Thrombotic microangiopathy

Summary

Thrombotic microangiopathy (MONDO:0019737) is a disease with 4 cohort genes and 37 clinical trials. The dominant Reactome pathway is Regulation of Complement cascade (3 cohort genes). Top therapeutic interventions include ravulizumab, eculizumab, and iptacopan.

At a glance

• Cohort genes: 4
• ClinVar variants: 5
• Clinical trials: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombotic microangiopathy
Mondo ID	MONDO:0019737
MeSH	D057049
Orphanet	93573
ICD-10-CM	M31.1
NCIT	C62605
SNOMED CT	126729006
UMLS	C2717961
MedGen	403479
GARD	0019227
MedDRA	10043645
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood coagulation disease › thrombotic microangiopathy

Related subtypes (7): marantic endocarditis, hemolytic-uremic syndrome, coagulation protein disease, thrombophilia, hemorrhagic disease of newborn, inherited blood coagulation disorder, prekallikrein deficiency

Subtypes (2): atypical hemolytic-uremic syndrome, thrombocytopenic purpura

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

5 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 uncertain significance, 1 likely pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163189	NM_172351.3(CD46):c.287-2A>G	CD46	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344583	NM_033629.6(TREX1):c.830_833dup (p.Asp278fs)	ATRIP	Likely pathogenic	criteria provided, single submitter
347156	NM_000204.5(CFI):c.1322A>G (p.Lys441Arg)	CFI	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163680	NM_000186.4(CFH):c.2753G>A (p.Gly918Glu)	CFH	Uncertain significance	criteria provided, multiple submitters, no conflicts
294520	NM_000186.4(CFH):c.3148A>T (p.Asn1050Tyr)	CFH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATRIP	Orphanet:808	Seckel syndrome
CFH	Orphanet:200421	Immunodeficiency with factor H anomaly
CFH	Orphanet:244242	HELLP syndrome
CFH	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFH	Orphanet:329903	Immunoglobulin-mediated membranoproliferative glomerulonephritis
CFH	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFH	Orphanet:75376	Familial drusen
CFH	Orphanet:93571	Dense deposit disease
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
CD46	Orphanet:244242	HELLP syndrome
CD46	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATRIP	HGNC:33499	ENSG00000164053	Q8WXE1	ATR-interacting protein	clinvar
CFH	HGNC:4883	ENSG00000000971	P08603	Complement factor H	clinvar
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	clinvar
CD46	HGNC:6953	ENSG00000117335	P15529	Membrane cofactor protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATRIP	ATR-interacting protein	Required for checkpoint signaling after DNA damage.
CFH	Complement factor H	Glycoprotein that plays an essential role in maintaining a well-balanced immune response by modulating complement activation.
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
CD46	Membrane cofactor protein	Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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
Complement	2	134.0×	2e-04
Protease	1	9.2×	0.157
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATRIP	Other/Unknown	no		ATRIP
CFH	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
CFI	Protease	yes	3.4.21.45	SRCR, Trypsin_dom, Peptidase_S1A
CD46	Complement	yes		Sushi_SCR_CCP_dom, CD46, Sushi/SCR/CCP_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1
calcaneal tendon	1
right coronary artery	1
urethra	1
germinal epithelium of ovary	1
parietal pleura	1
right lobe of liver	1
adrenal tissue	1
mucosa of paranasal sinus	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATRIP	170	ubiquitous	yes	left testis, right testis, testis
CFH	267	ubiquitous	marker	urethra, calcaneal tendon, right coronary artery
CFI	240	broad	marker	germinal epithelium of ovary, parietal pleura, right lobe of liver
CD46	295	ubiquitous	marker	palpebral conjunctiva, adrenal tissue, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFH	1,844
CD46	1,780
ATRIP	1,544
CFI	1,120

