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Journal of Clinical Laboratory Analysis Sep 2022We reported a patient with congenital dysfibrinogenemia who was misdiagnosed and reviewed relevant literature, in order to discuss the methods to reduce misdiagnosis. (Review)
Review
BACKGROUND
We reported a patient with congenital dysfibrinogenemia who was misdiagnosed and reviewed relevant literature, in order to discuss the methods to reduce misdiagnosis.
METHODS
A 23-year-old pregnant woman was found to be with low fibrinogen in antenatal examination at another province teaching hospital, who was misdiagnosed to have hypofibrinogenemia. Fibrinogen infusion or cryoprecipitation was recommended if necessary. The patient came to our hospital for further diagnosis and treatment considering the safety of herself and the fetus. We examined the coagulation function and gene sequencing of the pregnant woman and her family members.
RESULTS
Fibrinogen (Clauss method) was significantly reduced in the patient and her mother, while the level of fibrinogen (PT-derived method) was normal. Thrombin time was prolonged. Heterozygous mutation site was found in exon 2 of the FGA gene, c.104G > A(p.Arg35His).
CONCLUSION
When the fibrinogen (Clauss method) is significantly reduced and the thrombin time is prolonged, PT-derived method and the investigation of family coagulation function should be added, which can be used to diagnose and distinguish congenital dysfibrinogenemia from hypofibrinogenemia.
Topics: Adult; Afibrinogenemia; Diagnostic Errors; Exons; Female; Fibrinogen; Humans; Pregnancy; Young Adult
PubMed: 35949040
DOI: 10.1002/jcla.24624 -
International Journal of Molecular... May 2018Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been... (Review)
Review
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed.
Topics: Afibrinogenemia; Fibrinogen; Humans
PubMed: 29844251
DOI: 10.3390/ijms19061597 -
Haemostasis 2001Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen... (Review)
Review
Snake venom toxins are invaluable for the assay of coagulation factors and for the study of haemostasis generally. Thrombin-like enzymes (SVTLE) are used for fibrinogen and fibrinogen breakdown product assays as well as detecting dysfibrinogenaemias. Since SVTLE are not inhibited by heparin, they can be used for assaying antithrombin III in samples containing heparin. Snake venom prothrombin activators are utilised in prothrombin assays, whilst Russell's viper venom (RVV) can be used to assay clotting factors V, VII, X and lupus anticoagulants (LA). Activators from the taipan, Australian brown snake and saw-scaled viper have also been used to assay LA. Protein C (PC) and activated PC (APC) resistance can be measured by means of RVV, Protac (from Southern copperhead snake venom) and STA-Staclot (from Crotalus viridis helleri) whilst von Willebrand factor can be studied with Botrocetin (Bothrops jararaca). Finally, snake venom C-type lectins and metalloproteinase disintegrins are being used to study platelet glycoprotein receptors and show great potential for use in the routine coagulation laboratory.
Topics: Animals; Anticoagulants; Blood Coagulation Tests; Coagulants; Hemostasis; Humans; Snake Venoms
PubMed: 11910187
DOI: 10.1159/000048065 -
Research and Practice in Thrombosis and... Jul 2023Variants of fibrinogen sequences that bind to thrombin's catalytic sites are mostly associated with bleeding phenotypes, while variants with fibrinogen...
BACKGROUND
Variants of fibrinogen sequences that bind to thrombin's catalytic sites are mostly associated with bleeding phenotypes, while variants with fibrinogen nonsubstrate-thrombin-binding sites are commonly believed to cause thrombosis. AαGlu39 and BβAla68 play important roles in fibrin(ogen)-thrombin-nonsubstrate binding. The BβAla68Thr variant has been described in several unrelated families with apparent thrombotic phenotypes.
OBJECTIVES
Homozygous AαGlu39Lys variant (fibrinogen BOE II) was identified in a boy with dysfibrinogenemia who had multiple cerebral hemorrhages. A series of analyses were performed to assess the variant's functions and elucidate underlying bleeding mechanisms.
METHODS
Abnormal fibrinogen was purified from plasma and subjected to Western blot, fibrinogen and fibrin monomer polymerization, clottability, fibrinopeptides release, activated factor (F)XIII (FXIIIa) cross-linking, fibrinolysis, and scanning electron microscopy analyses.
