Congenital dysfibrinogenemia in major surgery: A description of four cases and review of the literature.

BACKGROUND: Congenital dysfibrinogenemia is characterized by qualitatively abnormal fibrinogens with resultant blood coagulation dysfunction. The clinical manifestations are high heterogeneity. Treatment for dysfibrinogenemia should be personalized. Here, we reported four congenital dysfibrinogenemia patients with the major surgery, in order to discuss the treatment and diagnosis of congenital dysfibrinogenemia. METHODS: We reported four asymptomatic congenital dysfibrinogenemia patients with the major surgery (valve replacement, brain surgery, tumorectomy, hysterectomy) in our study. Routine coagulation tests, hepatorenal function and gene analysis, thrombelastogram were performed. RESULTS: Four congenital dysfibrinogenemia patients all showed prolonged TT, low level of activity fibrinogen and normal fibrinogen antigen. Case1 showed a heterozygous mutation in exon 2 of the FGA, c.1223G > C, which turns the codon for residue Aα Gly13 into Arg (p. Gly13Arg). DNA sequencing of case2 showed that a heterozygous mutation in exon 8 of the FGG (c.5877G > A) with being responsible for the Arg â†’ His substitution at position 301 of the γ chain (p. Arg301His). Case3 and case 4 failed to do genetic testing for other reason. Four congenital dysfibrinogenemia patients were asymptomatic in the daily life. Personal and family history revealed no abnormal bleeding or thrombotic events. These four patients did not receive special treatment and management before surgery. They all had a smooth operation. CONCLUSIONS: Misdiagnosis and unnecessary infusion bring huge health risks to patients. Correct diagnosis of congenital dysfibrinogenemia is the key to avoid misdiagnosis or unnecessary infusion. Asymptomatic patients with congenital dysfibrinogenemia do not need cryoprecipitate or fibrinogen input before major surgery.

Anesthesia Experience for Tonsillectomy in a Patient With Hypofibrinogenemia: A Case Report.

A 26-year-old male patient with hypofibrinogenemia was scheduled to undergo tonsillectomy. Hypofibrinogenemia, defined as low plasma fibrinogen (Fbg) concentration, is a type of congenital Fbg deficiency and is a rare coagulopathy. Perioperative replenishment of Fbg is performed during minor surgeries, aimed at maintaining plasma Fbg concentrations of 50 mg/dL. In this case, failure to replenish Fbg during the postoperative period may have caused the postoperative hemorrhage. Considering the half-life of Fbg (3-4 days), the plasma Fbg concentration should be monitored for ≥6 postoperative days, aiming at a target level of 50 mg/dL during the postoperative period.

Dysfibrinogenemia in a patient undergoing artificial abortion after misdiagnosis and review of the literature.

BACKGROUND: Dysfibrinogenemia is characterized by dysfunction induced by an abnormal fibrinogen molecule structure that results in blood coagulation dysfunction. The clinical manifestations are diverse. Dysfibrinogenemia is misdiagnosed or miss diagnosis in the absence of an appropriate laboratory examination. Treatment during pregnancy or surgery is suggested to be adapted to the individual patient. METHODS: A 26-y-old woman took drugs that may cause fetal malformation during early pregnancy. She required an artificial abortion in a local municipal hospital and was misdiagnosed with hypofibrinogenemia. RESULTS: A preoperative coagulation test revealed a fibrinogen concentration of 0.56g/l, prompting a diagnosis of hypofibrinogenemia at the local municipal hospital. She underwent fresh plasma and cryoprecipitate infusion with a poor outcome. However, the coagulation test results in our hospital showed a prothrombin time of 12.60s, activated partial thromboplastin time of 34.60s, thrombin time of 25.30s, and fibrinogen concentrations of 0.51g/l (Clauss method) and 3.82g/l (immunoturbidimetry). Ultrasound examination showed early intrauterine pregnancy with a fetal heartbeat. The patient was finally diagnosed with dysfibrinogenemia. A detailed inquiry regarding her personal and family histories revealed no abnormal bleeding or thrombotic events. Therefore, other therapies were not conducted and operation was successfully performed. No abnormal bleeding or thrombotic events occurred postoperatively. CONCLUSIONS: Simultaneous determination of fibrinogen concentrations using the Clauss method, prothrombin time-derived method, and immunoturbidimetry as well as measurement of the thrombin time, reptilase time, prothrombin time, activated partial thromboplastin time and so on can effectively distinguish dysfibrinogenemia from other diseases. Special treatment of asymptomatic dysfibrinogenemia is not needed during pregnancy or surgery in the absence of bleeding or thrombotic events in the patient's personal or family history.

