Atiq F, Blok R, van Kwawegen CB, et al. Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF. Blood. 2025;146(3):369–381.
Clinical Question
Among patients with persistent VWF activity of 30–50 IU/dL and VWF antigen above 50 IU/dL, is this mild qualitative phenotype more closely aligned with quantitative low VWF or with classical type 2 VWD—particularly type 2M when the activity-to-antigen ratio is below 0.7?
Why This Study Matters
Clinicians traditionally distinguish two broad VWF abnormalities:
- quantitative deficiency — too little VWF
- qualitative deficiency — VWF is present but functions abnormally
The 2021 ASH/ISTH/NHF/WFH guideline uses a platelet-dependent VWF activity-to-antigen ratio below 0.7 as a signal to evaluate for type 2 VWD. But does the same ratio carry the same biological meaning when VWF activity is mildly reduced at 45 IU/dL as when it is severely reduced at 10 IU/dL?
This matters because some patients have:
- persistent VWF activity between 30 and 50 IU/dL
- VWF antigen above 50 IU/dL
- clinically important bleeding
The investigators termed this pattern qualitative low VWF, or low VWF–QL.
The deeper question is not simply whether this phenotype exists. It is whether the activity-to-antigen ratio should be used to subdivide mild VWF deficiency at all.
A ratio can identify disproportionate function. It does not necessarily identify mechanism.
Background
Low VWF has traditionally been viewed as a quantitative disorder, with VWF antigen and activity reduced proportionately.
However, previous cohorts included patients whose diagnosis rested on a persistent reduction in VWF activity rather than antigen. These patients had normal VWF antigen but mild functional impairment.
Under a rigid laboratory interpretation, patients with:
- reduced VWF activity
- preserved VWF antigen
- a ratio below 0.7
- preserved high-molecular-weight multimers
might progress toward evaluation for type 2M VWD.
But whether mild functional abnormalities in the 30–50 IU/dL range share the genetics, pathophysiology, bleeding phenotype, and treatment response of classical type 2 VWD had not been established.
Study Design
The low-VWF analysis included 214 patients drawn from:
- the Low VWF in Ireland Cohort: 118
- the Low VWF Erasmus MC cohort: 96
A separate cohort of 295 patients with type 2A, 2B, or 2M VWD from the Willebrand in the Netherlands study served as the classical type 2 comparator.
Enrollment in the low-VWF cohorts required a historical VWF antigen and/or activity in the 30–50 IU/dL range together with an abnormal ISTH-BAT.
The low-VWF cohort was divided into:
- low VWF–QT: VWF antigen 30–50 IU/dL
- low VWF–QL: VWF activity 30–50 IU/dL with VWF antigen above 50 IU/dL
Laboratory and mechanistic assessments included, in selected participants:
- VWF antigen
- platelet-dependent VWF activity
- VWF collagen binding
- factor VIII
- VWF propeptide
- multimer analysis
- VWF sequencing
- desmopressin response
- platelet aggregation and nucleotide studies
Principal Analyses
The investigators asked:
- How frequently was low VWF–QL identified within these selected symptomatic cohorts?
- Did patients with low VWF–QL have clinically important bleeding?
- Did the 0.7 activity-to-antigen ratio distinguish bleeding severity?
- Was low VWF–QL similar to quantitative low VWF?
- Was the subgroup with ratios below 0.7 biologically similar to classical type 2 VWD, particularly type 2M?
- Should mild low-VWF phenotypes continue to be subdivided by the ratio?
Key Results
1. Low VWF–QL was common within these selected symptomatic cohorts
Among 214 low-VWF patients:
- 103 patients (48.1%) had VWF activity between 30 and 50 IU/dL with VWF antigen above 50 IU/dL
- 111 patients (51.9%) had quantitative low VWF
This does not estimate the prevalence of low VWF–QL in the general population or among all people with mildly reduced VWF activity. Both cohorts were referred, bleeding-enriched populations.
The activity-to-antigen difference was persistent over a mean interval of approximately 8.2 years.
In 63 of 103 patients (61.2%), the functional abnormality was demonstrated by at least two VWF activity assays. Forty patients were classified using one assay type, including 16 with persistently reduced VWF ristocetin cofactor activity alone.
Thus, assay artifact is unlikely to explain the entire phenotype, although assay heterogeneity remains an important limitation.
2. Normal VWF antigen did not exclude clinically important bleeding
Patients with low VWF–QL had ISTH-BAT scores similar to those with quantitative low VWF.
Among 75 women with low VWF–QL:
- 32 (42.7%) had ISTH-BAT scores of 10 or higher
There were no significant differences between low VWF–QL and low VWF–QT in total BAT score or individual BAT domains.
