Pathology Student

Q. I’ve never been clear on the way iron is handled and was hoping you could clarify. Basically, I don’t understand the difference between serum iron and serum ferritin. And then to confuse me even more is distinguishing the difference between serum ferritin and transferrin…I was hoping you could walk me through the journey that iron takes among these various proteins.

A. Let’s break down our discussion of iron into 5 categories: absorption, circulation, distribution, metabolism, and storage. And then we’ll talk a little bit about how you might actually use this information in the real world of pathology…

Absorption
Iron is absorbed (in the ferrous state) in the duodenum and proximal jejunum. Generally, we eat about 1-2 mg of iron per day. By the way, we lose about 1-2 mg of iron a day too (through mucosal cell sloughing and menstruation, mostly). How balanced is that!

Circulation
In the blood, iron moves about bound to a molecule called transferrin. Transferrin carries iron (in the ferric state) to the bone marrow (where red cell precursors await) and to other organs.

Distribution
Most of the iron in the body is found in hemoglobin (in the adult male that accounts for about 2300 mg; in the female, it’s about 1750 mg). A smaller percentage is present in storage forms (1000 mg in males, 400 mg in females), even less is found in organs, such as the liver (500 mg in males, 350 in females), and a very small amount (3 mg) is present in the transport form (attached to transferrin).

Metabolism
Most of the circulating iron is taken up by red cell precursors and incorporated into heme (which is then combined with globin chains to make hemoglobin).

Storage
There are two storage forms of iron: ferritin and hemosiderin. Ferritin is the main storage form of iron. It is a protein released by the reticuloendothelial system, and it is a reflection of the tissue stores of iron (in other words, if you’ve got a ton of iron in your tissues, your ferritin levels will go up). It is a labile form of iron storage, meaning that iron can get in and out of this form quickly. It’s also an acute phase protein, which means that it goes up in certain conditions, like chronic inflammation. Hemosiderin, which consists of ferritin and cell debris, is a stable form of storage, but iron in this form is less readily accessible.

And this is important why?
Well, for one thing, you can measure serum iron, total iron-binding capacity of transferrin (TIBC), and ferritin to help you diagnose different types of anemia. In iron-deficiency anemia, for example, the serum iron is down (well, obviously). The TIBC is increased (because the body makes more transferrin, plus much of the transferrin is sitting around without iron bound to it – hence the iron-binding capacity is increased), and the ferritin is decreased (because there’s less iron around, so there’s less in storage form).

In another form of anemia known as anemia of chronic disease, there is a problem with iron but it is different than the problem in iron-deficiency anemia. It seems to have something to do with the over-production of something called hepcidin, a liver protein that regulates iron metabolism. Anyway – in this type of anemia, the serum iron is decreased, the ferritin is increased (because it is an acute phase reactant, not because there is a ton of iron around), and the TIBC is normal to decreased (because the body is producing less transferrin, for reasons that are not well explained).

The image of the cool Iron Maiden keyring was posted on Flickr by Howard Gees (http://www.flickr.com/photos/cyberslayer/523100679/) under cc license.

Here’s a little quiz on anemia. Answers are in the first comment following this post.

1. Which of the following is a sign of red cell destruction?

A. ↑ haptoglobin
B. ↓ LDH
C. ↑ bilirubin
D. ↑ reticulocytes
E. ↑ LAP

2. Your patient is a 68 year old male who has very pale, almost bluish fingertips. When you question him about this, he says that it gets worse when he’s out in the cold, and that his doctor says he has some kind of anemia.

Which of the following is probably true?

A.He is making IgG antibodies against his red cells
B. His DAT would be negative
C. The spleen is the major site of red cell destruction in this patient
D. His blood smear would show schistocytes
E. Complement is attacking his red cells

3. What is the defect in hereditary spherocytosis?

A. A point mutation in a hemoglobin chain gene
B. Absence of one or more hemoglobin chain genes
C. Absence of a red cell enzyme
D. A spectrin abnormality
E. Inability to incorporate iron into hemoglobin

4. Your apparently healthy, 75-year-old grandfather was found to have an abnormality on his blood smear during a routine physical. His indices are as follows:

Hgb  8 g/dL (12-16)
MCV 70 fL(80-100)
RDW 15% (12 – 13.5)
RBC 3.5 x 10^12/L (4.5-6.0)
WBC 10 x 10^9/L (4-11)
Plt 300 x 10^9/L (150-450)

What should be done next?

