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Hematology/oncology Clinics of North... Dec 2021Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a... (Review)
Review
Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a scaffold and immune effector before being broken down by the fibrinolytic system. Given its importance, abnormalities in fibrin(ogen) and fibrinolysis result in a variety of disorders with hemorrhagic and thrombotic manifestations. This review summarizes (i) the basic elements of fibrin(ogen) and its role in coagulation and the fibrinolytic system; (ii) the laboratory evaluation for fibrin(ogen) disorders, including the use of global fibrinolysis assays; and (iii) the management of congenital and acquired disorders of fibrinogen and fibrinolysis.
Topics: Blood Coagulation; Fibrin; Fibrinogen; Fibrinolysis; Hemostatics; Humans; Thrombosis
PubMed: 34404562
DOI: 10.1016/j.hoc.2021.07.011 -
Research and Practice in Thrombosis and... Aug 2021Hypodysfibrinogenemia (HD) is a heterogeneous disorder in which plasma fibrinogen antigen and function are both reduced but discordant. This report addresses the key...
Hypodysfibrinogenemia (HD) is a heterogeneous disorder in which plasma fibrinogen antigen and function are both reduced but discordant. This report addresses the key clinical question of whether genetic analysis enables clinically useful subclassification of patients with HD. We report a new case and identify a further eight previously documented cases that have the laboratory features of HD but biallelic inheritance of quantitative and qualitative fibrinogen gene variants. The cases displayed both bleeding and thrombosis and sometimes had undetectable fibrinogen activity. In all cases, the predicted effect of the coinherited variants is reduced levels of circulating fibrinogen that is all dysfunctional. We propose the term for this subtype of recessively inherited HD that is distinct from the more commonly recognized monoallelic HD caused by a single fibrinogen gene variant.
PubMed: 34458664
DOI: 10.1002/rth2.12568 -
Hamostaseologie Dec 2022Thrombophilia leads to an increased risk of venous thromboembolism. Widely accepted risk factors for thrombophilia comprise deficiencies of protein C, protein S, and... (Review)
Review
Thrombophilia leads to an increased risk of venous thromboembolism. Widely accepted risk factors for thrombophilia comprise deficiencies of protein C, protein S, and antithrombin, as well as the factor V "Leiden" mutation, the prothrombin G20210A mutation, dysfibrinogenemia, and, albeit less conclusive, increased levels of factor VIII. Besides these established markers of thrombophilia, risk factors of unclear significance have been described in the literature. These inherited risk factors include deficiencies or loss-of-activity of the activity of ADAMTS13, heparin cofactor II, plasminogen, tissue factor pathway inhibitor (TFPI), thrombomodulin, protein Z (PZ), as well as PZ-dependent protease inhibitor. On the other hand, thrombophilia has been linked to the gain-of-activity, or elevated levels, of α2-antiplasmin, angiotensin-converting enzyme, coagulation factors IX (FIX) and XI (FXI), fibrinogen, homocysteine, lipoprotein(a), plasminogen activator inhibitor-1 (PAI-1), and thrombin-activatable fibrinolysis inhibitor (TAFI). With respect to the molecular interactions that may influence the thrombotic risk, more complex mechanisms have been described for endothelial protein C receptor (EPCR) and factor XIII (FXIII) Val34Leu. With focus on the risk for venous thrombosis, the present review aims to give an overview on the current knowledge on the significance of the aforementioned markers for thrombophilia screening. According to the current knowledge, there appears to be weak evidence for a potential impact of EPCR, FIX, FXI, FXIII Val34Leu, fibrinogen, homocysteine, PAI-1, PZ, TAFI, and TFPI on the thrombotic risk.
Topics: Humans; Plasminogen Activator Inhibitor 1; Endothelial Protein C Receptor; Thrombophilia; Thrombosis; Factor IX; Fibrinogen
PubMed: 36549289
DOI: 10.1055/s-0042-1757562 -
Ugeskrift For Laeger Jan 2024Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia.... (Review)
Review
Congenital fibrinogen disorders are rare pathologies of the haemostasis, comprising afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia and hypodysfibrinogenaemia. Phenotypic manifestations are variable, patients may be asymptomatic or suffer from bleeding or thrombosis. Most of congenital fibrinogen disorders are coincidentally discovered. Fibrinogen concentrate is used to treat bleeding, whereas low-molecular weight heparin is most often administered for the treatment of thrombotic complications. The aim of this review is to provide an update of the knowledge of congenital fibrinogen disorders for Danish physicians.
Topics: Humans; Fibrinogen; Afibrinogenemia; Hemorrhage; Hemostasis; Hemostatics; Thrombosis
PubMed: 38235772
DOI: 10.61409/V04230274 -
Blood Nov 2021Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen...
Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.
Topics: Afibrinogenemia; Disease Management; Female; Hemorrhage; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombosis
PubMed: 33895794
DOI: 10.1182/blood.2020010116 -
European Journal of Case Reports in... 2022Fibrinogen deficiencies are very rare. Qualitative fibrinogen deficiencies (dysfibrinogenaemia and hypodysfibrinogenemia) are functional disorders that can present with...
