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PNH in Brief
Paroxysmal Nocturnal Hemoglobinuria in Brief: Clinical Management Today

Released: March 12, 2026

Carlos M. De Castro
Carlos M. De Castro, MD
David Dingli
David Dingli, MD, PhD, FRCP, FRCPEd, FACP, FRCPath
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Key Takeaways
  • Suspected paroxysmal nocturnal hemoglobinuria is diagnosed by flow cytometry with fluorescein-labeled proaerolysin reagent to identify the absence of GPI-linked proteins.
  • C5 inhibitors such as eculizumab or ravulizumab control intravascular hemolysis and were established as primary therapy, but some patients may remain anemic due to extravascular hemolysis.
  • Proximal inhibitors targeting C3, Factor B, or Factor D help to mitigate both intravascular and extravascular hemolysis.

Diagnosis of Paroxysmal Nocturnal Hemoglobinuria

Carlos De Castro, MD:
In clinical practice, the presentation that should prompt suspicion for paroxysmal nocturnal hemoglobinuria (PNH) is typically an acquired hemolytic anemia with fatigue and dyspnea that may be accompanied by dark, “tea‑colored” morning urine, jaundice, and smooth muscle symptoms such as abdominal pain or esophageal spasm. The hemolysis in PNH is intravascular and releases free hemoglobin, depleting nitric oxide. This nitric oxide depletion helps explain several of the nonhematologic manifestations and contributes to endothelial dysfunction and a heightened thrombotic risk. Venous thromboses can occur in both usual and unusual sites, notably in the splanchnic beds, and arterial events are also seen, so atypical thrombosis in the setting of hemolysis should raise a flag for PNH. Early recognition matters because modern complement inhibition dramatically reduces thrombotic complications and improves outcomes.

David Dingli, MD:
The initial laboratory evaluation should confirm hemolysis and help differentiate PNH from more common entities. I obtain a complete blood count, reticulocyte count, metabolic panel, lactose dehydrogenase (LDH), and haptoglobin. In untreated PNH, the Coombs test is generally negative, LDH and reticulocytes are elevated, and haptoglobin is low, often with urine hemosiderin. I also check a D‑dimer to gauge thrombotic risk. Screening for a PNH clone is appropriate in acquired bone marrow failure syndromes, and the differential diagnosis includes warm autoimmune hemolytic anemia (Coombs positive), hereditary hemolytic states, and traumatic or microangiopathic causes, depending on the clinical context. Once the healthcare professional suspects PNH, the diagnostic step is straightforward: high‑sensitivity flow cytometry using FLAER or fluorescein-labeled proaerolysin reagent to identify loss of the glycosylphosphatidylinositol (GPI) anchor together with panels for GPI‑anchored proteins (eg, CD14, CD24, CD55/CD59) across granulocytes, monocytes, and red blood cells. We typically estimate clone size on granulocytes and monocytes; red blood cell clone sizes can appear smaller in untreated patients owing to ongoing hemolysis.

Treatments for PNH

Carlos De Castro, MD:
Complement inhibition has reshaped the prognosis of PNH. With effective therapy, intravascular hemolysis is controlled, thrombotic events are markedly reduced, and many patients return to near‑normal daily function. Our treatment goals now extend beyond survival and transfusion avoidance to sustained symptom control and quality of life. At the same time, we recognize that a subset of patients treated with terminal complement (C5) blockade remain anemic because of C3‑mediated opsonization and extravascular hemolysis (EVH). That observation led to the development of proximal inhibitors that act upstream to address both intravascular hemolysis and EVH, giving us multiple, highly effective options to personalize therapy.

David Dingli, MD:
Among approved therapies, there are 3 C5 inhibitors and 3 proximal inhibitors, and their differences in target, route, schedule, indications, and switching considerations drive shared decision‑making.

Eculizumab is the first‑in‑class C5 monoclonal antibody dosed intravenously every 2 weeks following loading. It established the modern standard by controlling intravascular hemolysis and lowering thrombosis rates. Ravulizumab, a longer‑acting C5 antibody, achieves noninferior disease control with weight‑based IV dosing every 8 weeks after loading, a meaningful convenience advantage that is approved from infancy through adulthood. Crovalimab is a C5 antibody initiated with an IV loading dose followed by weekly subcutaneous loading and then subcutaneous maintenance every 4 weeks; in C5‑naive patients, it has shown noninferiority to eculizumab, and it binds both wild‑type C5 and certain C5 variants that confer resistance to eculizumab. When switching from another anti‑C5, we counsel about transient drug–target–drug complexes that can cause a serum‑sickness–like reaction after the first dose; this phenomenon is typically self‑limited but warrants anticipatory guidance.

Pegcetacoplan, a subcutaneous C3 inhibitor self administered twice weekly, was superior to eculizumab for hemoglobin improvement in the PEGASUS trial and mitigates both intravascular hemolysis and EVH; benefits have proved durable in long‑term follow‑up and in treatment‑naive cohorts. Safe switching is essential: when transitioning from eculizumab, we overlap by initiating pegcetacoplan and continuing eculizumab at its current dose, then discontinue eculizumab and proceed with pegcetacoplan monotherapy after 4 weeks; from ravulizumab, pegcetacoplan should begin no more than 4 weeks after the last ravulizumab dose.