In the LVEMC longitudinal follow-up subgroup:
- 96 patients were followed
- 40 had low VWF–QL
- mean follow-up was 6.6 ± 3.4 years
Patients with low VWF–QL had a higher recorded incidence of:
- bleeding during follow-up
- bleeding requiring treatment
than those with quantitative low VWF.
This was an observational record-based follow-up analysis, not a prospectively designed intervention study, and no adjusted hazard model was reported.
3. The 0.7 ratio threshold identified laboratory subgroups but not bleeding severity
Among the 103 patients with low VWF–QL:
- 51 had an activity-to-antigen ratio below 0.7
- 52 had a ratio of 0.7 or higher
ISTH-BAT scores did not differ significantly between these groups.
When analysis was restricted to the newer VWF:GPIbM assay:
- 25 of 150 low-VWF patients had a GPIbM-to-antigen ratio below 0.7
- bleeding scores again did not differ between those below and above the threshold
The ratio therefore identified disproportionate activity loss but did not discriminate bleeding severity, as measured by total ISTH-BAT, within this selected low-VWF cohort.
This does not mean that the ratio has no diagnostic value. It remains useful for recognizing a qualitative laboratory pattern and prompting multimer analysis or subtype evaluation.
4. Low VWF–QL resembled quantitative low VWF more than classical type 2 VWD
The paper’s clinical conclusion is not that low VWF–QL should become a new permanent subtype.
Rather, low VWF–QL and low VWF–QT were broadly similar in:
- bleeding phenotype
- surrogate synthesis and clearance markers
- desmopressin responsiveness
- overall genetic findings
This similarity underpins the authors’ argument that there is little clinical rationale for subdividing patients in the 30–50 IU/dL range into qualitative and quantitative low VWF based on the ratio alone.
The practical direction is therefore lumping, not splitting.
5. The low-ratio subgroup differed from classical type 2 VWD
The clearest mechanistic comparison involved patients with low VWF and a VWF:GPIbM-to-antigen ratio below 0.7.
Among the small sequenced subgroup:
- 5 of 10 patients with low VWF and a ratio below 0.7 had likely pathogenic VWF variants
- 226 of 228 patients (99.1%) in the classical type 2 comparator group had likely pathogenic variants
No classical type 2 sequence variants were identified in the sequenced low-VWF subgroup with GPIbM-to-antigen ratios below 0.7.
However, this genetic comparison rests on a very small low-VWF denominator and was not available across the entire cohort.
6. Preserved multimers focused the comparison on type 2M
No loss of high-molecular-weight multimers was observed among low-VWF patients with activity-to-antigen ratios below 0.7.
This made classical type 2A or 2B less likely and focused the direct comparison on type 2M.
Compared with type 2M, the low-VWF low-ratio subgroup differed in:
- ABO distribution
- sex distribution
- frequency and pattern of VWF variants
- surrogate markers of synthesis/secretion
- surrogate markers of clearance
- desmopressin response
These findings support the authors’ conclusion that mild low-VWF functional abnormalities are not simply equivalent to classical type 2M VWD.
But the comparator groups were unmatched and differed substantially in baseline severity, demographics, and cohort origin. Some observed differences may reflect the contrast between activity levels of 30–50 IU/dL and activity below 30 IU/dL rather than a wholly separate biological entity.
7. The mechanistic data suggest endothelial production or processing of functionally reduced VWF
Compared with classical type 2 VWD, low VWF–QL showed less marked abnormalities in the surrogate ratios used to assess:
- VWF synthesis or secretion
- VWF clearance
After desmopressin, patients with low VWF–QL released substantial amounts of VWF. However, the activity-to-antigen ratio remained reduced in the low-ratio subgroup.
These findings support the hypothesis that altered endothelial production, intracellular processing, post-translational modification, or secretion contributes to the release of functionally reduced VWF.
The study did not directly examine endothelial cells, glycosylation, intracellular trafficking, or biosynthesis. The endothelial mechanism is therefore a biologically plausible inference from surrogate markers and desmopressin responses—not a directly demonstrated cellular lesion.
8. Desmopressin responses were much better than in type 2M
In the tested subgroup, complete desmopressin responses were substantially more frequent in low VWF with a GPIbM-to-antigen ratio below 0.7 than in type 2M VWD.
Patients with low VWF–QL also showed strong peak and sustained VWF activity responses after desmopressin.
These findings support the clinical usefulness of a desmopressin trial. They do not eliminate the need for individual response testing, assessment of durability, or attention to contraindications.
