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Blood Mar 2022Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice...
Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated small interfering RNA (siRNA) targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga messenger RNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16%, and 4% of normal within 1 week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with 0.5, 1.0, and 2.0 mg/kg doses, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumor cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provides the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.
Topics: Afibrinogenemia; Animals; Blood Platelets; Disease Models, Animal; Female; Fibrin; Fibrinogen; Gene Knockdown Techniques; Humans; Liposomes; Male; Mice; Nanoparticles; RNA, Small Interfering
PubMed: 34958662
DOI: 10.1182/blood.2021014559 -
Proceedings (Baylor University. Medical... Jul 2019Combined pulmonary-renal hydralazine-induced vasculitis is rare, and hereditary afibrinogenemia is also rare. We present a case of a 62-year-old man with a history of...
Combined pulmonary-renal hydralazine-induced vasculitis is rare, and hereditary afibrinogenemia is also rare. We present a case of a 62-year-old man with a history of hereditary afibrinogenemia who presented with hemoptysis and hematuria. Although he had prior episodes of hemoptysis that resolved with repletion of fibrinogen levels, a hydralazine-induced vasculitis was the ultimate cause of his recurrent hemoptysis and hematuria. Hydralazine was held and after transfusion with cryoprecipitate, he was treated with prednisone and rituximab.
PubMed: 31384199
DOI: 10.1080/08998280.2019.1619397 -
Cureus Oct 2020Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet... (Review)
Review
Platelets play an important role in hemostasis through platelet plug formation by a phenomenon of adhesion; activation; secretion and aggregation. Defects in platelet hemostatic mechanisms can be congenital or acquired. Congenital platelet disorders are rare and manifestations range from asymptomatic to sometimes severe bleeding. The disorders arise due to diverse mechanisms. Congenital platelet disorders include thrombocytopathies and thrombocytopenia (platelet count <150 x 10/L) or thrombocytosis (platelet count > 450 x 10/L). Congenital thrombocytopathies include disorders of adhesion like von Willebrand's disease or Bernard-Soulier syndrome. The disorders of aggregation include congenital afibrinogenemia and Glanzmann thrombasthenia. Disorders of storage granules are gray platelet syndrome and Quebec platelet disorder. Congenital thrombocythopathy and thrombocytopenia often occur in conjunction. In this article, we have a detailed literature review of these rare thrombocytopathies, their presentation and treatment.
PubMed: 33274150
DOI: 10.7759/cureus.11275 -
BioMed Research International 2018Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM)... (Review)
Review
Fibrinogen is crucial for the formation of blood clot and clinical outcomes in major bleeding. Both Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) have been increasingly used to diagnose fibrinogen deficiency and guide fibrinogen transfusion in trauma and surgical bleeding patients. We conducted a comprehensive and comparative review on the technologies and clinical applications of two typical functional fibrinogen assays using TEG (FF TEG) and ROTEM (FIBTEM) for assessment of fibrinogen level and deficiency, and prediction of transfusion requirement. Clot strength and firmness of FF TEG and ROTEM FIBTEM were the most used parameters, and their associations with fibrinogen levels as measured by Clauss method ranged from 0 to 0.9 for FF TEG and 0.27 to 0.94 for FIBTEM. A comparison of the interchangeability and clinical performance of the functional fibrinogen assays using the two systems showed that the results were correlated, but are not interchangeable between the two systems. It appears that ROTEM FIBTEM showed better associations with the Clauss method and more clinical use for monitoring fibrinogen deficiency and predicting transfusion requirements including fibrinogen replacement than FF TEG. TEG and ROTEM functional fibrinogen tests play important roles in the diagnosis of fibrinogen-related coagulopathy and guidance of transfusion requirements. Despite the fact that high-quality evidence is still needed, the two systems are likely to remain popular for the hemostatic management of bleeding patients.
Topics: Afibrinogenemia; Blood Coagulation Tests; Blood Transfusion; Fibrinogen; Humans; Thrombelastography; Thrombosis
PubMed: 30596098
DOI: 10.1155/2018/7020539 -
Journal of Clinical Pathology Sep 1965Platelet fibrinogen has been studied in normal, thrombasthenic, and hypofibrinogenaemic subjects. It has been differentiated into adsorbed (plasma) and extractable...
Platelet fibrinogen has been studied in normal, thrombasthenic, and hypofibrinogenaemic subjects. It has been differentiated into adsorbed (plasma) and extractable (intraplatelet) fractions. Isotopic studies suggest that exchange does not occur between intraplatelet and plasma fibrinogen and it appears possible that the intra-platelet fraction may be derived from the megakaryocyte. Six of nine thrombasthenic patients were found to have a severe deficiency of both adsorbed and extractable fibrinogen. Since the remaining three had near-normal platelet fibrinogen and all nine failed to aggregate it is improbable that the failure to adsorb fibrinogen is responsible for the defect in aggregation. Magnesium partially corrects adhesion to fibrin and clot retraction by these platelets, but has not been found to influence their fibrinogen adsorption. It is considered that the basic platelet surface defect, of varying severity, is responsible for the abnormalities of adsorption, aggregation, and adhesion in thrombasthenia. In the case of congenital hypofibrinogenaemia, fibrinogen transfusion corrects the long bleeding time, platelet-adsorbed fibrinogen, and the ability of platelets to spread on glass. It is possible that fibrinogen influences the surface properties of human platelets, although the final mechanism is not determined.
