Quantitative fibrinogen disorders: A retrospective study from a tertiary care centre in India

Methods

This retrospective analysis was undertaken by the department of Pathology, King George’s Medical University, Lucknow, Uttar Pradesh, India. The study was conducted after obtaining ethical approval from the Institutional ethics committee. We conducted a retrospective analysis of cases diagnosed with quantitative fibrinogen disorders over a 20-year period at our tertiary care centre.

Results

The retrospective data of patients diagnosed with quantitative fibrinogen disorders at a tertiary care centre in Northern India over a period of 20 years (2003-2024) are presented. The majority (65%) of the cases were diagnosed in the last 10 years. Diagnosis of all cases was made based on prolonged PT and APTT tests, as well as undetectable fibrinogen levels. All patients presented during the neonatal period, with a median age of onset of symptoms of 4 days (1-30 days). The median age at first visit to the hospital for an appropriate diagnostic workup was 4 years (4 months-12 years). A delay in visiting the hospital for appropriate diagnostic workup was noted in most cases, with a median delay of 4 years (4 months-12 years). Only three cases received a timely diagnosis, two of which belonged to the same city. The cases visiting our centre come from distant rural and urban areas of the State (urban to rural ratio 9:8) ( Figure). The median distance of visit for patients was 130 kilometres (4.5 km - 403 km). The delay in diagnosis for rural cases was higher compared to urban cases (median was 6 years vs. 1.5 years). The literacy status of family members (primary education vs. illiterate) did not vary between rural and urban cases. The cases were distributed among both genders, with a male-to-female ratio of 10:7. Siblings with a history of a similar illness were noted in 6 out of 17 patients (35%). Nearly half of the cases (8/17) resulted from a consanguineous marriage. Consanguinity was primarily observed in Muslim patients.

Close

Figure Uttar Pradesh State map, showing distribution of cases originating from various districts. Cases 1-4: Lucknow, Case 5: Barabanki, Case 6-7: Sitapur, Case 8: Gonda, Case 9: Ayodhya, Case 10: Basti, Case 11-12: Gorakhpur, Case 13: Banda, Case 14: Hardoi, Case 15: Saharanpur, Case 16: Budaun, Case 17: Bijnor [Source: the map was adopted from online source (Wikimedia) and edited on Adobe Stock (https://stock.adobe.com/search?k=uttar+pradesh+map)].

Export to PPT

Discussion

As per the International Society of Thrombosis and Haemostasis, quantitative fibrinogen deficiency may be classified as mild hypofibrinogenemia (lower limit of normal to 1g/L), moderate hypofibrinogenemia (0.9-0.5g/L), severe hypofibrinogenemia (0.5-0.1g/L) and afibrinogenemia (unmeasurable fibrinogen level <0.1g/L). ⁴ Clinically, bleeding episodes are the main symptoms in afibrinogenemia, whereas in hypofibrinogenemia, cases are more often asymptomatic. Although cases often present early in life, a delay in timely diagnosis and intervention is frequently observed. Comparing the data from two decades, we can observe that the number of diagnosed cases nearly doubled in the last decade. This could be attributed to the improved approachability of patients to the diagnostic facility. However, patient awareness does not seem to have improved, as the median delay in diagnosis did not show a significant difference. The higher median delay observed in cases from rural areas again highlights the lack of patient awareness.

Most cases presented in the neonatal period, as previously reported. ^3,6 However, the median age of presentation to our hospital for complete diagnostic work is lower as compared to previous Indian reports. ^5,6,10 The registered cases involve both genders; however, a male predominance was observed in our study, consistent with previous reports. ⁵ Other Indian studies have shown a female predominance. ¹⁰ History of consanguineous marriage has been reported in all previous Indian studies with variable proportion (ranging from 33 to 74%) attributable to the regional social and cultural practices ^2,3,5,6 similar to our study.

A family history of an affected sibling was observed in nearly one-third of the cases in our data, which aligns with previous studies (ranging from 25 to 42%). None of the parents was affected, pointing towards the recessive pattern of inheritance. Additionally, cases from both genders can be attributed to an autosomal recessive inheritance pattern in our study group. According to current practice, when dealing with patients exhibiting bleeding symptoms, the use of a bleeding assessment tool is recommended. We have tried to score all our cases according to the ISHT-BAT score. As previously proposed, all our cases belong to a severe bleeding phenotype. ⁷

Umbilical bleeding was observed uniformly in all cases. The reported literature shows a highly variable prevalence of umbilical cord bleed (12.5% to 62%). ^5,6,10 In many of the studies, post-traumatic bleed has been reported as the most common symptom (46% to 100%). ^5,6,10 In our study, it was the second most common symptom, followed by cutaneous bleeding. Mucosal bleed in the form of gum bleeding and epistaxis was observed in a proportion comparable to previous reports. Muscle hematoma was observed in a single case (6%) in our study, much higher prevalence has been previously reported. ^5,6,10 We did not observe post-surgical, gastrointestinal bleeding or delayed wound healing, although these symptoms have been reported in varying proportions in previous studies. Menorrhagia has been reported in cases of the reproductive age group, as per the previous reports. ^5,6 We had a single case of a female in the reproductive age group, who was symptomatic for menorrhagia. As our cases comprised the paediatric age group, we could not evaluate for post-partum haemorrhage and recurrent abortion.

The study data have limitations in not categorising cases as afibrinogenemia and hypofibrinogenemia, as we have not evaluated fibrinogen antigen levels. Our data lacks genetic information that could have contributed to the correlation between genotype and phenotype. Although we evaluated retrospective cases over a two-decade period, the overall sample size may still be limited, which could affect the generalisability of our findings. As the follow-up data remains incomplete, we cannot fully comprehend treatment response, prognosis, and symptoms in later life, including thrombotic episodes. The possibility of recall bias in symptom scoring cannot be ruled out.

Overall, this study presents the demographic and clinical profiles of quantitative fibrinogen deficiency diagnosed over 20 years. A point of significant concern is the diagnostic delay these patients suffer due to a lack of appropriate testing facilities and a diagnostic approach that is not followed. The rural population bears the brunt of these pitfalls in our healthcare facilities; they often need to travel long distances for an appropriate diagnosis, which is frequently delayed. Appropriate screening tests should be done either manually or on automated analysers in patients suspected of bleeding disorders to differentiate the rare bleeding disorders from haemophilia. Our study incorporates the standardisation of bleeding symptoms assessment through the ISHT-BAT scoring system, a practice often overlooked in previous studies. This systemic approach not only enhances the reliability of symptom reporting but also facilitates a clearer understanding of bleeding phenotype in affected patients.

The ongoing need for lifelong follow up and appropriate management of patients is evident, with a significant proportion actively engaged in treatment. While fresh-frozen plasma remains the primary therapeutic option, our findings highlight the need to improve access to advanced treatments.