Van Kwawegen CB, Atiq F, Edenburg D, et al. Genetic variants, thrombocytopenia, and clinical phenotype of type 2B von Willebrand disease: a median 16-year follow-up study. J Thromb Haemost. 2024 Dec;22(12):3460-3472.
Clinical Question
What are the determinants of thrombocytopenia in type 2B von Willebrand disease (VWD), and how does genotype influence clinical phenotype?
Background
Type 2B VWD results from gain-of-function mutations in exon 28 of the von Willebrand factor (VWF) gene, causing amino acid substitutions in the A1 domain that increase VWF affinity for platelet GPIbα receptors. This spontaneous VWF-platelet binding leads to thrombocytopenia in many patients. This study aimed to fill two gaps in the understanding of type 2B VWD.
The first was the pattern in which thrombocytopenia occurred. Previous studies found 30% of patients had baseline thrombocytopenia. However, long-term data on thrombocytopenia incidence and associated risk factors were lacking. Case studies suggested endothelial activation episodes (pregnancy, delivery, DDAVP infusion, infection) influence platelet counts, with 76% of exposed patients developing transient thrombocytopenia. The relationship between specific VWF variants, VWF protein folding, and thrombocytopenia risk remained incompletely characterized.
A second aim was to identify risk factors associated with thrombocytopenia: limited data existed on bleeding risk in type 2B VWD, particularly during high-risk hemostatic challenges like pregnancy. One study suggested that thrombocytopenic patients had higher bleeding risk, but more data were needed, especially given discrepancies in recommended VWF and FVIII trough levels between guidelines.
Guidelines
The American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH), recommend maintaining VWF activity levels ≥0.50 IU/mL (50 IU/dL) for major surgery and neuraxial anesthesia in patients with VWD (Connell et al. Blood Adv. 2021).
The guidelines specifically note that many patients with type 2B VWD will require treatment with VWF concentrate rather than desmopressin, as desmopressin is relatively contraindicated in type 2B disease due to the risk of exacerbating thrombocytopenia.
The primary discrepancies in recommended VWF and FVIII trough levels relate to pregnancy management rather than general surgical care. A 2023 international study highlighted that target safe VWF levels and ideal monitoring approaches remain unknown for pregnant women with type 2B VWD.
Most experts recommend monitoring FVIII and VWF levels prior to delivery and initiating treatment when levels remain below 0.50 IU/mL. However, Dutch guidelines from 2018 increased the third trimester threshold for prophylaxis from <50 IU/dL to <80 IU/dL. Importantly, this more aggressive approach did not reduce severe postpartum hemorrhage rates (de Vaan et al. J Thromb Haemost. 2026).
Study Design
- Retrospective cohort study
- National multicenter study (part of the “Willebrand in the Netherlands” [WiN] study)
- Multicenter at 10 Dutch hemophilia treatment centers
- Data collected retrospectively from electronic patient records
- Follow up: 16-year (median)
Populations
- Total enrolled: 72 type 2B VWD – 64 patients in the final analysis (8 excluded due to lack of follow-up data)
- 29 women (45.3%)
- Median age at baseline: 30.0 years (IQR, 9.5-44.0)
- Blood group O: 26 patients (40.6%)
- Genetic variants included:
- p.Arg1306Trp (most common – 50.0%)
- p.Arg1308Cys (second most common – 37.5%)
- Other variants in smaller numbers
- 4 women with full-term pregnancies (8 total deliveries) were specifically analyzed for pregnancy outcomes
- Inclusion criteria:
- Genetically confirmed type 2B VWD diagnosis
- Enrollment in the national “Willebrand in the Netherlands” (WiN) study
- Available electronic patient records for retrospective data collection
- Exclusion criteria:
- Lack of follow-up data
Interventions
- This was an observational study.
- Investigators analyzed platelet count trajectories over time; clinical outcomes including bleeding and annual bleeding rates; hemostatic challenges to DDAVP and pregnancy.
Results
- Incidence of thrombocytopenia
- Measurements: median of 11 measurements per patient
- 16 patients had thrombocytopenia at baseline, and 15 patients had persistent low platelet counts.
- 27 patients developed thrombocytopenia at least once.
- Median nadir was 83 × 109/L (IQR, 49-117).
- Based on VWF gene type: 75% in p.Arg1306Trp vs 58.3% in p.Arg1308Cys. Patients with the former had more continuous thrombocytopenia than the latter.
- Determinants of thrombocytopenia
- p.Arg1306Trp was a significant determinant for thrombocytopenia (OR, 25.1; 95% CI, 2.2-285.9; P < .01).