RESULTS
Fibrinogen BOE II weakened the binding capacity of thrombin to fibrinogen and delayed the formation of fibrin clots. The release of fibrinopeptides, polymerization of fibrinogen catalyzed by thrombin, and cross-linking of FXIIIa of fibrinogen BOE II were impaired. In contrast, batroxobin-catalyzed fibrinogen polymerization and desA/desAB fibrin monomer polymerization did not differ from those in normal controls. Fibrin clots formed by fibrinogen BOE II were composed of thicker fibrin fibers and showed a faster fibrinolysis rate.
CONCLUSION
Defective fibrin(ogen)-thrombin-nonsubstrate binding is not necessarily associated with thrombotic disorders. When the hypercoagulable state created by increased circulating free thrombin is insufficient to compensate for defective hemostasis caused by slowly formed but rapidly lysed clots, the primary concern of thrombin-binding deficiency dysfibrinogenemia appears to be hemorrhage rather than thrombosis.
PubMed: 37601017
DOI: 10.1016/j.rpth.2023.102145 -
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 -
Journal of Thrombosis and Haemostasis :... Oct 2006Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of... (Review)
Review
Hereditary fibrinogen disorders include type I deficiencies (afibrinogenemia and hypofibrinogenemia, i.e. quantitative defects), with low or unmeasurable levels of immunoreactive protein; and type II deficiencies (dysfibrinogenemia and hypodysfibrinogenemia, i.e. qualitative defects), showing normal or altered antigen levels associated with reduced coagulant activity. While dysfibrinogenemias are in most cases autosomal dominant disorders, type I deficiencies are generally inherited as autosomal recessive traits. Patients affected by congenital afibrinogenemia or severe hypofibrinogenemia may experience bleeding manifestations varying from mild to severe. This review focuses on the genetic bases of type I fibrinogen deficiencies, which are invariantly represented by mutations within the three fibrinogen genes (FGA, FGB, and FGG) coding for the three polypeptide chains Aalpha, Bbeta, and gamma. From the inspection of the mutational spectrum of these disorders, some conclusions can be drawn: (i) genetic defects are scattered throughout the three fibrinogen genes, with only few sites appearing to represent relative mutational hot spots; (ii) several different types of genetic lesions and pathogenic mechanisms have been described in affected individuals (including gross deletions, point mutations causing premature termination codons, missense mutations affecting fibrinogen assembly/secretion, and uniparental isodisomy associated with a large deletion); (iii) the possibility to express recombinant fibrinogen mutants in eukaryotic cells is rapidly shedding light into the molecular mechanisms responsible for physiologic and pathologic properties of the molecule; (iv) though mutation analysis of the fibrinogen cluster does not yield precise information for predicting genotype/phenotype correlations, it still provides a valuable tool for diagnosis confirmation, identification of potential carriers, and prenatal diagnosis.
Topics: Adolescent; Adult; Afibrinogenemia; Child; Child, Preschool; DNA Mutational Analysis; Female; Fibrinogen; Gene Deletion; Genotype; Hemostasis; Humans; Infant; Infant, Newborn; Male; Phenotype; Point Mutation
PubMed: 16999847
DOI: 10.1111/j.1538-7836.2006.02094.x -
Diagnostics (Basel, Switzerland) Nov 2021Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia... (Review)
Review
Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
PubMed: 34829490
DOI: 10.3390/diagnostics11112140 -
Frontiers in Pediatrics 2020Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction,... (Review)
Review
Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction, and on occasion to life threatening cerebral edema and hemorrhage. Pediatric Acute Liver Failure is defined as severe acute hepatic dysfunction accompanied by encephalopathy and liver-based coagulopathy defined as prolongation of International Normalized Ratio (INR) >1.5. However, coagulopathy in PALF is complex and warrants a deeper understanding of the hemostatic balance in acute liver failure. Although an INR value of >1.5 is accepted as the evidence of coagulopathy and has historically been viewed as a prognostic factor of PALF, it may not accurately reflect the bleeding risk in PALF since it only measures procoagulant factors. Paradoxically, despite the prolongation of INR, bleeding risk is lower than expected (around 5%). This is due to "rebalanced hemostasis" due to concurrent changes in procoagulant, anticoagulant and fibrinolytic systems. Since the liver is involved in both procoagulant (Factors II, V, IX, XI, and fibrinogen) and anticoagulant (Protein C, Protein S, and antithrombin) protein synthesis, PALF results in "rebalanced hemostasis" or even may shift toward a hypercoagulable state. In addition to rebalanced coagulation there is altered platelet production due to decreased thrombopoietin production by liver, increased von Willebrand factor from low grade endothelial cell activation, and hyperfibrinolysis and dysfibrinogenemia from altered synthetic liver dysfunction. All these alterations contribute to the multifactorial nature of coagulopathy in PALF. Over exuberant use of prophylactic blood products in patients with PALF may contribute to morbidities such as fluid overload, transfusion-associated lung injury, and increased thrombosis risk. It is essential to use caution when using INR values for plasma and factor administration. In this review we will summarize the complexity of coagulation in PALF, explore "rebalanced hemostasis," and discuss the limitations of current coagulation tests. We will also review strategies to accurately diagnose the coagulopathy of PALF and targeted therapies.
