The Study Of Congenital And Acquired Fibrinogen Disorders

Objective: To analyze the correlation between clinical phenotype and genotype in patients with congenital fibrinogen disorders and to investigate the pathogenic mechanism of hypofibrinogenemia.To investigate the clinical significance of coagulation indicators such as fibrinogen in predicting the prognosis of patients with thrombotic thrombocytopenic purpura(TTP)and hemophagocytic lymphohistiocytosis(HLH).Methods:(1)A total of 65 patients diagnosed with congenital fibrinogen disorders and their family lines from June 2015 to February 2022 at Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology were included in this study,and the clinical and laboratory data of the patients were retrospectively analyzed and grouped according to different clinical phenotypes and different genotypes to compare the differences in fibrinogen levels between groups.The recombinant mutant fibrinogen expression vectors were constructed for the three novel mutations,and the levels of fibrinogen assembly and secretion were detected by ELISA,and the structure of the mutant FGA,FGB and FGG peptide chains were predicted by SWISS-MODEL homology modeling.(2)This study included patients with acquired TTP diagnosed at Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January2016 to September 2022,retrospectively analyzed the clinical and laboratory data of the patients and followed up their prognosis by telephone,and divided into a death group and a non-death group according to the follow-up results,and compared the differences of clinical characteristics,treatment,trends in fibrinogen levels and DIC scores between the two groups.(3)This study included patients with HLH diagnosed at Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from May 2018 to December 2021,retrospectively analyzed the clinical and laboratory data of the patients and followed up their prognosis by telephone,and divided into a death group and a non-death group according to the follow-up results,and compared the differences of basic clinical characteristics,trends in fibrinogen levels and DIC scores between the two groups,and analyzed the correlation between fibrinogen levels and ferritin levels.Results:(1)There was no significant difference in fibrinogen levels between patients with different clinical phenotypes.There was a sequential decrease in fibrinogen activity levels in patients carrying mutations at the FGG c.902G>A,FGA c.104G>A,and FGG c.901C>T,respectively.The FGA c.551G>T(p.Cys184Phe)missense mutation may affect fibrinogen secretion,but did not result in significant structural changes in the FGA peptide chain;the FGB c.923C>A(p.Thr308Asn)missense mutation may affect both fibrinogen assembly and secretion,but did not result in significant structural changes in the FGB peptide chain.The FGG c.1063C>T(p.Gln355Ter)nonsense mutation may affect both fibrinogen assembly and secretion,and resulted in a shortened structure of the FGG peptide chain.(2)A total of 72 patients with acquired TTP were included in this study.There were 44 females and 28 males,and the mean age of the patients was(47.33 ± 18.64)years.There were 36 in the death group and 36 in the non-death group,with a mortality rate of 50%.At the time of initial diagnosis,there was no statistical difference in platelet levels,prothrombin time,activated partial thromboplastin time and fibrinogen level between the patients in the death group and the non-death group.Thrombin time was statistically different between the two groups,but they were within the normal range.Patients with a decreasing trend of fibrinogen level but recovered in a short time had a higher survival rate(14/16,87.5%),and the median time of fibrinogen recovery to normal level was 7 days;patients with a continuous decrease of fibrinogen level had a higher mortality rate(18/27,66.7%),and the median time from normal fibrinogen level to death was 5 days.When fibrinogen was at its lowest level,the mean DIC score of patients in the death group was 4.47,which was higher than the mean DIC score of patients in the non-death group of2.69;and the proportion of patients with DIC score ≥5 in the death group(12/36,33.3%)was much higher than that of patients with DIC score ≥5 in the non-death group(2/36,5.5%)(P<0.05).(3)A total of 77 patients with HLH were included in this study.Among them,28 were female and 49 were male,and the mean age of the patients was(45.27 ±18.16)years.There were 29 in the death group and 48 in the non-death group,with a mortality rate of 37.7%.Patients whose fibrinogen levels recovered in a shorter period of time had a higher survival rate(20/27,74.1%),and the median time for fibrinogen recovery to normal levels was 20 days;patients whose fibrinogen levels failed to recover had a higher mortality rate(16/31,51.6%).Fibrinogen levels were negatively correlated with ferritin levels(P<0.05)with a correlation coefficient of-0.294.As the disease progressed,elevated ferritin levels led to a decrease in fibrinogen levels,which in turn led to a poor prognosis.At admission,the mean DIC score of patients in the death group was 2.90,which was higher than the mean DIC score of patients in the non-death group,which was 1.96(P<0.05).The difference between the proportion of patients in the death group with a DIC score ≥5(6/29,20.7 %)and the proportion of patients in the non-death group with a DIC score ≥5(6/48,12.5 %)was not statistically significant.When fibrinogen was at its lowest level,the mean DIC score of patients in the death group was 4.41,which was higher than the mean DIC score of patients in the non-death group,which was 2.83(P<0.05).And the proportion of patients with DIC score ≥5 in the death group(14/29,48.3%)was higher than the proportion of patients with DIC score ≥5 in the non-death group(11/48,22.9%)(P<0.05).Conclusions:(1)Differences in genetic mutations in CFD patients may have some degree of influence on fibrinogen expression levels,and there may be a correlation between clinical phenotype and genotype.In addition,the FGA c.551G>T mutation leads to the development of hypofibrinogenemia by affecting the secretion of fibrinogen,and the FGB c.923C>A and FGG c.1063C>T mutations lead to the development of hypofibrinogenemia by affecting the assembly and secretion of fibrinogen.(2)The trend of decreasing fibrinogen levels correlates with the prognosis of TTP patients.(3)The insignificant trend of recovery of fibrinogen levels correlated with the poor prognosis of HLH patients.