Paroxysmal Nocturnal Hemoglobinuria

• Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired blood disorder caused by a mutation in blood stem cells.
• PNH leads to the destruction of red blood cells (hemolysis), increasing the risk of blood clots and bone marrow dysfunction.
• Common symptoms include fatigue, dark urine, abdominal pain, and difficulty swallowing.
• Diagnosis primarily relies on flow cytometry to detect the absence of specific proteins on blood cell surfaces.
• Treatment often involves complement inhibitors to prevent red blood cell destruction and supportive care.

What is Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening blood disorder that results from an acquired genetic mutation in hematopoietic stem cells. This mutation, specifically in the PIGA gene, leads to a deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins on the surface of blood cells, including red blood cells, white blood cells, and platelets. Among these crucial proteins are CD55 and CD59, which normally protect blood cells from destruction by the body’s own complement system.

The primary mechanism underlying the causes of paroxysmal nocturnal hemoglobinuria is the uncontrolled activation of the complement system against these unprotected blood cells. This leads to chronic intravascular hemolysis, where red blood cells are prematurely destroyed within the bloodstream. This destruction releases hemoglobin into the plasma, which can cause symptoms such as dark urine (hemoglobinuria) and contribute to kidney damage. PNH affects approximately 1 to 1.5 people per million worldwide, according to the National Organization for Rare Disorders (NORD).

Symptoms and Diagnosis of PNH

The manifestations of PNH symptoms and diagnosis can vary widely among individuals, ranging from mild to severe. Due to chronic hemolysis, common symptoms often include profound fatigue, anemia, and dark-colored urine, particularly noticeable in the morning. Other symptoms may involve abdominal pain, difficulty swallowing (dysphagia), erectile dysfunction, and shortness of breath. The uncontrolled activation of the complement system also increases the risk of life-threatening blood clots (thrombosis), which can occur in unusual locations such as the hepatic, cerebral, or abdominal veins.

Diagnosing PNH requires specialized testing. The gold standard for diagnosis is high-sensitivity flow cytometry, which detects the absence of GPI-anchored proteins (like CD55 and CD59) on the surface of red blood cells, white blood cells, and platelets. This test can identify the PNH clone and quantify its size, which is important for guiding treatment decisions. Additional tests may include complete blood counts to assess anemia and platelet levels, as well as measurements of lactate dehydrogenase (LDH) and haptoglobin, which are markers of red blood cell destruction.

Treatment Options for PNH

Advancements in medical science have significantly improved the prognosis for individuals with PNH. The primary goal of PNH treatment options is to control complement-mediated hemolysis, reduce the risk of thrombosis, and alleviate symptoms. The cornerstone of therapy involves complement inhibitors, which are monoclonal antibodies that block specific components of the complement system, thereby preventing the destruction of red blood cells. Eculizumab and ravulizumab are examples of such inhibitors that have revolutionized PNH management.

In addition to complement inhibitors, supportive care is crucial. This may include iron and folic acid supplementation to help the bone marrow produce new red blood cells, and blood transfusions for severe anemia. Anticoagulants may be prescribed to prevent or treat blood clots, especially in patients who are not receiving complement inhibitor therapy or have a history of thrombosis. In rare cases, for patients with severe bone marrow failure or those who do not respond to other treatments, hematopoietic stem cell transplantation (HSCT) may be considered, though it carries significant risks.