Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic blood condition characterized by the abnormal breakdown of erythrocytes. This releases hemoglobin into the urine for excretion, often presenting as dark-colored urine in the morning.1
Paroxysmal nocturnal hemoglobinuria is caused by various somatic mutations in the PIGA gene that result in the production of faulty hematopoietic stem cells that lack glycosylphosphatidylinositol (GPI) anchor proteins.2 GPI anchor proteins attach to the surface membranes of erythrocytes. They are classified as complement-regulating surface proteins because they interact with complement proteins (usually C3b and C4b) and prevent activation of the complement system. Because GPI anchor proteins are lacking in PNH, the complement system is activated, leading to the premature destruction of erythrocytes.3
Available treatments for PNH include complement inhibitors, stem cell transplantation, corticosteroids, and supplementation for anemia. Special care must be given to pregnant women with PNH due to the increased risk of complications during pregnancy.
The US Food and Drug Administration (FDA) has approved the use of 3 complement inhibitors — Soliris® (eculizumab), Ultomiris® (ravulizumab), and Empaveli™ (pegcetacoplan) — for the treatment of PNH in 2007, 2018, and 2021, respectively. Soliris and Ultomiris inhibit the C5 complement component from cleaving into C5a and C5b, while Empaveli inhibits the C3 complement protein from cleaving into its C3b activation fragment.4,5
The inhibition of these complement proteins reduces the complement activation system’s proinflammatory effects and the formation of membrane attack complexes, which in turn reduces the premature hemolysis of erythrocytes in patients with PNH.6
While Soliris and Ultomiris control intravascular hemolysis, Empaveli additionally has the potential to control extravascular complement-mediated hemolysis due to its inhibition of C3, which is further upstream from C5 in the complement activation system. Empaveli binds to C3 and C3b with a pegylated 15-amino acid cyclic peptide, preventing uncontrolled complement activation and assembly of membrane attack complex (MAC).7
Read more about PNH therapies
Thrombosis is one of the life-threatening complications of PNH. Soliris and Ultomiris reduce the likelihood of acute thrombosis or thrombotic extension. Anticoagulants such as heparin or warfarin can be used emergently or for maintenance; however, it is possible that heparin may worsen thrombosis by activating complement. Other anticoagulants used for prophylaxis or maintenance include aspirin, ibuprofen, and sulfinpyrazone.4
Although thromboembolism prophylaxis is highly recommended in this patient population, an ongoing debate exists regarding whether anticoagulation is effective for patients with PNH.4
Read more about PNH complications
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNH because it replaces the dysfunctional hematopoietic stem cells in patients with PNH with functional stem cells from a histocompatible, healthy donor. However, this ideal scenario is not realistic for many patients with PNH. Therefore, HSCT is set aside for patients with severe cases of PNH that have either transformed to leukemia or co-occurred with aplastic anemia, which are both potentially fatal complications of PNH.4
Indications for allogeneic HSCT include4:
- Bone marrow failure
- Persistent thrombosis
- Severe hemolysis
Hematopoietic stem cell transplantation also carries with it a high post-transplant mortality rate. Between the years of 1978 and 1995, the 2-year survival rate following HSCT among 48 recipients of identical sibling transplants was 56%, according to the International Bone Marrow Transplant Registry.8,9
Another study from Italy reported similar mortality rates among 23 PNH patients who received transplants from human leukocyte antigen-identical donors. Around 57% of patients obtained 10-year disease-free survival, while 42% died following transplant. Additionally, 8% of these 23 patients developed graft failure after HSCT.8.10
A more recent retrospective study analyzed outcomes in 21 patients with PNH who were previously treated with Soliris before undergoing HSCT. While the mortality rates were lower than previous studies, almost 30% of these patients died from post-transplant infections or acute graft-versus-host disease.8,11
All of these potential complications must be considered prior to suggesting HSCT as a treatment for PNH.
