Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease of pluripotent hematopoietic stem cells. PNH is characterized by hemolytic anemia, hemoglobinuria, and symptoms such as fatigue and shortness of breath.1-3
Etiology of PNH
PNH is linked to a somatic mutation of the phosphatidylinositol glycan class A (PIGA) gene in hematopoietic stem cells.1,2 This mutation results in a deficiency of glycosylphosphatidylinositol (GPI) protein, which anchors other proteins to the surface of red blood cells. Complement inhibition is prevented as CD55 and CD59 proteins are unable to attach to affected cells; the result is chronic complement-mediated hemolysis of PNH cells.2,3
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Epidemiology of PNH
PNH affects both men and women, with an estimated prevalence of 15.9 individuals per million people worldwide.1-3 Patients can be of any age, but PNH often develops in patients between 30 and 40 years old. Children are not often affected.2
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Symptoms of PNH
The symptoms of PNH result from the production of abnormal blood cells and the insufficient production of blood cells in the bone marrow. The severity of symptoms varies among patients, ranging from mild and stable to life-threatening.1
Due to hemolysis, hemoglobin is present in the urine. Hemoglobinuria may present as dark-colored or blood-colored urine, although the hemoglobin is not always visible to the naked eye. Hemolysis can be exacerbated by stress, trauma, or infection.1 Mild hemolysis can cause headache, chest pain, and difficulty breathing. Severe hemolysis can result in disabling fatigue, dysphagia, and esophageal spasm. Patients with PNH are susceptible to the development of thrombosis, which can be life-threatening.1
Severe bone marrow dysfunction in PNH results in pancytopenia. The reduced number of red blood cells (anemia) causes symptoms such as dizziness, headache, and chest pain.1
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Diagnosis of PNH
PNH can be diagnosed through patient history, complete clinical evaluation, and medical testing. The presence of hemolytic anemia can indicate PNH.4 PNH cells are identified and the diagnosis is confirmed by flow cytometry.1,4 The differential diagnosis includes other hemolytic anemias and conditions that cause thrombotic events and bone marrow failure, such as aplastic anemia, autoimmune hemolytic anemia, primary bone marrow disorders, and disseminated intravascular coagulation.2
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Complications of PNH
Complications of PNH include hepatic, cerebral, and abdominal venous/arterial thrombosis. Acute or chronic renal disease and pulmonary hypertension may also develop.2
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Treatment of PNH
Currently, various therapeutic approaches to PNH focus on blocking alternative complement pathways. These include the drugs Soliris® (eculizumab), Ultomiris® (ravulizumab), and Empaveli® (pegcetacoplan), in addition to allogeneic hematopoietic stem cell transplant.1,2
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Soliris was the first drug approved by the US Food and Drug Administration (FDA) to treat PNH. Approval was granted in 2007. Soliris helps to slow the destruction of red blood cells, reduce the risk for thrombosis, and improve quality of life by blocking the complement system.1
Ultomiris was approved by the FDA in 2018. With a mechanism of action similar to that of Soliris, Ultomiris has been shown to be clinically noninferior to Soliris, while having a longer half-life and a better cost-effective profile.
More recently, in 2021, Empaveli was also approved by the FDA for the treatment of PNH. Empaveli is the first approved therapy that binds to the complement protein C3.1
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Bone Marrow Transplant
Bone marrow transplant is the only curative option for patients with PNH. The procedure carries a risk for morbidity and mortality and therefore is indicated only for patients who present with severe complications of the disease, such as bone marrow failure and recurrent blood clotting.1
Other supportive treatments, including folic acid supplements and anticoagulants (heparin and coumarin derivatives), can be used to manage PNH. Blood transfusions can be administered to correct anemia, and treatment with synthetic growth factors that stimulate the production of red blood cells and/or granulocytes may be prescribed.1,5 Short-term steroids in cases of symptomatic extravascular hemolysis may also be used.5
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1. Paroxysmal nocturnal hemoglobinuria. National Organization for Rare Disorders (NORD). Accessed November 6, 2022.
2. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls [Internet]. Updated August 1, 2022. Accessed November 6, 2022.
3. Devalet B, Mullier F, Chatelain B, Dogné JM, Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. Eur J Haematol. 2015;95(3):190-198. doi:10.1111/ejh.12543
4. Paroxysmal nocturnal hemoglobinuria. Orphanet. Accessed November 6, 2022.
5. Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs. J Manag Care Spec Pharm. 2020;26(12-b Suppl):S14-S20. doi:10.18553/jmcp.2020.26.12-b.s14
Reviewed by Kyle Habet, MD, on 11/28/2022.