A. Check his blood smear at his next annual physical
B. Give him iron replacement
C. Perform a complete physical, including testing for blood in the stool
D. Give him steroids
E. Do a bone marrow biopsy

5. Your next patient, a 65 year old Finnish bachelor, is a self-proclaimed heavy drinker. He has the following indices:

Hgb  8 g/dL (12-16)
MCV 110 fL(80-100)
RDW 13% (12 – 13.5)
RBC 3.5 x 10^12/L (4.5-6.0)
WBC 7.2 x 10^9/L (4-11)
Plt 420 x 10^9/L (150-450)

What is the most likely diagnosis?

A. Iron-deficiency anemia
B. Thalassemia
C. Megaloblastic anemia
D. Hereditary spherocytosis
E. Sickle cell anemia

Q. Could you explain the “defect in spectrin” in hereditary spherocytosis—how does this cause cells to become spherocytes?

A. Several mutations have been described in hereditary spherocytosis, each with a slightly different spectrin defect. In all of the mutations, though, there is a problem with the connection between spectrin (a long heterodimer situated just inside the cell membrane) and the cell membrane itself. The cell membrane becomes unstable, and as a result, bits of membrane are lost (but the volume inside the red cell remains intact). When you lose membrane, but keep the cell contents intact, the cell starts to “round up”, and instead of being a biconcave disk, it turns into a ball, or spherocyte. Spherocytes are inherently more fragile than regular old biconcave-disk-shaped red cells. They also are less able to maneuver through tight spaces. So they are more likely to break, causing a hemolytic anemia.

Q. In microangiopathic hemolytic anemia, how does clot formation cause red cells to get “ripped” up? Is it because they have less room to maneuver through the vessel? Also, could you give me an example of an obstetric complication that would cause this anemia?

A. When you form a clot, you start by sticking platelets together, and then through a series of enzymatic steps, you make a long polymer called fibrin that sort of cements the platelets together. Sometimes the fibrin strands (especially if you’re forming a lot of them) can ensnare red blood cells as they are flowing through the vessel. The cells get snagged on the strands of fibrin, and they get ripped apart, forming fragmented red cells (schistocytes) that you can see on a blood smear. This is the mechanism for most cases of microangiopathic hemolytic anemia. However, there are some cases that are due to other mechanisms (one example would be a patient with an old-fashioned, ball-and-socket artificial heart valve that smashes a few red cells every time it closes). These cases are less common, and they really aren’t “microangiopathic” since the problem isn’t really in little vessels. But they’re lumped into the same category because they show fragmented red cells.

In some deliveries, especially difficult or traumatic ones, amniotic fluid can leak into the mother’s blood. Amniotic fluid has procoagulant substances in it that kick off the coagulation cascade (the part of clot formation in which you make fibrin). If you’re making lots of fibrin, chances are the red cells are going to get trapped in the fibrin strands, as described above.

Q. In autoimmune hemolytic anemia, I am confused with the warm and cold types. Does IgG stick better to cells in warm temperatures and IgM in cold? How does agglutination cause anemia? Is it because there are less red cells to circulate freely?

A. Some antibodies tend to stick better to red cells at warm temperatures, and some tend to stick better at cold temperatures. You’re right; for some reason, the antibodies that bind better at warm temperatures tend to be IgG, where as the cold-binding antibodies tend to be IgM.

In cold autoimmune hemolytic anemia, there are two things going on:

1) IgM sticks to the red cells at cold temperatures (like in blood in the fingers and earlobes), where it agglutinates red cells and forms big clumps. This doesn’t cause anemia, and it doesn’t really do much damage – it usually just causes some decreased blood flow to these regions (the agglutination goes away when you warm up those body parts).

2) Complement binds to the red cells (why this happens in cold, but not warm, autoimmune hemolytic anemia, nobody knows). This is bad. Complement pokes holes in the red cells, causing hemolysis. So this is what leads to the anemia – not the agglutination.

In warm autoimmune hemolytic anemia, the anemia is due to macrophages either 1) totally engulfing the IgG-coated red cells (and thus removing them from the circulation), or 2) chewing off bits of membrane (and thus turning the red cell into a spherocytes, which is more fragile than a regular red cell).

Q. Why is LDH increased in hemolytic anemia?

A. Lactate dehydrogenase (LDH) is an enzyme that is present in lots of cells in the body: heart, lung, kidney, liver, muscle, and red blood cells. It’s also present in some tumor cells. Any time these cells are destroyed, LDH is released, and you can measure it in the serum. There are different isozymes (red cells have the LDH-2 isozyme), and you can measure these independently in the serum, so you know where the LDH is coming from.

