Definitions:
- Hematocrit <41% in men or <36 in women
- Hemoglobin <13.5 gm\dL in men or <12 gm\dL in women
a. Microcytic Anemia:Â
1. Iron deficiency:
- MCC: blood loss (GI, menstrual)
- Presentation: depends on severity (usual presentation of anemia): fatigue, palpitations, SOB, pallor, nail changes (brittle, spoon-shaped), glossitis, pica.
- Moderate – severe anemia -> systolic ejection murmur (“flow” murmur)
- Labs: ↓ Hgb, ↓ MCV, ↓ MCH, ↓ ferritin, ↓ iron, ↓ retics, ↑ TIBC, ↑ RDW
- Tx: most effective is oral therapy w\ ferrous sulfate tablets
2. Anemia of chronic disease:
- Chronic inflammation -> hepcidin -> binds to ferroportin -> traps iron w\in macrophages + prevents gut iron absorption
- Labs: ↓ Hgb, ↓ MCV, ↓ MCH, ↓ iron, ↓ retics, ↓ TIBC, ↑ ferritin
- Tx: correct underlying cause. If renal ds or chemo\radio-therapy related anemia -> iron supplementation and erythropoietin
3. Sideroblastic anemia:
- Defect in iron metabolism -> iron is trapped in the mitochondria of nucleated RBCs
- Hereditary: defect in aminolevulinic acid synthase or vit B6 metabolism
- Acquired: chloramphenicol, isoniazid, alcohol, lead poisoning
- Can progress into AML
- Labs: ↓ Hgb, ↓ MCV, ↑ ferritin, ↑ iron, ↑ retics, ↓ TIBC
- Specific Dx: Prussian Blue stain of RBCs in BM -> ringed sideroblasts + basophilic stippling
- Tx: best first step: pyridoxine -> response indicates underlying cacuse. Transfusion. BMT.
4. Thalessemia:
Alpha thalessemia:
- 1 genes deleted -> normal pt
- 2 genes deleted -> silent carrier or mild anemia (Hct 30-40%), very low MCV.
- 3 genes deleted -> Hemoglobin H: profound anemia (Hct 20-30%), very very low MCV
- 4 genes deleted -> Hemoglobin Barts: death in utero (hydrops fetalis)
Beta thalassemia:
- Trait -> mild anemia + markedly low MCV
- Major (Cooley anemia) -> sx start after the age of 6 mo (switch from fetal Hgb to adult Hgb) -> growth failure, hepatosplenomegaly, jaundice, bony deformities (extramedullary hematopoiesis) -> chronic anemia + transfusion dependence -> hemochromatosis, cirrhosis, CHF
- Labs: ↓ Hgb, ↓↓ MCV (disproportionate to the anemia), N ferritin, N iron, N TIBC, N RDW
- Specific Dx: Hemoglobin electrophoresis.
- Beta thalassemia: high levels of Hgb F and A2
- Alpha thalassemia: normal levels of Hgb F and A2, if 3 genes deleted -> Hgb H
- Blood smear -> target cells, poiklocytes
- Tx:
- Trait -> no Tx
- Beta thalassemia major -> transfusion once\twice a mo
- Chronic transfusion -> iron overload -> oral deferasirox (or deferoxamine via subQ pump)
- Splenectomy reduces transfusion requirement (indicated in hypersplenism)
- BMT
- Iron supplementations is contraindicated
b. Macrocytic Anemia:Â
1. Vitamin B12 (Cyanocobalamine) deficiency:
- MCC: pernicious anemia -> autoimmune destruction of parietal cells -> ↓production of intrinsic factor
- Sx: peripheral neuropathy, position\vibration\autonomic\motor\cranial nerves abnormalities, psychiatric, bowel\bladder\sexual dysfunx, glossitis, diarrhea, abd pain
- Labs: ↓ Hgb, ↑ MCV, ↓ retics, ↓ B12
- Smear: hypersegmented neutrophils, RBCs are oval macrocytes (while in hemolysis, liver ds, myelodysplasia give round macrocytes)
- Specific Dx: antibodies to IF
- Tx: replacement w\ vit B12 -> oral daily or parenteral (IM or subQ) monthly (recommended for neuropathy pts)
- Early in Tx, pts might experience hypokalemia and fluid overload due to ↑ erythropoiesis, cellular uptake of K, and ↑ blood volume
2. Folic acid deficiency:
- Causes: ↓ dietary intake, pregnancy, skin losses in eczema, ↑ loss from dialysis, phenytoin, alcohol
- Same labs and presentation as vit B12 def, except ↓ folic acid
- Tx: oral replacement
c. Hemolytic Anemia:Â
- Can happen in:
- Spleen\liver -> extravascular
- Vasculature itself -> intravascular -> hemoglobinuria
- General Sx: splenomegaly, jaundice, icterus, pruritus, gallstones, hemosiderinuria
- General Labs: normocytic anemia, ↑ LDH, ↓ haptoglobin “hemoglobin eats haptoglobin”, ↑ total bilirubin (indirect specifically), ↑ retics (unlike anemia of chronic ds)
- All hemolytic anemia pt should get folate supplementation!
