PNH

**Pathophysiology** - Acquired somatic mutation of the **PIGA** gene (X-linked) in a hematopoietic stem cell. PIGA is needed to synthesize the glycosylphosphatidylinositol (GPI) anchor. - Without the GPI anchor, cells lack **CD55 (decay-accelerating factor, DAF)** and **CD59 (membrane inhibitor of reactive lysis, MIRL/protectin)**. These normally inhibit the C3 convertase and the membrane attack complex (MAC). - RBCs are therefore susceptible to **complement-mediated intravascular hemolysis**. It is not inherited, and it is a clonal expansion of the mutated cells. - Hemolysis may worsen at night because mild respiratory acidosis during sleep activates complement. Infection, surgery, and stress also trigger it. Despite the name, hemoglobinuria is often not strictly nocturnal or paroxysmal.

**Clinical features** - Intravascular hemolytic anemia (Coombs-negative): ↑LDH, ↑indirect bilirubin, ↓haptoglobin, free plasma hemoglobin, hemoglobinuria (dark/cola-colored urine, especially in the morning), and hemosiderinuria. - **Thrombosis** is the leading cause of death. It occurs in unusual sites: hepatic veins (**Budd-Chiari syndrome**), portal, mesenteric, and cerebral venous sinuses. Causes include free hemoglobin scavenging nitric oxide and platelet activation by complement. - Smooth muscle dystonia from NO depletion: abdominal pain, esophageal spasm, dysphagia, erectile dysfunction. - Pancytopenia or cytopenias because of an association with **aplastic anemia** (bone marrow failure). PNH clones can evolve from or into aplastic anemia, and rarely MDS/AML. - Iron deficiency from chronic urinary iron loss. - Chronic kidney disease from hemosiderin deposition and microthrombi.

**Diagnosis** - **Flow cytometry** is the gold standard. It shows absent CD55 and CD59 on RBCs and WBCs. FLAER (fluorescent aerolysin) detects GPI-anchored proteins on granulocytes and monocytes. - The historical Ham (acidified serum) test and the sucrose lysis test are no longer used. - Coombs test negative, which distinguishes PNH from autoimmune hemolytic anemia. - Suspect PNH in unexplained Coombs-negative hemolysis with thrombosis or cytopenias.

**Treatment** - **Eculizumab** and **ravulizumab** are monoclonal antibodies against **C5**. They block MAC formation and reduce hemolysis and thrombosis. The key adverse effect is increased risk of **Neisseria meningitidis** (encapsulated organism) infection, so patients need meningococcal vaccination (and often prophylactic antibiotics). Pegcetacoplan (C3 inhibitor) is an alternative. Iptacopan (factor B inhibitor) is an oral option. - Anticoagulation for thrombosis. - Supportive: transfusions, folate, iron as needed. - **Allogeneic hematopoietic stem cell transplant** is the only cure. It is reserved for severe marrow failure or refractory disease.

**High-yield associations** - Acquired, not inherited (contrast with hereditary spherocytosis, G6PD deficiency). - Triad: hemolytic anemia + thrombosis + pancytopenia. - Budd-Chiari syndrome in a young patient with hemolysis suggests PNH. - Only common hemolytic anemia with a complement-mediated, intravascular mechanism and a Coombs-negative result. - Eculizumab leaves patients at risk for meningococcal infection (terminal complement deficiency C5-C9).