Strengths
- Relatively large, deeply phenotyped multicenter low-VWF cohort
- Persistence of the activity-to-antigen discrepancy over approximately eight years
- Reproduction of the functional abnormality with more than one assay in most low VWF–QL patients
- Direct comparison with quantitative low VWF
- Direct comparison with pooled type 2 VWD and a specific type 2M subgroup
- Integration of bleeding phenotype, genetics, multimer analysis, surrogate pathophysiology, and treatment response
- Inclusion of longitudinal bleeding follow-up in one cohort
- Evaluation of platelet and coagulation factor abnormalities as alternative explanations
- Direct challenge to the assumption that a ratio cutoff necessarily identifies a mechanism
Limitations
- Strong selection bias: LoVIC and LVEMC were specialist, symptomatic cohorts requiring an abnormal BAT. The study cannot estimate population prevalence, bleeding penetrance, or diagnostic specificity.
- Comparator non-equivalence: The type 2 cohort differed in sex, ABO distribution, cohort origin, enrollment criteria, and severity of VWF deficiency.
- Small mechanistic subgroups: Key genetic, VWF propeptide, desmopressin, and type 2M comparisons often involved only 10–25 low-VWF patients.
- Assay heterogeneity: VWF:RCo, antibody-based activity assays, VWF:GPIbM, VWF:GPIbR, and VWF:CB were used across cohorts and time.
- Incomplete genetic testing: Sequencing was not performed in the LVEMC cohort and was limited in several key subgroups.
- Predominantly female cohort: Women made up 85% of the low-VWF cohort.
- Limited statistical adjustment: The analysis relied heavily on t tests, χ² tests, and log-rank tests with little multivariable adjustment.
- Multiple comparisons: Numerous subgroup, mechanistic, and bleeding analyses were performed without broad correction for multiple testing.
- Record-based longitudinal outcomes: Follow-up bleeding may have been affected by surveillance, documentation, treatment, and referral differences.
- Indirect mechanistic measures: FVIII:C-to-antigen and VWF propeptide-to-antigen ratios cannot directly distinguish synthesis, secretion, processing, glycosylation, proteolysis, and clearance.
- Threshold-dependent entity construction: A patient with activity 49 IU/dL and antigen 51 IU/dL is labeled low VWF–QL, whereas activity 49 IU/dL and antigen 49 IU/dL is labeled low VWF–QT. Biology may be continuous across that boundary.
- No outcome-based validation: The study did not show that relabeling patients improves bleeding prediction, treatment selection, procedural outcomes, counseling, or quality of life.
Why This Paper Changes How We Think
This paper does not simply identify a new laboratory pattern.
It challenges the clinical meaning assigned to a familiar ratio.
The activity-to-antigen ratio is useful because it detects discordance between VWF quantity and function. But in the mild 30–50 IU/dL range, the ratio did not separate patients by bleeding severity and did not identify the genetics, clearance abnormalities, or desmopressin behavior typical of classical type 2 VWD.
The most important result is therefore not:
“Qualitative low VWF is a new subtype.”
It is:
Within the mild low-VWF range, there may be little clinical rationale for subdividing patients according to whether the activity-to-antigen ratio lies above or below 0.7.
The authors distinguish low VWF–QL from classical type 2 VWD while arguing that low VWF–QL and low VWF–QT should not necessarily be separated from one another.
That is the paper’s practical reversal:
The ratio identifies a pattern, but in mild disease it may not justify a different label.
The mechanistic implications are equally important. The study suggests that some patients secrete VWF that is quantitatively near normal but functionally reduced, often without an identifiable classical VWF variant. This raises the possibility of abnormalities in endothelial processing, glycosylation, secretion, or other modifiers outside the VWF coding sequence.
A disorder of VWF function may therefore not always be, in the narrow sense, a disorder caused by a pathogenic VWF variant.
For a mechanism-based curriculum, this is the most provocative lesson in the paper.
Guideline Implications
The 2021 ASH/ISTH/NHF/WFH guideline uses a platelet-dependent activity-to-antigen ratio below 0.7 as a trigger for further type 2 evaluation. It is not stand-alone proof of type 2 VWD.
This study suggests that, in patients with VWF activity between 30 and 50 IU/dL:
- a ratio below 0.7 should prompt subtype evaluation rather than automatic type 2 assignment
- preserved high-molecular-weight multimers make classical type 2A and 2B less likely and shift the differential toward type 2M
- mild low-ratio phenotypes may differ substantially from classical type 2M in genetics, pathophysiology, and desmopressin response
- the ratio did not distinguish bleeding severity within the low-VWF cohort
- low VWF–QL and low VWF–QT appeared sufficiently similar that subclassifying them by ratio may add little clinical value
- integrated interpretation remains essential, incorporating absolute VWF activity, antigen, multimer pattern, bleeding phenotype, family history, genetics, and desmopressin response
A reduced ratio should be treated as a signal for mechanistic evaluation, not as mechanistic proof.
