Extrinsic hemolytic normocytic anemia: Pathology review

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Case Study0:00–1:07

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.

Pathology1:07–5:05

So microcytic anemia is where the MCV is lower than 80 fL, normocytic, with an MCV between 80 and 100 fL, and macrocytic, with an MCV larger than 100 fL.
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.
So for your exams, it’s important to know that in hemolytic anemias there’s an increased reticulocyte production index of over 2%, while in non-hemolytic anemias it’s lower than 2%.
Alright, now hemolytic anemias can be classified as intrinsic or extrinsic hemolytic anemias. In intrinsic hemolytic anemias, RBCs are destroyed because they’re defective, while in extrinsic hemolytic anemias, RBCs are normal but are later destroyed outside the bone marrow.
In this video, let’s focus on extrinsic hemolytic anemias that include autoimmune hemolytic anemia, microangiopathic hemolytic anemia, macroangiopathic hemolytic anemia and infections.
Now, we can divide extrinsic hemolysis into intravascular, meaning RBCs are destroyed within the vasculature, or extravascular, meaning that they are removed by macrophages in the spleen and liver.
Microangiopathic and macroangiopathic hemolytic anemias are intravascular, autoimmune hemolytic anemia is usually extravascular, while infections can cause both intravascular and extravascular.
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.
RBCs are usually destroyed in the spleen causing splenomegaly or the liver causing hepatomegaly. 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. Heme is converted into unconjugated, or indirect, bilirubin which is then taken up by the liver cells and eventually secreted out with bile.
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.
Also, when there’s too much bilirubin in the bile, it can form pigmented gallstones. Some of the bilirubin is converted to urobilin which is what gives urine that yellow color, but if there’s too much of it, the urine becomes a much darker, tea-like color.
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.

Autoimmune 5:05–6:33

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.
Cold agglutinin disease is often seen in CLL, Waldenstrom macroglobulinemia, a rare type of malignant lymphoma, and infections like infectious mononucleosis and mycoplasma pneumoniae infections.

Microangiopathic6:33–7:01

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 these disorders, there’s excessive clot formation so when normal RBCs flow through these blood vessels, they get banged up and damaged, leading to intravascular hemolysis.
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.

TTP7:01–7:43

So When there’s not enough ADAMTS-13, there’s excessive clot formation, and these clots end up damaging RBCs. TTP can be caused by a genetic mutation or it can develop after exposure to antiplatelet medications like ticlopidine and clopidogrel, or chemotherapeutic agents like cyclosporine and gemcitabine.
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. The most common is Escherichia coli, but others include shigella, and salmonella.

HUS7:43–8:41

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.

DIC8:41–9:03

Next up is DIC, where there is a massive overactivation of the coagulation system in response to something like sepsis or trauma.
This leads to widespread clotting, organ ischemia, and microangiopathic hemolytic anemia, while at the same time depletes platelets and clotting factors, which paradoxically, leads to bleeding.
Alright, now microangiopathic anemia can also occur in hypertensive emergencies and in HELLP syndrome which is an acronym for a triad of findings, H for hemolysis, EL for elevated liver enzymes, and LP for low platelets.

HELLP Syndrome9:03–9:49

HELLP occurs as a complication of preeclampsia and eclampsia which are hypertensive disorders in pregnancy. High blood pressure can damage the vascular endothelium and activate the coagulation cascade leading to the formation of blood clots, depleting the platelets.
The clots are responsible for the destruction of RBCs as they circulate through the clotted vessels. The clots also deposit in the hepatic blood vessels causing congestion and increased intrahepatic pressure, leading to liver damage.
Okay, moving on to macroangiopathic hemolytic anemia where the destruction of RBC happens in the larger vessels. Actually most of the time, this happens inside the heart.

Macroangiopathic9:49–10:11

One example is aortic stenosis where the RBCs are damaged when squeezing past the damaged valves. Prosthetic heart valves can also cause the same problem.
Hemolysis also occurs with a parasitic infection like plasmodium falciparum that causes malaria, and babesia species, a tick transmitted parasite that causes babesiosis.

Parasitic Infections10:11–10:31

These parasites love to infect and live inside RBCs, eventually causing them to rupture, leading to hemolysis. Alright, now all types of hemolytic anemia can present with symptoms of anemia like fatigue, parlor and shortness of breath.

