Paroxysmal Nocturnal Hemoglobinuria (PNH)

Acquired clonal hematopoietic stem cell disorder — complement-mediated intravascular hemolysis, thrombosis, and the modern era of terminal and proximal complement inhibition

Key Points

• PNH is an acquired clonal disorder caused by a somatic PIGA mutation in a hematopoietic stem cell, which blocks synthesis of GPI anchors and leaves blood cells deficient in the complement regulators CD55 and CD59 — exposing red cells to uncontrolled complement attack.
• The clinical triad is Coombs-negative intravascular hemolysis, thrombosis (the leading cause of death), and some degree of bone marrow failure — PNH frequently overlaps with aplastic anemia and MDS.
• Diagnosis is by high-sensitivity peripheral-blood flow cytometry (FLAER-based) quantifying the GPI-deficient clone size on granulocytes/monocytes and RBCs — not by the historical Ham or sucrose lysis tests.
• Terminal complement (C5) inhibitors — eculizumab, ravulizumab, and crovalimab — abolish intravascular hemolysis and thrombosis risk but require meningococcal vaccination and carry a boxed warning for Neisseria infection.
• Proximal inhibitors — pegcetacoplan (C3), iptacopan (Factor B), and danicopan (Factor D) — also control the C3-mediated extravascular hemolysis that limits C5 inhibitors, and iptacopan and pegcetacoplan can raise hemoglobin as oral or subcutaneous monotherapy.
• All complement inhibitors abrogate protection against encapsulated bacteria: meningococcal (and often pneumococcal/Hib) vaccination at least 2 weeks before the first dose, plus a high index of suspicion for breakthrough infection, is mandatory.

Pathophysiology

PNH arises from a somatic loss-of-function mutation in the X-linked PIGA gene within a hematopoietic stem cell. PIGA encodes an enzyme required for the first step in biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. Without a functional GPI anchor, an entire family of cell-surface proteins that are normally tethered by GPI cannot be expressed on the membrane of the affected clone and all of its progeny. Two of those missing proteins are the critical complement regulators: **CD55 (decay-accelerating factor)** normally accelerates decay of the C3 and C5 convertases, limiting…

Clinical Manifestations

PNH is classified into three overlapping categories that guide management: **Classic (hemolytic) PNH:** Florid intravascular hemolysis with a large granulocyte clone (often >50%), reticulocytosis, elevated LDH, and normal-to-hypercellular marrow. These patients have the most to gain from complement inhibition. **PNH in the setting of another bone marrow failure syndrome:** A smaller PNH clone detected alongside aplastic anemia or MDS; hemolysis may be modest and marrow-directed therapy predominates. **Subclinical PNH:** A tiny GPI-deficient clone without clinical or laboratory hemolysis,…

Diagnosis — High-Sensitivity Flow Cytometry

Peripheral-blood flow cytometry is the diagnostic gold standard and has replaced the obsolete Ham (acidified serum) and sucrose lysis tests. The assay detects the absence of GPI-anchored proteins on the surface of circulating cells and quantifies the size of the PNH clone. **Recommended panel (per international clinical cytometry consensus):** - Analyze at least two cell lineages and at least two GPI-linked markers per lineage. - **Granulocytes and monocytes** are preferred for measuring true clone size because, unlike red cells, they are not selectively destroyed by hemolysis or diluted by…

Complement Inhibition — Terminal (C5) vs Proximal Inhibitors

Complement inhibition transformed PNH from a disease with a median survival of ~10–15 years into a largely controllable chronic condition. The central therapeutic distinction is where in the cascade the drug acts. **Terminal (C5) inhibitors** block cleavage of C5, preventing MAC formation and abolishing intravascular hemolysis and its thrombotic consequences. However, because upstream C3 remains active, PNH red cells accumulate C3 fragments (opsonization) and can be cleared by splenic macrophages — producing **C3-mediated extravascular hemolysis**, a common reason some patients on eculizumab…

Choosing and Sequencing Therapy

**Treatment indications:** Complement inhibition is indicated for classic PNH with symptomatic hemolysis, transfusion dependence, thrombosis, or other complement-mediated complications. A small subclinical clone without hemolysis does not require complement inhibition — monitor instead. **Terminal inhibitor as a starting point:** Ravulizumab (8-weekly IV) or crovalimab (4-weekly SC) are convenient modern C5 inhibitors; eculizumab remains effective but requires 2-weekly infusions. All rapidly control intravascular hemolysis and reduce thrombotic risk. **Managing residual (extravascular)…

Thrombosis, Supportive Care, and the Marrow-Failure Overlap

**Thrombosis management:** Complement inhibition markedly reduces the incidence of thrombosis and is the most effective thromboprophylaxis in PNH. Acute PNH thrombosis (e.g., Budd-Chiari syndrome, cerebral sinus thrombosis) is treated with therapeutic anticoagulation in addition to urgent complement inhibition; catheter-directed thrombolysis is considered for life- or organ-threatening events. The role of primary pharmacologic thromboprophylaxis in patients on a complement inhibitor is individualized. **Supportive care:** - Folic acid supplementation for the chronic high-turnover hemolytic…

Investigational Directions

The proximal-inhibition strategy continues to expand. Oral Factor D inhibition is being explored as monotherapy with **vemircopan (ALXN2050)**. C5 synthesis can be silenced at the source with the subcutaneous siRNA **cemdisiran**, studied both alone and in a fixed combination with the anti-C5 antibody pozelimab to achieve deep, durable, infrequent dosing. Next-generation subcutaneous C5 blockers such as the anti-C5 nanobody **gefurulimab (ALXN1720)** aim to further improve convenience. The overall trajectory is toward oral or low-frequency subcutaneous regimens that control both…