1) Coomb’s (-) = Hereditary = Not immune-related:
- Sickle cell disease (AR)
- Hereditary spherocytosis (AD)
- Paroxysmal nocturnal hemoglobinuria (PNH) (NOT HEREDITARY!)
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency (XLR)
2) Coomb’s (+) = Acquired = immune related -> sudden, associated w\ constitutional sx:
- Warm autoimmune hemolytic anemia
- Cold-agglutinin hemolytic anemia
- Drug-induced hemolytic anemia
1. Sickle cell disease:
Pathogenesis:
- Autosomal recessive, homozygous: normal Hb A -> mutant Hb S
- Point mutation: 6th position of B-chain: valine -> glutamic acid
- Hypoxia, acidosis, temp changes, dehydration, infec -> Hb molecules polymerize -> RBCs sickle -> obstruct vessels -> ischemia
Sickle cell trait:
- Heterozygous, identified by screening (clinically asx) -> genetic counselling
- Not anemic, normal life expectancy
- Associated w\ Isosthenuria (inability to conc urine)
Clinical features:
- Hemolytic anemia:
- Jaundice, pallor
- Pigmented gallstones
- Leads to high-output CHF
- Aplastic crisis: provoked by virus (human parvovirus B19) -> treated by blood transfusion (recovers in 7-10 days)
- Vaso-occlusion:
- Painful crisis involving bone, multiple sites, self-limiting (2-7 d)
- Hand-foot syndrome (dactylitis):
- Avascular necrosis of metacarpal\metatarsal bones -> painful swelling of dorsa of hands + feet -> in infants\early child (4-6 mo)
- Often first manifestation of SCD
- Acute chest syndrome:
- Due to repeated episodes of pulmn infarctions
- Same presentation as pneumonia: chest pain, resp distress, pulmn infiltrates, hypoxia
- Splenic infarctions (repeated episodes) -> autosplenectomy (large spleen in childhood -> not palpable by 4 yo; reduced to a small calcified ruminant)
- Avascular necrosis of joints: MC hip and shoulder
- Priapism:
- Erection lasting for 30m-3hr due to vaso-occlusion, if lasting > 3hrs -> medical emergency
- After passing urine, light exercise, cold shower -> usually subsides spont
- Prevention: hydralazine or nifedipine or using antiandrogen
- Delayed growth and sexual maturation; esp boys
- CVA: due to cerebral thrombosis, mainly in children
- Eye complications: retinal infarcts, vitreous hemorrhage, proliferative retinopathy, retinal detachment
- Renal papillary necrosis + painless hematuria: common, may cease spont
- Chronic leg ulcers: due to vaso-oculsion, typically: over lateral malleoli
- Infections:
- Functional asplenia -> more susceptible to infections (esp encapsulated bacteria: Hemophilus influenza and Strept pneumoniae)
- Splenic malfunction -> predisposition to Salmonella osteomyelitis
Diagnosis:
- Labs: ↓ Hgb, ↑ retics (bc of chronic compensated hemolysis), ↑ LDH, ↑ bilirubin
- Initial test: peripheral smear: Sickle-shaped RBCs (negative in sickle cell trait) + Howell-Jolly bodies (precipitated remnants of nuclear material in RBCs of asplenic pts)
- Most accurate: Hb electrophoresis
- The first clue to parvovirus is a sudden drop in reticulocyte level
Treatment:
- Pt education: avoid high altitudes, maintain fluid intake, treat infections promptly
- Vaccination (S. pneumoniae, H. influenza, Neisseria meningitides)
- Prophylactic penicillin for children (4 mo – 18 yr)
- Folic acid supplement (bc of chronic hemolysis)
- Painful crises: hydration, morphine, keep pt warm, supplemental oxygen
- Hydroxyurea: enhances Hb F levels -> interferes w\ sickling, reduces incidence of painful crises, accelerates healing of leg ulcers
- Blood transfusion: based on clinical condition and not Hb levels
