hereditary von Willebrand disease

Summary

hereditary von Willebrand disease (MONDO:0019565) is a disease (an umbrella term covering 5 Mondo subtypes) with 1 cohort gene and 81 clinical trials. Top therapeutic interventions include tranexamic acid, vonicog alfa, and octocog alfa.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 234
• Phenotypes (HPO): 20
• Clinical trials: 81

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001872	Abnormality of thrombocytes	Very frequent (80-99%)
HP:0001928	Abnormality of coagulation	Very frequent (80-99%)
HP:0008330	Reduced von Willebrand factor activity	Very frequent (80-99%)
HP:0011869	Abnormal platelet function	Very frequent (80-99%)
HP:0000132	Menorrhagia	Frequent (30-79%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0000471	Gastrointestinal angiodysplasia	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001633	Abnormal mitral valve morphology	Frequent (30-79%)
HP:0003125	Reduced factor VIII activity	Frequent (30-79%)
HP:0030129	Impaired ristocetin cofactor assay activity	Frequent (30-79%)
HP:0000967	Petechiae	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001935	Microcytic anemia	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0003645	Prolonged partial thromboplastin time	Occasional (5-29%)
HP:0004097	Deviation of finger	Occasional (5-29%)
HP:0005261	Joint hemorrhage	Occasional (5-29%)
HP:0005293	Venous insufficiency	Occasional (5-29%)
HP:0040242	Muscle hemorrhage	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary von Willebrand disease
Mondo ID	MONDO:0019565
MeSH	C531844
Orphanet	903
DOID	DOID:12531
ICD-11	2112021600
SNOMED CT	234446004
UMLS	C5703318
MedGen	1814986
MedDRA	10047715
Is cancer (heuristic)	no

Also known as: congenital von willebrand’s disease · hereditary von Willebrand disease · hereditary von Willebrand disease (hereditary or acquired) · vascular haemophilia · vascular hemophilia · von Willebrand disease · von Willebrand disorder · von Willebrand’s-Jurgens’ disease · von Willebrand-Jurgens disease

Data availability: 234 ClinVar variants · 47 ClinGen variant curations · 1 cell line.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › hereditary von Willebrand disease

Related subtypes (27): inherited bleeding disorder, platelet-type, factor VII deficiency, factor X deficiency, purpura, vascular hemostatic disease, congenital factor V deficiency, congenital high-molecular-weight kininogen deficiency, congenital factor XII deficiency, alpha-2-plasmin inhibitor deficiency, hemophilia A, hemophilia B, East Texas bleeding disorder, congenital factor XI deficiency, inherited prekallikrein deficiency, congenital plasminogen activator inhibitor type 1 deficiency, thrombomodulin-related bleeding disorder, congenital vitamin K-dependent coagulation factors deficiency, hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, congenital factor XIII deficiency, congenital fibrinogen deficiency, combined deficiency of factor V and factor VIII, acquired hemophilia, fetal and neonatal alloimmune thrombocytopenia, acquired von willebrand syndrome, prothrombin deficiency, hemophilia B leyden

Subtypes (5): platelet-type von Willebrand disease, von Willebrand disease 1, von Willebrand disease 3, Von Willebrand disease, X-linked form, von Willebrand disease 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

