What is your differential diagnosis?

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What are your next few steps?

What is your next step in diagnosis?

Thrombotic microangiopathy (TMA) such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)

Acute hemolytic transfusion reaction (AHTR)

Disseminated intravascular coagulation (DIC)

Clostridial sepsis

RBC parasite (eg, malaria, Babesia)

Drug-induced immune hemolysis

Drug-induced hemolysis associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency

Drug-induced thrombotic microangiopathy (DITMA)

Autoimmune hemolytic anemia (AIHA)

G6PD deficiency

Pyruvate kinase (PK) deficiency

Beta thalassemia

Alpha thalassemia

Sickle cell disease

Unstable hemoglobin

Mechanical hemolysis from aortic stenosis or prosthetic heart valve

Mechanical hemolysis from marching or bongo drumming

Osmotic lysis from hypotonic infusion

Snake bite

Paroxysmal nocturnal hemoglobinuria (PNH)

Paroxysmal cold hemoglobinuria (PCH)

Delayed hemolytic transfusion reaction (DHTR)

Hereditary spherocytosis (HS)

Hereditary elliptocytosis (HE)

Hereditary stomatocytosis (HSt)

Hereditary xerocytosis (HX)

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Framework for Hemolytic Anemia

• Intracorpuscular vs Extracorpuscular
• Immune vs Non-Immune
• Intravascular vs Extravascular
• Congenital vs Acquired

When to suspect hemolytic anemia

• Chronic or new onset symptoms of anemia (eg, fatigue, weakness, shortness of breath)
• A low hemoglobin level
• An increased reticulocyte count that is not explained by
• accelerated RBC production due to recent bleeding;
• repletion of iron, vitamin B12, folate, or copper
• administration of erythropoietin

History and Physical Pearls

• Jaundice is consistent with brisk hemolysis that overwhelms the capacity of the reticuloendothelial system to convert bilirubin to storage iron.
• Splenomegaly suggests expansion of the reticuloendothelial capacity.
• Dark urine is consistent with intravascular hemolysis.
• Recent blood transfusion suggests possible acute hemolytic transfusion reaction; transfusion in the previous four weeks also raises the possibility of a delayed hemolytic transfusion reaction
• Initiation of a new medication with potential for causing hemolysis suggests possible drug-induced etiology.
• History of hemolytic anemia or unexplained anemia in family members suggests an inherited disorder; this is more likely if multiple first degree family members are affected.
• History of pigmented gallstones or presence of gallstones implies chronic hemolysis that overwhelms the reticuloendothelial system.

Corrected Reticulocyte Count & Reticulocyte Index

CRC = % retics x (Patient hematocrit ÷ Normal hematocrit)

RI = Corrected Retic Count ÷ Maturation Factor

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Retic Index > 2% = increased production� ~1 = normal� < 2% = hypoproliferation

Hct ≥ 35% : 1.0�35% > Hct ≥ 25% : 1.5� 25% > Hct ≥ 20% : 2.0� 20% > Hct : 2.5

Labs

• Haptoglobin – A low haptoglobin is likely to be due to hemolysis, and an undetectable haptoglobin level is almost always due to hemolysis.
• In one series, the combination of an increased serum LDH and a reduced haptoglobin was 90 percent specific for diagnosing hemolysis
• The combination of a normal serum LDH and a serum haptoglobin >25 mg/dL was 92 percent sensitive for ruling out hemolysis

Peripheral Smear

• Extremely Important
• Schistocytes → thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP), DIC, or drug-induced TMA (DITMA)
• Organisms → infections such as malaria or Babesia
• Alterations to structure → Heinz bodies or bite cells suggesting hemolysis due to an oxidant drug in a patient with G6PD deficiency

Atypical Presentations

• Hemolysis without reticulocytosis → marrow failure (deficiencies, suppression, etc)
• Hemolysis without anemia → marrow able to overcome loss
• Reticulocytosis without hemolysis → recovery from bleeding, repletion of iron/B12/folate, EPO, recovery from marrow insult (parvovirus, meds, EtOH)

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WARM Autoimmune Hemolytic Anemia

• Caused by IgG antibodies to erythrocyte Rh antigens at 37.0°C (99.0°F)
• The direct Coombs (antiglobulin) test is used to diagnose WAIHA and is typically positive for IgG and negative or only weakly positive for complement (C3)
• First-line therapy for WAIHA consists of corticosteroids, which interfere with antibody production and macrophage-mediated clearance. ⅔ of pts will respond.
• Splenectomy is considered for nonresponders, patients who relapse, and those requiring chronic corticosteroids. Immunosuppressants can also be used off-label

Splenectomy

If a patient will be undergoing elective splenectomy, we recommend that the pneumococcal, meningococcal, and Haemophilus influenzae vaccines be administered at least 14 days prior to surgery. If it is not possible to administer these vaccines prior to splenectomy, they can be given after the 14th postoperative day.

COLD Agglutinin Disease

• Caused by IgM antibodies to erythrocyte antigens, at temperatures below 37.0 °C (99.0 °F), with maximal activity around 4.0°C (39.0 °F)
• IgM antibodies fix complement to the erythrocyte membrane, leading to erythrocyte clearance by direct intravascular lysis or through binding to macrophages in the liver
• CAD occasionally develops a few weeks after infection with mycoplasma or Epstein-Barr virus, often after typical clinical symptoms have resolved.
• Avoidance of cold temperatures is the typical initial treatment
• When further treatment becomes necessary, chemotherapeutic agents such as chlorambucil, cyclophosphamide, and, more recently, rituximab, have shown benefit.
• Corticosteroids and splenectomy are typically ineffective.