Here are some great questions about anemia I’ve received from students in past years. I thought I’d post them (with some links to short explanations of the diseases) in case you had the same questions.

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

A. Spectrin is a long heterodimer that forms a major part of the red cell cytoskeleton, which is directly connected to the red cell membrane. The cytoskeleton is what keeps the red cell in its nice biconcave shape.

Several slightly different spectrin gene mutations have been described in hereditary spherocytosis. In all of the mutations, though, there is a problem with the connection between the cytoskeleton and the cell membrane.

The cell membrane becomes unstable in the parts where it’s not connected to the cytoskeleton, and as a result, bits of membrane are lost (but the volume inside the red cell remains pretty much the same). 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 biconcave-disk-shaped red cells. They break more easily when they try to maneuver through tight spaces – which is why this is classified as hemolytic anemia. The other thing that happens is they get eaten up by macrophages in the spleen (who are always on the lookout for old red cells or red cells with abnormalities).

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. Great questions! When you form a clot, you start by sticking platelets together. That’s not permanent enough to plug up the hole in the vessel – so in order to cement that plug together and make it permanent, the body makes a long polymer called fibrin.

Usually, clots are kept to the smallest necessary size – and you don’t run around making them unless you have a hole in a vessel that you need to plug up.

But sometimes, clotting can be stimulated when it shouldn’t be. Often, the problem is excessive fibrin production (many things can cause this). The excess fibrin strands are made in blood vessels, and they sort of drape themselves across vessels. In doing so, they 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.

As for the second part of your question: 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 which is a series of steps that result in the formation of fibrin.

Placental tissue also has a substance in it which can initiate the coagulation cascade and result in the formation of fibrin. If you’re making lots of fibrin, chances are the red cells are going to get trapped in the fibrin strands in small vessels, 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) In addition, complement binds to the red cells (IgM is particularly attractive to complement components). 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 lysed, 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 isozymes independently in the serum, so you know where the LDH is coming from.