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Neurochemical Research Nov 2023Multiple sclerosis (MS) is an autoimmune demyelinating neurodegenerative disease of the central nervous system (CNS) due to injury of the myelin sheath by immune cells.... (Review)
Review
Multiple sclerosis (MS) is an autoimmune demyelinating neurodegenerative disease of the central nervous system (CNS) due to injury of the myelin sheath by immune cells. The clotting factor fibrinogen is involved in the pathogenesis of MS by triggering microglia and the progress of neuroinflammation. Fibrinogen level is correlated with MS severity; consequently, inhibition of the fibrinogen cascade may reduce MS neuropathology. Thus, this review aimed to clarify the potential role of fibrinogen in the pathogenesis of MS and how targeting of fibrinogen affects MS neuropathology. Accumulation of fibrinogen in the CNS may occur independently or due to disruption of blood-brain barrier (BBB) integrity in MS. Fibrinogen acts as transduction and increases microglia activation which induces the progression of inflammation, oxidative stress, and neuronal injury. Besides, brain fibrinogen impairs the remyelination process by inhibiting the differentiation of oligodendrocyte precursor cells. These findings proposed that fibrinogen is associated with MS neuropathology through interruption of BBB integrity, induction of neuroinflammation, and demyelination with inhibition of the remyelination process by suppressing oligodendrocytes. Therefore, targeting of fibrinogen and/or CD11b/CD18 receptors by metformin and statins might decrease MS neuropathology. In conclusion, inhibiting the expression of CD11b/CD18 receptors by metformin and statins may decrease the pro-inflammatory effect of fibrinogen on microglia which is involved in the progression of MS.
Topics: Humans; Multiple Sclerosis; Fibrinogen; Neuroinflammatory Diseases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neurodegenerative Diseases; Myelin Sheath; Fear
PubMed: 37442896
DOI: 10.1007/s11064-023-03981-1 -
International Journal of Molecular... Jul 2023Hypercoagulability and formation of extensive and difficult-to-lyse microclots are a hallmark of both acute COVID-19 and long COVID. Fibrinogen, when converted to...
Hypercoagulability and formation of extensive and difficult-to-lyse microclots are a hallmark of both acute COVID-19 and long COVID. Fibrinogen, when converted to fibrin, is responsible for clot formation, but abnormal structural and mechanical clot properties can lead to pathologic thrombosis. Recent experimental evidence suggests that the spike protein (SP) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly bind to the blood coagulation factor fibrinogen and induce structurally abnormal blood clots with heightened proinflammatory activity. Accordingly, in this study, we used molecular docking and molecular dynamics simulations to explore the potential activity of the antiparasitic drug ivermectin (IVM) to prevent the binding of the SARS-CoV-2 SP to fibrinogen and reduce the occurrence of microclots. Our computational results indicate that IVM may bind with high affinity to multiple sites on the fibrinogen peptide, with binding more likely in the central, E region, and in the coiled-coil region, as opposed to the globular D region. Taken together, our in silico results suggest that IVM may interfere with SP-fibrinogen binding and, potentially, decrease the formation of fibrin clots resistant to degradation. Additional in vitro studies are warranted to validate whether IVM binding to fibrinogen is sufficiently stable to prevent interaction with the SP, and potentially reduce its thrombo-inflammatory effect in vivo.
Topics: Humans; COVID-19; Fibrin; Fibrinogen; Hemostatics; Ivermectin; Molecular Docking Simulation; Post-Acute COVID-19 Syndrome; SARS-CoV-2; Thrombosis
PubMed: 37511206
DOI: 10.3390/ijms241411449 -
Shock (Augusta, Ga.) May 2021We recently demonstrated that fibrinogen stabilizes syndecan-1 on the endothelial cell (EC) surface and contributes to EC barrier protection, though the intracellular...
