Objective: To investigate the clinicopathological and molecular characteristics of hepatic fibrinogen storage disease (FSD) in children. Methods: The clinical, histopathologic, immunophenotypic, ultrastructural and gene sequencing data of 4 FSD cases were collected from September 2019 to January 2021 in the Children's Hospital of Fudan University, Shanghai, China. Retrospective analysis and literature review were conducted. Results: There were 4 cases of FSD, 3 males and 1 female, aged 3 years and 3 months to 6 years (median age, 3 years and 4 months). The clinical manifestations were abnormal liver function and abnormal blood coagulation function, for which 2 cases had family genetic history. Liver biopsies revealed that, besides liver steatosis, fibrosis and inflammation, there were single or multiple eosinophilic inclusion bodies of various sizes and surrounding transparent pale halo in hepatocytes. Immunohistochemistry showed that the inclusion bodies were positive for anti-fibrinogen. Under the electron microscope, they corresponded to the dilated cisternae of the rough endoplasmic reticulum, which were occupied by compactly packed tubular structures and arranged into a fingerprint-like pattern with curved bundles. Gene sequencing revealed that the 2 cases of FGG mutation were located in exon 8 c.1106A>G (p.His369Arg) and c.905T>C (p.Leu302Pro), and 1 case was located in exon 9 c.1201C>T (p.Arg401Trp). No pathogenic variant was detected in the other case. Conclusions: FSD is a rare genetic metabolic disease and clinically manifests as abnormal liver function with hypofibrinogenemia. In the background of liver steatosis, fibrosis and inflammation, there are eosinophilic inclusions with pale halo in the hepatocytic cytoplasm, which can be identified by anti-fibrinogen immunohistochemical staining. The fingerprint-like structures under electron microscope are helpful for the diagnosis, while FGG sequencing detects the pathogenic mutation of exon 8 or 9 that can clearly explain the phenotype. However, the diagnosis of FSD cannot be completely ruled out if the relevant mutations are not detected.
Child ; Child, Preschool ; China ; Female ; Fibrinogen/chemistry* ; Humans ; Liver/pathology* ; Liver Diseases/pathology* ; Male ; Metabolic Diseases/pathology* ; Retrospective Studies

OBJECTIVETo explore the genetic basis for a Chinese pedigree affected with congenital hypofibrinogenamia.

METHODSPeripheral blood samples were collected from 9 members from the pedigree. Routine coagulation tests including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT) were carried out. The activity of fibrinogen (Fg: C) was measured using Clauss method, and fibrinogen antigen (Fg: Ag) was measured with immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain genes were amplified using PCR, which was followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing. The mutant fibrinogen was analyzed with Swiss-PdbViewer.

RESULTSThe proband showed prolonged APTT, PT and TT. Her functional fibrinogen (Fg: C) and antigen fibrinogen (Fg: Ag) levels were reduced to 0.69 g/L and 0.72 g/L, respectively. Her mother and grandmother also had a low levels of fibrinogen, which were 0.99 g/L and 0.83 g/L for Fg: C, 1.02 g/L and 0.87 g/L for Fg: Ag, respectively. The results of other members from the pedigree were all within the normal range. Genetic analysis reveled a heterozygous G>T mutation at nucleotide 7590 in exon 8 of γ gene in the proband, which was predicted to be a novel Ser313Ile mutation. The mutation was also found in her mother and grandmother. Model analysis showed that the Ser313Ile mutation disturbed the hydrogen bonds between Ser313, Asn319 and Asp320. Moreover, the mutation also altered the mutual electrostatic force and affected the folding and instability of the mutant fibrinogen.

CONCLUSIONThe heterozygous Ser313Ile mutation probably underlies the hypofibrinogenemia in this pedigree.

