Paroxysmal Nocturnal Haemoglobinuria

A rare acquired clonal haematopoietic stem cell disorder caused by a somatic mutation in the PIGA gene, resulting in deficient glycosylphosphatidylinositol (GPI) anchor synthesis and consequent absence of GPI-anchored complement regulatory proteins (CD55 and CD59) on the surface of affected blood cells, leaving them vulnerable to unchecked complement-mediated destruction. Classically presents with the triad of haemolytic anaemia, thrombosis and cytopenias, though the classical nocturnal haemoglobinuria is present in only a minority.

Pathophysiology

CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis) normally protect host cells from complement attack by inhibiting the C3/C5 convertases and the membrane attack complex respectively.

Their absence on the PNH clone renders red cells susceptible to complement-mediated intravascular haemolysis, releases free haemoglobin that scavenges nitric oxide (driving smooth muscle dystonia --- abdominal pain, oesophageal spasm, erectile dysfunction, pulmonary hypertension), and activates platelets, producing the characteristic marked thrombotic tendency, particularly in unusual sites (hepatic, portal, mesenteric, cerebral venous sinuses).

Association with aplastic anaemia

PNH clones are frequently found in patients with aplastic anaemia (and vice versa --- PNH can evolve from or into aplastic anaemia), reflecting a shared underlying immune-mediated marrow injury from which the PNH clone has a relative survival advantage.

• Fatigue and pallor from chronic intravascular haemolytic anaemia.
• Haemoglobinuria, classically dark morning urine (nocturnal exacerbation historically attributed to complement activation favoured by the relative acidosis of sleep, though the mechanism is debated), present in a minority of patients as the presenting feature.
• Smooth muscle dystonia from nitric oxide scavenging: abdominal pain, dysphagia/oesophageal spasm, erectile dysfunction, and fatigue disproportionate to the anaemia.
• Thrombosis, the leading cause of death, occurring in unusual sites --- hepatic vein (Budd-Chiari syndrome), portal/mesenteric veins, cerebral venous sinuses, dermal veins, in addition to conventional deep vein thrombosis/pulmonary embolism.
• Cytopenias reflecting the underlying marrow disorder (bone marrow failure spectrum), sometimes with overt or subclinical aplastic anaemia.
• Chronic kidney disease from recurrent haemoglobinuria-induced tubular injury and iron deposition (haemosiderosis).
• Pulmonary hypertension from chronic nitric oxide depletion.

• Flow cytometry (high-sensitivity, using fluorescent aerolysin --- FLAER --- along with CD55/CD59) on peripheral blood is the diagnostic test of choice, quantifying the PNH clone size across granulocyte, monocyte and red cell populations.
• Full blood count with reticulocyte count, LDH (markedly elevated, a key marker of intravascular haemolysis and disease activity), haptoglobin (low/absent), unconjugated bilirubin.
• Direct antiglobulin test is negative (complement-mediated, not antibody-mediated), a key distinguishing feature from autoimmune haemolytic anaemia.
• Urinalysis for haemoglobinuria and haemosiderinuria.
• Bone marrow examination to assess for underlying aplastic anaemia or myelodysplastic features, given the close biological relationship.
• Screen for thrombosis actively where clinically suggested (imaging for hepatic/portal/cerebral venous thrombosis) given the high burden and atypical presentation.
• Iron studies (chronic haemoglobinuria causes iron deficiency despite haemolysis, an important and sometimes overlooked coexisting deficiency).

• Complement inhibition is the disease-modifying treatment of choice for clinically significant PNH (haemolysis with symptoms, transfusion dependence, thrombosis, or significant clone size with symptoms): eculizumab or ravulizumab (terminal complement C5 inhibitors, given intravenously), which dramatically reduce intravascular haemolysis, transfusion requirement and thrombotic risk.
• Newer proximal complement inhibitors (pegcetacoplan, targeting C3; danicopan, an oral factor D inhibitor as add-on therapy) address breakthrough extravascular haemolysis that can occur with C5 inhibition alone (since C3 opsonisation still occurs, allowing extravascular clearance).
• Meningococcal vaccination (and often prophylactic antibiotics) is mandatory before starting complement inhibitors, given markedly increased risk of meningococcal infection with terminal complement blockade; vaccinate at least 2 weeks before starting where possible, or cover with antibiotics if urgent initiation is required.
• Anticoagulation for established thrombosis, and consideration of prophylactic anticoagulation in patients with significant PNH clones and additional risk factors, given the very high thrombotic burden of this disease.
• Folic acid and iron supplementation as needed given chronic haemolysis and haemoglobinuria-associated iron loss.
• Transfusion support for symptomatic anaemia.
• Allogeneic haematopoietic stem cell transplantation is the only curative option, reserved for patients with concurrent severe aplastic anaemia, evolution to myelodysplasia/leukaemia, or complement-inhibitor-refractory disease with life-threatening complications, given transplant-related morbidity.
• Lifelong monitoring of clone size, haemolysis markers, renal function and thrombotic risk, with close haematology follow-up.