INTRODUCTION
We recently demonstrated that fibrinogen stabilizes syndecan-1 on the endothelial cell (EC) surface and contributes to EC barrier protection, though the intracellular signaling pathway remains unclear. P21 (Rac1) activated kinase 1 (PAK1) is a protein kinase involved in intracellular signaling leading to actin cytoskeleton rearrangement and plays an important role in maintaining endothelial barrier integrity. We therefore hypothesized that fibrinogen binding to syndecan-1 activated the PAK1 pathway.
METHODS
Primary human lung microvascular endothelial cells were incubated in 10% lactated Ringers (LR) solution or 10% fibrinogen saline solution (5 mg/mL). Protein phosphorylation was determined by Western blot analysis and endothelial permeability measured by fluorescein isothiocyanate (FITC)-dextran. Cells were silenced by siRNA transfection. Protein concentration was measured in the lung lavages of mice.
RESULTS
Fibrinogen treatment resulted in increased syndecan-1, PAK1 activation (phosphorylation), cofilin activation (dephosphorylation), as well as decreased stress fibers and permeability when compared with LR treatment. Cofilin is an actin-binding protein that depolymerizes F-actin to decrease stress fiber formation. Notably, fibrinogen did not influence myosin light chain activation (phosphorylation), a mediator of EC tension. Silencing of PAK1 prevented fibrinogen-induced dephosphorylation of cofilin and barrier integrity. Moreover, to confirm the in vitro findings, mice underwent hemorrhagic shock and were resuscitated with either LR or fibrinogen. Hemorrhage shock decreased lung p-PAK1 levels and caused significant lung vascular leakage. However, fibrinogen administration increased p-PAK1 expression to near sham levels and remarkably prevented the lung leakage.
CONCLUSION
We have identified a novel pathway by which fibrinogen activates PAK1 signaling to stimulate/dephosphorylate cofilin, leading to disassembly of stress fibers and reduction of endothelial permeability.
Topics: Actin Depolymerizing Factors; Animals; Endothelial Cells; Fibrinogen; Male; Mice; Mice, Inbred C57BL; Signal Transduction; p21-Activated Kinases
PubMed: 32433215
DOI: 10.1097/SHK.0000000000001564 -
Molecular Medicine (Cambridge, Mass.) 2011Hemorrhagic coagulopathy (without neurological injuries) constitutes 40% of injury-related death in civilian hospitals and on the battlefield, and the underlying...
Hemorrhagic coagulopathy (without neurological injuries) constitutes 40% of injury-related death in civilian hospitals and on the battlefield, and the underlying contributing mechanisms remain unclear. The purpose of this study is to investigate the effects of fibrinogen availability on coagulation function after hemorrhage in pigs. Sixteen crossbred commercial Yorkshire swine were randomized into the control group (group C) (n = 8) and hemorrhage group (group H) (n = 8). Hemorrhage was induced in group H by bleeding 35% of the estimated total blood volume, followed by resuscitation with lactated Ringer solution at three times the bled volume. Pigs in group C were not hemorrhaged or resuscitated. Blood samples were withdrawn at baseline, 15 min, 3 h, 6 h, and 24 h after hemorrhage and lactated Ringer (LR) resuscitation (H-LR). Coagulation was assessed by using thrombelastography. All baseline measurements were similar between groups C and H. Hemorrhage caused a decrease in mean arterial pressure and an increase in heart rate in group H, but LR resuscitation corrected these changes within 1 h. Compared to baseline values, fibrinogen concentrations in group H decreased at 15 min, 3 h and 6 h after H-LR, but increased to double that of the baseline value at 24 h; platelet counts decreased throughout the study; clot strength was decreased at 15 min, 3 h and 6 h, but returned to baseline value at 24 h after H-LR. Hemorrhage caused decreases in fibrinogen and platelets, and compromised clot strength. The rebound of fibrinogen at 24 h restored clot strength despite platelet deficit. These data suggest the potential compensatory role of fibrinogen in restoring coagulation function in vivo after hemorrhagic shock.
Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Blood Pressure; Breeding; Female; Fibrinogen; Isotonic Solutions; Male; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Random Allocation; Resuscitation; Ringer's Lactate; Shock, Hemorrhagic; Swine; Thrombelastography; Time Factors
PubMed: 21327301
DOI: 10.2119/molmed.2010.00093 -
Scandinavian Journal of Trauma,... Mar 2013Haemodilution and hypothermia induce coagulopathy separately, but their combined effect on coagulation has not been widely studied. Fibrinogen concentrate can correct...
BACKGROUND
Haemodilution and hypothermia induce coagulopathy separately, but their combined effect on coagulation has not been widely studied. Fibrinogen concentrate can correct dilutional coagulopathy and has an additional effect when combined with factor XIII concentrate. However, their effect on dilutional coagulopathy concomitant with hypothermia has not been studied previously. Free oscillation rheometry - FOR (Reorox®) - is a novel viscoelastic haemostatic assay that has not been studied in this context before.
METHODS
Blood from 10 healthy volunteers was diluted by 33% with hydroxyethyl starch or Ringer's acetate solutions. Effects of fibrinogen added in vitro with and without factor XIII were studied at 33°C and 37°C. Coagulation velocity (coagulation time) and clot strength (elasticity) were assessed with FOR. Coagulation was initiated in vitro with thromboplastin alone, or thromboplastin plus a platelet inhibitor.
RESULTS
Hydroxyethyl starch increased the coagulation time and decreased clot strength significantly more than Ringer's acetate solution, both in the presence and absence of a platelet inhibitor. There was a significant interaction between haemodilution with hydroxyethyl starch and hypothermia, resulting in increased coagulation time. After addition of fibrinogen, coagulation time shortened and elasticity increased, with the exception of fibrinogen-dependent clot strength (i.e., elasticity in the presence of a platelet inhibitor) after hydroxyethyl starch haemodilution. Factor XIII had an additional effect with fibrinogen on fibrinogen-dependent clot strength in blood diluted with Ringer's acetate solution. Hypothermia did not influence any of the coagulation factor effects.
CONCLUSIONS
Both haemodilution and mild hypothermia impaired coagulation. Coagulopathy was more pronounced after haemodilution with hydroxyethyl starch than with Ringer's acetate. Addition of fibrinogen with factor XIII was unable to reverse hydroxyethyl starch induced clot instability, but improved coagulation in blood diluted with Ringer's acetate solution. Fibrinogen improved coagulation irrespective of hypothermia.
Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Viscosity; Coagulants; Female; Fibrinogen; Fibrinolysin; Fibrinolytic Agents; Hemodilution; Hemorheology; Hemostatics; Humans; Hypothermia; Male; Middle Aged; Monitoring, Physiologic; Thrombelastography
PubMed: 23517637
DOI: 10.1186/1757-7241-21-20 -
Molecules (Basel, Switzerland) Mar 2022Liquid platelet-rich fibrin (PRF) is produced by fractionation of blood without additives that initiate coagulation. Even though liquid PRF is frequently utilized as a...
Liquid platelet-rich fibrin (PRF) is produced by fractionation of blood without additives that initiate coagulation. Even though liquid PRF is frequently utilized as a natural source of fibrinogen to prepare sticky bone, the concentration of fibrinogen and the overall amount of "clottable PRF" components have not been evaluated. To this aim, we prepared liquid PRF at 300, 700, and 2000 relative centrifugal force (RCF), for 8 min and quantified the fibrinogen levels by immunoassay. We report here that, independent of the RCF, the fibrinogen concentration is higher in the platelet-poor plasma (PPP) compared to the buffy coat (BC) fraction of liquid PRF and further decreases in the remaining red fraction. We then determined the weight of the clotted PRF fractions before and after removing the serum. The PPP and BC fractions consist of 10.2% and 25.3% clottable matrix suggesting that more than half of the weight of clottable BC is caused by cellular components. Our data provide insights into the distribution of fibrinogen in the different fractions of liquid PRF. These findings suggest that PPP is the main source of clottable fibrinogen, while the BC is more a cell source when it comes to the preparation of sticky bone.