Image credit: Eleaf (http://www.flickr.com/photos/eleaf/2536358399/), under cc license.

Q. How is G6PD deficiency self-limiting? Does it mean the anemia is short-lived?

A. When new red cells are formed, they have a lot of G6PD in them. As they age, there’s lots of nasty stuff formed during cell metabolism, and the G6PD gets used up. By the end of the cell’s lifespan, there’s less G6PD around (but still enough, in a person without G6PD, to handle all the nasty metabolites that are formed).

In a patient with G6PD, the red cells don’t have as much G6PD to begin with (and by the end of their lifespan, there’s very little G6PD around at all). If a person with G6PD deficiency eats a bunch of fava beans, or ingests some other oxidant, the red cells (particularly those that are older) will have a hard time handling the nasty substances that are formed, and the patient will get an anemia characterized by bite cells. However, the new red cells that get released into the circulation will have at least some G6PD, and they’ll be better equipped to handle the oxidant. As each new wave of red cells appears, the anemia becomes less and less severe, until finally it disappears (assuming the ingestion is a one-time, defined event, and not a ongoing occurrence). So yes, it does mean the anemia is short-lived – and that it goes away on its own without additional therapy. If it’s really severe, the patient may need supportive therapy – red cell transfusions, for example – but that’s just to help get the patient through the crisis.

Gorgeous image of fava beans by Andrew Huff (http://www.flickr.com/photos/51035597898@N01/499585508/), under cc license.

Q. What is the difference between schistocytes, spherocytes, and bite cells?

A. Schistocytes are fragmented red cells. You see them in microangiopathic hemolytic anemia. Their presence means that red cells are being ripped apart for some reason (and it’s important to find out that reason).

Spherocytes are ball-shaped red cells. They look smaller than regular red cells, and they don’t have a zone of central pallor. Their presence means that there is some sort of hemolysis going on (all hemolytic anemias can have spherocytes – they are formed by different mechanisms, all of which involve the loss of cell membrane but preservation of cell contents, so that the cell “rounds up” as described above).

Bite cells are present in G6PD deficiency. When you don’t have enough G6PD around, you can’t reduce toxic metabolites (like peroxides). When you’re exposed to an oxidant substance, you get lots of these nasty substances, and they start attacking the bonds between heme and globin. The globin chains break free and form a little ball that sticks to the inside of the cell membrane (this little ball is called a Heinz body). Macrophages in the spleen see these Heinz bodies and bite them out, forming “bite cells”.

Image credit: pterjan (http://www.flickr.com/photos/cmoi/866125948/) under cc license

Q. I’m confused how in megablastic anemia, cells become macrocytic due to immature nuclei when RBCs don’t have nuclei—is it referring to the erythroblast precursors before the nuclei are lost?

A. Great question. In megaloblastic anemia, cells have a hard time making DNA (because there’s a lack of B12 and/or folate) – but RNA production proceeds normally. So you end up with cells that have normally maturing cytoplasm, but slowly-maturing nuclei. This means that the cell grows pretty large before the nucleus gets mature enough to signal division (so the cells end up being larger than normal). Also, when you look at the nucleus, it looks more immature than the cytoplasm (hence the term “nuclear-cytoplasmic asynchrony). You’re right: these changes are easiest to see when you look at erythroblast precursors (which have nuclei). You can also see the same changes in neutrophil precursors (you’d have to look at the marrow to see both of these types of precursor cells).

When you look at the blood, you can’t see these precursors. But you do see macrocytes (larger-than-normal mature red blood cells) and hypersegmented neutrophils. The reason the mature red cells are bigger than usual has to do with the fact that the red cell precursors get bigger than normal before each cell division, as described above…and that translates into bigger-than-normal mature (non-nucleated) red blood cells. The reason for the hypersegmented neutrophils is less clear; it has something to do with the abnormal, asynchronous maturation going on in the neutrophil series – but how the mature neutrophil winds up with a nucleus with more lobes (or segments) than normal is kind of a mystery.

Well, if you read last Friday’s post, you already know: it’s used for determining the amount of fetal blood that has backed up into the mom’s circulation. It’s usually done for the purpose of determining Rhogam dose. You need to make sure you give enough Rhogam to suppress the mom’s immune response. If there has been a little bleed, you give a little; if there has been a big bleed, you need to give more. Take a look at this chart if you want to know exact doses.

