibrinogen after exposure to oxidants. In vitro evidence suggests that Aα-C domain methionine sulfoxide formation, in particular, can induce conformational changes that prevent lateral aggregation of fibrin protofibrils during polymerization. We used mass spectrometry of plasma from trauma patients to find that fibrinogen Aα-C domain methionine sulfoxide content was selectively-increased in patients with coagulopathy vs. those without coagulopathy. This evidence supports a novel linkage between oxidative stress, coagulopathy, and bleeding after injury.

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Section: Discussionmentioning

confidence: 99%

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

White

Wang

et al. 2016

Free Radical Biology and Medicine

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“…O'Brien and colleagues propose another mechanism in which fibrin thin films serve as a precursor to fiber formation (21). In these experiments, fibrin thin films self-assemble in gaps (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) web. However, it is unknown whether these thin films can form in vivo on a more complex surface like the subendothelial matrix and in the presence of endogenous thrombin inhibitors like thrombomodulin.…”

Section: Discussionmentioning

confidence: 99%

“…This proposed mechanism is based on the transitions we observed from a three-dimensional gel with mature fibers to a two-dimensional dense mat of very thin fibers, and finally to a thin film with no discernable fibers. The quenching of lateral aggregation could be due to diminished interaction between adjacent aC domains on protofibrils, which has been shown to lead to thinner fibers in certain dysfibrinogenemias (32).…”

Section: Discussionmentioning

confidence: 99%

Thrombin Flux and Wall Shear Rate Regulate Fibrin Fiber Deposition State during Polymerization under Flow

Neeves

Illing

Diamond

2010

Biophysical Journal

125

123

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Thrombin is released as a soluble enzyme from the surface of platelets and tissue-factor-bearing cells to trigger fibrin polymerization during thrombosis under flow conditions. Although isotropic fibrin polymerization under static conditions involves protofibril extension and lateral aggregation leading to a gel, factors regulating fiber growth are poorly quantified under hemodynamic flow due to the difficulty of setting thrombin fluxes. A membrane microfluidic device allowed combined control of both thrombin wall flux (10(-13) to 10(-11) nmol/mum(2) s) and the wall shear rate (10-100 s(-1)) of a flowing fibrinogen solution. At a thrombin flux of 10(-12) nmol/mum(2) s, both fibrin deposition and fiber thickness decreased as the wall shear rate increased from 10 to 100 s(-1). Direct measurement and transport-reaction simulations at 12 different thrombin flux-wall shear rate conditions demonstrated that two dimensionless numbers, the Peclet number (Pe) and the Damkohler number (Da), defined a state diagram to predict fibrin morphology. For Da < 10, we only observed thin films at all Pe. For 10 < Da < 900, we observed either mat fibers or gels, depending on the Pe. For Da > 900 and Pe < 100, we observed three-dimensional gels. These results indicate that increases in wall shear rate quench first lateral aggregation and then protofibril extension.

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“…To evaluate thrombin-induced clots and platelet binding to adsorption induced fibers, scanning electron microscopy was employed. 9 36 Gel-sieved platelets 105 × 10 3 /μL TBS-EDTA buffer (vides supra) were applied to fibers preformed on PS coated wafers and placed on a shaker at 60 rpm for 30 minutes. After washing with buffer wafers were subjected to fixation by 2% glutaraldehyde (v/v in TBS) for 12 hours at ambient temperature.…”

Section: Methodsmentioning

confidence: 99%

Fibers Generated by Plasma Des-AA Fibrin Monomers and Protofibril/Fibrinogen Clusters Bind Platelets: Clinical and Nonclinical Implications

Galanakis

Protopopova

Zhang

et al. 2021

TH Open

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Objective Soluble fibrin (SF) is a substantial component of plasma fibrinogen (fg), but its composition, functions, and clinical relevance remain unclear. The study aimed to evaluate the molecular composition and procoagulant function(s) of SF. Materials and Methods Cryoprecipitable, SF-rich (FR) and cryosoluble, SF-depleted (FD) fg isolates were prepared and adsorbed on one hydrophilic and two hydrophobic surfaces and scanned by atomic force microscopy (AFM). Standard procedures were used for fibrin polymerization, crosslinking by factor XIII, electrophoresis, and platelet adhesion. Results Relative to FD fg, thrombin-induced polymerization of FR fg was accelerated and that induced by reptilase was markedly delayed, attributable to its decreased (fibrinopeptide A) FpA. FR fg adsorption to each surface yielded polymeric clusters and co-cryoprecipitable solitary monomers. Cluster components were crosslinked by factor XIII and comprised ≤21% of FR fg. In contrast to FD fg, FR fg adsorption on hydrophobic surfaces resulted in fiber generation enabled by both clusters and solitary monomers. This began with numerous short protofibrils, which following prolonged adsorption increased in number and length and culminated in surface-linked three-dimensional fiber networks that bound platelets. Conclusion The abundance of adsorbed protofibrils resulted from (1) protofibril/fg clusters whose fg was dissociated during adsorption, and (2) adsorbed des-AA monomers that attracted solution counterparts initiating protofibril assembly and elongation by their continued incorporation. The substantial presence of both components in transfused plasma and cryoprecipitate augments hemostasis by accelerating thrombin-induced fibrin polymerization and by tightly anchoring the resulting clot to the underlying wound or to other abnormal vascular surfaces.

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The Ultrastructure of Fibrinogen Caracas II Molecules, Fibers, and Clots

Cited by 65 publications

References 46 publications

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

Thrombin Flux and Wall Shear Rate Regulate Fibrin Fiber Deposition State during Polymerization under Flow

Fibers Generated by Plasma Des-AA Fibrin Monomers and Protofibril/Fibrinogen Clusters Bind Platelets: Clinical and Nonclinical Implications

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