Natural history of patients with congenital dysfibrinogenemia.

We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean follow-up of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event.

In vitro rescue of FGA deletion by lentiviral transduction of an afibrinogenemic patient's hepatocytes.

BACKGROUND: Congenital afibrinogenemia is a rare inherited autosomal recessive disorder in which a mutation in one of three genes coding for the fibrinogen polypeptide chains Aα, Bß and γ results in the absence of a functional coagulation protein. A patient with congenital afibrinogenemia, resulting from an FGA homozygous gene deletion, underwent an orthotopic liver transplant that resulted in complete restoration of normal hemostasis. The patient's explanted liver provided a unique opportunity to further investigate a potential novel treatment modality. OBJECTIVE: To explore a targeted gene therapy approach for patients with congenital afibrinogenemia. METHODS AND RESULTS: At the time of transplant, the patient's FGA-deficient hepatocytes were isolated and transduced with lentiviral vectors encoding the human fibrinogen Aα-chain. FGA-transduced hepatocytes produced fully functional fibrinogen in vitro. CONCLUSIONS: Orthotopic liver transplantation is a possible rescue treatment for failure of on-demand fibrinogen replacement therapy. In addition, we provide evidence that hepatocytes homozygous for a large FGA deletion can be genetically modified to restore Aα-chain protein expression and secrete a functional fibrinogen hexamer.

Spontaneous epidural and subdural hematoma in a child with afibrinogenemia and postoperative management.

Congenital afibrinogenemia is a rare coagulation disorder that exhibits recessive inheritance. The prevalence of this disease is around 1 per 1 000 000, but it is increased in countries where consanguineous marriages are common. Umbilical cord bleeding during the neonatal period is generally the first manifestation of the disease, but a later age of onset is not uncommon. This disease may also be manifested by gastrointestinal, genitourinary, mucosal, muscular, articular, and intracranial bleeding during childhood. Intracranial hemorrhage is a rare condition, but it is the leading cause of death in patients with afibrinogenemia. In this report, we present the case of a 13-year-old female patient with afibrinogenemia who underwent an operation for spontaneous massive extradural and subdural hematoma.

Spontaneous extra-axial intracranial hemorrhage followed by thrombosis in congenital afibrinogenemia: perioperative management of this rare combination.

BACKGROUND: Although congenital afibrinogenemia can commonly present with hemorrhage from the umbilical cord at birth, or with spontaneous mucosal or intracranial hemorrhage in the neonatal period, life-threatening intracerebral hemorrhage in adults is infrequent. CASE DESCRIPTION: We report a 32-year-old woman with congenital afibrinogenemia. Postoperatively, she developed bilateral pulmonary emboli despite the fact that her INR was elevated to 2.3. Highly purified fibrinogen concentrate infusion may have partly contributed to this complication. An inferior vena caval filter was used successfully to prevent further pulmonary emboli. CONCLUSIONS: Spontaneous intracerebral hemorrhage must be included in the differential diagnosis in patients with known afibrinogenemia presenting with symptoms suggesting raised intracranial pressure. Immediately after surgery, intracranial pressure monitoring of patients is mandatory to pick up further intracranial bleeding early. Fibrinogen replacement therapy is recommended before surgery, but its use as a long-term prophylaxis against hemorrhage should be weighed against the risk of thrombosis.