Normocytic Anemias with Predominant Intravascular Hemolysis Flashcards
What is Paroxysmal Nocturnal Hemoglobinuria?
Episodic intravascular hemolysis that occurs generally at night resulting in hemoglobinuria in the morning and hemosiderinuria days later.
What is the molecular mechanism that causes Paroxysmal Nocturnal Hemoglobinuria?
An ACQUIRED mutation causes myeloid SCs to be deficient in glycosylphosphatidylinositol (GPI) which makes cells vulnerable to lysis. Decay accelerating factor (DAF) is normally attached to the RBC surface via GPI. DAF inhibits C3 convertase, stopping complement activity. If GPI is absent, DAF has nothing to bind to and therefore making RBCs susceptible.
Explain why PNH hemolysis occurs at night.
Shallow breathing during sleep causes respiratory acidosis which activates complement. RBCs, Platelets, and WBCs undergo intravascular hemolysis resulting in hemoglobinemia and hemoglobinuria, and days later, hemosiderinuria.
On what cells is DAF found?
On platelets, RBCs, and WBCs along with other cells in the body.
Describe 3 tests used to Dx PNH
Sucrose test - Introduce sucrose into serum, PNH if lysis occurs; Ham’s Acid Test - Introduce RBCs in mild acid, PNH if lysis occurs; Flow cytometry for lack of CD55 (DAF)
Complications and main cause of death from PNH
Iron-deficiency anemia, Acute Myeloid Leukemia (B/c PNH is acquired hematopoietic mutation, a mutation causing AML can also be acquired). Death from thrombosis of hepatic, portal, or cerebral veins - destroyed platelets induce thrombosis
Describe molecular mechanism resulting in intravascular hemolysis from G6PD deficiency
GSH neutralizes H2O2 but becomes oxidized in process. GSSG is converted back to GSH using NADPH. NADPH is made via G6PD. If G6PD is deficient, NADPH decreases, Reduced GSH decreases, oxidative stress/injury increases, intravascular hemolysis
What are the two major G6PD deficiency variants. Why do high rates of carriers of these deficiencies persist?
African variant - mildly reduced t1/2 of G6PD leading to mild intravascular hemolysis. Mediteranean variant - marked reduced t1/2 of G6PD leading to marked intravascular hemolysis. Carrying deficiency results in protection against Plasmodium falciparum.
What histologic findings are characteristic of G6PD deficiency? What are some common causes of oxidative stress?
With ox stress, Hb precipitates as Heinz bodies. Splenic macrophages remove Heinz bodies forming Bite Cells; Infection, Drugs (primaquine, sulfa, dapsone), fava beans
What is the general presentation of G6PD?
Following oxidative stress, patient experiences hemoglobinuria and back pain (Hb is nephrotoxic)
What type of histologic preparation is used to screen for G6PD disease?
Heinz preparation - Heinz stain shows precipitated Hb and enzyme studies confirm deficiency
When do you perform enzyme studies for G6PD deficiency? Why?
Weeks following an oxidative stress attack. The only RBCs following an attack are the ones with sufficient G6PD. Your G6PD levels will therefore be falsely high.
What is Immune Hemolytic Anemia?
Either IgG or IgM mediated destruction of RBCs
Describe IgG-mediated IHA
Typically extravascular hemolysis, Auto-Ab attaches to RBC. The membrane-Ab complex is consumed by splenic macrophages resulting in membrane loss and sphereocytes.
What is the most common cause of IgG-mediated IHA? How do drugs induce IgG-mediated IHA?
SLE, CLL, certain drugs (classically penicillin, cephalosporins) Drug attaches to RBC wich is then bound by an Ab OR Drug induces production of auto-Abs (Alpha-methyldopa)
