Subgaleal Hematoma in a Pediatric Patient with Factor XI Deficiency: A Case Report of Combined Rare Pathologies

Introduction

Factor XI (FXI) deficiency, also referred to as hemophilia C or Rosenthal disease, is a rare autosomal inherited bleeding disorder with an estimated global prevalence of approximately 1 in 1 000 000. It is most commonly observed among individuals of Ashkenazi Jewish descent. The condition arises from mutations in the F11 gene, located on chromosome 4q35, resulting in either quantitative or qualitative defects in FXI. To date, more than 190 pathogenic variants of F11 have been identified, the majority of which are missense mutations [1–3].

Unlike hemophilia A and B, the severity of bleeding in FXI deficiency does not consistently correlate with plasma FXI levels or genotype. Some individuals with severe deficiency (FXI activity <20%) can remain asymptomatic, whereas others with mild or moderate deficiency can experience significant bleeding episodes. Mucocutaneous bleeding, particularly following trauma or surgical procedures, is the most frequently reported clinical manifestation, while spontaneous hemarthrosis or intracranial hemorrhage is uncommon [4].

FXI deficiency is typically diagnosed in adolescence or adulthood, with a median age at diagnosis of 22 years. Pediatric cases are rarely reported. Management is generally guided by clinical bleeding history rather than FXI levels alone and can include fresh frozen plasma (FFP), FXI concentrate, recombinant activated factor VII (rFVIIa), or antifibrinolytic agents, depending on the clinical context and severity of bleeding. [5]

In this report, we describe a unique case of a 6-year-old Saudi girl with recurrent subgaleal hematomas following minor head trauma. Her clinical course was notable for a persistently prolonged activated partial thromboplastin time (aPTT), borderline FXI activity, and reduced von Willebrand factor (VWF) activity, raising suspicion for a combined bleeding disorder. This case highlights the diagnostic complexity and therapeutic challenges of atypical bleeding presentations in pediatric FXI deficiency, particularly when coexisting with additional hemostatic defects.

Case Report

A 6-year-old Saudi girl, born to consanguineous parents with a family history suggestive of bleeding disorders, presented to the Pediatric Emergency Department with a progressively enlarging scalp swelling. She had previously received a diagnosis of FXI deficiency at the age of 2 years, with an initial FXI activity reported as less than 15%.

Three days prior to presentation, the patient sustained a minor head injury after falling from a swing (approximately 0.5 m in height). On examination, she was alert and hemodynamically stable but exhibited a large, fluctuant, and tender scalp swelling measuring approximately 12×8 cm. The swelling extended from the right temporal region to the frontal and parietal areas. There was no initial skin discoloration or bruising, but mild periorbital puffiness was observed. The mass was compressible, non-pulsatile, and without palpable crepitus or signs of skull fracture. The neurological examination was unremarkable, with no signs of raised intracranial pressure or focal deficits.

A non-contrast-enhanced computed tomography (CT) scan of the head revealed a right parieto-occipital subgaleal hematoma. Initial coagulation studies showed a markedly prolonged aPTT of 71.2 s, with a prothrombin time (PT) of 17.4 s and an international normalized ratio (INR) of 1.28.

The patient was admitted under hematology care and commenced on FFP at 10 mL/kg once daily. FXI levels were pending at the time. Despite 2 doses of FFP, the scalp swelling expanded, involving the right periorbital area. A repeat CT scan revealed hematoma progression, with an acute bleed overlying a subacute collection, and features consistent with evolving cellulitis (Figure 1). A concurrent hemoglobin drop of 2 g/dL was noted. The patient was transferred to the Pediatric Intensive Care Unit for close monitoring and escalation of therapy.

Her treatment regimen was intensified to FFP every 8 h (10 mL/kg), a single dose of rFVIIa at 30 μg/kg, and intravenous antibiotics for presumed secondary infection. FXI activity, reported during this admission, was 18%. Over subsequent days, the hematoma began to regress, and bleeding stabilized. The patient was discharged in stable condition, with outpatient follow-up instructions. A timeline summarizing the clinical course during the initial admission is provided in Table 1.