Intra-cohort edges

A	B	Sources
CD46	CFI	intact, string_interaction
CFH	CFI	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFH	P08603	51
ATRIP	Q8WXE1	11
CD46	P15529	7
CFI	P05156	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of Complement cascade	3	174.8×	9e-06	CFH, CFI, CD46
Diseases of DNA Double-Strand Break Repair	1	203.9×	0.034	ATRIP
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	203.9×	0.034	ATRIP
Complement cascade	1	158.6×	0.034	CD46
Diseases of DNA repair	1	142.8×	0.034	ATRIP
Homologous DNA Pairing and Strand Exchange	1	95.2×	0.034	ATRIP
Homology Directed Repair	1	77.2×	0.034	ATRIP
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.034	ATRIP
Impaired BRCA2 binding to RAD51	1	77.2×	0.034	ATRIP
Activation of ATR in response to replication stress	1	75.1×	0.034	ATRIP
HDR through Single Strand Annealing (SSA)	1	73.2×	0.034	ATRIP
Fanconi Anemia Pathway	1	69.6×	0.034	ATRIP
Presynaptic phase of homologous DNA pairing and strand exchange	1	68.0×	0.034	ATRIP
DNA Double-Strand Break Repair	1	62.1×	0.034	ATRIP
HDR through Homologous Recombination (HRR)	1	47.6×	0.042	ATRIP
G2/M Checkpoints	1	33.6×	0.052	ATRIP
Regulation of TP53 Activity	1	33.2×	0.052	ATRIP
G2/M DNA damage checkpoint	1	30.1×	0.052	ATRIP
Regulation of TP53 Activity through Phosphorylation	1	29.4×	0.052	ATRIP
Processing of DNA double-strand break ends	1	28.6×	0.052	ATRIP
DNA Repair	1	24.6×	0.057	ATRIP
Cell Cycle Checkpoints	1	22.1×	0.061	ATRIP
Transcriptional Regulation by TP53	1	15.5×	0.082	ATRIP
Cell Cycle	1	9.0×	0.133	ATRIP
Innate Immune System	1	6.4×	0.178	CD46
RNA Polymerase II Transcription	1	5.6×	0.192	ATRIP
Gene expression (Transcription)	1	4.5×	0.229	ATRIP
Generic Transcription Pathway	1	3.8×	0.257	ATRIP
Disease	1	3.3×	0.275	ATRIP
Immune System	1	3.2×	0.275	CD46

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
complement activation, classical pathway	2	271.8×	5e-04	CFI, CD46
obsolete sequestering of extracellular ligand from receptor	1	4213.0×	0.003	CD46
regulation of complement activation, alternative pathway	1	2106.5×	0.004	CFH
regulation of complement-dependent cytotoxicity	1	842.6×	0.007	CFH
negative regulation of complement activation, classical pathway	1	601.9×	0.007	CD46
regulation of complement activation	1	526.6×	0.007	CFH
positive regulation of transforming growth factor beta production	1	526.6×	0.007	CD46
positive regulation of memory T cell differentiation	1	468.1×	0.007	CD46
T cell mediated immunity	1	247.8×	0.009	CD46
complement activation, alternative pathway	1	247.8×	0.009	CFH
central nervous system myelination	1	247.8×	0.009	CFH
positive regulation of regulatory T cell differentiation	1	234.1×	0.009	CD46
regulation of Notch signaling pathway	1	210.7×	0.009	CD46
proteolysis	2	17.1×	0.009	CFH, CFI
innate immune response	2	16.8×	0.009	CFI, CD46
complement activation	1	156.0×	0.011	CFH
regulation of double-strand break repair	1	145.3×	0.011	ATRIP
nucleobase-containing compound metabolic process	1	131.7×	0.011	ATRIP
positive regulation of interleukin-10 production	1	100.3×	0.014	CD46
DNA damage checkpoint signaling	1	98.0×	0.014	ATRIP
positive regulation of T cell proliferation	1	64.8×	0.020	CD46
single fertilization	1	45.8×	0.027	CD46
adaptive immune response	1	21.1×	0.055	CD46
negative regulation of gene expression	1	17.3×	0.064	CD46
DNA repair	1	16.0×	0.066	ATRIP
positive regulation of gene expression	1	9.7×	0.102	CD46
inflammatory response	1	9.4×	0.102	CFH

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ravulizumab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Pegcetacoplan.

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATRIP	3	3
CFH	0	0
CFI	0	0
CD46	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATRIP	31	Binding:31
CFH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFI	3.4.21.45	complement factor I

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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.

Compound	Max phase	Cohort target (bioactivity)
CERALASERTIB	3	ATRIP
ELIMUSERTIB	1	ATRIP
M4344	1	ATRIP

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	1	ATRIP
C	Druggable family + PDB, no drug	3	CFH, CFI, CD46
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CFH	1	—
CFI	0	—
CD46	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 37.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE3	8
PHASE2	6
PHASE2/PHASE3	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07279610	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	N-Acetylcysteine as Therapy for Transplantation- Associated Thrombotic Microangiopathy
NCT03205995	PHASE3	TERMINATED	Safety and Efficacy Study of OMS721 in Patients With Atypical Hemolytic Uremic Syndrome
NCT03252925	PHASE3	COMPLETED	A Safety and Efficacy Study of NAC in Patients With TA-TMA
NCT04543591	PHASE3	COMPLETED	Ravulizumab in Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant
NCT04557735	PHASE3	COMPLETED	Study of Ravulizumab in Pediatric Participants With HSCT-TMA
NCT04570397	PHASE3	UNKNOWN	Ravulizumab and COVID-19
NCT04743804	PHASE3	TERMINATED	Ravulizumab in Thrombotic Microangiopathy Associated With a Trigger
NCT04784455	PHASE3	TERMINATED	Nomacopan (rVA576) in Transplant Associated Thrombotic Microangiopathy
NCT05702996	PHASE3	UNKNOWN	Multicenter, Uncontrolled Pilot Study Evaluating the Efficacy of Eculizumab in the Treatment of Gemcitabine-induced Thrombotic Microangiopathies
NCT05855083	PHASE2	RECRUITING	Efficacy and Safety Study of Narsoplimab in Pediatric Patients With High-Risk Hematopoietic Stem Cell Transplant TMA
NCT07459114	PHASE1/PHASE2	NOT_YET_RECRUITING	TGD001 Treatment in Thrombotic Microangiopathies
NCT00726544	PHASE2	TERMINATED	Clinical Outcome Study of ARC1779 Injection in Patients With Thrombotic Microangiopathy
NCT02222545	PHASE2	COMPLETED	Safety and Efficacy Study of OMS721 in Patients With Thrombotic Microangiopathies
NCT03384693	PHASE2	COMPLETED	Defibrotide TMA Prophylaxis Pilot Trial
NCT03518203	PHASE2	COMPLETED	Eculizumab to Treat Thrombotic Microangiopathy/Atypical Hemolytic Uremic Syndrome -Associated Multiple Organ Dysfunction Syndrome in Hematopoietic Stem Cell Transplant Recipients
NCT06182410	PHASE2	WITHDRAWN	Defibrotide Prophylaxis of Transplant Associated-Thrombotic Microangiopathy for Neuroblastoma
NCT06291415	PHASE1	WITHDRAWN	The Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HMPL-523 in Adult Subjects With Immune Thrombocytopenia (ITP)
NCT02355782	Not specified	AVAILABLE	OMS721 Compassionate Use in Patients With Thrombotic Microangiopathy
NCT04098445	Not specified	RECRUITING	TRANSPIRE: Lung Injury in a Longitudinal Cohort of Pediatric HSCT Patients
NCT04745195	Not specified	RECRUITING	Complement Prospective Evaluation of Thrombotic Microangiopathy on Endothelium
NCT05634928	Not specified	RECRUITING	Construction of a Database for TMA
NCT06102694	Not specified	RECRUITING	Identification of Plasma Biomarkers for Early Diagnosis of Transplant-associated Thrombotic Microangiopathy
NCT06291025	Not specified	RECRUITING	Efficacy and Safety of Immunosuppression, Caplacizumab and Plasma Infusion Without Therapeutic Plasma Exchange in Immune-mediated Thrombotic Thrombocytopenic Purpura
NCT06727669	Not specified	RECRUITING	Longitudinal Cohort of Thrombosis and Hemostasis Diseases
NCT07059026	Not specified	RECRUITING	Thrombotic Microangiopathy (TMA) Associated With Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adult Patients
NCT07205861	Not specified	RECRUITING	Retrospective Epidemiological Study of Patients in the National Cohort of the French TMA Center
NCT07347990	Not specified	NOT_YET_RECRUITING	Safety and Efficacy of Iptacopan in Patients With High-Risk Transplantation-Associated Thrombotic Microangiopathy
NCT00593229	Not specified	TERMINATED	International Registry and Biorepository for TMA(Thrombotic Microangiopathy)
NCT02134171	Not specified	COMPLETED	Early Predictive Factors of Cardiac and Cerebral Involvement in TMA
NCT02373267	Not specified	UNKNOWN	Screening of TMA Patients für ADAMTS13 Activity (Adamscreen)
NCT02604420	Not specified	COMPLETED	Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants
NCT03605511	Not specified	UNKNOWN	TTP and aHUS in Complicated Pregnancies
NCT04845022	Not specified	UNKNOWN	Incidence of Snakebite Associated Thrombotic Microangiopathy & Role of Peripheral Blood Smear as a Predictor of Clinical Outcome
NCT04970004	Not specified	WITHDRAWN	Study in Adult and Pediatric Patients With HSCT-TMA
NCT05991245	Not specified	UNKNOWN	French National Cohort MATRIX Renal and Systemic Thrombotic Microangiopathy
NCT05996679	Not specified	UNKNOWN	Automated Surveillance, Alert, and Rapid Diagnosis of Thrombotic Microangiopathies: the ASARD-TMA Study
NCT06098378	Not specified	UNKNOWN	Study of Patients With Thrombotic Microangiopathy Associated With Mitomycin C, Treated or Not With Eculizumab

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RAVULIZUMAB	4	4
ECULIZUMAB	4	3
IPTACOPAN	4	1
NARSOPLIMAB	3	4
DEFIBROTIDE	3	2
NOMACOPAN	3	1
SOVLEPLENIB	3	1
EGAPTIVON PEGOL	2	1
CHEMBL5435500	0	1