### Date : 2024-12-03 14:01 ### Topic : Paroxysmal Nocturnal Hemoglobinuria (PNH) #hematology ---- ### **Paroxysmal Nocturnal Hemoglobinuria (PNH)** **Paroxysmal nocturnal hemoglobinuria (PNH)** is a **rare acquired hematologic disorder** characterized by **intravascular hemolysis** (destruction of red blood cells) and **bone marrow failure**. The disease is caused by mutations in the **PIGA gene**, leading to a **deficiency** of certain proteins that protect red blood cells from being destroyed by the **complement system**. --- ### **Pathophysiology** - **PIGA mutation**: PNH is caused by a **somatic mutation** in the **PIGA gene**, which is responsible for the production of a protein involved in the synthesis of **glycosylphosphatidylinositol (GPI)** anchors. - **GPI anchors** are essential for attaching complement regulatory proteins (such as **CD55** and **CD59**) to the surface of red blood cells and other cells. - In **PNH**, the mutation results in a **deficiency** of these complement regulatory proteins on the surface of **red blood cells**, **platelets**, and **leukocytes**. - Without **CD55** and **CD59**, the red blood cells are vulnerable to **complement-mediated lysis** (destruction), particularly in the **blood vessels**. - **CD55** regulates **C3 convertase** activity, while **CD59** inhibits the **membrane attack complex (MAC)**. - This leads to **hemolysis** and the release of **hemoglobin** into the blood, which can be detected in the urine, especially at night (hence the name "nocturnal"). --- ### **Symptoms of PNH** The symptoms of **PNH** are often related to **hemolysis** and **bone marrow failure**. Common clinical features include: 1. **Hemolysis** (due to complement activation): - **Hemoglobinuria**: The presence of **hemoglobin** in the urine, particularly in the **morning** (after the patient has been lying down at night, leading to concentrated urine). - **Fatigue**: Due to the destruction of red blood cells, leading to anemia. - **Jaundice**: Due to the increased breakdown of red blood cells. - **Abdominal pain**: Resulting from the release of hemoglobin and other breakdown products, which can lead to **hemosiderin deposition**. - **Shortness of breath** and **exercise intolerance** due to anemia. 2. **Thrombosis**: - **Increased risk of blood clots** is a hallmark feature of PNH. Clots can form in large veins, especially in the **abdomen**, **brain**, and **lungs**, which can result in **deep vein thrombosis (DVT)**, **pulmonary embolism (PE)**, or **cerebral vein thrombosis**. 3. **Bone Marrow Failure**: - Some patients with PNH develop **bone marrow failure** leading to **pancytopenia** (deficiency of red blood cells, white blood cells, and platelets), causing symptoms like **infections**, **easy bruising**, and **bleeding**. 4. **Other Symptoms**: - **Dark-colored urine**, especially in the morning (due to hemoglobin). - **Fatigue**, **headaches**, **dizziness**, and **palpitations** due to anemia. --- ### **Diagnosis of PNH** 1. **Flow Cytometry**: - The **gold standard** for diagnosing PNH is **flow cytometry**, which detects the absence or decreased expression of **CD55** and **CD59** on the surface of red blood cells, platelets, and leukocytes. - A positive result suggests **PNH**, as the loss of these proteins is characteristic of the disease. 2. **Urine Test**: - **Hemoglobinuria** (the presence of **hemoglobin** in the urine) is a common finding in PNH, especially in the early morning. This is due to **intravascular hemolysis**. - **Urine dipstick** for **hemoglobin** can provide a clue, but **urine microscopy** is often needed to differentiate between hemoglobinuria and myoglobinuria. 3. **Complete Blood Count (CBC)**: - Anemia and **pancytopenia** may be present, but these findings are nonspecific. 4. **Serum Lactate Dehydrogenase (LDH)**: - Elevated **LDH** levels are seen due to the ongoing hemolysis. 5. **Bone Marrow Biopsy**: - Bone marrow failure may be assessed, particularly in patients with severe pancytopenia. However, bone marrow biopsy is not always necessary for diagnosis. --- ### **Treatment of PNH** 1. **Eculizumab (Soliris)**: - The mainstay of treatment for PNH is **eculizumab**, a **monoclonal antibody** that inhibits the **complement system**, specifically **C5**, thereby preventing the formation of the **membrane attack complex (MAC)**. - This prevents **complement-mediated hemolysis**, reducing **hemoglobinuria**, improving **anemia**, and **reducing the risk of thrombosis**. - **Eculizumab** is **lifelong therapy** and requires regular intravenous infusions. 2. **Ravulizumab (Ultomiris)**: - A newer alternative to eculizumab, ravulizumab is a longer-acting **C5 inhibitor**. It is administered less frequently (every 8 weeks after the initial doses), making it a more convenient option for some patients. 3. **Bone Marrow Transplantation**: - **Allogeneic stem cell transplantation** may be considered in patients with severe PNH and **bone marrow failure** or for those with **refractory disease** who do not respond to complement inhibition therapy. 4. **Supportive Treatment**: - **Blood transfusions** may be needed to manage **severe anemia**. - **Anticoagulation therapy** may be required for patients with significant **thrombosis risk** (e.g., those with previous **thrombotic events**). - **Iron supplementation** for patients with chronic hemolysis and iron deficiency. 5. **Management of Symptoms**: - **Pain management** for **abdominal pain** due to hemolysis. - **Monitor for infections**, as **pancytopenia** can predispose to infections. --- ### **Prognosis** - The prognosis of **PNH** depends on several factors, including the severity of **hemolysis**, the presence of **thrombosis**, and the degree of **bone marrow failure**. - With **eculizumab** treatment, the **prognosis** has improved significantly, with reduced rates of **hemolysis** and **thrombosis**. - Without treatment, **PNH** can lead to severe complications, including **chronic kidney disease** (from hemoglobinuria), **thrombotic events**, and **bone marrow failure**. --- ### **Summary** **Paroxysmal nocturnal hemoglobinuria (PNH)** is a rare, acquired hematologic disorder caused by a mutation in the **PIGA gene**, resulting in **deficient complement regulation** on red blood cells. This leads to **intravascular hemolysis**, **hemoglobinuria**, **anemia**, and an increased risk of **thrombosis**. **Eculizumab** is the cornerstone of treatment, as it inhibits the complement system and prevents hemolysis. Early diagnosis and treatment significantly improve outcomes and quality of life for patients with PNH. ### Reference: - ### Connected Documents: -