Adult ; Afibrinogenemia ; genetics ; Female ; Fibrinogen ; chemistry ; genetics ; Heterozygote ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree

Bone sialoprotein-binding protein (Bbp), a MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) family protein expressed on the surface of Staphylococcus aureus (S. aureus), mediates adherence to fibrinogen α (Fg α), a component in the extracellular matrix of the host cell and is important for infection and pathogenesis. In this study, we solved the crystal structures of apo-Bbp(273-598) and Bbp(273-598)-Fg α(561-575) complex at a resolution of 2.03 Å and 1.45 Å, respectively. Apo-Bbp(273-598) contained the ligand binding region N2 and N3 domains, both of which followed a DE variant IgG fold characterized by an additional D1 strand in N2 domain and D1' and D2' strands in N3 domain. The peptide mapped to the Fg α(561-575) bond to Bbp(273-598) on the open groove between the N2 and N3 domains. Strikingly, the disordered C-terminus in the apo-form reorganized into a highly-ordered loop and a β-strand G'' covering the ligand upon ligand binding. Bbp(Ala298-Gly301) in the N2 domain of the Bbp(273-598)-Fg α(561-575) complex, which is a loop in the apo-form, formed a short α-helix to interact tightly with the peptide. In addition, Bbp(Ser547-Gln561) in the N3 domain moved toward the binding groove to make contact directly with the peptide, while Bbp(Asp338-Gly355) and Bbp(Thr365-Tyr387) in N2 domain shifted their configurations to stabilize the reorganized C-terminus mainly through strong hydrogen bonds. Altogether, our results revealed the molecular basis for Bbp-ligand interaction and advanced our understanding of S. aureus infection process.
Bacterial Proteins ; chemistry ; genetics ; metabolism ; Carrier Proteins ; chemistry ; genetics ; metabolism ; Crystallography, X-Ray ; Fibrinogen ; metabolism ; Ligands ; Models, Molecular ; Mutation ; Peptide Fragments ; chemistry ; metabolism ; Protein Binding ; Protein Structure, Tertiary ; Staphylococcus aureus

OBJECTIVE: To explore the related risk facts of pulmonary thromboembolism (PTE) and analyze the relation between PTE and the trauma or medical behavior by investigating the cases of PTE. METHODS: Thirty-three cases were selected from Institute of Forensic Science (IFS) from 2000 to 2014. RESULTS: In 33 cases, 16 decedents were male, 17 decedents were female; different degrees of dyspnea, chest tight- ness and syncope symptoms were the clinical manifestation of the deceased; the thrombus was mainly distributed in the left and right pulmonary arteries. The main source of embolism was the deep vein of lower limb and the left probability was higher. Trauma, limited position, operation and cardiovascular disease showed high-risk factors of PTE; D-Dimer test, hemolytic test and computer tomography pul- monary angiography were the diagnostic tools for PTE. In some cases, trauma and medical malpractice could be involved in the cause of death. CONCLUSION Non-typical clinical symptoms present in the most cases caused by PTE, and these cases always show many high-risk factors. The relation between PTE and injury or medical behavior should be considered carefully in the forensic pathological practice.
Female ; Fibrin Fibrinogen Degradation Products/chemistry* ; Forensic Pathology ; Humans ; Lower Extremity/pathology* ; Lung/pathology* ; Male ; Malpractice ; Pulmonary Embolism/mortality*

OBJECTIVETo investigate the relationship between emotion and plasma fibrinogen level in train crew.

METHODSA cross-sectional study was conducted in 350 male workers of passenger car, freight car, shunting locomotive for passenger service, and high-speed car from a locomotive depot. The factors involved in this study were as follows: common factors including educational level, physical exercise, smoking, drinking, and physical environment, emotional/characteristic factors including sleep quality, depression, and coping strategies, and working -related factors including effort -reward imbalance, working age, responsibility for people, responsibility for work, intragroup conflicts, and intergroup conflicts. Variables were measured with common rating scales at home and abroad. Plasma fibrinogen level was determined by immunological turbidimetry. The Spearman rank correlation test and multiple stepwise regression were used to analyse the influential factors for fibrinogen level. The original concentration of fibrinogen was subjected to logarithmic transformation in statistical analysis.