Clinical Pearls
- Normal VWF antigen does not exclude clinically important functional VWF impairment in a selected symptomatic patient.
- In these bleeding-enriched cohorts, nearly half of low-VWF patients had activity of 30–50 IU/dL with antigen above 50 IU/dL.
- The 0.7 ratio threshold identified laboratory subgroups but did not distinguish ISTH-BAT bleeding severity.
- Only a minority of the overall low-VWF cohort had a modern VWF:GPIbM-to-antigen ratio below 0.7.
- The low-ratio low-VWF subgroup differed from classical type 2M, but key genetic and mechanistic comparisons were small and unmatched.
- Low VWF–QL and quantitative low VWF were broadly similar, supporting the authors’ argument against subdividing mild low VWF by ratio alone.
- Indirect data suggest endothelial production or processing of functionally reduced VWF, but the cellular mechanism was not directly demonstrated.
- In tested patients, desmopressin responses were substantially better than in type 2M, making a formal desmopressin trial clinically useful.
- A laboratory ratio identifies discordance. It does not, by itself, identify the disease mechanism.
Bottom Line
In two selected symptomatic low-VWF cohorts, nearly half of patients had persistent VWF activity between 30 and 50 IU/dL despite antigen levels above 50 IU/dL. These patients had bleeding scores comparable to those with quantitative low VWF, and a longitudinal subgroup experienced more recorded bleeding and treatment-requiring bleeding.
Among patients with GPIbM-to-antigen ratios below 0.7, genetic, multimer, surrogate synthesis and clearance, and desmopressin findings differed from classical type 2 VWD—particularly type 2M—although the key mechanistic subgroups were small, unmatched, and differed in baseline disease severity.
The study therefore supports two related conclusions:
- A ratio below 0.7 in the mild 30–50 IU/dL range should trigger further evaluation rather than automatic type 2 classification.
- The study found little clinical rationale for subdividing mild low VWF into qualitative and quantitative categories based on the ratio alone.
The paper’s direction is not to create another subtype. It is to trust the ratio less when the functional defect is mild.
Where This Fits in the VWD Module
This paper creates productive tension with several parts of the module:
- Interpreting VWF Laboratory Tests — reinforces the value of calculating the activity-to-antigen ratio but challenges the assumption that crossing 0.7 establishes mechanism.
- Classification as a Tool — shows that classification can organize a phenotype without perfectly mapping onto biology.
- Low VWF versus Type 1 VWD — supports the heterogeneity of mild VWF deficiency while arguing against further subdivision by ratio alone.
- Where Diagnostic Thresholds Break Down — demonstrates that the meaning of a cutoff may depend on the absolute severity of the abnormality.
- Genetics of VWD — highlights that functional VWF impairment may occur without an identifiable classical VWF sequence variant.
- Endothelial Biology of VWF — raises the possibility that mild qualitative dysfunction reflects endothelial processing, secretion, glycosylation, or other noncoding and extragenic modifiers.
- Reading Clinical Practice Guidelines — illustrates why a guideline threshold should initiate reasoning rather than terminate it.
- Self-assessment Sections 3 and 4 — requires an explicit caveat: a ratio below 0.7 appropriately triggers type 2 evaluation, but in the mild 30–50 IU/dL range it does not, by itself, establish classical type 2 VWD.
This paper and the age-dependent BAT study form a particularly important pair:
- the BAT study shows that the phenotype instrument is age and opportunity dependent
- this study shows that the laboratory ratio may not map consistently onto mechanism in mild disease
Together, they show why the diagnostically ambiguous 30–50 IU/dL range cannot be resolved by thresholds alone.
Discuss
- Is low VWF–QL a discrete entity, or the mild end of a continuous spectrum?
- How much of the difference from type 2 VWD reflects comparison with more severe disease?
- Should the significance of the 0.7 ratio depend on the absolute VWF activity level?
- Which assay should define a mild functional defect: VWF:GPIbM, VWF:GPIbR, VWF:RCo, VWF:CB, or concordant abnormalities across assays?
- Does preserved multimer structure plus a ratio below 0.7 necessarily imply type 2M?
- How should a patient with activity 45 IU/dL, antigen 55 IU/dL, normal multimers, and significant bleeding be labeled today?
- Would labeling the patient low VWF–QL rather than type 2M change treatment or counseling?
- Does the stronger desmopressin response prove a different mechanism, or simply reflect milder disease?
- What experiment would directly demonstrate abnormal endothelial biosynthesis or post-translational processing?
- What outcome should validate classification: future bleeding, procedural bleeding, treatment response, genotype, or patient-reported outcomes?