Paroxysmal nocturnal haemoglobinuria

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

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.

Treatment is phenotype led. Support folate, transfuse when clinically indicated and manage iron according to measured deficiency or loading. Complement inhibitors require specialist commissioning, vaccination and infection governance. Breakthrough haemolysis may follow infection, underexposure or intense complement activation and needs pharmacological and trigger review. Residual anaemia may reflect C3-mediated extravascular haemolysis, marrow failure, iron deficiency, renal disease or another cause rather than automatic drug failure. Acute thrombosis involves a PNH centre and thrombosis team because complement control and anticoagulation decisions are linked.

Key points

PNH is an acquired clonal haematopoietic stem-cell disorder caused by a somatic PIGA mutation and loss of glycosylphosphatidylinositol-anchored surface proteins.
Deficiency of CD55 and CD59 leaves blood cells vulnerable to complement, producing predominantly intravascular haemolysis, thrombosis and variable marrow failure.
Haemoglobinuria may be absent or intermittent; unexplained Coombs-negative haemolysis, abdominal pain, dysphagia, cytopenias or thrombosis at an unusual site should prompt testing.
Flow cytometry using FLAER and lineage-specific GPI-linked markers on granulocytes and monocytes establishes and measures the clone; red-cell results are altered by haemolysis and transfusion.
Thrombosis may involve hepatic, portal, mesenteric or cerebral veins and is a leading source of morbidity, sometimes preceding obvious haemoglobinuria.
PNH frequently overlaps aplastic anaemia or myelodysplastic disease, so clone size must be interpreted alongside marrow cellularity, counts and morphology.
Terminal C5 inhibition with eculizumab or ravulizumab reduces intravascular haemolysis and thrombosis in eligible symptomatic disease but increases susceptibility to meningococcal infection.
Proximal complement inhibitors may control both intravascular and C3-mediated extravascular haemolysis in selected adults through current NICE and specialist eligibility.
Vaccination, antimicrobial planning and explicit emergency fever instructions must precede or accompany urgent complement blockade; neither vaccines nor prophylaxis confer complete protection.
Allogeneic stem-cell transplantation can eradicate the clone but is generally reserved for severe associated marrow failure because procedure risk exceeds that of controlled isolated PNH.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Somatic PIGA mutation

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.

Marrow selection

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.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Uncontrolled terminal complement
Loss of CD55 and CD59 permits complement amplification and membrane-attack-complex formation, lysing affected erythrocytes within the circulation and releasing free haemoglobin.
2
Nitric-oxide depletion
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.
3
Thrombo-inflammatory state
Complement activation, abnormal platelets, endothelial injury, free haemoglobin and impaired fibrinolysis combine to create a marked venous and arterial thrombotic tendency.
4
Clonal marrow overlap
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.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Coombs-negative haemolysis

Raised LDH, low haptoglobin, reticulocytosis and haemoglobinuria occur without red-cell antibody coating in classical untreated disease.

Smooth-muscle symptoms

Recurrent abdominal or chest pain, dysphagia and erectile dysfunction can accompany haemolytic episodes through nitric-oxide depletion.

Atypical thrombosis

Budd-Chiari syndrome, abdominal venous thrombosis or cerebral venous thrombosis should trigger a search for PNH and other causes.

Meningococcal warningRed flag

Fever, headache, rash, meningism or shock during complement inhibition requires immediate sepsis treatment and specialist notification.

Marrow-failure phenotype

Neutropenia or thrombocytopenia disproportionate to haemolysis suggests aplastic overlap, clonal disease or another marrow process.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Full blood count, reticulocytes and filmFirst step
Why
Measure anaemia, compensation and additional cytopenias.
Interpretation and limitations
Reticulocytes rise with preserved marrow reserve; pancytopenia or dysplasia changes the need for marrow investigation, while schistocytes suggest a competing process.
02
LDH, bilirubin and haptoglobin
Why
Quantify the intravascular haemolysis pattern.
Interpretation and limitations
A disproportionate LDH rise and depleted haptoglobin support active haemolysis; serial values help assess complement-inhibitor response and breakthrough.
03
High-sensitivity flow cytometry
Why
Detect and size GPI-deficient cell populations.
Interpretation and limitations
FLAER and lineage markers on granulocytes and monocytes define the clone; red-cell proportions underestimate it after transfusion or ongoing lysis.
04
Direct antiglobulin test
Why
Assess immune haemolysis and treatment-related C3 coating.
Interpretation and limitations
Untreated PNH is usually negative; C3 positivity can appear during terminal-complement blockade and must be interpreted with the treatment context.
05
Targeted venous imaging
Why
Confirm thrombosis at the symptomatic anatomical site.
Interpretation and limitations
Use Doppler, CT or MR venography for hepatic, abdominal or cerebral symptoms; a negative leg ultrasound does not address unusual-site disease.
06
Bone-marrow examination
Why
Characterise cytopenia, cellularity and clonal evolution.
Interpretation and limitations
Hypocellularity supports aplastic overlap; dysplasia, cytogenetic change or blasts require a myeloid-neoplasm pathway separate from clone size.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Autoimmune haemolysis

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.

Microangiopathic haemolysis

TTP, HUS and mechanical fragmentation produce schistocytes with thrombocytopenia or device context, whereas classical PNH often has smooth intravascular haemolysis without fragmentation.

Primary marrow failure

Aplastic anaemia or myelodysplasia can produce pancytopenia with little haemolysis; marrow assessment and clone measurement define whether PNH is incidental, contributory or classical.

