severe hemophilia A

Summary

severe hemophilia A (MONDO:0015719) is a disease with 1 cohort gene and 31 clinical trials. Top therapeutic interventions include emicizumab, octocog alfa, and efmoroctocog alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 27
• Clinical trials: 31

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.8	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0003125	Reduced factor VIII activity	Very frequent (80-99%)
HP:0003645	Prolonged partial thromboplastin time	Very frequent (80-99%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001058	Poor wound healing	Frequent (30-79%)
HP:0001386	Joint swelling	Frequent (30-79%)
HP:0001934	Persistent bleeding after trauma	Frequent (30-79%)
HP:0004846	Prolonged bleeding after surgery	Frequent (30-79%)
HP:0005261	Joint hemorrhage	Frequent (30-79%)
HP:0030140	Oral cavity bleeding	Frequent (30-79%)
HP:0000132	Menorrhagia	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0003121	Limb joint contracture	Occasional (5-29%)
HP:0005187	Progressive joint destruction	Occasional (5-29%)
HP:0008330	Reduced von Willebrand factor activity	Occasional (5-29%)
HP:0012233	Intramuscular hematoma	Occasional (5-29%)
HP:0012541	Cephalohematoma	Occasional (5-29%)
HP:0012587	Macroscopic hematuria	Occasional (5-29%)
HP:0030137	Prolonged bleeding following circumcision	Occasional (5-29%)
HP:0100309	Subdural hemorrhage	Occasional (5-29%)
HP:0100310	Epidural hemorrhage	Occasional (5-29%)
HP:0100769	Synovitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe hemophilia A
Mondo ID	MONDO:0015719
Orphanet	169802
SNOMED CT	16872008
UMLS	C0272322
MedGen	543973
GARD	0017059
Is cancer (heuristic)	no

Also known as: severe factor VIII deficiency · severe haemophilia type A · severe hemophilia type A

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › hemophilia A › severe hemophilia A

Related subtypes (4): hemophilia A with vascular abnormality, moderately severe hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10192	NM_000132.4(F8):c.902G>A (p.Arg301His)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
3337861	NM_000132.4(F8):c.954_955del (p.Leu319fs)	F8	Pathogenic	criteria provided, single submitter
4813311	NM_000132.4(F8):c.7016G>T (p.Arg2339Met)	F8	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
F8	Strong	X-linked	hemophilia A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
F8	Orphanet:169802	Severe hemophilia A
F8	Orphanet:169805	Moderate hemophilia A
F8	Orphanet:169808	Mild hemophilia A
F8	Orphanet:177926	Bleeding disorder in hemophilia A carriers

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
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.

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)
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf

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
heart right ventricle	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F8	266	broad	marker	left ventricle myocardium, heart right ventricle, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F8	1,900

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F8	P00451	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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 accelerates dissociation of the A2 domain	1	11420.0×	5e-04	F8
Defective F8 binding to the cell membrane	1	11420.0×	5e-04	F8
Defective F8 secretion	1	11420.0×	5e-04	F8
Defective F8 binding to von Willebrand factor	1	5710.0×	5e-04	F8
Defective factor IX causes thrombophilia	1	3806.7×	5e-04	F8
Defective F8 cleavage by thrombin	1	3806.7×	5e-04	F8
Defective cofactor function of FVIIIa variant	1	3806.7×	5e-04	F8
Defective F9 variant does not activate FX	1	3806.7×	5e-04	F8
Defective F8 sulfation at Y1699	1	3806.7×	5e-04	F8
Amplification and propagation of coagulation cascade	1	634.4×	0.003	F8
Initiation of coagulation cascade	1	475.8×	0.003	F8
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	423.0×	0.003	F8
Cargo concentration in the ER	1	335.9×	0.004	F8
Regulation of clotting cascade	1	233.1×	0.005	F8
COPII-mediated vesicle transport	1	163.1×	0.007	F8
Platelet degranulation	1	87.8×	0.011	F8

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
blood coagulation, intrinsic pathway	1	2106.5×	0.001	F8
acute-phase response	1	421.3×	0.004	F8
blood coagulation	1	173.7×	0.006	F8

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
F8	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
F8	8	Binding:8