Two days after discharge, the patient re-presented with recurrent swelling in the same scalp region, gradually increasing in size over 24 h. No history of re-injury, fever, or systemic symptoms was reported. On examination, the swelling was again fluctuant and tender, involving the right temporal, frontal, and parietal areas, with signs suggestive of re-bleeding into the previous subgaleal space. There was no overlying skin warmth, erythema, or disruption. Neurological and systemic examinations remained normal.

Vital signs were stable, and laboratory investigations showed persistent aPTT prolongation (72.8 s), mildly prolonged PT (16.2 s), and INR of 1.19. Hemoglobin levels remained stable compared with discharge values. A CT scan confirmed an acute-on-chronic subgaleal hematoma, with redistribution of the collection.

The patient was readmitted and started on an intensified FFP protocol: a 20 mL/kg loading dose followed by 10 mL/kg every 8 h. She received an additional rFVIIa dose (30 μg/kg), and tranexamic acid was started at 10 mg/kg intravenously 3 times daily. Over a 2-week hospitalization, the hematoma stabilized without further progression. Repeat FXI levels measured 52% and 44%, respectively, during this admission. Despite clinical improvement, the aPTT remained markedly prolonged (up to 89.7 s). No surgical intervention was necessary, and the patient was treated conservatively with supportive care and compressive head bandaging.

A detailed timeline of the second admission is provided in Table 2, and coagulation trends over time are illustrated in Figure 2.

Further review of prior medical records revealed a similar episode at age 2 years, involving a subperiosteal hematoma of the periorbital region after minor trauma, which required surgical evacuation. At that time, her aPTT was 69 s, and FXI levels measured 55% and 59%, respectively, after partial correction with FFP.

Retrospective laboratory analysis during this and previous admissions raised suspicion for a combined bleeding disorder. In addition to FXI deficiency, she demonstrated reduced VWF activity: VWF antigen was 59.3% (reference range: 50–160%), while ristocetin cofactor activity was markedly decreased at 33.9% (reference range: 47.8–173.2%). Other coagulation factors, including II, V, IX, and X, were within the reference range. A mixing study excluded the presence of FXI inhibitors. Regrettably, comprehensive VWF assay testing was not available during this acute phase, limiting full characterization of VWF function.

Notably, during the neonatal period, the patient presented with facial petechiae within the first 24 h of life and an isolated aPTT prolongation of 64 s. Although genetic testing has not been performed, her clinical history, repeatedly low FXI levels, and family background are highly suggestive of a congenital bleeding disorder. Further hematologic and genetic evaluation is warranted.

Discussion

FXI deficiency is an uncommon autosomal recessive bleeding disorder marked by significant clinical heterogeneity. In contrast to the bleeding severity in hemophilia A and B, the bleeding severity in FXI deficiency does not reliably correlate with plasma FXI levels, FXI antigen concentrations, APTT values, or specific genetic variants [1–3,10]. While individuals with severe deficiency (FXI <20%) are generally at increased risk of bleeding, many remain asymptomatic, whereas those with only mild to moderate reductions can experience clinically significant hemorrhage. This case illustrates the discrepancy, as our patient exhibited recurrent, substantial bleeding despite FXI levels ranging from less than 20% to over 50% during different admissions.

Recent evidence has demonstrated that patients with a bleeding phenotype exhibit impaired clot architecture, including reduced fibrin network density, as observed via laser scanning confocal microscopy [6]. Such findings may help explain bleeding variability in FXI deficiency, particularly in individuals with borderline or fluctuating factor levels.

Subgaleal hematomas are rare outside the neonatal period and are typically associated with traumatic deliveries. In older children, they are extremely uncommon and only sporadically reported in the literature [7,8]. Our case, involving a non-neonatal child with repeated subgaleal hemorrhage triggered by minor trauma, highlights a rare and clinically significant manifestation of FXI deficiency, complicated by a second undiagnosed hemostatic defect.