Here’s how it’s done:

1. Prepare blood smear from mom’s blood.

2. Expose blood smear to acid bath (this removes adult hemoglobin, which is acid-sensitive) but not fetal hemoglobin.

3. Stain smear (fetal cells appear pink; maternal cells look like “ghosts”). Take a look at this nice blood smear to see what this looks like.

4. Count lots of cells and report percentage of cells that are fetal (specifically: you count the number of fetal blood cells per 50 low power fields. If you see 5 cells per 50 low power fields, that’s equivalent to a 0.5 mL fetomaternal hemorrhage).

If you want to get really fancy, you can look for fetal blood cells using flow cytometry. Using a sample of mom’s blood, apply an anti-HbF (fetal hemoglobin) antibody, and then run the sample through the flow cytometer. In the little printout, look for cells that stain intensely with HbF: these are baby’s cells! A few of mom’s cells will have weak HbF staining – this is normal in adults.

Image credit: adamr.stone (http://www.flickr.com/photos/adamrstone/3098924060/) via cc license.

Hemolytic disease of the newborn (HDN) is a disease in which there is hemolysis in a newborn or fetus caused by blood-group incompatibility between mother and child.

There are a bunch of related terms:

• Immune hydrops (Hydrops means accumulation of edema fluid in the fetus during intrauterine growth. It is not specific to HDN, but can occur in many different fetal conditions including cardiovascular conditions, chromosomal disorders like Down syndrome, non-immune fetal anemia, twin-twin transfusion, infections, tumors, and metabolic disorders. Whew.)
• Hydrops fetalis (When the accumulation of fluid – from whatever cause – is severe and generalized, it is called hydrops fetalis.)
• Erythroblastosis fetalis (Erythroblastosis means that early red cell precursors are showing up in the peripheral blood. This can happen in any severe anemia, not just HDN.)

Mechanism of HDN

1. Fetus inherits blood group antigens (usually Rh D antigen or ABO antigens) from the father that are foreign to the mother.
2. Fetal blood gets into mom’s circulation (either during last trimester of pregnancy, when cytotrophoblast is no longer present, or during childbirth).
3. Mom makes antibodies to these blood group antigens.
4. Antibodies cross the placenta, attack baby’s red cells, causing hemolytic anemia and its consequences.

The consequences of hemolysis are numerous. One such consequence is extramedullary hematopoiesis. If the anemia is mild, extramedullary hematopoiesis in the liver and spleen may produce enough red cells to maintain normal numbers.

Other consequences are not so happy. If the anemia is severe, the heart and liver may suffer hypoxic injury, resulting in circulatory and hepatic failure. Liver failure causes decreased protein levels (proteins are synthesized in the liver) and a reduction in oncotic pressure in the circulation. Heart failure causes an increase in venous pressure (blood is backing up behind the failing heart). If severe enough, the combination of reduced oncotic pressure and increased venous pressure leads to generalized edema and ascites, a condition called hydrops fetalis, which can be fatal. Lesser degrees of edema can also occur.

If hemolysis is severe, jaundice can occur due to accumulation of unconjugated bilirubin. Unconjugated bilirubin is water insoluble; it binds to lipids in the brain (the blood-brain barrier in the fetus is poorly developed), causing serious damage to the CNS, termed kernicterus. The affected brain is enlarged, edematous, and yellow.

Rh-mediated HDN

Rh-mediated HDN most often involves the D antigen (sometimes it involves E or c; rarely it involves e or C). The baby inherits the D antigen from father, and mom is D negative (same as saying “Rh negative”). Fetal blood gets into mom’s circulation (through trauma, ruptures in the placenta during pregnancy, medical procedures carried out during pregnancy that breech the uterine wall, or childbirth). As a result, mom makes anti-D antibodies (the amount of antibody made depends on dose of antigen received from baby! Mom only makes anti-Rh antibodies when the she has received more than 0.5- 1 mL of Rh + cells.). Just like any other developing antibody, IgM appears first, and IgG appears later. This is important because IgG can cross the placenta, but IgM can’t. So HDN is uncommon in a first pregnancy. But if the mom gets pregnant again, and the fetus inherits D again, mom will now make IgG antibodies, and HDN can happen then.

