The diagnosis is in the ratio, not the level alone.
A low von Willebrand level tells you there may be disease; the activity-to-antigen ratio tells you which kind. A ratio below 0.7 points to a qualitative type 2 defect — protein that is functionally defective, not simply reduced — and that distinction changes treatment. Collagen binding adds sensitivity to the loss of high-molecular-weight multimers that ristocetin cofactor can miss. elixir represents Technoclone's Technozym vWF:Ag (antigen) and vWF:CBA (collagen binding) assays as its UK partner, and advises on the vWF activity assay — a GPIb-based method from outside the Technoclone line — that completes the activity-to-antigen picture.
How von Willebrand factor holds a platelet at the wound.
Under shear, the largest von Willebrand multimers unfold and tether platelets through the GPIb receptor. Lose the high-molecular-weight multimers — as in type 2A — and that tethering fails even when the antigen looks adequate. This is why a single level is not enough.
Under shear, a high-molecular-weight von Willebrand multimer unfolds and tethers platelets through the GPIb receptor. Loss of the largest (high-molecular-weight) multimers — the lesion in type 2A — breaks this tethering even when the antigen level looks adequate.
What the published data says — and how the methods compare.
von Willebrand activity is measured several ways, and the methods do not all agree to the same degree. The figures below are presented on the shared, defensible axes — between-method variability, correlation against the legacy reference, and sensitivity to multimer loss — with the named comparator alongside.
Illustrative — schematic, not data
On the activity-to-antigen ratio scale (0–1.5), a worked point at 0.90 sits above the 0.70 cut-off. A ratio below 0.7 reclassifies a low level from a simple quantitative (type 1) deficiency to a qualitative (type 2) defect; type 1 von Willebrand disease is confirmed at a level below 0.30 IU/mL regardless of bleeding — or 0.30–0.50 IU/mL in a patient with abnormal bleeding — with a preserved activity-to-antigen ratio.
The ratio is a typing tool, not a single positive-or-negative test: collagen binding can miss type 2M, so a GPIb-based activity assay is needed alongside — the methods are complementary. Technoclone does not publish a lower limit of quantitation or CV for these kits, so we do not quote one — a disclosed uncertainty beats a brochure figure, and we will establish your own values on your platform rather than borrow theirs.
7–24 % inter-lab CV
Inter-laboratory CV runs from 7% to 24% across von Willebrand activity methods — the spread sits with the choice of method, not with any one assay. Sensitivity to the loss of high-molecular-weight multimers is highest for collagen binding and for the GPIb-based activity assays.
The 7–24% range is attributable to the various methods in use, not to ristocetin cofactor specifically. The spread widens at low VWF levels, where between-assay disagreement and imprecision are greatest — precisely the range that matters most for diagnosis.
r = 0.927
A GPIb-based activity assay (vWF:GPIbM) correlates with the legacy ristocetin cofactor assay (vWF:RCo) at a Pearson r of 0.927. The newer activity methods track the older reference closely while avoiding ristocetin's poor reproducibility at low levels.
Correlation is method-to-method agreement, not a claim that either assay is the definitive standard; vWF:RCo is the legacy reference, not current best practice.
Collagen binding (vWF:CBA) reached 100% sensitivity for type 2A and type 2B disease at a CBA-to-antigen ratio of 0.6 (type III collagen substrate) in Flood's variant-VWD cohort. Because the largest multimers carry most of the collagen-binding capacity, their loss shows up here even when the antigen reads near-normal — the same lesion the multimer figure above describes.
Collagen binding is method-dependent — type I and type III collagen substrates are not interchangeable — and vWF:CBA does not detect type 2M, where a GPIb-based activity assay is required as well. The two are complementary, not substitutes.
A panel, represented and advised — not a single number.
von Willebrand testing is a panel by design: antigen for quantity, an activity assay for function, and collagen binding to catch the multimer loss the activity assay may not. elixir advises on which combination answers your clinical question.
vWF activity (GPIb-based)
Functional activity gives the activity-to-antigen ratio that separates quantitative type 1 from qualitative type 2 disease. GPIb-based activity assays sit outside the Technoclone line — we advise on pairing one with the antigen and collagen-binding assays.
Technozym vWF:Ag
Antigen — the amount of protein present. The denominator of the diagnostic ratio, and the measure behind the type 1 threshold: below 0.30 IU/mL regardless of bleeding, or 0.30–0.50 IU/mL with abnormal bleeding.
Technozym vWF:CBA
Collagen binding. Sensitive to high-molecular-weight multimer loss — 100% for type 2A and 2B at a CBA/Ag ratio of 0.6 in Flood's published cohort.
- We advise on which substrate or assay suits the question in front of you.
- We set the comparison fairly: the legacy ristocetin cofactor assay (vWF:RCo) is the historical reference these methods are measured against, and we say where each method is the better answer for your laboratory.
- Where typing is ambiguous, we advise on the complementary assay needed — for example a GPIb-based activity test to cover type 2M, which collagen binding alone will miss.
- Where interpretation of multimer structure or assay behaviour is needed, we advise directly against the published evidence, with the reasoning shown — no black-box scoring.
Where another method or assay is the better answer for your laboratory, we say so. To discuss the panel, email hello@elixir-consulting.co.uk.
Every figure on this page, sourced.
Favaloro EJ, et al. Differential sensitivity of von Willebrand factor activity assays to reduced VWF molecular weight forms: a large international cross-laboratory study. Thromb Res 2018;166:96-105. Inter-laboratory CV 7–24% across von Willebrand activity methods. PMID 29727738
Friedman KD, et al. Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays. Res Pract Thromb Haemost 2024;8(4):102422. Pearson r = 0.927 (vWF:GPIbM vs automated vWF:RCo; reportable range validated to ~4 IU/dL). PMC11152683
Higgins & Goodwin. Am J Hematol 2019;94(4):496-503. GPIb-based activity assays show lower CV and higher reproducibility than ristocetin cofactor at low VWF levels. PMID 30592326
Flood VH, et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem 2013;59(4):684–691. 100% sensitivity for type 2A and 2B at CBA/Ag ratio 0.6 (type III collagen) in the study cohort. PMC3852672
James PD, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021;5(1):280. Activity/antigen ratio < 0.7 for type 2; type 1 VWF < 0.30 IU/mL regardless of bleeding, or 0.30–0.50 IU/mL with abnormal bleeding. PMC7805340
Tell us which part of the von Willebrand panel you need.
Send a short note about the assays, the typing question, or the reagent in front of you. We will reply with how we would approach it, what it would involve, and an honest quote — usually within two working days.