RESULTSThe Spearman rank correlation test showed that plasma fibrinogen level was significantly correlated with age(r = 0.228, P = 0.001), working age(r = 0.231, P = 0.001), and emotion (r = -0.138, P = 0.016), but showed no significant relationship with other variables (P > 0.05). The multiple stepwise regression with fibrinogen level as a dependent variable was performed in four models. Model 1 showed that emotion and age were included in the regression after adjustment for common factors (P < 0.05). Model 2 also showed inclusion of emotion and age in the regression after adjustment for common factors and occupational stress factors (P < 0.05). Model 3 showed inclusion of emotion in the regression after adjustment for common factors, occupational stress factors, and psychological factors (P < 0.05). Model 4 showed inclusion of emotion and age after adjustment for common factors, occupational stress factors, psychological factors, and relief factors (P < 0.05).

CONCLUSIONThe emotion of train crew is correlated with plasma fibrinogen level.

Adult ; Cross-Sectional Studies ; Emotions ; Fibrinogen ; analysis ; Humans ; Male ; Middle Aged ; Occupational Diseases ; blood ; Plasma ; chemistry ; Railroads ; Risk Factors ; Stress, Psychological ; blood ; Surveys and Questionnaires

This study was aimed to investigate the correlation of coagulation indicators [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB), antithrombinIII (ATIII), D-dimer (D-D) levels] with inflammatory markers [procalcitonin (PCT), C reactive protein (CRP), interleukin-6 (IL-6), serum amyloid A (SAA)] for sepsis in hematologic malignancy patients. A total of 326 febrile in patients with hematologic diseases from 2062 patients in West China Hospital, Sichuan University from March 2011 to April 2013 were retrospectively analyzed. The patients were divided into sepsis group(n = 72), non-sepsis group(n = 176) and non-sepsis with low Alb group (n = 78) according to blood culture. The results showed that the values of PT, APTT, D-dimer, Plt in sepsis group were higher than those in non-sepsis group, and the difference between them was statistically significant. While the ATIII level in the sepsis group was lower than that in non-sepsis group, and the difference between them was statistically significant (P < 0.05). And the four inflammatory biomarkers in the sepsis patients were higher than those in non-sepsis patients (P < 0.05). TT and FIB level were not significantly different (P > 0.05). There was not a significant difference in these indicators between non-sepsis group and non-sepsis with low Alb group. The correlation analysis suggested that the level of PCT positively correlated with APTT, D-dimer level (P < 0.05); and negatively correlated with the ATIII (P < 0.05). It is concluded that sepsis results in the concurrent activation of inflammatory and procoagulant pathways. The hematologic malignancy patients with sepsis have an obviously higher systemic inflammatory response, and accompanied with coagulation dysfunction.
Biomarkers ; Blood Coagulation ; C-Reactive Protein ; Calcitonin ; Calcitonin Gene-Related Peptide ; Fibrin Fibrinogen Degradation Products ; Hematologic Neoplasms ; chemistry ; complications ; Humans ; Interleukin-6 ; Partial Thromboplastin Time ; Protein Precursors ; Retrospective Studies ; Sepsis ; complications ; Serum Amyloid A Protein ; Thrombin Time

BACKGROUNDThere are controversies about the use of artificial colloids. This research was aimed to determine the effect of various artificial colloids on blood coagulation in the shock stage of severe burn injury.

METHODSTotally, 18 female Ba-Ma mini-pigs were subjected to a 40% total body surface third-degree flame burn under anesthesia. Resuscitation therapy was applied 2 hours after the injury, using the burn shock fluid resuscitation formula commonly accepted in the surgical treatment of burns. The Ba-Ma mini-pigs were randomly assigned to three groups (six pigs in each group): succinylated gelatin group (the artificial colloid used was succinylated gelatin Injection), hydroxyethyl starch group (the artificial colloid used was hydroxyethyl starch (130/0.4)), and allogeneic plasma group (the colloid used was allogeneic plasma). Blood samples were collected from the animals prior to the burn injury and again at intervals of 4, 8, 24 and 48 hours post-injury. The platelet count (PLT), prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen (Fib) were measured, followed by a statistical analysis of all results.