Rh-mediated HDN is diagnosed using a direct antiglobulin test (DAT). This test will be positive in the baby (baby’s cells are coated with mom’s antibodies). An indirect antiglobulin test  will be positive in mother (though if the mother has received Rhogam at 28 weeks – keep reading – the IAT will be artificially positive!). Administration of anti-D antibody (Rhogam) at 28 weeks and again within 72 hours of delivery to Rh-negative moms prevents HDN in the current pregnancy (and, if mom has not produced anti-D yet, protects future pregnancies too) by coating any circulating D+ fetal red cells before mom is able to make any anti-D antibodies! The incidence of Rh-mediated HDN has gone way down since Rhogam was developed.

In order to determine the appropriate dose of Rhogam to give the mom, you have to quantify the amount of fetomaternal hemorrhage. This is done using either the Kleihauer-Betke test or an immunophenotyping assay. We’ll discuss these tests in our next post.

ABO-mediated HDN

ABO incompatibility occurs in 20-25% of pregnancies…but laboratory evidence of hemolytic disease occurs only in 1 of 10 such infants, and the hemolytic disease is severe enough to require treatment in only 1 in 200 cases.

There are a number of reasons why ABO incompatibility is rarely serious:

1. Most anti-A and anti-B antibodies are IgM (hence they don’t cross the placenta).
2. Neonatal RBCs express A and B poorly (the expression of A and B antigens increases as the baby grows).
3. Many cells other than red cells express A and B antigens and thus sop up some of the transferred antibody.

ABO hemolytic disease occurs almost exclusively in infants of A or B type born of group O mothers. Normal anti-A and anti-B antibodies are IgM and therefore don’t cross the placenta. For reasons not understood, however, some group O women have IgG anti-A and anti-B even without prior sensitization! In this situation, a firstborn child may be affected. Fortunately, even with transplacentally acquired antibodies, lysis of infant red cells is minimal.

ABO incompatibility is diagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betke test). There’s no effective protection against ABO incompatibility reactions! Good thing they’re not very common.

Treatment of HDN

It’s obviously way better to prevent HDN than to try treat it once it’s developed. That’s why the mother’s blood type is determined very early in pregnancy, and Rhogam is administered if mom is D negative.

If HDN does develop, there are several options for treatment. Minimally affected newborns can be treated with phototherapy (as in the photo above). Light oxidizes unconjugated bilirubin (toxic) to water-soluble, readily-excreted dipyrroles (harmless). Severely affected fetuses can be treated by total exchange transfusion of the infant (through umbilical vein). The mother can be treated with plasmapheresis (which removes antibody). High-dose intravenous immunoglobulin can be used too – but the best dosage and timing are not well-defined.

Photo credit:  treehouse1977 (http://www.flickr.com/photos/treehouse1977/3310309612/in/photostream/), under cc license.

The second most common type of anemia (after iron-deficiency anemia) is anemia of chronic disease (ACD). This is a mild to moderate anemia accompanying infections, inflammatory disorders or malignant diseases that persist more than 1-2 months (examples include pulmonary infections endocarditis, rheumatoid arthritis, lupus, carcinoma, lymphoma, and myeloma). It’s characterized by low serum iron, despite lots of macrophage storage iron.

The pathogenesis of this anemia is multifactorial. Part of the problem is related to iron metabolism. For the most part, mucosal cells absorb iron okay, but they don’t release it into plasma (so the iron never makes it into red cell precursors!). Macrophages take up iron okay, but they release it very slowly. All of this is mediated, at least in part, by a substance called hepcidin, which is produced by the liver and released in response to inflammation (which, of course, you see in most chronic diseases).

In addition to the iron metabolism stuff, the red cells in this anemia have a shortened lifespan. The weird thing is that if you put cells from patients with ACD into normal patients, the red cells have a normal lifespan; but if you put cells from a normal patient into a patient with ACD, those red cells will die early! To top it all off, there is an impaired bone marrow response to anemia. There’s not enough iron available to make enough red blood cells; also, there’s not enough erythropoietin around, and bone marrow can’t respond to what little there is. Ugh. You’d think with all that stuff going on, the anemia would be severe – but it generally isn’t. Patients usually have no real symptoms related to the anemia; they have enough trouble with whatever chronic disease they suffer from.

The anemia is normochromic and normocytic, usually.  Some cases (about 25%) are microcytic (but MCV rarely gets below 72 fL). There is minimal anisocytosis and poikilocytosis. There’s really not a lot to look at under the microscope!