Read more about PNH prognosis
Corticosteroids, often prescribed as 20 to 40 mg of prednisone daily, are often used to treat hemolysis, as this treatment has been shown to improve hemoglobin levels in approximately 70% of adults with PNH. Once remission is achieved, the dose of corticosteroids is reduced to alternating days as long-term corticosteroid use results in treatment-related complications.4
Low-dose prednisone reduces the need for red blood cell transfusions in patients with PNH who do not respond well to Soliris. According to clinical studies conducted, no severe adverse side effects were reported with low-dose administration of prednisone. Low-dose prednisone can also be used to control extravascular hemolysis in patients dependent on red blood cell transfusions, which may occur despite long-term eculizumab treatment.12
Treatments for Anemia
Patients with PNH who become anemic due to hemolysis, deficient erythropoiesis, and/or severe iron deficiency caused by the loss of hemoglobin may require a combination of iron supplementation, blood transfusions, oral folic acid supplementation, and oral ferrous sulfate, depending on the main causes of the anemia. Other treatments that replenish lost red blood cells by stimulating erythropoiesis include the use of androgenic hormones and recombinant erythropoietin therapy.13
Read more about PNH comorbidities
Treatments During Pregnancy
Patients with PNH who are pregnant have increased risks of thrombosis and hypoplastic anemia. Thrombotic prophylaxis using low-molecular-weight heparin is currently recommended during pregnancy. After the first trimester, warfarin may be used as an alternative.14
The use of Soliris has been found to be safe and effective during pregnancy in women with PNH, with low maternal complication rates and high fetal survival rates. Soliris has also not been detected in breast milk.14
- Besa EC. Paroxysmal nocturnal hemoglobinuria: practice essentials. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Besa EC. Paroxysmal nocturnal hemoglobinuria: etiology. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Besa EC. Paroxysmal nocturnal hemoglobinuria: pathophysiology. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Besa EC. Paroxysmal nocturnal hemoglobinuria treatment & management: approach considerations. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Risitano AM, Frieri C, Urciuoli E, Marano L. The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: from a pathogenic mechanism to a therapeutic target. Immunol Rev. Published online September 15, 2022. doi:10.1111/imr.13137
- Hillmen P, Muus P, Röth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2013;162(1):62-73. doi:10.1111/bjh.12347
- Wong RSM, Pullon HWH, Amine I, et al. Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria. Ann Hematol. 2022;101(9):1971-1986. doi:10.1007/s00277-022-04903-x
- Besa EC. Paroxysmal nocturnal hemoglobinuria treatment & management: hematopoietic stem cell transplantation. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Sašo R, Marsh J, Čevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1999;104(2):392-396. doi:10.1046/j.1365-2141.1999.01195.x
- Santarone S, Bacigalupo A, Risitano AM, et al. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Haematologica. 2010;95(6):983-988. doi:10.3324/haematol.2009.017269
- Vallet N, de Fontbrune FS, Loschi M, et al; Société Francophone de Greffe de Moelle et Thérapie Cellulaire. Hematopoietic stem cell transplantation for patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a retrospective study of 21 patients from SFGM-TC centers. Haematologica. 2018;103(3):e103-e105. doi:10.3324/haematol.2017.182360
- Moon JY, Jo DY, Lee SY, Kim DY, Baek SW, Song IC. Low-dose prednisolone in patients with paroxysmal nocturnal hemoglobinuria and inadequate response to eculizumab. Blood Res. 2017;52(4):337-339. doi:10.5045/br.2017.52.4.337
- Besa EC. Paroxysmal nocturnal hemoglobinuria treatment & management: treatment of anemia. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
- Besa EC. Paroxysmal nocturnal hemoglobinuria treatment & management: treatment in pregnancy. Medscape. Updated May 20, 2021. Accessed November 22, 2022.
Reviewed by Debjyoti Talukdar, MD, on 11/28/2022.