UNLABELLED
Fibrinogen deficiencies are very rare. Qualitative fibrinogen deficiencies (dysfibrinogenaemia and hypodysfibrinogenemia) are functional disorders that can present with both haemorrhagic symptoms and with thrombotic phenomena as unique and paradoxical manifestation. We present the case of a 77-year-old man being investigated for a partially thrombosed abdominal aortic aneurysm as well as an ischaemic stroke 20 years previously. Basic coagulation tests were normal but extended tests revealed a lengthened thrombin time (TT) combined with a significant drop in fibrinogen concentration measured with the Clauss assay and by nephelometry. After secondary fibrinogen deficiencies were ruled out, a heterozygous variant in the FGG gene was detected by next-generation sequencing, and congenital hypodysfibrinogenemia was diagnosed. Acenocumarol was initiated and no new thrombotic or haemorrhagic events had occurred after a year of follow-up. In almost 25% of cases, thrombotic events may be the only clinical manifestation of functional fibrinogen deficiencies. They are a rare cause of thrombophilia, and are probably underdiagnosed due to normal standard coagulation test results as well as a possible absence of haemorrhagic events. Consequently, a TT test (an initial 'rule out' test) should be requested in order to promptly identify these patients. Moreover, discrepancies in derived and Clauss fibrinogen test results should suggest a functional disorder. Finally, new coagulation techniques based on the functional characterization of clot formation, such as ROTEM or thrombin generation assay, could help characterize these entities and suggest new therapeutic approaches.
LEARNING POINTS
Functional fibrinogen deficiencies can present with thrombotic manifestations only, and are a rare and probably underdiagnosed cause of thrombophilia.Thrombin time is a highly sensitive test to rule out other conditions as aPTT and PT results may be within normal ranges, especially in functional deficiencies.Discrepancies between derived and Clauss fibrinogen findings, fibrinogen protein measurements and the use of new techniques (ROTEM or thrombin generation) are important for correct approach.
PubMed: 35821906
DOI: 10.12890/2022_003400 -
Journal of Thrombosis and Haemostasis :... Apr 2023Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment... (Observational Study)
Observational Study
BACKGROUND
Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment strategies based on data derived from trauma studies.
OBJECTIVES
To investigate hemostatic changes associated with PPH.
PATIENTS/METHODS
From a population of 11 279 maternities, 518 (4.6%) women were recruited with PPH ≥ 1000 mL or placental abruption, amniotic fluid embolism, or concealed bleeding. Routine coagulation and viscoelastometric results were collated. Stored plasma samples were used to investigate women with bleeds > 2000 mL or those at increased risk of coagulopathy defined as placenta abruption, amniotic fluid embolism, or need for blood components. Procoagulant factors were assayed and global hemostasis was assessed using thrombin generation. Fibrinolysis was investigated with D-dimer and plasmin/antiplasmin complexes. Dysfibrinogenemia was assessed using the Clauss/antigen ratio.
RESULTS
At 1000 mL blood loss, Clauss fibrinogen was ≤2 g/L in 2.4% of women and 6/27 (22.2%) cases of abruption. Women with very large bleeds (>3000 mL) had evidence of a dilutional coagulopathy, although hemostatic impairment was uncommon. A subgroup of 12 women (1.06/1000 maternities) had a distinct coagulopathy characterized by massive fibrinolysis (plasmin/antiplasmin > 40 000 ng/mL), increased D-dimer, hypofibrinogenemia, dysfibrinogenemia, reduced factor V and factor VIII, and increased activated protein C, termed acute obstetric coagulopathy. It was associated with fetal or neonatal death in 50% of cases and increased maternal morbidity.
CONCLUSIONS
Clinically significant hemostatic impairment is uncommon during PPH, but a subgroup of women have a distinct and severe coagulopathy characterized by hyperfibrinolysis, low fibrinogen, and dysfibrinogenemia associated with poor fetal outcomes.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Male; Postpartum Hemorrhage; Fibrinolysin; Afibrinogenemia; Embolism, Amniotic Fluid; Antifibrinolytic Agents; Placenta; Blood Coagulation Disorders; Fibrinogen; Cohort Studies; Hemostatics
PubMed: 36696216
DOI: 10.1016/j.jtha.2022.11.036 -
Biomedicines Dec 2023Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional... (Review)
Review
Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional microvasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) with increased pulmonary arterial pressure and pulmonary vascular resistance, which, if left untreated, can lead to right heart failure and death. The pathobiology of CTEPH has been challenging to unravel due to its rarity, possible interference of results with anticoagulation, difficulty in selecting the most relevant study time point in relation to presentation with acute pulmonary embolism (PE), and lack of animal models. In this article, we review the most relevant multifaceted cross-talking pathogenic mechanisms and advances in understanding the pathobiology in CTEPH, as well as its challenges and future direction. There appears to be a genetic background affecting the relevant pathological pathways. This includes genetic associations with dysfibrinogenemia resulting in fibrinolysis resistance, defective angiogenesis affecting thrombus resolution, and inflammatory mediators driving chronic inflammation in CTEPH. However, these are not necessarily specific to CTEPH and some of the pathways are also described in acute PE or deep vein thrombosis. In addition, there is a complex interplay between angiogenic and inflammatory mediators driving thrombus non-resolution, endothelial dysfunction, and vascular remodeling. Furthermore, there are data to suggest that infection, the microbiome, circulating microparticles, and the plasma metabolome are contributing to the pathobiology of CTEPH.
PubMed: 38255153
DOI: 10.3390/biomedicines12010046 -
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 -
International Journal of Molecular... Dec 2021Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are... (Review)
Review
Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
Topics: Blood Coagulation; Blood Coagulation Tests; Fibrinogen; Hemorrhage; Humans; Mutation; Thrombosis
PubMed: 35008554
DOI: 10.3390/ijms23010132