-
Frontiers in Medicine 2020A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months,...
A previously hemostatically asymptomatic patient with common variable hypogammaglobulinemia was given everolimus to prevent growth of her liver. Within several months, the patient developed a severe bleeding disorder. The bleeding was due to fibrin polymerization defect that upon sequencing was shown to be dysfibrinogenemia Krakow III. Elimination of the mTor inhibitor ameliorated the clinical bleeding state.
PubMed: 33330551
DOI: 10.3389/fmed.2020.591546 -
TH Open : Companion Journal To... Jan 2022
PubMed: 35088022
DOI: 10.1055/s-0041-1740644 -
International Journal of Hematology Jun 2020Congenital dysfibrinogenemia (CD) is a rare disorder of hemostasis. The majority of cases are caused by heterozygous missense mutations in one of the three fibrinogen... (Comparative Study)
Comparative Study
Congenital dysfibrinogenemia (CD) is a rare disorder of hemostasis. The majority of cases are caused by heterozygous missense mutations in one of the three fibrinogen genes. Patients with CD may experience bleeding and thrombosis, but many are asymptomatic. To better describe the clinical, laboratory, and genotypic picture of CD, we evaluated 31 patients from seven unrelated families using standard coagulation tests and genetic analysis. The clinical phenotype consisted of bleeding in 13/31 (42%) patients; other patients (18/31; 58%) were asymptomatic. Among patients with bleeding, symptoms were mostly in single anatomical sites, with variable intensity of bleeding. Compared to results from a previous large systematic survey, our results showed a similar mean bleeding score, but a higher incidence of bleeding episodes without thrombotic complications. In the present study, we identified three known pathogenic point mutations in the FGA (c.95G > A, c.104G > A) and FGB (c.586C > T) genes. The variants of CD identified in this cross-sectional study were either asymptomatic or had bleeding manifestations and showed similar laboratory features, irrespective of genotype. Results from genetic and clinical studies will continue to yield valuable information on the structure and function of the fibrinogen molecule.
Topics: Adolescent; Adult; Afibrinogenemia; Asymptomatic Diseases; Child; Child, Preschool; Cross-Sectional Studies; Female; Fibrinogen; Genotype; Hemorrhage; Humans; Male; Middle Aged; Phenotype; Point Mutation; Rare Diseases; Slovakia; Young Adult
PubMed: 32166693
DOI: 10.1007/s12185-020-02842-9 -
Blood Coagulation & Fibrinolysis : An... Dec 2020: The aim of this study was to elucidate the molecular defects in a Chinese family with dysfibrinogenemia. The fibrinogen activity was measured by the one-stage clotting...
: The aim of this study was to elucidate the molecular defects in a Chinese family with dysfibrinogenemia. The fibrinogen activity was measured by the one-stage clotting method. The fibrinogen antigen was measured with immunoturbidimetry. The fibrinogen gene was amplified by PCR with direct sequencing. Suspected mutation was confirmed by reverse sequencing. Bioinformatics and model analysis were used to study the conservatism and harm of the mutation. The proband had a history of menorrhagia. Study showed fibrinogen activity at 0.35 g/l and fibrinogen antigen at 2.05 g/l. Sequencing analysis detected a heterozygous c.1178T>C missense mutation in exon 9 of FGG gene resulting in p.IIe367Thr. The bioinformatics and model analysis indicated that the IIe367Thr mutation may disrupt the activation of the fibrinogen. We detected a novel IIe367Thr missense mutation in the FGG. To our knowledge this is causative mutation has not been reported so far.
Topics: Adult; Afibrinogenemia; Asian People; China; DNA Mutational Analysis; Female; Fibrinogen; Heterozygote; Humans; Male; Mutation, Missense; Pedigree
PubMed: 32833807
DOI: 10.1097/MBC.0000000000000948 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Sep 2019To analyze the phenotype and genotype of a pedigree affected with congenital dysfibrinogenemia.
OBJECTIVE
To analyze the phenotype and genotype of a pedigree affected with congenital dysfibrinogenemia.
METHODS
Liver and kidney functions of the proband and her relatives were determined. Coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time(TT), fibrin(ogen) degradation products (FDPs), D-dimer(D-D) and the calibration experiment of protamine sulfate of against plasma TT were detected in the proband and her predigree members. The activity and antigen of fibrinogen (Fg) in plasma were measured by Clauss method and immunonephelometry method, respectively. All of the exons and exons-intron boundaries of the three fibrinogen genes (FGA, FGB and FGG) were subjected to PCR amplification and Sanger sequencing. Potential influence of the suspected mutations were analyzed with bioinformatics software including PolyPhen-2, SIFT and Mutation Taster.
