Misdiagnosis of a patient with congenital dysfibrinogenemia: A case report and literature review

Abstract 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.

clinical manifestations. 5 The current methods for automatic fibrinogen detection are the Clauss method and PT-derived fibrinogen assay. CD is prone to misdiagnosis or missed diagnosis if only one method is used to detect fibrinogen levels. Herein, we report a case of CD misdiagnosis and review the relevant literature to discuss a method that can reduce misdiagnosis or missed diagnosis.

| Patient
A 23-year-old pregnant woman had an induced abortion. In the 14th week of the second pregnancy (March 24, 2020), the obstetric examination at the Souzhu Hospital Affiliated to the M Medical University in other provinces revealed that her fibrinogen level was significantly reduced. Her vital signs were stable, and she presented with no signs of vaginal bleeding in the first trimester. Thromboelastography, routine blood examination, and genetic testing for thalassemia revealed no abnormalities. Fetal ultrasound measurements showed that the baby had grown well. The patient had been previously healthy. She and her family members had no history of unexplained bleeding and denied a family history of a consanguineous marriage. An expert consultation was held by nine experts from the departments of obstetrics and gynecology, laboratory, pediatrics, rheumatology, and immunology in Souzhu hospital. She was then diagnosed with hypofibrinogen and was considered to have an increased risk of bleeding or thrombosis that might endanger her life during pregnancy or delivery. Fibrinogen or cryoprecipitate infusion was recommended, if necessary. The patient complained that after being diagnosed with hypofibrinogenemia, she had trouble sleeping and eating, became depressed, and was often worried about the safety of herself and her fetus. During this period, she visited another provincial maternal and child hospital for diagnosis and treatment, but no definite diagnosis was made. On July 7, 2020, the patient presented to our hospital for further diagnosis and treatment.

| Laboratory examinations
Written informed consent was obtained from the patient and her family members. Ethical approval was obtained from the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (approval no. 2015-KY-Guoji-115) on 3/3/2015. Peripheral venous blood samples were collected to test liver, kidney, and coagulation functions of the patient and her family members. They had normal liver and kidney function. Four blood coagulation parameters were assessed. The thrombin time of the patient and her mother was prolonged, and the fibrinogen level (measured by the Clauss method) was significantly decreased; however, the fibrinogen level (measured by PT-derived fibrinogen assay) was within the normal range. There were no abnormalities in the coagulation function of her sister or father (Table 1). Whole blood DNA was extracted from the patient and her family members, and the FGA, FGB, and FGG genes were amplified and sequenced to determine the mutation sites. DNA sequencing results showed that the patient and her mother had a heterozygous mutation c.104G > A (p.Arg35His) in exon 2 of the FGA gene. This mutation was not detected in other family members. Fibrinogen gene sequencing results for this family are shown in Figure 1.

| RE SULTS
Based on coagulation function and gene sequencing results, the patient (proband) and her mother were diagnosed with CD. The patient and her family members had no history of bleeding or thrombosis. She showed normal results on thromboelastography, with no need for special treatments, such as fibrinogen infusion, during pregnancy, and before delivery. The patient presented with no abnormalities during pregnancy, and she delivered a full-term baby naturally in our hospital on September 13, 2020. The delivery process went well. Soft birth canal examination showed the cervix was intact. The posterior vaginal wall was naturally lacerated and approximately 1 cm long, followed by a routine suture.
There was less blood loss, approximately 110 ml within 2 h after delivery. The patient was discharged on the third day after the delivery.

| DISCUSS ION
Congenital dysfibrinogenemia diagnosis and differential diagnosis mainly rely on laboratory tests, and fibrinogen is a key diagnostic indicator. Among the Clauss method and PT-derived assay currently    the results are often normal or higher, making it prone to a missed diagnosis. 10 The pregnant woman subsequently visited our hospital for diagnosis and treatment; her coagulation function test results were as follows (Table 1).
Zhou et al. 11 reported that a patient with CD who was misdiagnosed with hypofibrinogenemia suffered a pulmonary embolism after fibrinogen infusion, which caused serious adverse effects on the patient. Therefore, the treatment of patients with CD must be

CO N FLI C T O F I NTE R E S T
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.