- Endothelial activation was not a determinant of thrombocytopenia.
- Bleeding phenotype
- Median bleeding score was high at 16 (IQR, 10-22), with no significant difference based on variant.
- Type 2B patients had a median of 0.14 (IQR, 0.04-0.34) bleeding episodes requiring treatment per year.
- There was no difference in bleeding score between patients with continuous or intermittent thrombocytopenia.
- Hemostatic challenges: DDAVP administration
- Desmopressin may be contraindicated in type 2B VWD because of increased platelet binding with subsequent thrombocytopenia.
- Desmopressin response test was performed in 10 type 2B patients before they were classified as having type 2B. All but one of these patients had normal platelet counts before administration of desmopressin.
- Two patients did not respond to DDAVP and did not develop thrombocytopenia.
- Four patients had thrombocytopenia 1 hour after administration of DDAVP (one of them was already thrombocytopenic at baseline), followed by an increase of platelet counts after 2 hours.
- Hemostatic challenges: pregnancy
- Study involved 10 pregnancies, 4 patients with full-term deliveries
- All patients showed declining platelet counts in the third trimester with sharp decrease in the week before delivery
- VWF:Ag increased >0.50 IU/mL, but VWF:Act remained <0.50 IU/mL in all pregnancies
- Postpartum hemorrhage occurred in all women despite prophylactic VWF concentrates
Commentary
This study by van Kwawegen, et al. represents the largest and longest follow-up of genetically characterized type 2B VWD patients to date. The median 16-year observation period provides us with important insights into the history of this bleeding disorder, specifically regarding association between phenotypes and risk of thrombocytopenia and bleeding rates.
The authors suggest that the p.Arg1306Trp variant may be a dominant determinant of thrombocytopenia. This variant appeared to confer a more severe phenotype of continuous thrombocytopenia, lower platelet nadirs, and potentially worse bleeding outcomes. The mechanistic explanation likely relates to enhanced shear stress sensitivity of VWF multimers carrying this substitution, leading to more avid platelet binding and consumption.
Further, it is important to discuss what the study did not find: by not showing an association between endothelial activation and thrombocytopenia, it challenged the notion that stress, infection, or surgery are triggers of thrombocytopenic episodes. The one exception would be pregnancy, where all women had worsening thrombocytopenia independent of genetic variant.
The pregnancy data deserves special consideration: postpartum hemorrhage (defined as estimated blood loss >500 mL after vaginal delivery) occurred in most deliveries, regardless of administration of VWF-concentrates and/or platelet transfusions. The authors comment that standard protocols for management of women with type 2B VWD during delivery are urgently needed.
Then there is the discussion regarding the use of desmopressin (DDAVP) in patients with type 2B VWD. DDAVP has historically been contraindicated in type 2B because of the unique pathophysiology of this subtype. The gain of function in the A1 domain makes VWF bind spontaneously and excessively to platelet GPIb receptors – WVF is abnormal and hyperactive. It is believed that DDAVP could cause a sudden surge of these abnormal VWF multimers, causing excessive platelet binding and further worsening the thrombocytopenia (Kruse-Jarres et al. Blood. 2018). In this study, DDAVP administration (though limited to 10 patients) showed a mixed response, with a bit under 50% of patients developing thrombocytopenia. The study, however, could not predict which patients would respond to DDAVP with an adequate VWF:Act increase, and which patients would develop thrombocytopenia. The authors agree with currently guidelines saying DDAVP should be generally contraindicated in patients with type 2B VWD.
Key take-home points:
- Genotyping matters, and specific variants may confer a higher risk of thrombocytopenia
- Desmopressin remains relatively contraindicated in these patients
- Pregnant patients require closer surveillance and multidisciplinary management with hematology, maternal-fetal-medicine, and the blood bank.
References
- ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease: https://pmc.ncbi.nlm.nih.gov/articles/PMC7805326/
- de Vaan et al. Higher-dosed clotting factor prophylaxis fails to reduce postpartum hemorrhage in women with von Willebrand disease: findings from the observational PRegnancy and Inherited bleeding DisordErS study. https://www.jthjournal.org/article/S1538-7836(26)00003-6/fulltext
- Kruse-Jarres et al. How I treat type 2B von Willebrand disease. https://www.sciencedirect.com/science/article/pii/S0006497120323788?via%3Dihub
Cilomar Martins MD is a hematology-focused fellow at Beth Israel Deaconess Medical Center. He completed medical school in Brazil, where he also completed Internal Medicine residency and Palliative Care fellowship before moving to the United Stated. He then completed residency at Mass General Brigham, Salem Hospital. His clinical focus is both classical and malignant hematology.
