Unusual laboratory manifestations of fibrinogen γ chain p.Ala108Gly genetic variant: A case report Free

Introduction: Fibrinogen is a dimeric glycoprotein with monomers composed of Aα, Bβ, and γ subunits, which contributes necessary mechanical stability to clots after being activated by thrombin and polymerized into fibrin. Congenital fibrinogen deficiencies have been identified in all three subunits and can be classified into quantitative (hypofibrinogenemia or afibrinogenemia) or qualitative (dysfibrinogenemia or hypodysfibrinogenemia) disorders. Fibrinogen disorders are diagnosed based on activity such as the Clauss assay and antigenic assays, with activity to antigenic ratios <0.7 suggesting a qualitative disorder (Casini et al, 2018, Journal of thrombosis and haemostasis: JTH, 16(9), 1887–1890). Clinical manifestations of fibrinogen disorders vary greatly, with many patients remaining asymptomatic, some having bleeding phenotypes of variable severity, and some experiencing thrombotic events. We present a case of a known fibrinogen variant with an unusual laboratory presentation.

Case Presentation: Our proband, a 63 year old female, presented for bleeding disorder workup due to an abdominal hematoma that required transfusion following a Roux-en-Y gastric bypass procedure. She reported past bleeding history including heavy menstrual bleeding (HMB) requiring hysterectomy, post-partum haemorrhage, non-ruptured ectopic pregnancy with hemorrhage, and dental procedures with heavy bleeding that required repacking. ISTH-BAT score was 12 (>5 represents abnormal bleeding). The proband's family history is notable for fatal gastrointestinal hemorrhage in both the proband's grandmother and father, and HMB in her daughter (requiring hysterectomy) and granddaughters. Initial laboratory testing found normal PT, PTT, platelet count, von Willebrand Factor (VWF) activity, VWF antigen, and Clauss fibrinogen activity (2.76 ref: 1.90-4.23 mg/mL), with elevated factor VIII (238% ref: 61-173%). However concurrent genetic testing revealed proband is heterozygous for a missense mutation in the fibrinogen γ chain (FGG) gene (c.323C>G p.Ala108Gly, NM_021870.2).

After detection of genetic variant, proband's daughter (HMB requiring hysterectomy, ISTH-BAT score of 6) and two granddaughters (both with HMB) underwent laboratory and genetic testing. Daughter and both granddaughters had normal values for fibrinogen activity, and all patients had normal fibrinogen activity to fibrinogen antigen ratios. Though daughter and both granddaughters exhibit heavy menstrual bleeding, only the daughter was heterozygous for the genetic variant of interest. Euglobulin lysis time (ELT) testing suggests faster fibrinolysis in proband and daughter (258 and 166 minutes respectively) compared to granddaughters (486 and 480 minutes); normal reference range 94-450 minutes. Daughter had elevated factor VIII levels (194%), while normal factor VIII levels were observed in both granddaughters (135% and 139%).

Discussion: This case represents an interesting example of a known fibrinogen variant (p.Ala108Gly) presenting with normal fibrinogen laboratory values despite unusual bleeding patterns in multiple domains. Biochemical investigations by Brennan et al (Thromb Haemost, 2006. 96(4): p. 535-7) suggest that mutations in this region of the fibrinogen gamma chain leads to increased turnover of plasma fibrinogen, leading to the hypofibrinogenemia observed in prior studies. However, in our study, all affected family members presented with normal fibrinogen activity and antigen, despite bleeding symptoms (ISTH-BAT scores >5). Thus, genetic testing was instrumental in identifying bleeding etiology and treatment plan development.

One possible explanation of normal fibrinogen levels in patients with a hypofibrinogenemic genetic variant relates to the acute phase response. The acute phase inflammatory response can lead to significant elevation of both fibrinogen and factor VIII. Laboratory testing for the patients in our study may have been done during a period of inflammation in the proband and daughter, leading to transiently normal fibrinogen and the observed elevated factor VIII assays.Conclusion: Congenital fibrinogen disorders are difficult to identify and diagnose due to the range of causative genetic variants and the varied clinical presentation. The combination of clinical history and normal laboratory results in this case highlight the value of genetic testing in diagnosing bleeding etiology.