Topics: Afibrinogenemia; Agglutination Tests; Blood Platelet Disorders; Blood Platelets; Blood Transfusion; Fibrinogen; Hemostasis; Humans; In Vitro Techniques; Iodine Isotopes; Magnesium
PubMed: 5835438
DOI: 10.1136/jcp.18.5.579 -
Acta Haematologica 2021Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels... (Review)
Review
Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels (hypofibrinogenemia), absence of fibrinogen in circulation (afibrinogenemia), abnormal functioning (dysfibrinogenemia) or both reduced levels and abnormal functioning (hypodysfibrinogenemia) of fibrinogen. The decreased fibrinogen concentration in congenital fibrinogen deficiency necessitates fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, or human fibrinogen concentrate. However, the use of fresh frozen plasma and cryoprecipitate is limited owing to their longer transfusion time, requirement of high doses, volume overload, risk of viral transmission, and other safety concerns. The availability of human fibrinogen concentrate has made it the preferred replacement alternative due to its reduced risk of viral transmission, smaller infusion volume, and accurate dosing. The hemostatic efficacy and safety of human fibrinogen concentrate in congenital fibrinogen deficiency is well established in the literature. We review the prevalence of congenital fibrinogen deficiency in India and the current role of human fibrinogen concentrate in its management.
Topics: Afibrinogenemia; Blood Transfusion; Fibrinogen; Guidelines as Topic; Humans; India; Plasma
PubMed: 34091452
DOI: 10.1159/000516339 -
British Medical Journal Nov 1968
Topics: Afibrinogenemia; Antifibrinolytic Agents; Blood Coagulation; Fibrinogen; Humans
PubMed: 5683576
DOI: No ID Found -
Cureus Feb 2024Congenital afibrinogenemia is a rare inherited blood disorder characterized by a deficiency of fibrinogen, leading to abnormal blood clotting. It is caused by mutations...
Congenital afibrinogenemia is a rare inherited blood disorder characterized by a deficiency of fibrinogen, leading to abnormal blood clotting. It is caused by mutations in fibrinogen genes and results in a propensity for bleeding. We present the case of a one-year-old male child with congenital afibrinogenemia who developed a left-sided facial haematoma following a fall from a walker. The child had a history of active bleeding during cannulation and had not undergone circumcision due to the risk of bleeding. This case highlights the need for timely diagnosis and appropriate management of rare bleeding disorders such as congenital afibrinogenemia. Collaboration between different specialties, including haematology and genetic counseling, is crucial for comprehensive care. The rarity of the condition underscores the importance of raising awareness among healthcare professionals. Genetic counseling and family studies are essential for assessing genetic implications and guiding decision-making. Further advancements in diagnostic tests and replacement therapy are needed to improve the management of patients with afibrinogenemia, particularly in regions with a high prevalence of consanguineous marriages.
PubMed: 38496148
DOI: 10.7759/cureus.54229 -
Cellular and Molecular Life Sciences :... Jun 2004Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes... (Review)
Review
Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes (alpha, beta and gamma). However, it does not usually result in a clinically significant condition unless inherited in a homozygous or compound heterozygous state, where it results in a severe bleeding disorder, afibrinogenaemia. Various protein and expression studies have improved our understanding of how mutations causing hypo- and afibrinogenaemia affect secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations can perturb chain assembly as in the gamma153 Cys-->Arg case, while others such as the Bbeta Leu-->Arg and the Bbeta414 Gly-->Ser mutations allow intracellular hexamer assembly but inhibit protein secretion. An interesting group of mutations, such as gamma284 Gly-->Arg and gamma375 Arg-->Trp, not only cause hypofibrinogenaemia but are also associated with liver disease. The nonexpression of these variant chains in plasma fibrinogen is due to retention in the endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.
Topics: Afibrinogenemia; Amino Acid Sequence; Endoplasmic Reticulum; Fibrinogen; Heterozygote; Humans; Molecular Sequence Data; Mutation; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 15197468
DOI: 10.1007/s00018-004-3458-8 -
Indian Pediatrics Feb 2004Congenital afibrinogenemia/hypofibrinogenemia is an extremely rare coagulation disorder. We describe a case of congenital hypofibrinogenemia in a 6-year female child,...
Congenital afibrinogenemia/hypofibrinogenemia is an extremely rare coagulation disorder. We describe a case of congenital hypofibrinogenemia in a 6-year female child, who presented with recurrent ecchymotic spots with no frank bleeding.
Topics: Afibrinogenemia; Blood Coagulation Disorders; Child; Combined Modality Therapy; Female; Hemorrhage; Humans; India; Prognosis; Recurrence; Severity of Illness Index
PubMed: 15004306
DOI: No ID Found