Severe hypodysfibrinogenemia in a young patient with pulmonary thromboembolism: a case report

Fibrinogen is a complex large fibrous glycoprotein synthesized in the liver. It plays a key role in coagulation. Its normal concentration in blood plasma ranges from 1.5 to 4.0 g/l. The half-life of circulating fibrinogen is about 3 to 4 days.¹ The fibrinogen molecule is composed of 2 sets of 3 polypeptide chains encoded by 3 genes located contiguously on chromosome 4q23, that is, Aα chain encoded by the FGA gene, Bβ chain encoded by the FGB gene, and γ chain encoded by the FGG gene.² Lower fibrinogen concentrations are known to result in the formation of thicker fibrin fibers creating a looser meshwork, which in turn leads to an increased risk of bleeding. On the other hand, an abnormal irregular structure of fibrin, even at lower fibrinogen concentrations, may paradoxically increase thrombotic risk by impairing fibrin degradation by plasmin or facilitating clot fragmentation.³

Congenital fibrinogen disorders are the third most frequent rare coagulation defect. Mutations in fibrinogen genes can lead to quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia and hypodysfibrinogenemia) fibrinogen abnormalities.^2,4 According to the recommendations, congenital fibrinogen disorders are classified into 4 groups: 1) afibrinogenemia, 2) hypofibrinogenemia, 3) dysfibrinogenemia, and 4) hypodysfibrinogenemia.⁴ Hypodysfibrinogenemia, which is the least frequently reported congenital fibrinogen disorder, shares features with both hypo- and dysfibrinogenemia.¹

We present a case of a 44-year-old woman admitted to the Department of Infectious Diseases, Bieganski Hospital, Łódź, Poland in April 2020 on account of nonspecific chest pain, hemoptysis, and exacerbating cough. The patient’s history included anxiety disorders, right-sided oophorectomy due to a ruptured cyst, and appendectomy with no history of bleeding complications. It was impossible to obtain family history. On admission, the patient was in satisfactory general condition. On physical examination, the following were observed: body mass index of 23.2, tachycardia, hypertension, palpable enlargement of the thyroid gland, bilateral crepitations in the lungs, saturation of 95%. The results of laboratory tests showed elevated levels of inflammatory rates: C-reactive protein, 195 mg/l (reference range, 0–5 mg/l); white blood cells, 14.4 × 10³/μl with neutrophilia (reference range, 4–10 × 10³/μl); thyroid-stimulating hormone <⁠0.01 μU/ml (reference range, 0.27–4.2 μU/ml); free thyroxine, 47.5 pmol/ml (reference range, 12–22 pmol/ml); fibrinogen, 48 mg/dl (reference range, 200–470 mg/dl); thrombin time, 25.6 s (reference range, 11.8–17.6 s); and D-dimer, 1743 μg/l (reference range <⁠500 µg/l). A SARS-CoV-2 reverse transcriptase–polymerase chain reaction test was negative. Thyrotropin receptor antibodies were detected on extended thyroid tests. Hyperthyroidism was diagnosed and thiamazole therapy was implemented. Chest computed tomography (CT) revealed consolidations in both lungs which were typical of pneumonia. Antibiotic therapy and a prophylactic dose of enoxaparin were administered.

The patient was transferred to the Department of Internal Diseases and Clinical Pharmacology, Medical University of Lodz, Łódź, Poland, for further diagnosis and therapy. During the patient’s stay at the clinic, her condition deteriorated and she presented persistent dyspnea and hemoptysis. Follow-up laboratory test results were as follows: C-reactive protein, 339 mg/l; fibrinogen, 38 mg/dl; thrombin time, 20.3 s; D-dimer, 3873 µg/l; N-terminal fragment of the prohormone brain natriuretic peptide, 402 pg/ml (reference range, 0–125 pg/ml); Po₂, 86 mm Hg (Supplementary material, Table S1). Echocardiogram revealed ejection fraction of 60%, regular dimensions of the heart cavities, normal left ventricular function, and normal systolic function of the right ventricle. The Wells and revised Geneva scores indicated intermediate-risk pulmonary embolism and, due to an elevated D-dimer level, CT of the pulmonary arteries was performed. It revealed a massive embolism in the right pulmonary artery and its branches (Figure 1A and 1B). Venous thrombosis of the lower limbs was excluded by Doppler ultrasound. Based on the Pulmonary Embolism Severity Index (PESI) score, the patient was considered at low risk of early mortality (0–1.6%, class I).