RESULTSThe PLT of succinylated gelatin group and hydroxyethyl starch group at intervals of 24 and 48 hours were (124.3 ± 52.7), (78.8 ± 16.4) × 10(9)/L and (159.0 ± 62.8), (87.3 ± 32.0)× 10(9)/L respectively. But in the allogeneic plasma group at intervals of 8, 24, and 48 hours were (234.3 ± 52.6), (136.0 ± 47.4), (75.8 ± 31.0) × 10(9)/L. The decrease were all statistically significant (P < 0.05, P < 0.01) when compared to pre-burn ((383.3 ± 77.9), (382.7 ± 65.7), (381.0 ± 49.4)× 10(9)/L). The PLT among the three groups, at all the time points, had no statistical difference (P > 0.05). Compared to pre-burn ((10.8 ± 0.9), (11.4 ± 0.8), (10.6 ± 0.7) seconds), the PT of succinylated gelatin group and hydroxyethyl starch group at 24 hours were (14.5 ± 1.5) and (16.2 ± 1.3) seconds, whereas in the allogeneic plasma group at 8 and 24 hours the PT were (13.0 ± 0.9) and (14.5 ± 1.5) seconds, i.e., an increase in the statistical significance (P > 0.01). Statistical significance was observed at 8 and 48 hours between the succinylated gelatin group and hydroxyethyl starch group, and at 48 hours between the hydroxyethyl starch and allogeneic plasma group (P < 0.05). The INR at 24 hours were (1.26 ± 0.13) in the succinylated gelatin group, (1.40 ± 0.11) in the hydroxyethyl starch group, and (1.13 ± 0.07) and (1.26 ± 0.13) at 8 and 24 hours in the allogeneic plasma group. When compared with pre-burn ((0.94 ± 0.08), (0.99 ± 0.07), and (0.92 ± 0.06) seconds), the other groups have increased significantly (P > 0.01). The comparison at 8 and 48 hours between the succinylated gelatin group and the hydroxyethyl starch group, at 48 hours between hydroxyethyl starch group and allogeneic plasma group showed statistical difference (P < 0.01). The APTT of succinylated gelatin group and hydroxyethyl starch group at 24 hours were (13.1 ± 1.1) and (14.6 ± 2.9) seconds. The APTT of the allogeneic plasma group at 4, 8 and 24 hours were (10.9 ± 1.4), (11.8 ± 1.1), and (13.7 ± 1.5) seconds. Compared to pre-burn ((11.5 ± 4.2), (11.2 ± 3.3), (10.1 ± 1.4) seconds), they were statistically significant (P < 0.05). There was no statistical difference in the APTT between the three groups, at all the time points. The Fib of the succinylated gelatin group at 24 and 48 hours were (4.3 ± 0.3) and (4.7 ± 0.2) g/L, (4.1 ± 0.3), and (5.0 ± 0.1) g/L in allogeneic plasma group, and at 8, 24, and 48 hours the Fib for the hydroxyethyl starch group was (2.9 ± 0.4), (4.0 ± 0.5), and (4.6 ± 0.6) g/L. Compared to pre-burn ((2.4 ± 0.2), (2.5 ± 0.3), (2.6 ± 0.5) g/L), they were all statistically significant (P < 0.01). There was no statistical difference in APTT between the three groups, at all time points.

CONCLUSIONThe changes of the indices in blood coagulation during the shock phase of a severe burn injury correlate with the stress response to the burn, rather than to the application of HES (130/0.4) and succinylated gelatin.

Animals ; Blood Coagulation ; drug effects ; Burns ; drug therapy ; metabolism ; Colloids ; chemistry ; therapeutic use ; Female ; Fibrinogen ; metabolism ; Partial Thromboplastin Time ; Shock ; drug therapy ; metabolism ; Swine