Iptacopan, an oral factor B inhibitor taken twice daily, has shown superior hemoglobin outcomes vs continued anti‑C5 therapy in patients with residual anemia. Iptacopan has also shown meaningful gains in fatigue and transfusion avoidance, with supportive prospective data, even among patients who appeared reasonably controlled at baseline. When switching, initiate iptacopan no later than 1 week after the last eculizumab dose or within 6 weeks of the last ravulizumab dose to guard against breakthrough hemolysis.

Danicopan, an oral Factor D inhibitor that is dosed 3 times daily, is approved only as add‑on therapy to eculizumab or ravulizumab for clinically significant EVH. In randomized and long‑term studies, adding danicopan rapidly raised hemoglobin and improved fatigue, with sustained benefit during extension treatment. Danicopan also fills an important niche for patients who otherwise prefer to maintain their existing C5 regimen.

In parallel with complement‑directed therapy, supportive care includes immunizations and selective supplementation (eg, iron or vitamins if deficient). With modern inhibitors, routine anticoagulation is generally unnecessary in the absence of prior thrombosis. Allogeneic transplant remains an option for a minority—primarily those with bone marrow failure (eg, aplastic anemia), truly refractory disease, or recurrent thromboses despite adequate complement inhibition—but is rarely required in classic hemolytic PNH today.

Emphasis on Patient Education, Quality of Life, and Shared Decision-making

Carlos De Castro, MD:
Therapy selection is a shared decision that balances medical needs with actual life realities. We discuss route and frequency (IV every 2-8 weeks, subcutaneous every 4 weeks or twice weekly, or oral twice‑ or thrice‑daily), the practicality of home administration vs infusion center visits, storage needs for certain products, and the likelihood of adherence, which is particularly relevant for oral or more frequent regimens. Coverage and access issues often shape the final choice. For younger women, we plan proactively around pregnancy: most real‑world experience remains with eculizumab, dose adjustments may be required to maintain therapeutic levels during gestation, anticoagulation is commonly recommended from the second trimester until postpartum, and close collaboration between high‑risk obstetrics and a PNH specialist is essential. Above all, I stress that the goal is not just hematologic control but a return to normal activity and well‑being, and we tailor the regimen to support that goal.

David Dingli, MD:
Patient education and adherence are fundamental to sustained control since breakthrough hemolysis most often occurs at troughs or after missed doses. We set clear expectations that complement inhibitors carry a boxed warning for meningococcal infection and require enrollment in a REMS program. Meningococcal vaccination should be up to date before therapy when feasible, with antibiotic prophylaxis if treatment must start earlier. For proximal inhibitors such as pegcetacoplan, iptacopan, and danicopan, we also vaccinate against Streptococcus pneumoniae and Haemophilus influenzae according to ACIP guidance. We remind patients that no vaccine is 100% protective and that urgent evaluation is necessary if symptoms of meningitis or sepsis develop. Vaccines can activate complement. In patients not yet protected, a practical sequence is to start antibiotics, initiate the complement inhibitor, and then vaccinate shortly thereafter.

We give explicit instructions on when to contact the care team or seek urgent care. Patients should call immediately for high fever, severe headache with neck stiffness, petechial or purpuric rash, altered mental status, or rapid “flu‑like” deterioration that could indicate invasive meningococcal disease. They should also call for signs of breakthrough hemolysis, such as a sudden return of dark urine, new or worsening fatigue, tachycardia, chest or abdominal pain, dyspnea, or any rapid drop in hemoglobin if known. Symptoms concerning for thrombosis—unilateral leg swelling or pain, chest pain, shortness of breath, focal neurologic deficits, or severe abdominal pain suggesting splanchnic thrombosis—warrant emergency evaluation. When switching from one C5 inhibitor to another, patients should report new rashes or serum‑sickness–like symptoms because transient immune complexes can form, particularly with the first crovalimab dose after prior anti‑C5 exposure. These events are usually self‑limited but should be communicated. Finally, missed or delayed doses should prompt a call right away, since schedule adjustments or bridging can prevent pharmacokinetic breakthrough.

For persistent anemia on therapy, we take a structured approach. On anti‑C5 agents, a pattern of reticulocytosis with mild indirect hyperbilirubinemia suggests EVH from C3 opsonization. In such cases, switching to a proximal inhibitor—pegcetacoplan or iptacopan—can normalize hemoglobin and reduce transfusion needs. Alternatively, adding danicopan to ongoing eculizumab or ravulizumab is effective for clinically significant EVH while maintaining a familiar regimen. We also exclude iron deficiency or other nutritional gaps, evaluate for inflammatory states or chronic kidney disease that may depress erythropoiesis, and consider marrow failure in appropriate contexts. With good education and consistent dosing, breakthrough hemolysis becomes uncommon in my experience, and most patients live with few or no disease‑related symptoms.

Your Thoughts
What questions do you have about the care of patients with PNH? Do you have any experiences that you’d like to share with the healthcare community? Or maybe challenges that others might also be experiencing or have experienced and managed? Please leave a comment below.

For more information, visit Decera’s Rare Blood Diseases Resource Hub.

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