What is the initial workup for an inherited blood clotting disorder?

Initial Workup for Inherited Blood Clotting Disorders

Begin with a structured bleeding history using validated screening questions, followed by initial hemostasis tests (CBC, PT, PTT) and von Willebrand disease-specific assays (VWF:Ag, VWF:RCo, FVIII), as these three VWF tests are essential for diagnosing the most common inherited bleeding disorder and should be ordered together during the initial evaluation. 1

Clinical Evaluation: Bleeding History Assessment

Preoperative Screening Questions (for asymptomatic patients)

Ask these three initial questions to identify bleeding risk 2:

• Have you experienced excessive bleeding from minor wounds or surgical procedures?
• Do you have a family history of bleeding disorders?
• Have you had unexplained bruising or bleeding episodes?

Detailed Bleeding History (for positive screens or symptomatic patients)

If any initial question is positive, obtain detailed responses to nine additional bleeding-specific questions covering 2:

• Mucocutaneous bleeding patterns (epistaxis, gingival bleeding, menorrhagia)
• Post-surgical or post-traumatic bleeding complications
• Spontaneous bleeding episodes
• Family history details of bleeding disorders

An increasing number of positive responses directly correlates with higher likelihood of an inherited bleeding disorder. 2

Physical Examination Findings

Look specifically for 2:

• Bleeding manifestations: Ecchymoses, hematomas, petechiae, active bleeding sites
• Syndromic features: Joint and skin laxity (Ehlers-Danlos syndrome), telangiectasias (hereditary hemorrhagic telangiectasia)
• Secondary causes: Jaundice or splenomegaly (liver disease), gynecologic lesions
• Platelet morphology clues: Consider peripheral smear for platelet size abnormalities 3

Initial Laboratory Testing

First-Tier Hemostasis Tests

Order these basic coagulation studies first 2, 1:

• Complete blood count (CBC) - identifies thrombocytopenia or thrombocytosis
• Prothrombin time (PT) - screens for extrinsic pathway defects
• Activated partial thromboplastin time (PTT) - screens for intrinsic pathway defects

These tests do not diagnose von Willebrand disease but can identify coagulation factor deficiencies or platelet count abnormalities. 2

Essential von Willebrand Disease Testing

All three of these tests must be ordered simultaneously for initial VWD evaluation 1:

1. VWF antigen (VWF:Ag) - measures quantity of VWF protein
2. VWF ristocetin cofactor activity (VWF:RCo) - measures VWF function
3. Factor VIII coagulant activity (FVIII) - measures FVIII levels (often reduced in VWD)

Normal ranges are 50-200 IU/dL for all three tests; VWF:RCo <30 IU/dL confirms VWD diagnosis. 1

Critical Test Interpretation

• VWF:RCo/VWF:Ag ratio <0.5-0.7 suggests qualitative VWD (Type 2) rather than quantitative deficiency (Type 1) 2, 1
• VWF:RCo 30-50 IU/dL may still represent VWD if clinical or family history supports diagnosis 1

Sample Handling Requirements

Improper sample handling causes false results 1:

• Transport samples at room temperature (not refrigerated)
• Separate plasma from blood cells promptly at room temperature
• If testing delayed >2 hours, freeze at ≤-40°C

Factors That Elevate VWF Levels (Causing False Negatives)

Consider these confounders when interpreting results 1:

• Patient stress or recent exercise
• Inflammatory illness or infection
• Pregnancy
• Oral contraceptive use
• Blood type O individuals have 25-30% lower baseline VWF levels 1

Repeat testing may be necessary due to high test variability (VWF:RCo coefficient of variation 10-30%). 1

Advanced Testing for Abnormal Initial Results

When to Proceed with Specialized Testing

Order these if initial VWD tests show abnormalities 2, 4, 1:

• VWF multimer analysis - determines VWD subtype; technically complex, requires abnormal initial results to justify 2, 1
• Flow cytometry - evaluates platelet glycoproteins (GPIIb/IIIa, GPIb, GPIb/IX, GPIa/IIa, GPIV, GPVI) for inherited platelet disorders 4, 3
• Light transmission aggregometry (LTA) - tests platelet function with standard agonists (ADP, collagen, epinephrine, ristocetin) 3
• Transmission electron microscopy - assesses platelet granule content (α and δ granules) for storage pool disorders 4
• Genetic testing - identifies specific mutations in confirmed cases 4

Platelet Disorder Considerations

Do not exclude inherited platelet function disorders based solely on borderline thrombocytopenia, as several disorders present with reduced platelet counts. 4

Specific disorders to consider 4:

• Bernard-Soulier syndrome (affects GPIb/IX, abnormal ristocetin response)
• GATA1-related macrothrombocytopenia
• Familial platelet disorder with AML propensity (requires surveillance)

Common Pitfalls to Avoid

• Never rely on a single test - all three initial VWF tests are mandatory 1
• Never label as "bleeding disorder of unknown cause" prematurely - this closes diagnostic pathways and misses treatable conditions 4
• Never ignore inconclusive results - pursue specialized testing rather than stopping at first-tier tests 4
• Never test during acute illness or stress - physiologic VWF elevation causes false negatives 1
• Separate repeat testing by ≥1 month - allows clearance of acquired interfering factors 4
• Never forget ABO blood type - Type O patients have inherently lower VWF levels 1

Rare Autosomal Recessive Disorders

For patients with negative VWD testing but prolonged PT/PTT, consider rare factor deficiencies 5, 6:

• Prevalence 1:500,000 to 1:2,000 in general population
• More common in consanguineous populations
• Include deficiencies of factors II, V, VII, X, XI, XIII, fibrinogen
• Require specialized coagulation factor assays for diagnosis