During the hospitalization, the antibiotic treatment was modified, therapeutic doses of enoxaparin (60 mg/0.6 ml twice a day) were included because of the low level of anti-Xa activity (<⁠0.6 IU/ml; reference range, 0.6–1.0 IU/ml), the dose of enoxaparin was increased to 80 mg/0.8 ml twice a day. Due to no clinical improvement and persistent embolic lesions on angio-CT, unfractionated heparin was introduced. Because of the low level of fibrinogen, cryoprecipitate (1 unit per 10 kg of body weight) and fibrinogen concentrate (the dose was calculated according to the formula) were administered. Additionally, screening for thrombophilia and antiphospholipid syndrome was performed with negative results (Supplementary material, Table S1). Genetically determined disorders of fibrinogen were suspected, and a sample of material was collected for genetic testing. The patient was discharged from hospital after 5 weeks in good condition and prescribed rivaroxaban 20 mg/d.

After 6 weeks, in follow-up laboratory tests of complete hemostasis work-up showed decreased functional (Clauss method; 50 mg/dl; reference range, 200–400 mg/dl) and antigenic (130 mg/dl; reference range, 180–350 g/l) fibrinogen levels with a functional / antigenic ratio of 0.38 (cutoff, 0.7) and prolonged thrombin times, which indicated hypodysfibrinogenemia. The Next Generation Sequencing of the fibrinogen gene FGG (γ chain) revealed a heterozygous missense mutation in exon 8—p.1055G>C; p.Cys352Ser. The presence of variants in the fibrinogen genes was confirmed by the Sanger sequencing method. The diagnosis of severe hypodysfibrinogenemia was established.

Hypodysfibrinogenemia is the most rarely reported congenital disorder of fibrinogen characterized by a qualitative and quantitative deficiency in circulating fibrinogen and a strong clinical heterogeneity. The prevalence of hypodysfibrinogenemia is unknown as the disease is often asymptomatic.¹ The most extensive literature review published so far reports cases of 51 patients diagnosed with the disorder.⁵ Recent recommendations suggest classification of congenital fibrinogen disorders based on the clinical and biological (fibrinogen activity, antigen, and genotype) phenotype. The cutoff of 0.7 for the ratio of functional concentration of fibrinogen to its antigen level has a diagnostic sensitivity of 86% for hypodysfibrinogenemia.^1,3

In the presented case, hypodysfibrinogenemia was diagnosed in a 44-year-old patient with massive pulmonary thromboembolism based on a functional / antigenic fibrinogen ratio of 0.38 and a positive genetic analysis. Previous data showed that among 51 identified cases of hypodysfibrinogenemia, 11 patients (22%) were asymptomatic, 23 (45%) had a mild bleeding phenotype, whereas 22 (43%) had experienced at least 1 thrombotic event, including 23 venous and 8 arterial thromboses.⁴ According to the latest recommendations, type 4 hypodysfibrinogenemia levels are classified as: 1) severe hypodysfibrinogenemia with fibrinogen antigen of less than 0.5 g/l (subtype 4A); 2) moderate hypodysfibrinogenemia with fibrinogen antigen levels between 0.5 and 0.9 g/l (subtype 4B), or 3) mild hypodysfibrinogenemia with fibrinogen antigen levels from 1.0 g/l to a lower limit of the reference range (subtype 4C).¹ Based on the classification, our patient was diagnosed with subtype 4A, that is, severe hypodysfibrinogenemia.

The systematic review on hypodysfibrinogenemia described a total of 32 single causative mutations (10 in FGA, 5 in FGB, and 17 in FGG) mainly in the COOH-terminal region of the γ or Aα chains at heterozygous or homozygous state. Seven additional hypodysfibrinogenemias resulted from compound heterozygosity.⁴ The genetic analysis of our patient revealed a heterozygous missense mutation in the fibrinogen gene FGG (γ chain) in exon 8—p.1055G>C; p.Cys352Ser (p.Cys326Ser in the mature chain) resulting in an amino acid substitution of serine for cysteine. This mutation affects the same amino acid as Cordoba fibrinogen which, unlike in our patient, was associated with severe cerebral hemorrhage in a 56-year-old man.⁵ So far, 2 cases with a γCys326Ser mutation manifesting as venous thromboembolism have been reported in the fibrinogen variants database,⁶ and our case is the third one with the above-mentioned mutation and thrombotic complications. Data show that in the γCys326Ser type of mutation, the hypofibrinogenemic phenotype was a result of an impaired fibrinogen assembly and secretion, whereas the dysfibrinogenemic phenotype was mainly caused by a defective fibrin polymerization.^3,4

Due to the low prevalence, management of patients with congenital fibrinogen disorders and thrombosis is challenging as anticoagulant treatment may exacerbate the underlying bleeding risk which can be life threatening. The initial management of the thromboembolic disease in patients with fibrinogen disorders is principally the same as that in individuals without those disorders.⁶ Data indicate that thrombosis in patients with fibrinogen disorders requires simultaneous supplementation of fibrinogen and administration of anticoagulants, most often heparins, with close clinical supervision and laboratory monitor.¹ It is clinically important to detect coagulation abnormalities such as hypodysfibrinogenemia which may cause thrombosis, establish a proper anticoagulant therapy, and provide genetic consultation to asymptomatic family members.