234 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 42 pathogenic, 37 likely pathogenic, 26 conflicting classifications of pathogenicity, 19 likely benign, 16 benign, 15 pathogenic/likely pathogenic, 11 benign/likely benign, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
100175	NM_000552.5(VWF):c.1117C>T (p.Arg373Ter)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100179	NM_000552.5(VWF):c.1309_1326del (p.Asp437_Arg442del)	VWF	Pathogenic	criteria provided, single submitter
100257	NM_000552.5(VWF):c.3379+1G>A	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100264	NM_000552.5(VWF):c.3467C>T (p.Thr1156Met)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100268	NM_000552.5(VWF):c.3538G>A (p.Gly1180Arg)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100269	NM_000552.5(VWF):c.3568T>C (p.Cys1190Arg)	VWF	Pathogenic	reviewed by expert panel
100281	NM_000552.5(VWF):c.3802C>G (p.His1268Asp)	VWF	Pathogenic	reviewed by expert panel
100294	NM_000552.5(VWF):c.3863T>G (p.Leu1288Arg)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100301	NM_000552.5(VWF):c.3917G>T (p.Arg1306Leu)	VWF	Pathogenic	criteria provided, single submitter
100305	NM_000552.5(VWF):c.3925A>G (p.Ile1309Val)	VWF	Pathogenic	reviewed by expert panel
100307	NM_000552.5(VWF):c.3931C>T (p.Gln1311Ter)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100310	NM_000552.5(VWF):c.3943C>T (p.Arg1315Cys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100329	NM_000552.5(VWF):c.4120C>T (p.Arg1374Cys)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100330	NM_000552.5(VWF):c.4121G>A (p.Arg1374His)	VWF	Pathogenic	reviewed by expert panel
100331	NM_000552.5(VWF):c.4121G>T (p.Arg1374Leu)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100337	NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys)	VWF	Pathogenic	reviewed by expert panel
100338	NM_000552.5(VWF):c.421G>A (p.Asp141Asn)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100340	NM_000552.5(VWF):c.4213AAG[3] (p.Lys1408del)	VWF	Pathogenic	reviewed by expert panel
100344	NM_000552.5(VWF):c.4247T>A (p.Ile1416Asn)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100369	NM_000552.5(VWF):c.4517C>T (p.Ser1506Leu)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100376	NM_000552.5(VWF):c.4628C>T (p.Ser1543Phe)	VWF	Pathogenic	criteria provided, single submitter
100391	NM_000552.5(VWF):c.4790G>A (p.Arg1597Gln)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100395	NM_000552.5(VWF):c.4825G>A (p.Gly1609Arg)	VWF	Pathogenic	reviewed by expert panel
100467	NM_000552.5(VWF):c.7390C>T (p.Arg2464Cys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100469	NM_000552.5(VWF):c.7408C>T (p.Gln2470Ter)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100473	NM_000552.5(VWF):c.7437G>A (p.Ser2479=)	VWF	Pathogenic	no assertion criteria provided
100493	NM_000552.5(VWF):c.817C>T (p.Arg273Trp)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100512	NM_000552.5(VWF):c.970C>T (p.Arg324Ter)	VWF	Pathogenic	reviewed by expert panel
1333001	NM_000552.5(VWF):c.5621-50_5842+50del	VWF	Pathogenic	criteria provided, single submitter
1333002	Single allele	VWF	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VWF	Orphanet:166078	Von Willebrand disease type 1
VWF	Orphanet:166084	Von Willebrand disease type 2A
VWF	Orphanet:166087	Von Willebrand disease type 2B
VWF	Orphanet:166090	Von Willebrand disease type 2M
VWF	Orphanet:166093	Von Willebrand disease type 2N
VWF	Orphanet:166096	Von Willebrand disease type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VWF	HGNC:12726	ENSG00000110799	P04275	von Willebrand factor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VWF	von Willebrand factor	Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VWF	Other/Unknown	no		VWF_dom, VWF_type-D, VWF_A

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
tendon of biceps brachii	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VWF	289	broad	marker	urethra, tendon of biceps brachii, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VWF	5,204