Effects of the effective components group of Xiaoshuantongluo formula (XECG) on rat acute blood stasis model were studied under the guidance of the concept of effective components group. Rat acute blood stasis model was induced by subcutaneous injection of epinephrine combined with ice water bath. Hemorheology indices such as whole blood viscosity, plasma viscosity, erythrocyte aggregation index and platelet aggregation rate; coagulation parameters including PT, APTT, TT and FIB; 6-keto-PGF1alpha, TXB2 and D-dimer levels were determined to evaluate the effects of XECG. The results showed that XECG significantly reduced ADP-induced platelet aggregation, but showed little influence on the whole blood viscosity, plasma viscosity and erythrocyte aggregation rate. XECG extended PT and TT slightly, but had no effects on APTT and FIB content. D-dimer levels significantly decreased after administration of XECG with a little decrease of TXB2, but the content of 6-keto-PGF1alpha did not change significantly. The results suggest that the role of XECG of anti-aggregation is more prominent.
6-Ketoprostaglandin F1 alpha ; blood ; Animals ; Blood Coagulation ; drug effects ; Blood Coagulation Disorders ; blood ; Blood Viscosity ; drug effects ; Drug Combinations ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Erythrocyte Aggregation ; drug effects ; Fibrin Fibrinogen Degradation Products ; metabolism ; Hemorheology ; drug effects ; Male ; Partial Thromboplastin Time ; Plants, Medicinal ; chemistry ; Platelet Aggregation ; drug effects ; Prothrombin Time ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thrombin Time ; Thromboxane B2 ; blood

Fibrinogen is a key protein involved in coagulation and its deposition on blood vessel walls plays an important role in the pathology of atherosclerosis. Although the causes of fibrinogen (fibrin) deposition have been studied in depth, little is known about the relationship between fibrinogen deposition and reactive carbonyl compounds (RCCs), compounds which are produced and released into the blood and react with plasma protein especially under conditions of oxidative stress and inflammation. Here, we investigated the effect of glycolaldehyde on the activity and deposition of fibrinogen compared with the common RCCs acrolein, methylglyoxal, glyoxal and malondialdehyde. At the same concentration (1 mmol/L), glycolaldehyde and acrolein had a stronger suppressive effect on fibrinogen activation than the other three RCCs. Fibrinogen aggregated when it was respectively incubated with glycolaldehyde and the other RCCs, as demonstrated by SDS-PAGE, electron microscopy and intrinsic fluorescence intensity measurements. Staining with Congo Red showed that glycolaldehyde- and acrolein-fibrinogen distinctly formed amyloid-like aggregations. Furthermore, the five RCCs, particularly glycolaldehyde and acrolein, delayed human plasma coagulation. Only glycolaldehyde showed a markedly suppressive effect on fibrinogenesis, none did the other four RCCs when their physiological blood concentrations were employyed, respectively. Taken together, it is glycolaldehyde that suppresses fibrinogenesis and induces protein aggregation most effectively, suggesting a putative pathological process for fibrinogen (fibrin) deposition in the blood.
Acetaldehyde ; analogs & derivatives ; blood ; chemistry ; Acrolein ; blood ; chemistry ; Blood Coagulation ; Congo Red ; Electrophoresis, Polyacrylamide Gel ; Fibrinogen ; chemistry ; metabolism ; Glyoxal ; blood ; chemistry ; Humans ; Malondialdehyde ; chemistry ; Polymerization ; Protein Carbonylation ; Pyruvaldehyde ; blood ; chemistry ; Solutions ; Spectrometry, Fluorescence ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Thrombin ; chemistry

In this research,enzyme linked immunoassay (ELISA) was used to assay the fibrinogen (FIG) adsorbed on the Ti-O films and on the low temperature isotropic carbon (LTIC) films which were planted in the femoral arteries of 6 mongrel dogs for six months, respectively. The Ti-O films were planted in the dogs' left femoral arteries; the LTIC films as controls were planted in the dogs' right femoral arteries. The contents adsorbed in these two kinds of films were examined by scanning electron microscopy (SEM). The quantities of FIG adhered or denatured on the Ti-O films or LTIC films determined by ELISA, and the platelets adhered on the two kinds of films examined by SEM were of significant difference between the two groups. In the blood vessel, the amount of FIG adhered on biomaterial was related to its component and construction. FIG released electron to the biomaterial and induced the unfolding of C term of the gamma-chain of FIG, and the conjugation point and effect point were exposed. In conclusion, the biomaterial, which has the capability for resisting the electron release from FIG as well as for maintaining the invariable electric condition, will have excellent hemocompatibility.
Adsorption ; Animals ; Dogs ; Fibrinogen ; metabolism ; Heart Valve Prosthesis ; Histocompatibility ; Molecular Conformation ; Platelet Adhesiveness ; Prostheses and Implants ; Surface Properties ; Titanium ; chemistry