Identify complement-mediated intravascular haemolysis and unusual thrombosis, quantify the abnormal clone, distinguish marrow failure overlap, and use complement inhibition with infection safeguards.
A PIGA-mutant stem cell cannot complete the anchor that attaches multiple protective proteins to blood-cell membranes. Its progeny therefore lack complement regulators, particularly CD55 and CD59. Complement activation punctures vulnerable red cells, releasing free haemoglobin. The consequences extend beyond anaemia: nitric-oxide scavenging contributes to smooth-muscle dystonia, dysphagia and abdominal or chest pain, while endothelial activation, platelets and impaired fibrinolysis contribute to thrombosis.
The clinical spectrum ranges from a tiny asymptomatic clone found during aplastic-anaemia testing to classical PNH with substantial haemolysis and thrombosis. Laboratory features include raised LDH, reticulocytosis, low haptoglobin and haemoglobinuria, but marrow failure can blunt reticulocytes. Direct antiglobulin testing is usually negative before therapy. Flow cytometry should examine at least two GPI-linked markers in more than one lineage. Granulocyte and monocyte clone sizes better reflect the stem-cell clone than red cells after transfusion or complement-mediated selection.
An acquired mutation in a haematopoietic stem cell disrupts synthesis of the GPI anchor. The disorder is clonal rather than inherited and can affect erythroid, myeloid and platelet lineages.
Immune-mediated marrow injury appears to favour survival or expansion of GPI-deficient stem cells, explaining the close association between small PNH clones and aplastic anaemia.
Loss of CD55 and CD59 permits complement amplification and membrane-attack-complex formation, lysing affected erythrocytes within the circulation and releasing free haemoglobin.
Cell-free haemoglobin binds nitric oxide, promoting vasoconstriction and smooth-muscle symptoms such as abdominal pain, dysphagia and erectile dysfunction while contributing to vascular dysfunction.
Complement activation, abnormal platelets, endothelial injury, free haemoglobin and impaired fibrinolysis combine to create a marked venous and arterial thrombotic tendency.
The mutant clone may coexist with immune marrow failure or clonal evolution, producing cytopenias that are not explained by haemolysis and may persist despite complement control.
Raised LDH, low haptoglobin, reticulocytosis and haemoglobinuria occur without red-cell antibody coating in classical untreated disease.
Recurrent abdominal or chest pain, dysphagia and erectile dysfunction can accompany haemolytic episodes through nitric-oxide depletion.
Budd-Chiari syndrome, abdominal venous thrombosis or cerebral venous thrombosis should trigger a search for PNH and other causes.
Fever, headache, rash, meningism or shock during complement inhibition requires immediate sepsis treatment and specialist notification.
Neutropenia or thrombocytopenia disproportionate to haemolysis suggests aplastic overlap, clonal disease or another marrow process.
Warm or cold antibody disease can cause anaemia, jaundice and raised LDH; antiglobulin findings, spherocytes or agglutination and absence of a GPI-deficient clone distinguish it.
TTP, HUS and mechanical fragmentation produce schistocytes with thrombocytopenia or device context, whereas classical PNH often has smooth intravascular haemolysis without fragmentation.
Aplastic anaemia or myelodysplasia can produce pancytopenia with little haemolysis; marrow assessment and clone measurement define whether PNH is incidental, contributory or classical.
G6PD-related intravascular haemolysis, infection, burns, transfusion reactions and mechanical devices can darken urine; trigger history and targeted testing prevent anchoring on its timing.
Hepatic, portal, mesenteric, cerebral and dermal veins may thrombose, causing abdominal pain, Budd-Chiari physiology, neurological deficits or skin injury with high recurrence risk.
Free haemoglobin causes acute tubular toxicity during severe haemolysis and chronic haemosiderin deposition, while thrombosis and hypertension can add renal damage.
Terminal-complement blockade impairs killing of Neisseria, leaving substantial invasive-disease risk despite appropriate vaccination and any prescribed antimicrobial prophylaxis.
Associated marrow failure can persist or evolve toward myelodysplastic syndrome or acute myeloid leukaemia, requiring longitudinal blood counts and marrow reassessment when patterns change.
Haemolysis is not confined to sleep and visible haemoglobinuria is neither necessary nor sufficient for diagnosis.
Granulocytes and monocytes reveal clone size more reliably than erythrocytes removed by haemolysis or diluted by transfusion.
C3-mediated clearance, marrow failure, iron balance, renal impairment and bleeding should be separated before declaring terminal inhibition ineffective.
Complement is fundamental to Neisseria defence, so a vaccinated patient with compatible sepsis symptoms still needs immediate antibiotics.
Excluding PNH because haemoglobinuria is not nocturnal.
Measuring only the transfusion-distorted red-cell clone.
Calling every cytopenia complement-mediated haemolysis.
Treating unusual thrombosis without controlling active PNH.
Reassuring a febrile vaccinated complement-inhibitor recipient.
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A transfused patient has Coombs-negative intravascular haemolysis and suspected paroxysmal nocturnal haemoglobinuria. Which test most reliably establishes and sizes the abnormal clone?
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
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Vaccinate against available meningococcal serogroups at least 2 weeks before starting where treatment can safely wait; if urgent treatment starts sooner, give appropriate antibiotic prophylaxis until 2 weeks after vaccination. Infection can still progress rapidly despite both measures, so provide an emergency plan and review infusion reactions, weight change and pregnancy planning.
Apply the same meningococcal vaccination, antibiotic-bridging and emergency-infection safeguards as for ravulizumab. Monitor for breakthrough haemolysis, infusion effects and loss of control around surgery, pregnancy or other major complement activation.
Severe thrombocytopenia, varices, procedures and hepatic disease alter safety; anticoagulation alone does not control complement-mediated haemolysis.