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	F8

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)
F8	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	15
Not specified	5
PHASE4	4
PHASE1	4
PHASE1/PHASE2	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05181618	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Evaluate Overall Health, Physical Activity, and Joint Outcomes in Participants With Severe or Moderate Hemophilia A Without Factor VIII Inhibitors on Emicizumab Prophylaxis
NCT05935358	PHASE4	RECRUITING	Nuwiq for Perioperative Management Of Patients With Haemophilia A on Emicizumab Regular Prophylaxis Study
NCT00323856	PHASE4	COMPLETED	Safety Study of Alphanate in Previously Treated Patients With Severe Hemophilia A
NCT01085344	PHASE4	COMPLETED	Canadian Hemophilia Prophylaxis Study
NCT04431726	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors
NCT06136507	PHASE3	NOT_YET_RECRUITING	Study of Efficacy and Safety of FRSW107 in Pediatric Patients With Severe Hemophilia A
NCT06142552	PHASE3	RECRUITING	Phase 3 Clinical Project of Pegylated Recombinant Human Coagulation Factor VIII-Fc Fusion Protein
NCT01125813	PHASE3	COMPLETED	Efficacy and Safety Study of Human-cl rhFVIII in PTPs With Severe Hemophilia A
NCT01181128	PHASE3	COMPLETED	Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A
NCT01341912	PHASE3	COMPLETED	Study to Investigate the Long-term Efficacy and Safety of Human-cl rhFVIII in Previously Treated Patients (PTPs)
NCT01405742	PHASE3	TERMINATED	Hemophilia Adult Prophylaxis Study: Factor VIII in Severe Hemophilia A
NCT01712438	PHASE3	COMPLETED	Human Cell Line-derived Recombinant Factor VIII (Human-cl-rhFVIII) in Previously Untreated Patients
NCT01992549	PHASE3	COMPLETED	Study to Investigate Immunogenicity, Efficacy and Safety of Treatment With Human-cl rhFVIII
NCT02172950	PHASE3	COMPLETED	An Open-label Safety and Efficacy Study of Recombinant FVIII in Patients With Severe Hemophilia A
NCT02196207	PHASE3	WITHDRAWN	Hemophilia Inhibitor Clinical Trials (INHIBIT) Platform
NCT02502149	PHASE3	COMPLETED	Pharmacokinetics and Safety of rFVIIIFc Manufactured at 15,000 L (15K) Scale
NCT02954575	PHASE3	COMPLETED	Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A
NCT03376516	PHASE3	COMPLETED	Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
NCT06137092	PHASE3	COMPLETED	rFVIII-Fc (Produced by AryoGen Pharmed Co.) Pharmacokinetic Study
NCT07548411	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	To Evaluate the Safety and Efficacy of GS1191-0445 Injection in the Treatment of Severe Hemophilia A
NCT04046848	PHASE1/PHASE2	TERMINATED	Safety and Pharmacokinetics of Subcutaneous Injection of OCTA101 in Adult Patients With Severe Hemophilia A
NCT05265286	PHASE2	COMPLETED	A Study of Repeat Dosing of PEG Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection
NCT06703606	PHASE1	RECRUITING	A Study to Learn About How Changing Therapy From Emicizumab to Marstacimab Affects People With the Severe Hemophilia A.
NCT01027377	PHASE1	COMPLETED	Study of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Subjects With Severe Hemophilia A
NCT02083965	PHASE1	COMPLETED	Pharmacokinetics of rFVIIIFc at Two Vial Strengths
NCT04864743	PHASE1	COMPLETED	A Study to Evaluate the Pharmacokinetics，Safety and Tolerability of PEG Recombinant Human Coagulation Factor VIII-Fc Fusion Protein for Injection
NCT05802836	Not specified	RECRUITING	Dynamics of the Anti-factor VIII Antibody Signature During Treatment With Emicizumab
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT01051076	Not specified	COMPLETED	Rescue Immunotolerance Study in Induction of Immune Tolerance (ITI)-Experienced Patients (RES.I.S.T. Experienced)
NCT01051544	Not specified	WITHDRAWN	Study of First TIME Immunotolerance Induction in Severe Hemophilia A Patients With Inhibitor at High Risk of Failure: Comparison With FVIII Concentrates With or Without Von Willebrand Factor - RES.I.S.T. Naive
NCT05127681	Not specified	TERMINATED	Bone Microarchitecture in Men With Hemophilia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMICIZUMAB	4	3
OCTOCOG ALFA	4	2
EFMOROCTOCOG ALFA	4	1
LONOCTOCOG ALFA	4	1
MARSTACIMAB	4	1
SIMOCTOCOG ALFA	4	1