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VWF	P04275	48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective F8 binding to von Willebrand factor	1	5710.0×	0.002	VWF
Defective F8 cleavage by thrombin	1	3806.7×	0.002	VWF
Defective VWF binding to collagen type I	1	3806.7×	0.002	VWF
Enhanced cleavage of VWF variant by ADAMTS13	1	2855.0×	0.002	VWF
Defective VWF cleavage by ADAMTS13 variant	1	2855.0×	0.002	VWF
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	1631.4×	0.002	VWF
Defective binding of VWF variant to GPIb:IX:V	1	1631.4×	0.002	VWF
GP1b-IX-V activation signalling	1	951.7×	0.003	VWF
p130Cas linkage to MAPK signaling for integrins	1	761.3×	0.003	VWF
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	713.8×	0.003	VWF
Platelet Adhesion to exposed collagen	1	671.8×	0.003	VWF
Amplification and propagation of coagulation cascade	1	634.4×	0.003	VWF
Initiation of coagulation cascade	1	475.8×	0.004	VWF
Platelet Aggregation (Plug Formation)	1	439.2×	0.004	VWF
Integrin signaling	1	423.0×	0.004	VWF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	VWF
MAP2K and MAPK activation	1	285.5×	0.005	VWF
Signaling by RAF1 mutants	1	278.5×	0.005	VWF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	VWF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	VWF
Signaling downstream of RAS mutants	1	253.8×	0.005	VWF
Regulation of clotting cascade	1	233.1×	0.005	VWF
Signaling by BRAF and RAF1 fusions	1	170.4×	0.006	VWF
Integrin cell surface interactions	1	134.3×	0.008	VWF
Platelet degranulation	1	87.8×	0.011	VWF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hemostasis	1	1685.2×	0.004	VWF
cell-substrate adhesion	1	766.0×	0.004	VWF
positive regulation of intracellular signal transduction	1	648.1×	0.004	VWF
platelet activation	1	267.5×	0.006	VWF
response to wounding	1	221.7×	0.006	VWF
blood coagulation	1	173.7×	0.007	VWF
cell adhesion	1	37.5×	0.027	VWF

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VWF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
VWF	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VWF