Other haemoglobinuria

G6PD-related intravascular haemolysis, infection, burns, transfusion reactions and mechanical devices can darken urine; trigger history and targeted testing prevent anchoring on its timing.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Case findingTest the right haemolytic or marrow phenotypeFirst stepUnexplained antiglobulin-negative haemolysis, unusual thrombosis or aplastic cytopenia is present.

1Confirm haemolysis and review film, transfusion timing, renal function and all cytopenias rather than screening solely because urine once looked dark.
2Request high-sensitivity PNH flow cytometry on granulocytes, monocytes and red cells through an accredited laboratory, documenting recent complement therapy.
3Refer a confirmed clone to a specialist PNH or marrow-failure service to classify classical, marrow-overlap or subclinical disease and establish follow-up.

02Acute eventControl thrombosis and haemolysis togetherNew abdominal, neurological or cardiopulmonary symptoms suggest thrombosis or severe haemolysis.

1Stabilise physiology, obtain site-directed imaging and measure counts, LDH, renal function, urine and coagulation while contacting haematology immediately.
2Begin anticoagulation when indicated after individual bleeding and platelet review, and initiate or optimise complement inhibition through the specialist service.
3Treat infection, kidney injury, pain and symptomatic anaemia, then document long-term anticoagulation and disease-control decisions after the event.

03Complement treatmentBuild infection safety around blockadeSymptomatic haemolysis, thrombosis or another commissioned indication supports complement inhibition.

1Confirm current NICE eligibility and select the licensed inhibitor with the PNH centre, recording baseline haemolysis, organ status and reproductive considerations.
2Give recommended meningococcal vaccines and any required antimicrobial prophylaxis without delaying life-saving urgent treatment; provide a written emergency fever plan.
3Monitor haemoglobin, LDH, reticulocytes and symptoms, investigating breakthrough, extravascular haemolysis, marrow failure and adherence or interval issues separately.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Blocks complement component C5 to reduce intravascular haemolysis, transfusion burden and PNH-associated thrombosis in eligible patients.

Ravulizumab

For adults weighing at least 40 kg, give an intravenous loading dose of 2,400 mg at 40 to under 60 kg, 2,700 mg at 60 to under 100 kg or 3,000 mg at 100 kg or more. Give the first maintenance dose 2 weeks later, then 3,000 mg, 3,300 mg or 3,600 mg respectively every 8 weeks; use the licensed switch schedule when changing inhibitor.

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.

Terminal-complement inhibition controls clinically significant PNH haemolysis and reduces thrombotic risk.

Eculizumab

For adult PNH, give 600 mg intravenously once weekly for 4 weeks, 900 mg in week 5, then 900 mg every 14 days. The specialist service uses supplementary dosing after plasma exchange or infusion according to the product information.

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.

Treats acute venous or arterial thrombosis while disease-directed therapy reduces its PNH driver.

Anticoagulation for confirmed thrombosis

The thrombosis and PNH teams select agent, initial intensity and duration from anatomy, platelet count, renal or liver function, bleeding and concurrent complement control.

Severe thrombocytopenia, varices, procedures and hepatic disease alter safety; anticoagulation alone does not control complement-mediated haemolysis.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Unusual-site thrombosis

Hepatic, portal, mesenteric, cerebral and dermal veins may thrombose, causing abdominal pain, Budd-Chiari physiology, neurological deficits or skin injury with high recurrence risk.

Kidney injury

Free haemoglobin causes acute tubular toxicity during severe haemolysis and chronic haemosiderin deposition, while thrombosis and hypertension can add renal damage.

Meningococcal infection

Terminal-complement blockade impairs killing of Neisseria, leaving substantial invasive-disease risk despite appropriate vaccination and any prescribed antimicrobial prophylaxis.

Clonal evolution

Associated marrow failure can persist or evolve toward myelodysplastic syndrome or acute myeloid leukaemia, requiring longitudinal blood counts and marrow reassessment when patterns change.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Trend haemoglobin, reticulocytes, LDH, bilirubin, haptoglobin and transfusion need against symptoms and inhibitor timing.
Repeat renal function, urinalysis and blood pressure after major haemolysis and during chronic follow-up for haemoglobin-related kidney injury.
Review every fever or systemic illness urgently during complement blockade and reinforce patient-held meningococcal information at each specialist contact.
Track granulocyte and monocyte clone sizes at specialist-defined intervals, especially when counts, marrow disease or treatment decisions change.
Reassess cytopenias independently of LDH; persistent neutropenia, thrombocytopenia or low reticulocytes may require repeat marrow and cytogenetic evaluation.
After thrombosis monitor the affected organ, anticoagulant safety and evidence of breakthrough complement activity rather than relying on symptom resolution alone.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The name misleads

Haemolysis is not confined to sleep and visible haemoglobinuria is neither necessary nor sufficient for diagnosis.

Lineages matter

Granulocytes and monocytes reveal clone size more reliably than erythrocytes removed by haemolysis or diluted by transfusion.

Residual anaemia has mechanisms

C3-mediated clearance, marrow failure, iron balance, renal impairment and bleeding should be separated before declaring terminal inhibition ineffective.

Vaccines cannot normalise risk

Complement is fundamental to Neisseria defence, so a vaccinated patient with compatible sepsis symptoms still needs immediate antibiotics.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding PNH because haemoglobinuria is not nocturnal.
02
Measuring only the transfusion-distorted red-cell clone.
03
Calling every cytopenia complement-mediated haemolysis.
04
Treating unusual thrombosis without controlling active PNH.
05
Reassuring a febrile vaccinated complement-inhibitor recipient.