Fluctuating FXI activity – from less than 15% initially to more than 50% during subsequent admissions – posed a diagnostic challenge. This variability can reflect biological fluctuation, laboratory assay inconsistency, or factor consumption during active bleeding [9]. Importantly, even moderate FXI deficiency can be clinically relevant when compounded by additional coagulation abnormalities, such as von Willebrand disease.

The co-diagnosis of mild VWF deficiency in our patient likely contributed to the bleeding phenotype. VWF plays a central role in primary hemostasis by mediating platelet adhesion and stabilizing circulating factor VIII. Even partial VWF deficiency can worsen mucocutaneous or soft tissue bleeding when paired with intrinsic pathway defects, such as FXI deficiency [9,10].

Our case supports the growing recognition of congenital combined bleeding disorders – a rare but important diagnostic category characterized by the coexistence of 2 or more congenital coagulopathies. Ahmadi et al described 6 cases of combined bleeding disorders involving FXI or factor VII deficiency alongside von Willebrand disease. Five of these involved FXI deficiency in combination with either type 1 von Willebrand disease or low VWF levels. As noted in their report, such coagulopathies are uncommon and pose considerable diagnostic and therapeutic challenges [11].

Similarly, Asatiani et al analyzed a cohort of 986 patients with von Willebrand disease across 5 institutions in the United States and identified 16 individuals (1.5%) with additional co-inherited bleeding disorders, including FXI deficiency. These patients often required tailored, multi-modal treatment strategies because of the variable phenotypes and overlapping pathophysiology of the disorders involved [12].

The present case aligns with these findings, as our patient demonstrated reduced FXI activity and impaired VWF function, leading to a disproportionately severe bleeding phenotype not fully explained by either defect alone. This underscores the need for a comprehensive coagulation evaluation – including platelet function, VWF studies, and repeat factor assays – in pediatric patients presenting with unexplained or recurrent bleeding.

Therapeutically, FFP remains the cornerstone of FXI deficiency management, particularly in settings where FXI concentrate is unavailable. However, repeated FFP administration carries risks, such as volume overload and infectious transmission, and may not achieve optimal hemostasis [13,14]. In our case, adjunctive treatment with rFVIIa and tranexamic acid was effective in stabilizing bleeding. The use of rFVIIa, although off-label in FXI deficiency, has been reported in the literature and can be considered in life-threatening or refractory cases [5,13].

FXI inhibitors, though rare, must also be considered in patients who do not respond to replacement therapy. In the present case, a mixing study confirmed the absence of inhibitors.

Conclusions

This case highlights the diagnostic and therapeutic complexities of bleeding disorders in children, particularly when multiple coagulopathies coexist. Although FXI deficiency is often considered a mild bleeding disorder, its clinical manifestations can be unpredictable and severe – especially when accompanied by additional defects in hemostasis, such as VWF deficiency.

The patient’s presentation with recurrent, life-threatening subgaleal hematomas in the context of fluctuating FXI levels and reduced VWF activity underscores the importance of comprehensive hemostatic evaluation in pediatric patients with unusual or disproportionate bleeding. The observed discordance between laboratory findings and clinical severity further supports prior evidence that FXI levels alone are insufficient predictors of bleeding risk.

Management of such cases requires individualized, multi-modal therapeutic strategies. While FFP remains the mainstay of treatment, adjunctive agents, such as rFVIIa, and antifibrinolytics, such as tranexamic acid, can play a critical role in controlling hemorrhage. Given the rarity of congenital combined bleeding disorders, collaborative hematologic follow-up and, where available, genetic testing are recommended to guide future treatment decisions and procedural planning.

Ultimately, this case adds to the limited but growing body of literature documenting the co-expression of FXI deficiency and VWF abnormalities. It reinforces the need for heightened clinical vigilance and a multidisciplinary approach to diagnosing and treating children with complex bleeding phenotypes.