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
VWF	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 81.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	48
PHASE3	18
PHASE2	7
PHASE4	4
PHASE1/PHASE2	2
PHASE2/PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00555555	PHASE4	ACTIVE_NOT_RECRUITING	Efficacy of Alphanate FVIII/VWF Concentrate in Type 3 Von Willebrand Patients
NCT00168090	PHASE4	COMPLETED	Study of Safety and Efficacy of Antihemophilic Factor/Von Willebrand Factor Complex in Surgical Subjects With Von Willebrand Disease (vWD)
NCT02472665	PHASE4	WITHDRAWN	Efficacy and Safety of Fanhdi®, a High-purity Von Willebrand Containing FVIII Concentrate, in Pediatric Patients With Von Willebrand Disease
NCT02552576	PHASE4	COMPLETED	Study of Voncento® in Subjects With Von Willebrand Disease
NCT05582993	PHASE3	RECRUITING	A Study of Vonicog Alfa (rVWF) in Children With Severe Von Willebrand Disease (vWD)
NCT06205095	PHASE3	RECRUITING	A Pilot Crossover Trial of Prophylactic Wilate Compared to Placebo for Heavy Menstrual Bleeding in Patients with VWD
NCT07115004	PHASE3	RECRUITING	Study to Evaluate Subcutaneous (SC) VGA039 in Patients With Von Willebrand Disease (VWD)
NCT07129343	PHASE3	RECRUITING	A Study of Recombinant Von Willebrand Factor (rVWF) in Chinese Participants With Von Willebrand Disease (vWD)
NCT00387192	PHASE3	TERMINATED	A Study With OPTIVATE® in People With Von Willebrand Disease
NCT00404300	PHASE3	TERMINATED	Optivate in People With Von Willebrand Disease Undergoing Surgery
NCT00941616	PHASE2/PHASE3	COMPLETED	Study of a pd VWF/FVIII Concentrate, Biostate®, in Subjects With Von Willebrand Disease
NCT01213446	PHASE3	COMPLETED	Study of Biostate® in Children With Von Willebrand Disease
NCT01224808	PHASE3	COMPLETED	Extension Study of Biostate in Subjects With Von Willebrand Disease
NCT01410227	PHASE3	COMPLETED	Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD)
NCT02246881	PHASE3	COMPLETED	A Study to Compare the Pharmacokinetics and Safety of Current Factor VIII Concentrate and Optivate® in Haemophilia A.
NCT02283268	PHASE3	COMPLETED	Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery
NCT02606045	PHASE3	TERMINATED	Minimize Menorrhagia in Women With Von Willebrand Disease
NCT02932618	PHASE3	COMPLETED	A Study of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Children With Severe Von Willebrand Disease (VWD)
NCT02973087	PHASE3	COMPLETED	rVWF IN PROPHYLAXIS
NCT03879135	PHASE3	COMPLETED	A Study of Recombinant Von Willebrand Factor (rVWF) in Pediatric and Adult Participants With Severe Von Willebrand Disease (VWD)
NCT04052698	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients With VWD
NCT04344860	PHASE3	COMPLETED	Prevent Postpartum Hemorrhage in Women With Von Willebrand Disease: The VWD-WOMAN Trial
NCT04953884	PHASE3	COMPLETED	Efficacy, PK, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease (VWD) Patients <6 Years of Age
NCT05776069	PHASE1/PHASE2	RECRUITING	Study of VGA039 in Healthy Volunteers and Patients With Von Willebrand Disease (VIVID)
NCT06754852	PHASE1/PHASE2	RECRUITING	A Study Assessing HMB-002 in Participants With Von Willebrand Disease
NCT07575308	PHASE2	NOT_YET_RECRUITING	HMBeacon: A Phase 2 Study to Evaluate ALN-6400 in Adult and Adolescent Female Patients With VWD and HMB
NCT00151125	PHASE2	COMPLETED	Phase II Study of IL-11 (Neumega) in Von Willebrand Disease
NCT00524225	PHASE2	TERMINATED	IL-11 in Adults With Von Willebrand Disease Undergoing Surgery
NCT00524342	PHASE2	COMPLETED	IL-11 in Women With Von Willebrand Disease and Refractory Menorrhagia
NCT00694785	PHASE2	WITHDRAWN	A Study of the Pharmacokinetics, Pharmacodynamics, and Safety of ARC1779 Injection in Patients With Von Willebrand Disease Type 2B
NCT00994929	PHASE2	COMPLETED	Efficacy and Safety of IL-11 in DDAVP Unresponsive
NCT04677803	PHASE2	COMPLETED	BT200 in Hereditary Bleeding Disorders
NCT00816660	PHASE1	COMPLETED	Pharmacokinetic, Safety and Tolerability Study of Recombinant Von Willebrand Factor / Recombinant Factor VIII Complex in Type 3 Von Willebrand Disease
NCT03327779	Not specified	RECRUITING	World Bleeding Disorders Registry
NCT03773159	Not specified	RECRUITING	Development of a Device for Evaluating Primary Hemostasis Under Whole Blood Flow Conditions
NCT03853486	Not specified	ACTIVE_NOT_RECRUITING	ATHN 9: Severe VWD Natural History Study
NCT04119908	Not specified	RECRUITING	Videomicroscopy for the Prediction of Bleeding in Constitutional Haemorrhagic Diseases
NCT04146376	Not specified	RECRUITING	Von Willebrand Factor in Pregnancy (VIP) Study
NCT04398628	Not specified	RECRUITING	ATHN Transcends: A Natural History Study of Non-Neoplastic Hematologic Disorders
NCT05773638	Not specified	RECRUITING	Cardiovascular and Venous Thromboembolism Disease in Patients with Von Willebrand Disease in the French West

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRANEXAMIC ACID	4	4
VONICOG ALFA	4	4
OCTOCOG ALFA	4	2
DESMOPRESSIN ACETATE	4	1
NORETHINDRONE ACETATE	4	1
OPRELVEKIN	4	1
EGAPTIVON PEGOL	2	1
RONDAPTIVON PEGOL	2	1
CHEMBL4091490	0	1
ADENOSINE DIPHOSPHATE	0	1