PubMed: 33425821
DOI: 10.3389/fped.2020.618119 -
Hippokratia 2017The inherited dysfibrinogenemias comprise rare congenital coagulation disorders which are clinically characterized by bleeding diathesis and, in occasional patients, by...
BACKGROUND
The inherited dysfibrinogenemias comprise rare congenital coagulation disorders which are clinically characterized by bleeding diathesis and, in occasional patients, by thrombotic tendency or combined bleeding-thrombotic events. In recent years, accumulating evidence suggested that fibrinogen has a critical role in the pathogenesis of neuroinflammatory disorders, including multiple sclerosis. We describe the presentation and long-term follow-up of a patient with inherited dysfibrinogenemia and concomitant clinical and laboratory evidence of demyelinating disease. Case description: A 16-year-old male patient presented in 2003 with bilateral sensory symptomatology preceded by an episode of epistaxis. His past medical history included episodes of spontaneous nosebleeds as well as Duane syndrome and mild atrophy of the right upper limb. Coagulation testing of the patient and his asymptomatic father revealed in both the presence of a clotting defect, consistent with inherited dysfibrinogenemia (named Fibrinogen Thessaloniki). Within seven months, the patient presented with a new episode of motor semiology whereas serial brain magnetic resonance imaging (MRI) scans revealed T2 lesions with bilateral distribution, some of which with gadolinium enhancement. The cerebrospinal fluid examination disclosed the presence of oligoclonal bands in the central nervous system compartment. The patient was started on azathioprine (2.5 mg/kg/24h) which led to clinical and radiological stabilization for nine years. In 2013, the dose of azathioprine was reduced, due to an elevation of his amylase levels, resulting in radiological deterioration with an increased T2 lesion load. The reinstitution of azathioprine at therapeutic doses led to radiological improvement and clinical stability as of today.
CONCLUSION
The described case of inherited dysfibrinogenemia and concomitant multiple sclerosis provides speculative evidence for a causal link, rather than a chance association, between these two entities. Further studies are warranted to corroborate this hypothesis in experimental and clinical settings. HIPPOKRATIA 2017, 21(1): 49-51.
PubMed: 29904258
DOI: No ID Found -
International Journal of Molecular... Jan 2021Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human...
Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human coagulopathies. We aimed to determine whether zebrafish models of afibrinogenemia and dysfibrinogenemia have different thrombotic phenotypes. Laser injuries were used to induce venous thrombosis and the time-to-occlusion (TTO) and the binding and aggregation of fluorescent thrombocytes measured. The larvae failed to support occlusive venous thrombosis and showed reduced thrombocyte binding and aggregation at injury sites. The larvae were largely unaffected. When genome editing zebrafish to produce fibrinogen Aα R28C, equivalent to the human Aα R35C dysfibrinogenemia mutation, we detected in-frame skipping of exon 2 in the fga mRNA, thereby encoding Aα. This mutation is similar to Fibrinogen Montpellier II which causes hypodysfibrinogenemia. Aα fish had prolonged TTO and reduced thrombocyte activity, a dominant effect of the mutation. Finally, we used transgenic expression of fga R28C cDNA in fga knock-down or mutants to model thrombosis in dysfibrinogenemia. Aα R28C expression had similar effects on TTO and thrombocyte activity as Aα. We conclude that thrombosis assays in larval zebrafish can distinguish between quantitative and qualitative fibrinogen disorder models and may assist in anticipating a thrombotic phenotype of novel fibrinogen mutations.
Topics: Animals; Base Sequence; Biomarkers; Blood Coagulation; Blood Platelets; Disease Models, Animal; Exons; Fibrinogen; Gene Editing; Gene Expression; Plasmids; Platelet Activation; Sequence Deletion; Venous Thrombosis; Zebrafish; RNA, Guide, CRISPR-Cas Systems
PubMed: 33440782
DOI: 10.3390/ijms22020655