RESULTS
The proband had normal PT, APTT, FDPs, D-D and prolonged TT (31.8 s). The activity of fibrinogen (Fg) in plasma was significantly decreased but the antigen was normal. Genetic analysis revealed a heterozygous c.92G>A (p.Gly31Glu) mutation in exon 2 of the FGA gene. Family studies revealed that the mother carried the same mutation. Bioinformatic analysis suggested that the mutation may affect the function of Fg Protein.
CONCLUSION
The dysfibrinogenemia was probably caused by the novel Gly31Glu mutation of the FGA gene.
Topics: Afibrinogenemia; DNA Mutational Analysis; Female; Fibrinogen; Humans; Mutation; Pedigree; Phenotype
PubMed: 31515786
DOI: 10.3760/cma.j.issn.1003-9406.2019.09.012 -
Research and Practice in Thrombosis and... Nov 2020Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder characterized by reduced levels (afibrinogenemia, hypofibrinogenemia) or dysfunctional fibrinogen...
BACKGROUND
Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder characterized by reduced levels (afibrinogenemia, hypofibrinogenemia) or dysfunctional fibrinogen (dysfibrinogenemia), for which fibrinogen supplementation is the mainstay treatment.
OBJECTIVES
To assess the efficacy and safety of human fibrinogen concentrate (FCH) in patients with CFD.
METHODS
This was a multicenter, noninterventional, retrospective cohort study with a 12-month prospective follow-up period in the United States and Canada. Individuals with CFD who received FCH for the treatment of bleeding, perioperative hemostasis, or prophylaxis were included. Data were collected retrospectively from medical records and every 3 months during the prospective period. Hemostatic efficacy was rated by the investigators as effective or ineffective using a 4-point efficacy scale. Annualized bleeding rate (ABR) was summarized for patients who received FCH for routine prophylaxis.
RESULTS
Twenty-two patients were enrolled. FCH treatment was rated effective in treating ≥97.0% of bleeding events, in the retrospective and prospective periods. FCH was effective for perioperative hemostasis in ≥97.5% of minor and major surgeries across both periods. In patients treated with FCH for routine prophylaxis, the median ABRs for the retrospective and prospective period were 1.4 and 1.3, respectively. One adverse event (AE), thrombosis of the right cephalic vein, was reported as related to FCH treatment and resolved with a short course of anticoagulant. No serious AEs related to FCH or deaths were reported.
CONCLUSIONS
In patients with CFD, FCH is a well-tolerated and effective treatment to achieve hemostasis during bleeding events and surgery and associated with infrequent bleeding events when used prophylactically.
PubMed: 33313470
DOI: 10.1002/rth2.12433 -
Proceedings of the National Academy of... Jan 2020Upon activation, fibrinogen forms large fibrin biopolymers that coalesce into clots which assist in wound healing. Limited insights into their molecular architecture,...
Upon activation, fibrinogen forms large fibrin biopolymers that coalesce into clots which assist in wound healing. Limited insights into their molecular architecture, due to the sheer size and the insoluble character of fibrin clots, have restricted our ability to develop novel treatments for clotting diseases. The, so far resolved, disparate structural details have provided insights into linear elongation; however, molecular details like the C-terminal domain of the α-chain, the heparin-binding domain on the β-chain, and other functional domains remain elusive. To illuminate these dark areas, we applied cross-linking mass spectrometry (XL-MS) to obtain biochemical evidence in the form of over 300 distance constraints and combined this with structural modeling. These restraints additionally define the interaction network of the clots and provide molecular details for the interaction with human serum albumin (HSA). We were able to construct the structural models of the fibrinogen α-chain (excluding two highly flexible regions) and the N termini of the β-chain, confirm these models with known structural arrangements, and map how the structure laterally aggregates to form intricate lattices together with the γ-chain. We validate the final model by mapping mutations leading to impaired clot formation. From a list of 22 mutations, we uncovered structural features for all, including a crucial role for βArg'169 (UniProt: 196) in lateral aggregation. The resulting model can potentially serve for research on dysfibrinogenemia and amyloidosis as it provides insights into the molecular mechanisms of thrombosis and bleeding disorders related to fibrinogen variants. The structure is provided in the PDB-DEV repository (PDBDEV_00000030).
Topics: Albumins; Cross-Linking Reagents; Fibrin; Humans; Mass Spectrometry; Models, Structural; Mutation; Protein Conformation; Thrombosis
PubMed: 31924745
DOI: 10.1073/pnas.1911785117 -
BMJ Case Reports Jul 2019Patients with multiple myeloma (MM) are at risk for acquired dysfibrinogenemia resulting in laboratory abnormalities and/or bleeding complications. We describe a...