Symptoms10:31–12:55

Hemolysis present as jaundice, dark or tea-colored urine, and back pain due to kidney damage. Also, when there’s extravascular hemolysis, there’s also splenomegaly or hepatomegaly.
But in the exams, more specific symptoms will often help you identify the particular disease. For example autoimmune hemolytic anemia can occur suddenly with fever, syncope and congestive heart failure.
In addition, in cold agglutinin disease, when individuals are exposed to cold temperatures, IgM antibodies react with RBC antigens and make them agglutinate, or clot.
A high yield fact to remember is that these clots cause cyanosis and pain in the coolest areas of our bodies like ears, nose, fingers and toes.
Moving on to microangiopathic hemolytic anemia. For TTP, individuals classically develop five symptoms: thrombocytopenia causing mucocutaneous bleeding, microangiopathic hemolytic anemia, fever, renal insufficiency, which can cause hematuria and decreased urine output; and neurologic symptoms like headache and confusion.
Now, HUS is clinically similar to TTP. The classic presentation is a triad of thrombocytopenia, renal insufficiency, and microangiopathic hemolytic anemia.
These appear five to ten days after the gastroenteritis episode in typical HUS, or can happen on their own in atypical HUS.
A very high yield concept to remember is that unlike TTP, HUS doesn’t usually cause a fever or neurological symptoms, and instead the renal insufficiency symptoms predominate.
In DIC, initially, the patient is more likely to clot, and that leads to overconsumption of the coagulation factors, including fibrinogen, and platelets.
Then, there’s a period in which the patient is more likely to bleed, like from venipuncture sites. Macroangiopathic hemolytic anemia presents with the non-specific symptoms of anemia and symptoms of hemolysis.
Now, if there is hemolysis during an infection, like in malaria, symptoms may include fevers, headaches, extreme fatigue and symptoms of hemolysis like jaundice and splenomegaly.
Moving on to diagnosis. The most specific test to diagnose autoimmune hemolytic anemia is the positive Coombs test.

Diagnosis12:55–15:02

Direct Coombs test detects antibodies or complement found on the RBC membrane, while indirect Coombs indicates the presence of antibodies in the serum.
On the peripheral blood smear, spherocytes are often present. Spherocytes are small, round, dysmorphic RBCs with more intensely stained cytoplasm and no central pallor, but they are non-specific for autoimmune hemolytic anemia and are also present in hereditary spherocytosis.
Coombs test which is negative in hereditary spherocytosis can help distinguish these two conditions. Alright, in microangiopathic and macroangiopathic hemolytic anemia, an important clue is the presence of schistocytes on peripheral blood smear.
These are RBCs that break apart the bloodstream, forming cell fragments or ‘helmet’ cells which look like little red helmets with pointed ends after a bit of the cell broke off.
Now lab findings can help you identify the specific type of microangiopathic hemolytic anemia. In TTP, a CBC will show thrombocytopenia.
Creatinine levels may be elevated if there is kidney damage. Markers of secondary hemostasis like prothrombin time or PT, and partial thromboplastin time or PTT are normal, because they’re not involved in formation of the von willebrand factor multimers and platelets.
Laboratory studies in HUS are similar to TTP. In a child, where typical HUS is suspected, stool cultures can be sent off to look for E.
coli. In DIC, there’s usually thrombocytopenia and a prolonged PT, PTT.
Additionally, fibrinogen levels are decreased and there are elevated d-dimer levels indicate accelerated clot lysis. Now, to diagnose an infection as the cause of hemolysis, you need to confirm the presence of the causative organism.
For example, malaria is usually diagnosed with a blood smear that shows the parasite sitting within the red blood cell. All right, as a quick recap!

Review15:02–15:32

Extrinsic hemolytic anemias include autoimmune hemolytic anemia, microangiopathic hemolytic anemias such as TTP, HUS and DIC, macroangiopathic hemolytic anemia due to prosthetic heart valves and aortic stenosis, and infections causing hemolysis such as malaria and babesiosis.
A diagnosis can be made based on clinical presentation, lab findings, peripheral blood smear, and more specific tests like Coombs test.
Now, back to the patients! Both of them have normocytic hemolytic anemia.

Summary15:32–15:56

Due to his history of aortic valve replacement and the presence of schistocytes on peripheral blood smear, Will most likely has macroangiopathic hemolytic anemia.
Now, Hanna due to her history of SLE and the presence of spherocytes on blood smear, she could have warm antibody hemolytic anemia.
A positive Coombs test will confirm this diagnosis. ...And that’s the extrinsic hemolytic anemia pathology in a nutshell.