Topics: Blood Coagulation; Blood Platelets; Centrifugation; Fibrinogen; Plasma; Platelet-Rich Fibrin
PubMed: 35408442
DOI: 10.3390/molecules27072043 -
Thrombosis Research Jun 2014Thromboelastography (TEG), a widely used clinical point of care coagulation test, is poorly understood. To investigate its fibrin determinants we used normal and variant...
INTRODUCTION
Thromboelastography (TEG), a widely used clinical point of care coagulation test, is poorly understood. To investigate its fibrin determinants we used normal and variant fibrinogen isolates.
MATERIALS AND METHODS
We focused mainly on the TEG maximum signal amplitude (MA), a shear modulus and clot stiffness indicator. Isolates included normal des-αC, cord, and abnormal congenital variants with amino acid substitutions or deletions that impaired fibrin polymerization. Heterophenotypic congenital isolates were from cryoprecipitate-depleted plasma owing to their more diminished clot MA than their cryoprecipitate counterparts. By colorimetric assay, the amount of fibrinogen adsorbed by untreated TEG cups was 83.5±12.4 pM/cm(2), n=18. Thrombin-induced clots were obtained at pH6.4 or 7.4, the latter containing 8mM CaCl2, and 14% afibrinogenemic plasma with and without gel-sieved platelets.
RESULTS AND CONCLUSIONS
Measured by the water droplet contact angle, >90% reduction of surface hydrophobicity by exposure of TEG cup and pin to ozone plasma decreased MA by 74%. Increasing normal fibrinogen or thrombin concentrations progressively increased MA. Platelets increased MA further ~2 fold, except for ≥10 fold for des-αC clots. Examined in the absence of platelets, MA of heterophenotypic fibrin variants averaged 21%, n=15. The results imply that essential MA determinants include hydrophobic fibrinogen/fibrin adsorption and each polymerization contact site, with substantial enhancement by platelets. Also, cryoprecipitate-harvested soluble fibrinogen/fibrin complexes contained mostly normal molecules, while cryoprecipitate-depleted plasma contained mostly variant molecules. Moreover, significantly decreased MA by fibrinogen anomalies and/or low level thrombin generation can potentially impact clinical interpretation of MA.
Topics: Afibrinogenemia; Blood Platelets; Fibrin; Fibrinogen; Humans; Phenotype; Thrombelastography
PubMed: 24679643
DOI: 10.1016/j.thromres.2014.03.026 -
Clinical and Applied... 2020To investigate changes in coagulation during twin pregnancies. Methods: A total of 108 women with twin pregnancies and 442 women with singleton pregnancies were...
To investigate changes in coagulation during twin pregnancies. Methods: A total of 108 women with twin pregnancies and 442 women with singleton pregnancies were recruited. Coagulation tests, including fibrinogen (Fib), activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT), were performed during the course of the pregnancy. The level of fibrinogen gradually increased during singleton pregnancies, while the APTT and PT levels showed a decreasing trend with increasing gestational weeks. In twin pregnancies, the changes in PT and TT were similar, but other parameters displayed a different trend. Fibrinogen showed no significant difference between the second and third trimesters, while APTT showed an increasing trend from the second trimester to the third trimester. Compared with singleton pregnancies, the level of fibrinogen was higher in women pregnant with twins. APTT was longer in women pregnant with twins than in women with singleton pregnancies in the third trimester. PT was shorter in women pregnant with twins than in women with singleton pregnancies in the first and third trimesters. TT was shorter in women pregnant with twins than in women with singleton pregnancies in the first and second trimesters. Through this retrospective longitudinal analysis, this study presents the main coagulation parameter changes in singleton and twin pregnancies and confirms that coagulation is more enhanced in twin pregnancies than in singleton pregnancies.
