Combined factor v and VIII deficiency: A mucocutaneous bleeding phenotype driven predominantly by factor VIII – a retrospective study of 34 patients

Abstract

Abstract BACKGROUND Combine factor V and VIII deficiency (F5F8D) is a rare autosomal recessive bleeding disorder (<1/million) caused by LMAN1 or MCFD2 mutations which affects the intracellular transport of both factors. Despite simultaneous reduction in two critical coagulation factors, the clinical presentation is variable, ranging from minimal bleeding to severe haemorrhage. The factor which predominantly influences bleeding risk and whether global haemostatic assays can supplement traditional factor level testing in guiding management still remains unclear. AIM To evaluate the clinical bleeding phenotype in patients with F5F8D and identify laboratory predictors of bleeding severity, with a focus on the relative contribution of FV and FVIII levels. To assess the utility of global haemostatic assays (ROTEM, clot waveform analysis) in predicting bleeding phenotype. METHODS This was a retrospective cohort study conducted over a 10-year period (July 2016 to June 2025) at a tertiary care center with a dedicated coagulation laboratory. Inclusion criteria were: (i) Confirmed diagnosis of F5F8D by clot-based FV and FVIII assays showing concomitant reduction in both factors (ii) availability of complete clinical records including bleeding history and laboratory parameters, and (iii) Documented ISTH-BAT score. Exclusion criteria were: (i) acquired combined deficiencies due to liver disease, disseminated intravascular coagulation, or vitamin K deficiency, and (ii) incomplete laboratory or clinical documentation. Clinical bleeding phenotype was assessed using ISTH Bleeding Assessment Tool (BAT) and included mucocutaneous, musculoskeletal, and surgical bleeding events. FV and FVIII activity were measured using standard one-stage clotting assays on an automated coagulation analyzer. ROTEM parameters (CT, CFT, MCF, α-angle) were measured using citrated whole blood. APTT clot waveform analysis was performed for maximum velocity (Min1), acceleration (Min2), and deceleration (Max2) parameters. Statistical Analysis Continuous variables were summarized as mean ± SD or median (IQR). Correlations between factor levels and ISTH-BAT scores were analyzed using Spearman's rank correlation. Multiple linear regression was performed to identify independent predictors of bleeding severity. A p-value <0.05 was considered statistically significant. RESULTS Thirty-four patients were included, with a mean age of 23.1 ± 15.5 years (range 4–58 years); 71% were female. Most patients (88%) were from consanguineous backgrounds, reflecting the genetic basis of the condition in this region. Bleeding phenotype The clinical presentation was muco-cutaneous, with prolonged bleeding from minor wounds (47%) and gum bleeding (38%) being the most common manifestations. Epistaxis occurred in 26% of patients, menorrhagia in 68% of women, and postpartum haemorrhage in 15%. Haemarthrosis was not observed, even in patients with FVIII levels as low as 5%, highlighting the distinct joint-sparing, mucocutaneous-predominant phenotype of F5F8D compared to Hemophilia A. This pattern may reflect the combined effects of FV and FVIII deficiency on thrombin generation, selectively impairing primary hemostasis while mitigating joint bleeding risk.Mean ISTH-BAT score was 5.1 ± 3.2. Mean FV and FVIII levels were 9.5% and 13.9%, respectively. On univariate analysis, FVIII levels demonstrated a moderate inverse correlation with ISTH-BAT score (ρ = -0.37, p = 0.032), whereas FV showed no significant association (ρ = -0.13, p = 0.46). In multivariate linear regression, FVIII remained a statistically significant independent predictor of bleeding severity (β = -0.165, p = 0.049), while FV did not (p = 0.656). Global Haemostatic Assays ROTEM parameters and clot waveform analysis showed poor correlation with ISTH-BAT scores (all p > 0.1), suggesting limited clinical utility in predicting bleeding severity in F5F8D. CONCLUSION In F5F8D, bleeding severity is primarily determined by FVIII levels, not FV. The phenotype is predominantly mucocutaneous, with no joint involvement, and global assays add little predictive value. Clinical assessment should prioritize FVIII-centric risk stratification. These findings have implications for both diagnosis and treatment prioritization, important in low-resource settings.