This video, part 7 of a hemolytic anemia series from Pathology Made Simple, provides an overview of Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare acquired hemolytic anemia resulting from a mutation in hematopoietic stem cells. The video covers the definition, pathogenesis, clinical features, laboratory diagnosis, and treatment of PNH. It highlights the role of the PIGA gene mutation, the deficiency of GPI-anchored proteins (CD55 and CD59), and the resulting sensitivity of red blood cells to complement-mediated lysis. Clinical manifestations, including macroscopic hemoglobinuria and thromboembolic complications, are discussed. Diagnostic methods, particularly flow cytometry, and treatment options, including stem cell transplantation and monoclonal antibodies, are reviewed.
Understanding Paroxysmal Nocturnal Hemoglobinuria (PNH): From Pathogenesis to Treatment
0:00:14 Introduction to PNH: PNH is an acquired hemolytic anemia due to an abnormality in the red cell membrane.
0:00:41 Learning Objectives: Definition, pathogenesis, clinical features, lab diagnosis, and treatment of PNH.
0:00:57 What is PNH?: PNH is a disease of hematopoietic stem cells with an acquired mutation.
0:01:41 PIGA Gene: Somatic mutation in the PIGA gene leads to non-malignant clonal expansion, causing PNH.
0:02:26 GPI Anchor: The PIGA protein is involved in producing the GPI anchor, which attaches proteins like CD55 and CD59 to cells.
0:03:03 CD55 and CD59: These are complement regulatory proteins; CD55 prevents C3 convertase formation, and CD59 blocks the membrane attack complex (MAC).
0:03:52 Complement-Mediated Hemolysis: Deficiency of CD55 and CD59 results in complement-mediated intravascular hemolysis.
0:05:56 Pathogenesis Simplified: PNH is due to sensitivity to complement-mediated lysis caused by CD55 and CD59 deficiency, which is due to GPI anchor deficiency.
0:06:38 Alternate Pathway Activation: Under physiologic conditions, the alternate complement pathway is in continuous low-grade activation. PNH erythrocytes are sensitive, leading to chronic hemolysis with a lifespan of around six days.
0:07:15 Nocturnal Hemoglobinuria Explained: Original theory linked night-time hyperventilation-induced acidosis to complement activation, but hemolysis occurs throughout the day.
0:08:11 Paroxysmal Symptoms: Episodes of symptoms can be triggered by infections, drugs, trauma, or occur spontaneously.
0:08:36 Hemoglobinuria at Night: Hemoglobin accumulates in the bladder overnight, resulting in dark urine in the morning.
0:09:18 Classical Cases: Only 25% of PNH cases present with macroscopic hemoglobinuria. Onset typically in the fourth to fifth decades of life.
0:09:54 Non-Specific Symptoms: Remaining 75% have non-specific symptoms like lethargy, malaise, weakness, abdominal pain, backache, and headaches.
0:10:07 Thromboembolic Complications: Striking predisposition towards intravascular thrombosis, particularly in venous circulation (intra-abdominal, hepatic, cerebral, subdermal veins). This is a leading cause of death in PNH.
0:11:04 Renal Abnormalities: Hemoglobin shedding leads to iron accumulation, damaging tubular epithelial cells and causing renal insufficiency.
0:11:35 Dysphagia: Can occur due to nitric oxide deficiency (hemoglobin utilizes nitric oxide), affecting smooth muscle function.
0:12:00 Lab Findings - Anemia: Anemia is the most important finding, starting as normocytic but can become microcytic due to iron loss.
0:12:44 Leukopenia and Thrombocytopenia: Due to bone marrow destruction, not complement-mediated destruction.
0:12:58 Neutrophil Alkaline Phosphatase: Will be lower or absent (another GPI-Associated protein).
0:13:29 Bone Marrow: Initially, normoblastic hyperplasia; later, decreased megakaryocytes or hypoplastic marrow, leading to pancytopenia.
0:13:59 Urine Examination: Increased urobilinogen, hemoglobinuria, hemosiderinuria; early morning urine is dark-colored.
0:14:34 Diagnosis: Cannot be based on peripheral findings alone; requires demonstrating protein loss.
0:14:42 Flow Cytometry: Measures the percentage of cells deficient in GPI-anchored proteins.
0:15:07 Ham Test: Obsolete acidified serum lysis test.