AssessmentsExtrinsic hemolytic normocytic anemia: Pathology review
USMLE® Step 1 style questions USMLE
A 7-year-old boy comes to the emergency department complaining of 2 days of fatigue, large purple spots on his legs, and bleeding in his mouth from the gums. He has no significant past medical history, and family history is unremarkable. His temperature is 37°C (98.6°F), pulse is 86/min, respirations are 20/min, and blood pressure is 108/66 mmHg. Upon physical exam, he is found to have pale skin, large purpura on his legs bilaterally, and bleeding mucosal petechiae. Laboratory tests are obtained and the results are shown below. Direct Coombs test is positive.
|Mean corpuscular volume (MCV)||86 fL|
|Haptoglobin||100 mg/dL (N = 50-220)|
|Blood, plasma, serum|
|Lactate dehydrogenase (LDH)||1080 U/L|
Content Reviewers:Yifan Xiao, MD
At the family medicine center, two people came in with progressive fatigue.
One of them is a 60 years old named Will whose past medical history included an aortic valve replacement with a mechanical valve due to severe aortic stenosis.
There’s Hanna, a 28 years old female of African descent.
She was diagnosed a year ago with systemic lupus erythematosus, or SLE. CBC is ordered for both people and it shows low hemoglobin with normal mean corpuscular volume, or MCV and reticulocyte count index over 2%.
They also have increased LDH. Now, Will has schistocytes on peripheral blood smear, while Hanna has spherocytes.
Both Will and Hannah are suffering from anemia, which is defined as lower than average levels of hemoglobin, typically below 13.5 g/dL in adult men and below 12.0 g/dL in adult women.
For children, this level varies based on the age. Now, anemias can be broadly grouped into 3 categories based on =MCV, which reflects the volume of an RBC.
Normocytic anemias can be further classified as hemolytic when there’s increased destruction of RBCs, or hemolysis, and non-hemolytic when there’s decreased production of RBCs from the bone marrow.
When there’s hemolysis, the bone marrow revs up and starts pumping out immature RBCs called reticulocytes, but when there’s a bone marrow problem reticulocyte count is low.
There are findings that can help identify the type of hemolysis. In intravascular hemolysis, hemoglobin that is released inside the vessels gets bound by a protein called haptoglobin and because they’re removed together, haptoglobin decreases.
Also, when haptoglobin gets overwhelmed, the rest of hemoglobin goes via the blood through the kidneys and into the urine resulting in hemoglobinuria.
Now, when hemoglobin is inside the renal tubules, the cells lining the renal tubules reabsorb hemoglobin.
The heme component of hemoglobin contains iron which is stored as hemosiderin in tubular cells and after a few days, when tubular cells slough into urine, there’s hemosiderinuria. Hemoglobinuria and hemosiderinuria can damage the kidneys causing back pain.
Okay, now in extravascular hemolysis, RBCs are destroyed outside the vessels and so, haptoglobin is normal and there’s no hemoglobin or hemosiderin in the urine.
Alright, now whenever there’s RBC lysis, an intracellular enzyme called lactate dehydrogenase, or LDH, spills out directly into the plasma and builds up in the blood.
Hemoglobin also spills out of the cell and breaks up into globin and heme.
If all of a sudden, your body starts breaking down more RBCs than the liver cells can handle, the excess bilirubin stays in the blood and cause jaundice where the bilirubin deposits in the skin and the eyes, causing them to turn yellow.
Okay, so let’s take a closer look at these different extrinsic hemolytic anemias, starting with autoimmune hemolytic anemia where antibodies and complement are directed against RBCs, leading to their destruction.
It’s like the RBC equivalent of immune thrombocytopenic purpura, or ITP, a disorder where autoantibodies bind to the platelet receptor and cause them to be targeted by immune cells in the spleen for destruction.
In fact, some patients develop both conditions together, and that’s called Evan’s syndrome.
Based on the type of antibodies produced, autoimmune hemolytic anemia can be divided further into IgG, also called warm antibody, hemolytic anemia, and IgM hemolytic anemia, also called cold agglutinin disease.
Now, it’s important to remember the causes, since they might be the best clues for identifying autoimmune hemolytic anemia in the exams.
Warm antibody hemolytic anemia is typically seen in chronic lymphocytic leukemia, or CLL, systemic lupus erythematosus, or SLE, and with the use of antibiotics like penicillins and cephalosporins, sulfa drugs, and the antihypertensive drug, methyldopa.
Next up is microangiopathic hemolytic anemia that occurs in the small blood vessels and include thrombotic thrombocytopenic purpura, or TTP, hemolytic-uremic syndrome, or HUS, and disseminated intravascular coagulation, or DIC.
In TTP, there’s a deficiency of ADAMTS-13, a metalloproteinase that breaks Von willebrand factor, a protein needed for the formation of clots and their adhesion to the endothelial lining.
So When there’s not enough ADAMTS-13, there’s excessive clot formation, and these clots end up damaging RBCs.
In some cases it can also be associated with diseases like systemic lupus erythematosus.
Alright, moving onto HUS. Typical HUS, occurs after an infection by a shiga-toxin bacteria.
A high yield fact for your exams is that this often occurs in children after an episode of gastroenteritis caused by these bacteria.
The toxins they release destroys colonic epithelial cells, causing bloody diarrhea, and then enters the circulation, where it damages the endothelial cells causing massive release of von willebrand factor and excessive clot formation throughout the body.
Typical HUS has good prognosis. Now, the atypical HUS is not associated with shiga-toxin, may occur at any age, and has a relatively poor prognosis.
It is linked to a genetic mutation in factor H, a protein that controls the complement system. Without it, the complement system goes wild, causing damage to the endothelial cells and excessive clot formation.
- "Kaplan USMLE Step 2 CK Lecture Notes Internal Medicine" Kaplan Medical (2017)
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Hemolytic Anemia: Evaluation and Differential Diagnosis" Am Fam Physician (2018)
- "Autoimmune hemolytic anemia" Hematology (2018)
- "Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review" Wiener klinische Wochenschrift (2008)
- "Hemolytic uremic syndrome" Türk Pediatri Arşivi (2015)
- "Haemolytic uremic syndrome: diagnosis and management" F1000Research (2019)
- "Management of thrombotic thrombocytopenic purpura: current perspectives" Journal of Blood Medicine (2014)
- "Thrombotic microangiopathies: a general approach to diagnosis and management" Canadian Medical Association Journal (2016)
- "Relationships between anaemia and parasitic infections in Kenyan schoolchildren: A Bayesian hierarchical modelling approach" International Journal for Parasitology (2008)