Patients with multiple myeloma (MM) are at risk for acquired dysfibrinogenemia resulting in laboratory abnormalities and/or bleeding complications. We describe a 63-year-old man who presented with bleeding diathesis in the presence of a low fibrinogen activity level with a normal fibrinogen antigen level. Further studies revealed elevated levels of lambda free light chains, and he was diagnosed with MM. Despite initiating treatment with bortezomib/dexamethasone, he continued to have recurrent bleeds along with hypofibrinogenaemia, prompting a switch to carfilzomib/dexamethasone. The patient responded with improvement in bleeding symptoms, normalisation of fibrinogen activity and a decrease in serum free light chains.
Topics: Afibrinogenemia; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Drug Substitution; Hemorrhage; Humans; Immunoglobulin lambda-Chains; Male; Middle Aged; Multiple Myeloma; Oligopeptides
PubMed: 31320370
DOI: 10.1136/bcr-2019-229312 -
Journal of Thrombosis and Thrombolysis Feb 2020Recent guidelines recommend direct acting oral anticoagulants (DOAC) over vitamin-k antagonist (VKA) for acute venous thromboembolism (VTE). Non-adherence to...
Recent guidelines recommend direct acting oral anticoagulants (DOAC) over vitamin-k antagonist (VKA) for acute venous thromboembolism (VTE). Non-adherence to anticoagulation has been associated with increased frequency of VTE or stroke. This study evaluated 90 day persistence among patients prescribed rivaroxaban or warfarin for the treatment of acute VTE at an academic safety net hospital. We conducted a single center, retrospective cohort study of 314 consecutive patients newly prescribed rivaroxaban or warfarin for acute VTE between January 2016 and July 2017. Primary outcome was 90 day persistence, and secondary outcomes included 90 day readmission and/or ED visit, time to 90 m day readmission and/or ED visits, and attendance of direct oral anticoagulant education class. Of 314 patients, 78 were prescribed warfarin and 236 rivaroxaban. Patients had a mean age of 52 years, 62% were men, and 96% were diagnosed with deep vein thrombosis and/or pulmonary embolism. Persistence at 90 days was 52.6% among patients prescribed warfarin compared to 45.3% for patients prescribed rivaroxaban (p = 0.2678). Persistencewas associated with decreased 90 day hospital or ED readmission. Among patients prescribed rivaroxaban, attending a pharmacist led educational class was associated with a 2.5 fold increase in persistence (p < 0.0001). Among patients with new onset venous thromboembolism, 90 day persistence with anticoagulation was similarly low with either rivaroxaban or warfarin therapy. Participation in a pharmacist led DOAC class was associated with a 2.5-fold increase in persistence on rivaroxaban.
Topics: Academic Medical Centers; Adult; Aged; Anticoagulants; Factor Xa Inhibitors; Female; Humans; Male; Medication Adherence; Middle Aged; Patient Discharge; Retrospective Studies; Rivaroxaban; Safety-net Providers; Venous Thromboembolism; Warfarin
PubMed: 31598931
DOI: 10.1007/s11239-019-01959-x -
Open Medicine (Warsaw, Poland) 2020Congenital dysfibrinogenemia (CD) is a rare hereditary fibrinogen disorder characterized by normal fibrinogen antigen levels associated with lower functional activities....
Congenital dysfibrinogenemia (CD) is a rare hereditary fibrinogen disorder characterized by normal fibrinogen antigen levels associated with lower functional activities. The aim of this study is to analyze the phenotype and genotype of a family of CD. Routine coagulation screening tests were performed on the proband, her parents, and her grandparents. Then, the purified genomic DNA extracted from peripheral blood was amplified by PCR, and Sanger sequencing was performed to further confirm the mutation. The prothrombin time and activated partial thromboplastin time of the proband were normal, thrombin time prolonged, and the activity of fibrinogen (Fg:Ac) decreased significantly, but fibrinogen antigen (Fg:Ag) level was normal. The coagulation function indices of the proband's father and grandfather were similar to her, and the indices of her mother and grandmother were normal. Sequencing results showed that the proband had a heterozygous missense mutation in FGA gene c.92G > A, which caused the mutation of amino acid 31 from glycine to glutamic acid (p.Gly31Glu). Her father had the same heterozygous mutation. In conclusion, the proband suffered from CD. The change of Gly31Glu in A chain due to the c.92G > A heterozygous missense mutation in the FGA gene is the cause of CD in the family. To the best of our knowledge, the mutation site is new and first reported so far.
PubMed: 33336034
DOI: 10.1515/med-2020-0214