Day #39 - Anemia

Today we talked about a case of hemolytic anemia in a patient with rheumatoid arthritis on immunosuppressive medications including methotrexate, azathioprine and etanercept, as well as significant alcohol use and poor nutrition.

I suspect that the anemia in this case is multifactorial. The discussant took us through an approach to anemia. I like to approach anemia in two ways:

The first is based on the size of the RBC:

1. Microcytic -- iron deficiency, hemoglobinopathy, sideroblastic anemia (lead, ETOH)
2. Normocytic -- anemia of chronic disease, mixed microcytic/normocytic cause, hypothyoidism, renal failure, acute blood loss, early iron deficiency, sometimes bone marrow suppression
3. Macrocytic -- ETOH, drugs (methotrexate, AZT), B12/folate deficiency, myelodysplasia, hereditary spherocytosis, haemolysis, cirrhosis

The second is similar to the approach to thrombocytopenia

1. Decreased production -- EPO or substrate deficiencies, bone marrow problem (infiltrative process -- mets, infection, myelodysplasia/leukemia/stage IV lymphoma, toxins like ETOH or lead, hypothryoidism)
2. Blood loss -- if big drop and no obvious external bleeding, consider retroperitoneal bleed in the appropriate context
   
3. Destruction -- haemolytic anemia (intravascular and extravascular causes)

I integrate these two approaches to formulate a focussed differential diagnosis.

In all cases of anemia a thorough blood film review can be helpful. In cases where multiple lineages are involved (such as our case today where there was a leukopenia) a concomittent bone marrow cause should be considered.

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Approach to haemolytic anemia

Extravascular

• Hemoglobinopathies, Red Cell morphology defects (spherocytosis), G6PD/PDK deficiencies
• Hyperspenism, Infections (malaria), Toxins/drugs, Microangiopathic haemolytic anemia (MAHA -- eg TTP/HUS, malignant hypertension, scleroderma renal crisis, DIC)

Intravascular

• Prosthetic valves (low grade haemolysis)
• Transfusion reacton (incompatability)
• Hypotonic infusions (i.e. IV D5W too rapidly infused)
• Infection (i.e. severe malaria, Clostridial sepsis, paroxysmal nocturnal hemoglobinuria)
• Autoimmune Haemolytic Anemia
  

"Initial Haemolytic Workup"

• CBC with blood film: may see fragments (TTP/HUS), intracellular parasites (malaria), spherocytes (autoimmune) or clues to other causes (megaloblastic in B12, etc)
  
• Reticulocyte count: should be high if bone marrow is working properly. Inadequate reticulocyte response suggests some problem with production (including substrate deficiency)
  • Reticulocyte production index (RPI) = (Retic% * Hematocrit/0.45 )/RMT where RMT = 1 if HCT ~ 0.45, 1.5 if 0.35, 2 if 0.25, 2.5 if 0.15)
  • Normal RPI is 1; the RPI should be >2 in anemia
    
• Coombs test -- looks for antibody
• LDH: should be high
• Bilirubin (indirect) should be elevated
• Haptoglobin: should be low in
• D-Dimer, PT/INR elevated in DIC
• Fibrinogen decreased in DIC
• Urine haemosiderin elevated in intravascular haemolysis

From uptodate.com: "The combination of an increased LDH and reduced haptoglobin is 90 percent specific for diagnosing hemolysis, while the combination of a normal LDH and a serum haptoglobin greater than 25 mg/dL is 92 percent sensitive for ruling out hemolysis"

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This figure from uptodate is helpful: