| Domain | Key facts | Suggested ontology mappings* | Key evidence |
|---|---|---|---|
| Identity / identifiers | Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem-cell disorder characterized by complement-mediated hemolysis, thrombophilia, and variable bone-marrow failure; disease-level information here is derived from aggregated literature/registry resources rather than individual EHRs. Common synonyms: PNH; paroxysmal nocturnal haemoglobinuria. MONDO/OMIM/Orphanet/MeSH/ICD identifiers should be independently validated before KB ingestion if exact accession is required. | MONDO: PNH **[validate exact accession]**; MeSH: **[validate]**; ICD-10/11: **[validate]** | (pqac-00000000, pqac-00000006, pqac-00000021) |
| Cause / etiology | Primary cause is acquired somatic loss-of-function mutation of **PIGA** in hematopoietic stem cells on Xp22.1, causing GPI-anchor deficiency. PIGA mutation is necessary but often considered insufficient alone for overt disease; clonal expansion is linked to immune-mediated marrow failure context, especially aplastic anemia. No Mendelian inheritance pattern for classic PNH. | Gene: **PIGA**; CL: hematopoietic stem cell **[validate exact CL term]** | (pqac-00000002, pqac-00000005, pqac-00000017, pqac-00000021, pqac-00000022) |
| Core mechanism / pathophysiology | Loss of GPI anchors removes complement regulators **CD55/DAF** and **CD59** from RBCs (and other blood cells), permitting alternative-pathway amplification, terminal complement activation, and MAC-mediated intravascular hemolysis. Upstream C3 deposition also drives extravascular hemolysis under C5 blockade. Free hemoglobin scavenges nitric oxide, contributing to smooth-muscle dystonia, vasospasm, platelet activation, endothelial dysfunction, thrombosis, renal injury, and pulmonary hypertension. | GO: complement activation, alternative pathway **[validate]**; GO: membrane attack complex assembly **[validate]**; GO: hemolysis **[validate]**; GO: nitric oxide metabolic process **[validate]**; CL: erythrocyte **[validate]**, platelet **[validate]**, neutrophil **[validate]**; UBERON: bone marrow **[validate]**, blood **[validate]**, kidney **[validate]**, lung vasculature **[validate]** | (pqac-00000007, pqac-00000016, pqac-00000017, pqac-00000019, pqac-00000024) |
| Major phenotypes with frequencies | Registry baseline burden (untreated at enrollment): fatigue **80.9–81%**, dyspnea **45.3%**, hemoglobinuria **45.0%**, abdominal pain **35.2%**, impaired renal function **42.8%**, high disease activity **51.6%**, bone-marrow failure **62.6%**, RBC transfusion history **61.3%**, major adverse vascular events **18.8%**; thrombosis may affect up to **40%** in some series/reviews and can be the first manifestation, often at unusual venous sites. QoL study (China): anxiety/depression problems **81.5%**, pain/discomfort **69.9%**, mean EQ-5D-5L utility **0.76**, EQ-VAS **62.61**. | HPO: fatigue **[validate]**; dyspnea **[validate]**; hemoglobinuria **[validate]**; abdominal pain **[validate]**; anemia **[validate]**; thrombosis **[validate]**; bone marrow hypocellularity/failure **[validate]**; renal insufficiency **[validate]**; pulmonary hypertension **[validate]** | (pqac-00000000, pqac-00000010, pqac-00000014, pqac-00000020) |
| Diagnosis | Gold standard is high-sensitivity flow cytometry demonstrating GPI-deficient populations across ≥2 blood cell lineages, typically using **FLAER** with lineage markers for granulocytes/monocytes and CD55/CD59 or related markers on RBCs. In the APPLY/APPOINT trial population, diagnostic eligibility required flow-confirmed affected red-cell and white-cell populations ≥10%. Screening is particularly relevant in aplastic anemia and unexplained persistent cytopenias. | MAXO: flow cytometry assay **[validate]**; CL: granulocyte **[validate]**, monocyte **[validate]**, erythrocyte **[validate]** | (pqac-00000005, pqac-00000013, pqac-00000015, pqac-00000023) |
| Epidemiology / population | Reported prevalence ranges roughly **10–20 per million** globally; some reviews cite **13–38 per million**. Incidence is commonly **1–1.5 per million/year**; some sources report **0.08–0.57 per 100,000 person-years**. Median age at diagnosis/onset is typically **35–40 years**; no strong sex predilection is consistently observed. Italian real-world analysis estimated prevalence **17.6 per million** adults (Dec 2021) and incidence **1.5 per million/year**. | MONDO: PNH **[validate]** | (pqac-00000000, pqac-00000006, pqac-00000014, pqac-00000020) |
| Current therapies | Complement inhibition is standard of care for hemolytic PNH. Established agents: **eculizumab** (anti-C5; FDA 2007), **ravulizumab** (long-acting anti-C5; every 8 weeks), **pegcetacoplan** (C3 inhibitor; approved 2021), **iptacopan** (oral factor B inhibitor; FDA Dec 6, 2023), **danicopan** (factor D inhibitor; add-on/novel proximal inhibitor), and **crovalimab** (anti-C5; approved in 2024 in some jurisdictions per recent reviews). Supportive care includes RBC transfusion, anticoagulation when indicated, immunosuppressive therapy for marrow failure, and vaccination against encapsulated bacteria before complement inhibition; allogeneic HSCT remains the only curative option for selected fit patients, especially with severe marrow failure. | MAXO: complement inhibition therapy **[validate]**; monoclonal antibody therapy **[validate]**; blood transfusion **[validate]**; anticoagulation therapy **[validate]**; hematopoietic stem-cell transplantation **[validate]**; CHEBI/drug mappings **[validate separately]** | (pqac-00000000, pqac-00000008, pqac-00000009, pqac-00000014, pqac-00000019) |
| 2023–2024 advances | **Iptacopan** phase 3 (APPLY-PNH, APPOINT-PNH; NEJM 2024): in anti-C5-treated patients, **51/60** achieved Hb increase ≥2 g/dL without transfusion and **42/60** achieved Hb ≥12 g/dL without transfusion vs **0/35** on continued anti-C5; in complement-inhibitor–naive patients, **31/33** achieved Hb increase ≥2 g/dL without transfusion. **59/62** iptacopan-treated vs **14/35** anti-C5-treated patients avoided transfusion in APPLY; in APPOINT, no patients required transfusion. Reviews summarize ravulizumab as noninferior to eculizumab with fewer breakthrough hemolysis events and pegcetacoplan as superior to eculizumab for persistent anemia in PEGASUS, with PRINCE supporting first-line use. | MAXO: oral small-molecule therapy **[validate]**; complement factor B inhibition **[validate]**; complement C3 inhibition **[validate]** | (pqac-00000008, pqac-00000009, pqac-00000023, pqac-00000024) |
| Prognosis / outcomes | Pre-complement era mortality was substantial; some retrospective analyses cited ~**35% 5-year mortality** and ~**50% 10-year mortality**. Complement inhibition markedly improves survival and reduces thrombosis. Review data cite **5-year survival 95.5%** with eculizumab and thrombotic events decreasing from **5.6 to 0.8 per 100 patient-years**. Thrombosis remains the leading cause of death in untreated disease and still occurs at lower frequency in the complement-inhibitor era. | HPO: reduced survival **[validate]**; thrombosis **[validate]**; chronic kidney disease **[validate]** | (pqac-00000006, pqac-00000009, pqac-00000016) |
| Model systems / comparative biology | Mouse and rhesus macaque PIGA-loss models recapitulate GPI-AP-deficient blood cells, shortened erythrocyte lifespan, and complement sensitivity, but generally **do not develop full human clinical hemolysis/thrombosis** or sustained clonal expansion. These models suggest **PIGA mutation alone is insufficient** and that immune context/secondary factors are important. No strong evidence from collected sources for a naturally occurring veterinary analog was identified. | CL: hematopoietic stem/progenitor cell **[validate]**; GO: erythrocyte homeostasis **[validate]** | (pqac-00000021, pqac-00000022) |
| Important gaps / caution flags | Exact disease identifiers (MONDO/OMIM/Orphanet/MeSH/ICD/HPO/GO/CL/UBERON/MAXO accessions) were not directly verified in the collected evidence and should be checked against the source ontologies before production use. Recent literature mentions additional somatic mutations and clonal hematopoiesis in marrow-failure contexts, but no robust disease-specific modifier set with validated clinical effect was established from the collected evidence. Omics/single-cell/spatial transcriptomic evidence was not clearly available in the retrieved material. | All exact accession numbers: **independent validation required** | (pqac-00000017, pqac-00000021, pqac-00000022) |


*Table: This compact table summarizes core disease facts for paroxysmal nocturnal hemoglobinuria, including cause, mechanism, phenotypes, diagnosis, epidemiology, treatment advances, prognosis, and model systems. It also flags ontology mappings and identifiers that should be independently validated before database ingestion.*