Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen

Ni, Heyu; Denis, Cécile V.; Subbarao, Sangeetha; Degen, Jay L.; Sato, Thomas N.; Hynes, Richard O.; Wagner, Denisa D.

doi:10.1172/jci9896

Cited by 466 publications

(555 citation statements)

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“…In the absence of Fg, it is thought that VWF contributes to platelet adhesion and aggregation. 31 Even in the absence of both Fg and VWF, platelet thrombi can form in mice that lack both VWF and Fg, although adhesion and aggregation is delayed. 31 This finding shows that the abnormal bleeding in the uteri of FG Ϫ/Ϫ mice is not because of a compromise in platelet aggregation or formation of platelet thrombus.…”

Section: Discussionmentioning

confidence: 99%

“…31 Even in the absence of both Fg and VWF, platelet thrombi can form in mice that lack both VWF and Fg, although adhesion and aggregation is delayed. 31 This finding shows that the abnormal bleeding in the uteri of FG Ϫ/Ϫ mice is not because of a compromise in platelet aggregation or formation of platelet thrombus. Rather, the profuse bleeding in these animals is likely caused by the coagulation defect that results from lack of Fg.…”

Section: Discussionmentioning

confidence: 99%

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Fibrinogen Stabilizes Placental-Maternal Attachment During Embryonic Development in the Mouse

Iwaki

Sandoval-Cooper

Paiva

et al. 2002

The American Journal of Pathology

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Fibrinogen (Fg) is a 340-kd symmetrical heterodimeric protein consisting of three pairs of nonidentical polypeptide chains, and has an overall structure of (A␣/B␤/␥) 2 . This protein is the precursor of fibrin, formed during the hemostatic response. Three separate genes, FGA, FGB, and FGG, located on a 50-kb region of chromosome 4q28-q31, are translated in a coordinated fashion to code for the A␣-, B␤-, and ␥-chains, respectively, of Fg. 1 For its conversion into fibrin, thrombin first catalyzes release of fibrinopeptides A and B from the A␣ and B␤ chains, thus leading to exposure of polymerization sites that organize the initially formed fibrin monomers into a polymeric network of fibers that form the major protein component of the blood clot. This clot is ultimately covalently stabilized by crosslinking of specific ⑀-NH 2 groups of Lys and ␥-COOH groups of Glu residues of fibrin monomer, a process catalyzed by a transglutaminase, namely, activated Factor XIII (FXIIIa). 2

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fibrinogen Stabilizes Placental-Maternal Attachment During Embryonic Development in the Mouse

Iwaki

Sandoval-Cooper

Paiva

et al. 2002

The American Journal of Pathology

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“…A strip of filter paper (4 mm) was dipped in a 462 mM (7.5% wt/vol) FeCl 3 solution for 3 seconds, applied to a 2-to 5-mm length of arteriole for 4 minutes and then removed. 30,31 Z-stack images of the vessel were taken over 5 2-minute cycles (determined as the time the vessel begins to occlude). The rendered z-stack images were deconvolved with AxioVision Rel 4.6 software (Carl Zeiss), to produce a 3-dimensional image, and the volume of the thrombi were determined from the area and height of the clot.…”

Section: Ferric Chloride-induced Model Of Thrombosis and Intravital Mmentioning

confidence: 99%

CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo

Wong

Liu

Yip

et al. 2009

Blood

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Carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is a surface glycoprotein expressed on various blood cells, epithelial cells, and vascular cells. CEACAM1 possesses adhesive and signaling properties mediated by its intrinsic immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1 protein-tyrosine phosphatase. In this study, we demonstrate that CEACAM1 is expressed on the surface and in intracellular pools of platelets. In addition, CEACAM1 serves to negatively regulate signaling of platelets by collagen through the glycoprotein VI (GPVI)/Fc receptor (FcR)-␥-chain. ceacam1 ؊/؊ platelets displayed enhanced type I collagen and GPVI-selective ligand, collagen-related peptide (CRP), CRPmediated platelet aggregation, enhanced platelet adhesion on type I collagen, and elevated CRP-mediated alpha and dense granule secretion. Platelets derived from ceacam1 ؊/؊ mice form larger thrombi when perfused over a collagen matrix under arterial flow compared with wild-type mice. Furthermore, using intravital microscopy to ferric chloride-injured mesenteric arterioles, we show that thrombi formed in vivo in ceacam1 ؊/؊ mice were larger and were more stable than those in wild-type mice. GPVI depletion using monoclonal antibody JAQ1 treatment of ceacam1 ؊/؊ mice showed a reversal in the more stable thrombus growth phenotype. ceacam1 ؊/؊ mice were more susceptible to type I collagen-induced pulmonary thromboembolism than wild-type mice. Thus, CEACAM1 acts as a negative regulator of platelet-collagen interactions and of thrombus growth involving the collagen GPVI receptor in vitro and in vivo. (Blood.

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“…Patients with hypofibrinogenemia are often heterozygous carriers of afibrinogenemia mutations 6. Approximately 30% of patients with CAF or severe hypofibrinogenemia develop thrombosis, which may be due to embolism of an unstable thrombus 9, 10. Congenital dysfibrinogenemia (CD) is a qualitative defect classified by decreased functional activity despite normal antigen levels 11.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

Smith

Bornikova

Noetzli

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials Fibrinogen Disorders are characterized by variable expressivity.Patients with fibrinogen disorders can present with bleeding, thrombosis, or both.As previously reported, genotype‐phenotype correlations are difficult to establish.Molecular modeling may help to further understand the effects of mutations on the mature fibrinogen protein. IntroductionFibrinogen is a complex molecule comprised of two sets of Aα, Bβ, and γ chains. Fibrinogen deficiencies can lead to the development of bleeding or thromboembolic events. The objective of this study was to perform DNA sequence analysis of patients with clinical fibrinogen abnormalities, and to perform genotype‐phenotype correlations.Materials and Methods DNA from 31 patients was sequenced to evaluate disease‐causing mutations in the three fibrinogen genes: FGA,FGB, and FGG. Clinical data were extracted from medical records or from consultation with referring hematologists. Fibrinogen antigen and functional (Clauss method) assays, as well as reptilase time (RT) and thrombin time (TT) were obtained for each patient. Molecular modeling was used to simulate the functional impact of specific missense variants on the overall protein structure.ResultsSeventeen mutations, including six novel mutations, were identified in the three fibrinogen genes. There was little correlation between genotype and phenotype. Molecular modeling predicted a substantial conformational change for a novel variant, FGG p.Ala289Asp, leading to a more rigid molecule in a region critical for polymerization and alignment of the fibrin monomers. This mutation is associated with both bleeding and clotting in the two affected individuals.ConclusionsRobust genotype‐phenotype correlations are difficult to establish for fibrinogen disorders. Molecular modeling might represent a valuable tool for understanding the function of certain missense fibrinogen mutations but those should be followed by functional studies. It is likely that genetic and environmental modifiers account for the incomplete penetrance and variable expressivity that characterize fibrinogen disorders.

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Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen

Cited by 466 publications

References 52 publications

Fibrinogen Stabilizes Placental-Maternal Attachment During Embryonic Development in the Mouse

Fibrinogen Stabilizes Placental-Maternal Attachment During Embryonic Development in the Mouse

CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

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