- Exchange transfusion indications -> ACS, stroke, priapism, visual disturbance from retinal infarction. If exchange transfusion is not available -> give PRBCs
2. Hereditary spherocytosis:
- Autosomal dominant -> loss of spectrin in RBC membrane
- Sx: mile\moderate sx of anemia, splenomegaly, jaundice
- Labs: ↓ Hgb, -\↑MCV, ↑ MCHC, ↑retics, ↑ LDH, ↑ bilirubin
- Blood smear -> spherocytes 🙂
- Negative Coomb’s test
- + Osmotic fragility test -> cells have an ↑ sensitivity to lysis in hypotonic solution
- Tx: folate + elective splenectomy
3. Paroxysmal nocturnal hemoglobinuria (PNH):
- Idiopathic\not hereditary -> clonal defect of GPI in RBC membrane -> ↑ complementation -> intravascular hemolysis
- Why occurs at night? Complementation is encouraged by the slightly acidotic state during sleep
- Sx: anemia sx, dark\cola\tea-colored urine when pt wakes up -> normalizes as the day goes on, increased risk of venous thrombosis (hepatic “Budd-Chiari”, dermal “painful skin nodules)
- Dx: acidified serum lysis “Ham” test, flow cytometry for CD55\CD59
- Tx: iron + folate, steroids if severe, elective anticoagulation (mandatory if pregnant or thombo-embolic events have occured)
4. G6PD:
- X-linked recessive (more in boys) -> deficiency in G6PD -> reduction of NADPH (antioxidant)
- Sx: children + acute -> linked to infection, drugs (sulfas, nitrofurantoin), foods (fava beans)
- Blood smear -> Heinz bodies + Bite cells
- Tx: stop offending agent + hydration
5. Autoimmune\warm hemolytic anemia:
- Causes: idiopathic, lymphoproliferative ds (CLL, lymphoma), autoimmune ds (SLE, RA, scleroderma)
- Initial test -> Positive Coomb’s test = direct antiglobulin test (DAT)
- Negative cold-agglutinin titer
- Tx: folate + steroids, transfusion if necessary
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6. Cold-agglutinin hemolytic anemia:
- Causes: usually linked to an infection -> Mycoplasmia, EBV, HIV
- Key differentiator: worsend w\ exposure to cold -> purplish discoloration of fingers\toes
- Initial test -> Positive Coomb’s test = direct antiglobulin test (DAT)
- Positive cold-agglutinin titer
- Tx: folate + avoid cold conditions, Rituximab if necessary
7. Drug-induced hemolytic anemia:
- MCC: cephalosporin abx, levofloxacin, nitrofurantoin, rifampin, methyldopa
- Initial test -> Positive Coomb’s test = direct antiglobulin test (DAT)
- Tx: stop the drug + folate
d. Aplastic Anemia:
- Bone marrow failure -> pancytopenia (anemia, leukopenia, thrombocytopenia)
- Causes:
- Radiation
- Toxins: benzene
- Drugs: NSAIDs, chloramphenicol
- Alcohol
- Chemo: alkylating agents
- Infections: hepatitis, HIV, CMV, EBV, parvovirus B19
- Sx: bleeding (thrombocytopenia), fatigue (anemia), infections (neutropenia)
- Dx: pancytopenia, BM biopsy (confirmatory)
- Tx: BMT (if young and healthy), immunosuppressive agents (anti-thymocyte globulin, cyclosporine, prednisone)
Random notes:
- Ferritin and hepcidin are acute phase reactants -> elevated in any pt w\ inflammation
- TIBC = transferrin
- Hereditary spherocytosis, PNh, G6PD -> are at an increased risk of aplastic anemia (esp w\ parvovirus B19)
Anemia | Hgb | MCV | RDW | Retics | Ferritin | Iron | TIBC |
Iron deficiency | ↓ | ↓ | ↑ | ↓ | ↓ | ↓ | ↑ |
Anemia of chronic disease | ↓ | ↓ | ↑ | ↓ | ↑ | ↓ | ↓ |
Sideroblastic | ↓ | ↓ | ↑ | ↑ | ↑ | ↑ | ↓ |
Thalessemia | ↓ | ↓↓ | N | N | N | N |
Download the PDF version: here
References:
- Kaplan step 2 lecture notes
- Paul Bolin’s videos
- Step up to medicine