Concurrent Factor XI and Factor XII Deficiency with Suspected Diminished Factor XIII Activity in a Young Bangladeshi Male: A Rare Case Report

Technical Summary: Concurrent Factor XI and Factor XII Deficiency with Suspected Diminished Factor XIII Activity

Problem Statement
Hereditary coagulation factor deficiencies represent a heterogeneous group of rare bleeding disorders. While Factor XI (FXI) deficiency is associated with trauma- or surgery-related bleeding, and Factor XII (FXII) deficiency typically presents with laboratory abnormalities (prolonged activated partial thromboplastin time, or aPTT) without clinical bleeding, their concurrent occurrence is exceptionally rare. The coexistence of these deficiencies, particularly when complicated by a qualitative defect in Factor XIII (FXIII), poses a significant diagnostic challenge. This is especially true in resource-limited settings where access to specialized factor assays is restricted, often leading to prolonged diagnostic delays and misdiagnosis. This case report addresses the diagnostic complexity and management of a 23-year-old Bangladeshi male presenting with a lifelong history of prolonged bleeding, initially misdiagnosed as von Willebrand Disease, and ultimately found to have a triad of FXI, FXII, and suspected FXIII deficiencies.

Methodology
The study employs a retrospective case report design, adhering to CARE (CAse REport) guidelines. The methodology involved a systematic review of the patient's clinical history spanning nearly two decades (from age 3 to 23).

• Clinical Evaluation: The patient's history of bleeding following minor trauma (specifically a lip laceration) was documented, noting the absence of spontaneous bleeding, hemarthroses, or family history of bleeding disorders.
• Sequential Laboratory Investigation: A stepwise diagnostic approach was utilized over multiple years (2006, 2015, 2017) to rule out common coagulopathies.
  • Initial screening included platelet counts, bleeding time, coagulation time, Prothrombin Time (PT), and aPTT.
  • Specific factor assays were performed to exclude Hemophilia A (Factor VIII) and B (Factor IX), and von Willebrand Disease (vWF antigen).
  • Definitive testing included functional assays for FXI, FXII, and a qualitative assessment of FXIII activity.
• Literature Review: A systematic search was conducted using PubMed, Google Scholar, and ScienceDirect using MeSH terms for "Factor XI Deficiency" and "Factor XII Deficiency" to contextualize the rarity of the findings. Six relevant articles were identified and analyzed alongside the current case.
• Management: Therapeutic interventions were recorded, focusing on the use of Fresh Frozen Plasma (FFP) during acute bleeding episodes.

Key Results
The patient, a 23-year-old male, presented with a persistent, isolated prolongation of aPTT (ranging from 40 to 54 seconds) and a history of prolonged bleeding after minor mucosal injuries.

• Exclusion of Common Disorders: Repeated testing confirmed normal Factor VIII (70%), Factor IX (110%), and von Willebrand Factor antigen (102%), effectively ruling out Hemophilia A, Hemophilia B, and von Willebrand Disease.
• Definitive Diagnosis:
  • FXI Deficiency: Functional activity was measured at 23.20% (Reference: 70–120%), indicating a mild-to-moderate deficiency.
  • FXII Deficiency: Functional activity was measured at 31.20% (Reference: 70–120%), indicating a deficiency.
  • FXIII Deficiency: Qualitative assessment revealed diminished activity, though a formal quantitative assay was not performed due to resource constraints.
• Clinical Phenotype: The bleeding phenotype was characterized by delayed hemostasis following minor trauma (e.g., a 4-day bleeding episode from a lip laceration) but lacked spontaneous severe hemorrhage (e.g., intracranial or joint bleeding).
• Treatment Response: Hemostasis was successfully achieved in all documented acute episodes using Fresh Frozen Plasma (FFP) transfusions (2–3 units).

Key Contributions

1. First Reported Case in Bangladesh: To the authors' knowledge, this is the first documented case of concurrent congenital FXI and FXII deficiency with qualitatively diminished FXIII activity in Bangladesh, a region lacking a national registry for rare bleeding disorders.
2. Global Rarity: The literature review identified only a handful of cases globally involving concurrent FXI and FXII deficiency. This case is unique in its presentation of a potential third concurrent defect (FXIII), a combination not previously described in a single individual.
3. Diagnostic Algorithm Validation: The case underscores the necessity of a systematic, sequential investigation of all intrinsic pathway factors (including contact activation factors FXI and FXII) in patients with isolated prolonged aPTT and mild bleeding phenotypes, even when common causes like Hemophilia A/B are excluded.
4. Resource-Limited Context: The report highlights the significant diagnostic delay (nearly 20 years) caused by the unavailability of targeted factor assays in public referral centers in low- and middle-income countries, emphasizing the reliance on private tertiary institutions for definitive diagnosis.

Significance and Claims
The paper claims that this case demonstrates the critical importance of expanding the differential diagnosis for isolated prolonged aPTT beyond Hemophilia A and B to include rare intrinsic pathway defects like FXI and FXII.

• Pathophysiological Insight: The authors posit that while FXII deficiency alone does not typically cause clinical bleeding, its coexistence with FXI deficiency complicates the coagulation profile. The addition of diminished FXIII activity introduces a defect in clot stabilization, explaining the patient's specific history of delayed bleeding (clot formation occurred, but stability was lost).
• Clinical Management: The report confirms that FFP remains an effective treatment for acute hemostasis in such combined deficiencies in resource-limited settings, though it notes that FFP does not address the underlying diagnostic gap.
• Future Directions: The authors modestly conclude that while the clinical management was successful, the lack of molecular genetic analysis (e.g., whole exome sequencing of F11, F12, and F13A1/F13B loci) prevents a definitive genotype-phenotype correlation. They assert that molecular research is essential to understand the pathophysiology of such atypical combined deficiencies and to determine if they arise from shared genetic mechanisms or independent mutations.

The paper does not propose new experimental therapies or applications but serves as a cautionary and educational report for clinicians regarding the complexity of rare coagulopathies and the necessity for specialized diagnostic capabilities in developing nations.