Topics: Adult; Blood Coagulation; Blood Coagulation Tests; Female; Fibrinogen; Humans; Partial Thromboplastin Time; Pregnancy; Pregnancy, Twin; Prothrombin Time; Retrospective Studies
PubMed: 33372546
DOI: 10.1177/1076029620983898 -
Current Opinion in Anaesthesiology Jun 2015Major obstetric hemorrhage is a leading cause of maternal morbidity and mortality. We will review transfusion strategies and the value of monitoring the maternal... (Review)
Review
PURPOSE OF REVIEW
Major obstetric hemorrhage is a leading cause of maternal morbidity and mortality. We will review transfusion strategies and the value of monitoring the maternal coagulation profile during severe obstetric hemorrhage.
RECENT FINDINGS
Epidemiologic studies indicate that rates of severe postpartum hemorrhage (PPH) in well resourced countries are increasing. Despite these increases, rates of transfusion in obstetrics are low (0.9-2.3%), and investigators have questioned whether a predelivery 'type and screen' is cost-effective for all obstetric patients. Instead, blood ordering protocols specific to obstetric patients can reduce unnecessary antibody testing. When severe PPH occurs, a massive transfusion protocol has attracted interest as a key therapeutic resource by ensuring sustained availability of blood products to the labor and delivery unit. During early postpartum bleeding, recent studies have shown that hypofibrinogenemia is an important predictor for the later development of severe PPH. Point-of-care technologies, such as thromboelastography and rotational thromboelastometry, can identify decreased fibrin clot quality during PPH, which correlate with low fibrinogen levels.
SUMMARY
A massive transfusion protocol provides a key resource in the management of severe PPH. However, future studies are needed to assess whether formula-driven vs. goal-directed transfusion therapy improves maternal outcomes in women with severe PPH.
Topics: Adult; Blood Coagulation; Blood Coagulation Disorders; Blood Transfusion; Female; Fibrinogen; Humans; Labor, Obstetric; Postpartum Hemorrhage; Pregnancy
PubMed: 25812005
DOI: 10.1097/ACO.0000000000000180 -
Endokrynologia Polska 2011Various abnormalities of haemostasis have been described in patients with hyperthyroidism. The results of different studies point to the underlying thyroid disease,...
BACKGROUND
Various abnormalities of haemostasis have been described in patients with hyperthyroidism. The results of different studies point to the underlying thyroid disease, especially severity of hyperthyroidism and autoimmune processes, as important factors contributing to coagulation-fibrinolytic balance. The objective of this study was to investigate the association between hyperthyroidism (concerning severity of thyroid dysfunction and anti-thyroid perioxidase antibodies level) and plasma fibrinogen and D-dimers levels before and after radioiodine therapy.
MATERIAL AND METHODS
The study included 35 non-smoking, postmenopausal women, aged 51-69, with subclinical or overt hyperthyroidism treated with radioiodine. Analysis comprised serum TSH (thyroid stimulating hormone), fT4 (free thyroxine), fT3 (free triiodothyronine), TPO antibodies (anti-thyroid perioxidase) levels, and plasma D-dimers and fibrinogen levels before and 12-16 weeks and 24-28 weeks after radioiodine therapy.
RESULTS
Elevated fibrinogen (3.82 g/L ± 0.75, reference range 2-4.5 g/L) and D-dimers (674.26 ng/mL ± 652.71, reference range 70-490 ng/mL) levels were observed in subjects with hyperthyroidism. They decreased after radioiodine therapy. A negative correlation between plasma fibrinogen and D-dimers levels and anti-thyroid perioxidase antibodies level was found. TSH, fT4 and fT3 correlated with D-dimers level in overt hyperthyroidism.
CONCLUSIONS
Hyperthyroidism is associated with a tendency toward hypercoagulation and hyperfibrinolysis. The changes observed in plasma fibrinogen and D-dimers levels are reversible. Fibrinogen level decreases within reference range and D-dimers level decreases almost to the upper reference range. They depend on severity and autoimmunity of the underlying thyroid disease and may be modified by restoring euthyroidism.
Topics: Aged; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Hyperthyroidism; Iodine Radioisotopes; Middle Aged; Severity of Illness Index; Statistics as Topic; Thyroid Function Tests; Treatment Outcome
PubMed: 22069101
DOI: No ID Found