Pathophysiology
Summary
In intravascular hemolysis, RBCs lyse within the bloodstream, leading to a variety of systemic and biochemical changes, include the release of lactate dehydrogenase (LDH) and hemoglobin into the bloodstream system upon RBC lysis. The increased free hemoglobin is initially bound by haptoglobin, forming a complex that is subsequently cleared by liver macrophages, resulting in decreased serum haptoglobin levels.
A significant clinical sign of intravascular hemolysis is hemoglobinuria, which occurs as a consequence of hemoglobinemia and results in the degradation of urine hemoglobin into heme or methemoglobin, leading to brown-colored urine. Severe cases of intravascular hemolysis can result in acute tubular necrosis (ATN) and acute kidney injury (AKI), both a function of heme-related tubular obstruction, direct toxicity, and vasoconstriction in the kidneys.
Similar to extravascular hemolysis, intravascular hemolysis can also lead to unconjugated hyperbilirubinemia due to the breakdown of heme. The increase in serum unconjugated bilirubin results in increased levels of urobilinogen in both urine and stool, and can contribute to the formation of pigmented gallstones. Clinically, intravascular hemolysis is typically associated with a normocytic anemia (MCV 80-100) and an increased reticulocyte count (>3%) due to compensatory RBC production by the bone marrow.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired cause of intravascular hemolysis, originating from a mutation in the PIG-A gene, which codes for the first step in production of GPI anchor protein. This protein is responsible for affixing other proteins, such as complement inhibitor proteins CD55 and CD59, to the cell surface. Deficiency in the GPI anchor protein makes RBCs susceptible to complement-mediated lysis, contributing to intravascular hemolysis.
PNH is not only characterized by RBC lysis but also by a broader hematopoietic dysfunction, leading to pancytopenia. PNH is notable for nocturnal hemoglobinuria, presenting with dark urine in the morning due to mild respiratory acidosis during sleep that exacerbates complement activation. Moreover, PNH is associated with an increased risk of large vein thrombosis, especially in the abdominal and cranial veins. PNH is diagnosed through flow cytometry, which shows a deficiency of CD 55 & CD 59 on the cell surface.
Lesson Outline
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FAQs
Intravascular hemolysis refers to the destruction of red blood cells (RBCs) within the bloodstream, leading to the release of cellular contents like lactate dehydrogenase (LDH) and hemoglobin into circulation. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare condition that often results in severe intravascular hemolysis. In PNH, an acquired mutation in the PIGA gene leads to a deficiency in cell surface proteins, such as CD55 and CD59, that normally protect RBCs from immune-mediated destruction. This lack of protection makes RBCs susceptible to complement activation and subsequent lysis within the bloodstream.
The symptoms of PNH can vary widely among patients but commonly include fatigue, dyspnea, abdominal pain, and dark-colored urine, especially in the morning. More severe manifestations can involve thrombosis in large veins, kidney disease, and severe anemia. Signs of hemolysis, such as jaundice and hemoglobinuria, may also be present, indicating the ongoing destruction of red blood cells.
Diagnosis of PNH involves a combination of clinical findings and specialized laboratory tests. The gold standard for diagnosis is flow cytometry, which identifies the absence or reduction of specific cell surface proteins like CD55 and CD59. This test is both sensitive and specific for PNH. Additional tests may include a CBC, direct antiglobulin test, and markers of hemolysis such as elevated serum lactate dehydrogenase levels.
Treatment for PNH primarily focuses on symptom management and the prevention of complications. Blood transfusions may be used to address severe anemia, while anticoagulants can help prevent thrombotic events. Immunosuppressive medications may also be considered. A bone marrow transplant is the only curative treatment but is generally reserved for severe cases due to the associated risks of the procedure.
The prognosis for patients with PNH varies and is influenced by factors such as disease severity, presence of complications, and overall health. With appropriate treatment, many patients can achieve a normal or near-normal life expectancy. However, complications like thrombosis can pose serious, life-threatening risks.
