Ch5 - 6) Normocytic anemia with predominant intravascular hemolysis Flashcards
What are the normocytic anemias with predominant intravascular hemolysis?
1) paroxysmal nocturnal hemoglobinuria (PNH) 2) G6PD deficiency 3) Immune Hemolytic anema (INH) 4) Microangiopathic hemolytic anemia 5) Malaria
What is paroxysmal nocturnal hemoglobinuria?
Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction by complement
What is the relationship between blood cells and complement?
Blood cells coexist with complement.
What is DAF?
Decay accelerating factor (DAF) is on the surface of blood cells and protects against complement-mediated damage by inhibiting C3 convertase.
How is DAF secured to the cell membrane?
By GPI (an anchoring protein)
What does the absence of GPI on the RBC membrane leads to?
absence of DAF, rendering cells susceptible to complement-mediated damage.
How is intravascular hemolysis related to paroxysmal nocturnal hemoglobinuria?
Intravascular hemolysis occurs episodically, often at night during sleep,
What develops in paroxysmal nocturnal hemoglobinuria?
- Mild respiratory acidosis develops with shallow breathing during sleep and activates complement.
In paroxysmal nocturnal hemoglobinuria what is lysed?
RBCs, WBCs, and platelets are lysed
What test is used to screen for paroxysmal nocturnal hemoglobinuria?
Sucrose test
What is a confirmatory test for paroxysmal nocturnal hemoglobinuria?
Acidified serum test or flow cytometry to detect the lack of CD55 (DAF) on blood cells
What is the main cause of death in paroxysmal nocturnal hemoglobinuria?
It is thrombosis of the hepatic, portal, or cerebral veins.
In paroxysmal nocturnal hemoglobinuria what induces thrombosis?
Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis.
In paroxysmal nocturnal hemoglobinuria what are the complications?
iron deficiency anemia which is due to chronic loss of hemoglobin in the urine) and acute myeloid leukemia (AML), which develops in 10% of patients.
What is G6PD deficiency?
X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress
How does G6PD deficiency lead to intravascular hemolysis?
decreased G6PD ? decreased NADPH ? reduced glutathione ? oxidative injury by H202 ? intravascular hemolysis
What is the relationship between G6PD and RBCs?
RBCs are normally exposed to oxidant stresses particularly H2O2.
What neutralizes H2O2?
Glutathione (an antioxidant) neutralizes H2O2, but becomes oxidized in the process.
What is needed to regenerate glutathione?
NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione.
How many variants are there for G6PD deficiency?
There are two major variants; African variant and Mediterranean variant
What is seen with the African variant of G6PD deficiency?
mildly reduced half-life of G6PD leading to mild intravascular hemolysis with oxidative stress
What is seen in the Mediterranean variant of G6PD deficiency?
markedly reduced half-life of G6PD leading to marked intravascular hemolysis with oxidative stress
Explain the carrier frequency for both variants of G6PD deficiency?
High carrier frequency in both populations is likely due to protective role against falciparum malaria.
What is the relationship between G6PD deficiency and Heinz bodies?
Oxidative stress precipitates Hb as Heinz bodies
What are some causes of oxidative stress?
infections, drugs (e.g., primaquine, sulfa drugs, and dapsone), and fava beans.
What happens to Heinz bodies?
they are removed from RBCs by splenic macrophages, resulting in bite cells
Hb precipitating as Heinz bodies leads to what?
Predominantly leads to intravascular hemolysis
What does G6PD deficiency present with?
hemoglobinuria and back pain hours after exposure to oxidative stress
What is used to screen G6PD deficiency?
Heinz preparation is used to screen for disease
How can precipitated Hb be seen?
precipitated hemoglobin can only be seen with a special Heinz stain
What is used to confirm G6PD deficiency? When is it performed?
enzyme studies confirm deficiency (performed weeks after hemolytic episode resolves).
What is immune hemolytic anemia?
Antibody-mediated (IgG or IgM) destruction of RBCs
In IHA what does the IgG-mediated disease usually involve?
extravascular hemolysis.
In IgG mediated IHA how does spherocyte formation result?
IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin); membrane of antibody-coated RBC is consumed by SPLENIC macrophages, resulting in spherocytes
What is the most common cause of IgG mediated IHA?
SLE
What is IgG mediated IHA associated with?
SLE (most common cause), CLL, and certain drugs (classically, penicillin and cephalosporins)
How do certain drugs relate to IgG mediated IHA?
Drug may attach to RBC membrane (e.g., penicillin) with subsequent binding of antibody to drug-membrane complex. 2). Drug may induce production of autoantibodies (e.g., u-methyldopa) that bind self antigens on RBCs
What does the treatment of IgG mediated IHA involve?
cessation of the offending drug, steroids, IVIG, and, if necessary, splenectomy.
What does IgM-mediared IHA disease usually involve?
intravascular hemolysis.
What happens in IgM mediated IHA?
IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities (cold agglutinin).
What is the IgM mediated IHA associated with?
Mycoplasma pneumoniae and infectious mononucleosis
What test is used to diagnose IHA?
Coombs test is used to diagnose IHA; testing can be direct or indirect.
What is the Direct Coombs test?
confirms the presence of antibody-coated RBCs. Anti-IgG is added to patient RBCs; agglutination occurs if RBCs are already coated with antibody.
What is the most important test for IHA?
Direct Coombs test
What is the indirect Coombs test?
it confirms the presence of antibodies in patient serum. Anti-IgG and test RBCs are mixed with the patient serum; agglutination occurs if serum antibodies are present.
What is microangiopathic hemolytic anemia?
Intravascular hemolysis that results from vascular pathology; RBCs are destroyed as they pass through the circulation.
What occurs with chronic hemolysis?
Iron deficiency anemia
Microangiopathic hemolytic anemia occurs with what?
Occurs with microthrombi (TTP-HUS, DIG, HELLP), prosthetic heart valves, and aortic stenosis; microthrombi produce schistocytes on blood smear
What is malaria?
Infection of RBCs and liver with Plasmodium, transmitted by the female Anopheles mosquito
How does malaria affect RBCs?
RBCs rupture as a part of the Plasmodium life cycle, resulting in intravascular hemolysis and cyclical fever.
What does P falciparum present with?
daily fever
What does P vivax and P ovale present as?
fever every other day
What is the role of the spleen in malaria?
Spleen consumes some infected RBCs; results in mild extravascular hemolysis with splenomegaly
