Bone Marrow Failure

Question 1

aplastic anemia - overview

Answer 1

*failure of destruction of pluripotent hematopoietic stem cell
*results in a lack of ALL cell precursors, aka a pancytopenia
*can be congenital, acquired, or idiopathic
*categorized into: moderate, severe, and very severe

Question 2

causes of congenital aplastic anemia

Answer 2

*fanconi anemia (pancytopenia, congenital malformations)

Question 3

causes of acquired aplastic anemia

Answer 3

*direct stem cell destruction:
-large doses of radiation or chemo
-meds!
-viral infections
-immune disorders

commonly - it is idiopathic (unknown cause)

Question 4

idiopathic aplastic anemia

Answer 4

*unknown cause
*think the mechanism is immune-mediated
*drug, virus, or other unknown antigen leads to lymphocyte activation, leading to inappropriate destruction of the pluripotent stem cell

Question 5

bone marrow appearance in aplastic anemia

Answer 5

*EMPTY!

Question 6

CBC values in aplastic anemia

Answer 6

*PANCYTOPENIA (everything is low)
-leukopenia
-neutropenia
-anemia
-thrombocytopenia

Question 7

aplastic anemia - treatment

Answer 7

*withdraw potentially offending agents
*supportive care (antibiotics, transfusions of pRBCs and platelets)
*immunosuppressive regimens
*allogeneic bone marrow transplant

Question 8

paroxysmal nocturnal hemoglobinuria (PNH) - pathophysiology

Answer 8

defect in the *PIG A gene → increased complement-mediated intravascular hemolysis, especially at night

-normal RBCs are protected from complement attack by a shield of terminal complement inhibitors (CD55 and CD59)
-PNH patients have a defect in the PIG A gene that normally encodes for GPI-anchored proteins
-no anchor leads to no protection from complement-mediated lysis
-without the gene to encode for the proteins that anchor the protective shield proteins, the RBCs get destroyed by the complement cascade -> hemolysis

Question 9

paroxysmal nocturnal hemoglobinuria (PNH) - pathophysiology [simplified]

Answer 9

*complement-mediated intravascular hemolysis occurs due to an acquired PIG A mutation
*PIG A mutation -> impaired GPI anchor synthesis for DAF/CD55 and MIRL/CD59, which protect RBC membrane from complement

Question 10

paroxysmal nocturnal hemoglobinuria (PNH) - clinical course

Answer 10

*initially causes a hemolytic anemia (intracorpuscular, intravascular hemolysis)

*over time, patients develop pancytopenia
-progresses to aplastic anemia
-b/c ALL blood cells are GPI-deficient

Question 11

paroxysmal nocturnal hemoglobinuria (PNH) - natural history

Answer 11

*patients die of: infection, hemorrhage, thrombosis, or renal failure

*progression to myelodysplastic syndrome
*progression to acute myelogenous leukemia (AML)

Question 12

paroxysmal nocturnal hemoglobinuria (PNH) - treatment

Answer 12

*block complement with eculizumab: monoclonal antibody that targets the terminal complement protein C5

Question 13

myelodysplastic syndromes (MDS) - bone marrow

Answer 13

*HYPERCELLULAR with abnormal cells
*bone marrow blasts < 20%

Question 14

myelodysplastic syndromes (MDS) - overview

Answer 14

*stem cell disorders involving INEFFECTIVE HEMATOPOIESIS
*cells do not progress through the normal stages of maturation

Question 15

myelodysplastic syndromes (MDS) - peripheral blood

Answer 15

cytopenias (b/c there are not enough mature blood cells)

Question 16

myelodysplastic syndromes (MDS) - clinical presentation

Answer 16

*recurrent infections
*fatigue, pallor
*bleeding
*usually do NOT have splenomegaly [contrast to myeloproliferative disorders]

Question 17

myelodysplastic syndromes (MDS) - diagnosis

Answer 17

2 ways to diagnose (patients only need to meet 1 of these criteria):

1. hypercellular marrow & cytopenias with NORMAL number of myeloblasts (5% or less) and DYSPLASTIC cells
2. hypercellular marrow & cytopenias with INCREASED number of myeloblasts (6-19% blasts) with or without dysplastic cells

Question 18

2 biggest risk factors from developing AML from myelodysplastic syndromes (MDS)

Answer 18

1. increasing age
2. prognostic score (IPSS score - specifically, the % of blasts that the patient has in their bone marrow)

Question 19

MDS 5q- syndrome

Answer 19

*cytogenetics: 5q- (part of the long arm of chromosome 5 is missing)
*clinical course tends to be relatively more benign
*overall more responsive to certain treatment

Question 20

myelodysplastic syndromes (MDS) - treatment

Answer 20

*supportive care:
-antibiotics, transfusions
-growth factors: EPO, GCSF
-iron chelators (bind iron which gets excreted in urine and bile)
*chemo (gentle, outpatient)
*monitor for transformation to AML