Analysis Of Gene Mutation Spectrum And Pharmacokinetics Of Fibrinogen Infusion In Patients With Congenital Fibrinogen Disorders

Objective:To investigate the clinical type and gene mutations,clinical manifestations,laboratory tests,diagnosis and fibrinogen replacement therapy of congenital fibrinogen disorders.Methods:Clinical data of 146 patients with congenital fibrinogen disorders diagnosed from April 2000 to November 2020 were retrospectively analyzed.Coagulation function was detected in all patients,including activated partial thromboplastin time(APTT),prothrombin time(PT),thrombin time(TT),fibrinogen activity(FIB:C)and fibrinogen antigen(FIB:Ag).The clinical symptomatic information of 98 patients was collected,and the bleeding score of each patient was evaluated by ISTH-BAT[1]standard.Spearman correlation analysis was used to evaluate the relationship between fibrinogen concentration and bleeding BAT score.Fisher’s exact test and Kruskal-Wallis H test were used to compare the differences among these patients with afibrinogenemia,hypofibrinogenemia,dysfibrinogenemia and hypodysfibrinogenemia.Paired t-test was used to compare the changes of blood coagulation function before and after infusion.The IVR(in vivo recovery)[2]was calculated in order to evaluate the pharmacokinetic information of fibrinogen replacement therapy.Results:Among the 146 patients,61(42%)were male and 85(58%)were female,with a median age of 33.5(1-76)years.34 patients(35%)were found to suffer from the disease due to bleeding symptoms,33(34%)patients were found by preoperative examination.Among 98 patients with medical records,54 patients(55%)had at least one bleeding symptom,42 patients(43%)had no bleeding symptoms,and 2 patient(2%)had thrombotic symptoms.There was a negative correlation between fibrinogen activity concentration and bleeding ISTH-BAT[1]score,(rs=-0.41,P=0.001).Patients’ lower fibrinogen concentrations were associated with the greater risk of bleeding.The risk of bleeding is less when the fibrinogen concentration is higher than 1g/L.A total of 34 gene mutations were detected in 56 patients,among which 16 new mutations were found.Among these mutations,84%were missense mutations,7.9%were frameshift mutations,6.3%were nonsense mutations,and 1.6%were splice site mutations.FGA Exon2 and FGG Exon8 mutations accounted for 71%of all mutation sites.We classified patients according to the test standard that fibrinogen activity/antigen ratio is 0.7,and the accuracy of this value was 94.12%,which was verified by gene mutation analysis.Patients with afibrinogenemia were younger,with a median age of 2(1-12)years and an ISTH-BAT score of 4.They have relatively severe bleeding symptoms,and the types of gene mutations were all null mutations.The thrombin time(TT)of patients with dysfibrinogenemia was significantly longer than that of other types of patients,with a median value of 28.5(19.236.6)s,which can be used as a basis for preliminary diagnosis.The one hour in vivo recovery(IVR)after fibrinogen infusion was 127.19±44.03%,and the 24-hour IVR was 101.78±43.98%.In addition to the obvious increase in the concentration of fibrinogen activity,the TT and the PT both decreased significantly,and the TT decreased more significantly,with an average decrease of 15.2%compared to the baseline after 24 hours of infusion.Conclusion:Most patients with congenital fibrinogen disorders have mild or no bleeding symptoms.Patients with afibrinogenemia have more severe symptoms.There is a negative correlation between the fibrinogen and the degree of bleeding.The risk of bleeding is less when the fibrinogen concentration is higher than lg/L.Genetic test is helpful for the diagnosis of disease classification.FIB:C/FIB:Ag<0.7 can be used as a basis for clinical diagnosis.The TT can be used as the basis for the diagnosis of dysfibrinogenemia and the effectiveness of fibrinogen infusion.