Anemia

Definitions:

• Hematocrit <41% in men or <36 in women
• Hemoglobin <13.5 gm\dL in men or <12 gm\dL in women

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a. Microcytic Anemia: 

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

 

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b. Macrocytic Anemia: 

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

 

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c. Hemolytic Anemia: 

• 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: 6^th 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:

1. 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)

2. 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

 

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

 

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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)

 

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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

 

 

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Download the PDF version: here

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References:

• Kaplan step 2 lecture notes
• Paul Bolin’s videos
• Step up to medicine