To make the diagnosis, you need to do iron studies. In ACD, you’ll see the following:
•    ↓ serum iron
•    ↓ TIBC (total iron binding capacity)
•    ↓ transferrin saturation
•    ↑ ferritin (remember: ferritin is an acute phase reactant! So it’s increased in these patients, because there is chronic inflammation present.)
•    ↑ bone marrow storage iron

This anemia usually is so mild that treatment is not necessary. The anemia develops during the first 2 months of the chronic disease, and it doesn’t progress thereafter. The important thing to remember is that you need to distinguish it from iron-deficiency anemia (use iron studies for this). You wouldn’t want to mix the two up, because anemia of chronic disease requires no further treatment, whereas a diagnosis of iron-defieciency anemia necessitates a search for possible sites of blood loss.

Photo credit: Ethan Hein (http://www.flickr.com/photos/ethanhein/2383172799/), under cc license.

We’ve talked about a whole bunch of different hemolytic anemias over the past few weeks. We’ve gone through the main hereditary hemolytic anemias: hereditary spherocytosis (and its less-common counterpart, hereditary elliptocytosis), glucose-6-phosphate dehydrogenase deficiency, the hemoglobinopathies (like sickle cell anemia) and the thalassemias. We’ve also talked about immune-related hemolytic anemia (warm and cold), which is an acquired hemolytic anemia.

The last main type of hemolytic anemia on our list is microangiopathic hemolytic anemia, or MAHA for short, which falls under the acquired group of hemolytic anemias. In this type of hemolytic anemia, the red cells are ripped apart by physical trauma. Often the trauma results from red cells getting snagged as they try to pass through vessels laden with fibrin strands (there are a ton of situations in which this occurs, as we’ll see). Sometimes the trauma is due to other types of trauma (like an artificial heart valve that busts a few red cells each time it closes).

Let’s take a look at the other-types-of-trauma group first because it’s a little easier to conceptualize. There are two main causes of MAHA in this group: artificial heart valves and coarctation of the aorta. They really should call this group “macroangiopathic hemolytic anemia” because the problem is in big (macro) not tiny (micro) vessels, but they didn’t ask me. In both of these causes, red cells are getting ripped up in large spaces – either by the smashing of cells within an artificial heart valve (the old ball-and-socket valves were the worst for this; the newer models are much kinder to red cells), or by the ripping apart of red cells in turbulent blood flow (as you would get in coarctation of the aorta).

The remaining cases of MAHA are due to red cells getting snagged as they try to traverse fibrin-laden vessels. There are tons of situations in which the patient starts forming fibrin at an increased rate. If you look at Robbins, or any hematology textbook, you’ll be quickly overwhelmed by the sheer number of disorders and conditions that are associated with a microangiopathic hemolytic anemia, such as:

1. Disseminated intravascular coagulation (DIC) – a nasty condition in which there is bleeding and clotting at the same time in the patient. Lots of things can cause DIC (like malignancy, obstetric complications, trauma, and sepsis) – and it’s complicated enough that we’ll get into it in a future post.
2. Thrombotic thrombocytopenic purpura (TTP) – a syndrome in which the patient gets little thrombi within the microvasculature anywhere in the body, but especially the CNS and kidneys. We’ve talked a little about TTP before.
3. Hemolytic-uremic syndrome (HUS) – a disorder often related to ingestion of food (especially raw hamburger, but also spinach, other vegetables, you name it) containing E. coli 0157:H7. The bug makes a toxin that damages endothelial cells, and for some reason, the kidneys are hit the hardest.

The blood smear is where the action is in MAHA. If you look carefully at a blood smear from a patient with MAHA, you’ll see fragmented red cells, or schistocytes. Schistocytes are smaller than normal red cells, and they have points on them. There are all kinds of permutations on this theme – some schistocytes have just one point, some look like they have little horns, some just look like little ragged red cell shards. If you look at the image above, you’ll see a whole bunch of schistocytes of varying shapes.

The most specific type of schistocyte is the “triangulocyte” (that’s really the name; would I make that up?), which is, as the name suggests, a triangular fragment of a red cell. These aren’t as common as the other types of schistocytes (there isn’t a triangulocyte in the above image). If you see one of those puppies, you better figure out what’s going on with the patient.

And that’s the main point I want to make about this type of hemolytic anemia. Given all the causes of this anemia – many of which carry a high mortality – you can’t just say the patient has MAHA, and move on to the next blood smear. You have to figure out what’s causing the hemolysis (or, rather, the clinician needs to figure it out); don’t miss this one. It could be a matter of life and death.

Photo credit: Ed Uthman at http://commons.wikimedia.org/ (DIC_With_Microangiopathic_Hemolytic_Anemia_(301920983).jpg)