What tests are required to diagnose a bleeding disorder of unknown cause?

Diagnostic Tests Required for Bleeding Disorders of Unknown Cause (BDUC)

To diagnose a bleeding disorder of unknown cause, a comprehensive two-tiered testing approach is required, starting with first-line tests to rule out common bleeding disorders, followed by second-line tests if initial results are normal. 1

First-Line Testing (Required for All Patients)

• Basic Coagulation Tests:

  • Activated partial thromboplastin time (APTT) - performed by 100% of specialists 1
  • Prothrombin time (PT) - performed by 100% of specialists 1
  • Fibrinogen levels (Clauss and/or derived) - performed by 90% in first-line testing 1

• Factor Assays:

  • Von Willebrand factor (VWF) antigen and function - performed by 84% of specialists 1, 2
  • Factor VIII, IX, and XI assays - performed by 62% of specialists 1

• Additional Initial Laboratory Testing:

  • Full blood count (FBC) - performed by 65% of specialists 1
  • Iron studies/ferritin - performed by 69% of specialists 1
  • ABO blood group - performed by 70% of specialists 1
  • Thyroid function testing - performed by 45% of specialists 1

Second-Line Testing (If First-Line Tests Are Normal)

• Extended Coagulation Factor Testing:

  • Factor II (FII) - performed by 52% of specialists 1
  • Factor V (FV) - performed by 55% of specialists 1
  • Factor VII (FVII) - performed by 54% of specialists 1
  • Factor X (FX) - performed by 53% of specialists 1
  • Factor XIII (FXIII) - performed by 60% of specialists 1

• Platelet Function Testing:

  • Platelet function testing (light transmission aggregometry, platelet nucleotides, or release assay) - performed by 60% of specialists as second-line testing 1
  • Platelet function analyzer (PFA 100/200) - performed by 37% of specialists 1
  • Platelet flow cytometry - performed by 42% of specialists 1

• Advanced Hemostatic Testing:

  • Fibrinolysis assays - performed by 38% of specialists 1
  • Thrombin generation assay (TGA) - performed by 28% of specialists 1
  • Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) - performed by some specialists 1
  • Genetic testing - performed by 48% of specialists as second-line testing 1

Clinical Assessment Requirements

• Bleeding Assessment Tool (BAT) - used by 80% of specialists, with the ISTH BAT being most common (73%) 1, 2
• Family history assessment - performed by 98% of specialists 1
• Medication history - 88% of specialists record over-the-counter medication use or NSAID use 1
• Hypermobility assessment - performed by 55% of specialists 1

Diagnostic Algorithm

1. Perform complete first-line testing to rule out common bleeding disorders 2, 3
2. If first-line tests are normal but bleeding history is convincing, proceed to second-line testing 1, 3
3. If all tests remain normal despite a convincing bleeding history, diagnose as BDUC 4, 5

Common Pitfalls and Caveats

• Iron deficiency may be overlooked despite being common in people with bleeding disorders - ensure iron studies are included 1, 3
• Preanalytical variables can affect platelet function testing - medication use, sample processing, and patient stress level must be controlled 2, 5
• Bleeding assessment tools should guide testing strategy but not be the sole determinant for ordering tests 1, 2
• Hypermobility assessment is often neglected despite its association with bleeding symptoms - include Beighton score in initial assessment 1, 3
• ABO blood group is frequently tested but group-specific VWF reference ranges are not recommended 1
• Platelet function testing can be challenging and resource-intensive - standardize methodology to minimize preanalytical variability 1, 5

BDUC represents a diagnosis of exclusion that can only be made after thorough testing has ruled out all known causes of bleeding disorders, with up to 60-70% of patients with mild-moderate bleeding phenotypes falling into this category 2, 4.