1/4 Anemia3 - Wondisford Flashcards
comparison of lab findings in intravascular vs extravascular hemolysis
- serum haptoglobin
- urine hb
- urine hemosiderin
- unconj bilirubin
- serum LDH
in intravascular hemolysis, breakdown pdts either
- bound by haptoglobin
- excreted in urine
in extravascular hemolysis, breakdown pdts are picked up by macrophages in RES
- normally: brought to liver as unconjugated bilirubin, liver conjugates and releases into GI system
- when hemolysis is occuring: liver conjugation mechanism is overwhelmed, so unconj bilirubin builds up and you see jaundice
intrinsic hemolytic anemia
4 types: pathophys
1. hereditary spherocytosis: defect in proteins interacting with RBC membrane skeleton and plasma membrane → premature removal of RBCs by spleen
- findings: splenomegaly, aplastic crisis (parvovirusB19)
- labs: oxmotic fragility test
- tx: splenectomy resolves hemolysis, but Howell-Jolly bodies appear
2. G6PD deficiency: X-linked recessive G6PD def → no reduced glutathione available, so see incr RBC susceptibility to oxidant stress (sulfa drugs, antimalarials, infection, fava beans)
- findings: Heinz bodies, bite cells
- most common enzymatic disorder of RBCs
3. pyruvate kinase deficiency: defect in pyruvate kinase → decr ATP, rigid RBCs, extravasc hemolysis
- newborn hemolytic anemia
4. HbC: glutamic acid → lysine mutation in beta globin
- findings: target cells in homozygotes
- homozygotes (HbSS) are worse off than heterozygotes (HbSC)
sickle cell anemia
HbS point mutation (Glu → Val sub at position 6)
- 8% of AfAm carry the trait
sickling induced by Low O2, dehydration, or acidosis → anemia and vaso-occlusive disease
findings
- newborns initially asymptomatic (bc more HbF, less HbS)
- “crew cut” on skull xray (marrow expansion due to incr erythropoiesis)
- sickle cells on smear
complications
- aplastic crisis (parvovirus B19)
- autosplenectomy (Howell-Jolly bodies) → incr risk of infection by encapsulated orgs
- Salmonella osteomyelitis
- extramedullary hematopoiesis
- dactylitism (swollen fingers due to vaso-occlusion)
- acute chest syndrome
- renal papillary necrosis (due to low oxygen in papilla)
treatment
- hydroxyurea (increases HbF)
- hydration
paroxysmal nocturnal hemoglobinuria
acquired mutation in hematopoeitic stem cells
**only pure cause of intravascular hemolysis due to intrinsic RBC defect
- impaired synth of GPI anchor for decay accelerating factor which protects RBC membrane from complement → incr complement-mediated RBC lysis
- mild resp acidosis at night triggers hemolysis
- 10% of patients progress to acute leukemia
triad seen:
- Coombs- hemolytic anemia
- pancytopenia
- venous thrombosis (cause of death)
labs
- CD55/59- RBCs on flow cytometry
- low/no haptoglobulin
treatment: eculizumab (complement pathway inhib)
- specificall binds to C5 to block complement cascade activation
- bc phosphatidyl-inositol glycan A (PIGA) mutation affects the hematopoeitic stem cell, complement-mediated lysis of WBC and platelets also occur
direct vs indirect Coombs test
extrinsic hemolytic normocytic anemia
4 types
- autoimmune hemolytic anemia (AIHA)
- two types
- warm agglutinin (IgG): chronic anemia seen in…
- SLE (most common)
- CLL
- alpha-methyldopa
- penicillin
- cold agglutinin (IgM): acute anemia triggered by cold seen in…
- CLL
- mycoplasma
- mononucleosis
- often seen painful blue fingers/toes with cold exposure
- many warm/cold AIHA are idiopathic, but most are Coombs+
- warm agglutinin (IgG): chronic anemia seen in…
- microangiopathic anemia
- RBCs are damaged when passing through obstructed or narrowed vessel lumina
- DIC, TTP-HUS, SLE, malignant HTN
- schistocytes (helmet cells) due to mech destruction of RBCs
- macroangiopathic anemia
- prosthetic heart valves and aortic stenosis can cause hemolytic anemia secondary to mech destruction
- schistocytes on peripheral blood smear
- infections
* malaria, babesia invade RBCs and cause lysis
vitamin B12 (cobalamin)
function
link to folate
folate trap
fx: cofactor for methionine synthase (transfers methyl groups) and methylmalonylCoA mutase (metabolizes methylmalonylCoA)
- found in animal products (only synth’d by microbes)
FOLATE works w B12 to form methionine from homoCys - imp for many synthetic pathways, incl nucleotide synth
B12 required for THF regeneration
- folate deficiency manifests as inability to form purines/pyrimidines → issues with nucleus maturation → megaloblastic anemia (bc rapidly dividing cells)
BEWARE: folate trap with B12 deficiency
- B12 deficiency leads to accumulation of methylmalonyl CoA → CNS damage
- B12 deficiency also leads to folate deficiency → anemia
- tx with folate corrects anemia (bypasses B12 issue) BUT DOES NOTHING FOR NEURO DEFECTS!!!
megaloblastic anemia
impaired DNA synth → delayed maturation of nucleus (relative to cytoplasm) of precursor cells in bone marrow
- macrocytosis
- hypersegmented neutrophils
- glossitis
- folate deficiency (months to develop)
* causes: malnutrition (alcoholics), malabsorption, antifolates (methotrexate, trimethoprim, phenytoin), incr requirement (hemolytic anemia, pregnancy) - B12 deficiency (years to develop)
- causes: insufficient intake (vegans), malabsorption (Crohn disease), pernicious anemia (no IF), fish tapeworm, gastrectomy, pancreatic disease (no enzymes to free B12 to bind to IF)
- neuro sx: subacute combined degen (B12 involved in FA pathways and myelin synth)
- spinocerebellar tract, lateral corticospinal tract, dorsal column dysfx
- dx with Schilling test: oral radioactive B12 without IF (part1), then with IF (part2), then measure radioactive B12 in urine
- orotic aciduria
- autosomal recessive
- inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway)
- tx: UMP to bypass mutated enzyme
- CANT cure with folate/B12
megaloblastic anemia
- serum folate
- serum B12
- serum homoCys
- methylmalonic acid
comparison between folate def and B12 def
nonmegaloblastic macrocytic anemias
macrocytic anemia in which DNA synth unimpaired
causes:
- liver disease
- alcoholism
see RBC macrocytosis w/o hypersegmented neutrophils
what causes:
- mech fragmentation of RBCs
- increased susceptibility to lysis by complement
- nuclear maturation defects from impaired DNA synth
- hemolysis of antibody coated cells
- reduced deformability of RBC membrane
- production of abnormal Hb
- mech fragmentation of RBCs
- macroangiopathic or microangiopathic
- increased susceptibility to lysis by complement
- paroxysmal nocturnal hemoglobinuria
- nuclear maturation defects from impaired DNA synth
- megaloblastic anemia
- hemolysis of antibody coated cells
- autoimmune hemolytic anemia
- reduced deformability of RBC membrane
- hereditary spherocytosis
- production of abnormal Hb
- lots of stuff
summary3
extra notes:
- hemolytic anemia classically normocytic
- PNH is only one that is ONLY intravascular: complement mediated lysis of RBC/WBC/platelet
