Should a multimer test be done for a patient with a borderline VWF antigen activity ratio and normal RIPA test?

VWF Multimer Testing for Borderline VWF:RCo/VWF:Ag Ratio with Normal RIPA

Yes, a VWF multimer analysis should be performed for a patient with a borderline VWF:RCo/VWF:Ag ratio of 0.7 and normal RIPA test to properly classify the type of von Willebrand disease and guide appropriate treatment decisions. 1, 2

Rationale for Multimer Testing

A VWF:RCo/VWF:Ag ratio of 0.7 is at the borderline threshold that distinguishes between:

• Type 1 VWD (quantitative deficiency with normal multimer structure)
• Type 2 VWD variants (qualitative defects with abnormal multimer structure or function)

The diagnostic algorithm for VWD classification requires:

1. Initial screening tests (VWF:Ag, VWF:RCo, FVIII)
2. Calculation of VWF:RCo/VWF:Ag ratio
3. Additional specialized testing for borderline cases

Key Decision Points:

• VWF:RCo/VWF:Ag ratio <0.5-0.7 suggests Type 2 VWD variants (2A, 2B, 2M) 1
• Normal RIPA test helps rule out Type 2B VWD (which typically shows enhanced RIPA) 3
• Only multimer analysis can definitively distinguish between Type 1, Type 2A, and Type 2M VWD in borderline cases 4

Clinical Implications

The distinction between VWD types has critical treatment implications:

• Type 1 VWD: Typically responds well to desmopressin (DDAVP)
• Type 2A VWD: Variable response to DDAVP, may require VWF concentrates
• Type 2M VWD: Often requires VWF concentrates as DDAVP response may be inadequate
• Type 2B VWD: DDAVP is contraindicated due to risk of thrombocytopenia 2

With a borderline ratio of 0.7 and normal RIPA, the differential diagnosis includes:

• Type 1 VWD with mild functional discordance
• Type 2M VWD with preserved multimer structure but impaired function
• Acquired von Willebrand syndrome (AVWS)

Multimer Analysis Benefits

Multimer analysis provides crucial information by revealing:

1. Normal multimer distribution (Type 1 VWD)
2. Loss of high-molecular-weight multimers (Type 2A or AVWS)
3. Normal multimer structure but functional defect (Type 2M) 5

This test is particularly valuable in borderline cases where the VWF:RCo/VWF:Ag ratio alone cannot definitively classify the VWD type 4.

Potential Pitfalls

Several factors can affect test interpretation:

• Blood type O is associated with 25% lower VWF levels
• Stress, inflammation, or pregnancy can elevate VWF levels
• Sample processing issues can affect results
• Laboratory variability in VWF:RCo assay (10-30% coefficient of variation) 1

Algorithm for Approach

For a patient with VWF:RCo/VWF:Ag ratio of 0.7 and normal RIPA:

1. Perform VWF multimer analysis to assess multimer distribution pattern
2. Interpret results:
   • Normal multimer pattern → Type 1 VWD or mild Type 2M
   • Abnormal pattern with loss of high-molecular-weight multimers → Type 2A or AVWS
   • Abnormal pattern with smeared appearance but preserved large multimers → Variant Type 2M 6
3. Consider DDAVP challenge test to assess treatment response
4. Consider genetic testing if family history suggests hereditary VWD

Conclusion

The borderline VWF:RCo/VWF:Ag ratio of 0.7 represents a diagnostic challenge that requires multimer analysis for proper classification. While this ratio is at the upper threshold for suspecting Type 2 VWD, the normal RIPA test narrows the differential diagnosis. Multimer analysis is essential to distinguish between Type 1, Type 2M, and other potential diagnoses, which will directly impact treatment decisions and clinical outcomes 2, 4, 5.