cold AIHA

We talked recently about the direct antiglobulin test (DAT) which is a test used to find out whether a hemolytic anemia is immune-related or not. And we talked even more recently about the immune hemolytic anemias, starting off with warm autoimmune hemolytic anemia. As you now know, immune hemolytic amemias (also called autoimmune hemolytic anemias) come in two kinds: warm and cold. They are named that way because the antibodies in each type react best at different temperatures. That sounds like one of those useless, arcane facts likely to show up on a test somewhere. It may very well show up on a test somewhere (in which case, you’ll nail it), but it’s not arcane or useless, surprisingly; it has real relevance to what’s going on in the patient, as we’ll see in this post.

There are a couple things going on in cold autoimmune hemolytic anemia (AIHA): 1) the patient is making antibodies against his/her red cells, and 2) there is complement fixed to the patient’s red cells. As in warm AIHA, the patient is for some reason making antibodies to his or her red cells. The possible causes are numerous and include infections (like mycoplasma pneumoniae or infectious mononucleosis), lymphoproliferative disorders (like leukemia or lymphoma), and the good old “idiopathic” category (or, We Don’t Know What Is Causing It But We Don’t Want To Sound Silly). These antibodies are different than those in warm AIHA, though: they are IgM in nature (in warm AIHA they’re IgG), and they bind best at cold temperatures, like 4 degrees C or 39.2 degrees F (in warm AIHA, the antibodies bind best at warmer temperatures).

You may be thinking, yeah, so? Well, here’s the cool thing: because the antibodies bind best at cooler temperatures, they seem to bind to the red cells in distal parts of the body like the fingertips and earlobes (especially if the patient goes out in the cold), and they fall off in warmer, more central parts of the body. What’s more, because the antibodies are IgM in nature (remember, IgM is a pentamer), they are able to span several red cells, creating big agglutinates of red cells (you can see them in the image above). These agglutinates can plug up little vessels, creating ischemic conditions in these peripheral body parts. Which translates clinically into colorless (or blue), numb fingertips/earlobes/nose tips/whatever else is hanging out in the cold. Then, as the red cells circulate back into warmer, more central parts of the body, the IgM falls off, and the agglutination disappears.

So that’s the deal with the antibody. There’s also the matter of complement binding to the red cells. Here’s where the hemolytic part comes in in cold AIHA. Red cells can get busted open by complement (which is known for poking holes in things) right in the circulation. They can also get eaten up by macrophages in the spleen (complement can opsonize red cells just like antibody can!).

Cold AIHA can hit any age, race, or sex. When it happens in elderly patients, it is usually related to some lymphoproliferative disorder; when it happens in kids, it’s usually related to an infection. The anemia is usually pretty mild, and the patient gets pallor (paleness) and/or cyanosis (blue discoloration due to lack of oxygen) in peripheral body parts, especially when exposed to the cold, because of those red cell agglutinates in tiny vessels.

When you look at a blood smear from a patient with cold AIHA, you’ll see big red cell agglutinates (but only if you have smart lab techs who cool the blood down first before making the smear, so you can see the agglutinates! Most lab techs are very smart.) You might see some spherocytes here and there too (because there is a little bit of macrophage nibbling going on) but they are way less numerous than they are in warm AIHA. To prove that your patient’s anemia is, in fact, an autoimmune hemolytic anemia, you need to do a DAT. The DAT will be positive in cold AIHA because the DAT looks for both IgG and complement bound to the patient’s red cells. Good thing they include the complement in the test (if they just included IgG, then cold AIHA cases would have a negative DAT).

The treatment for cold AIHA is what you’d expect: get rid of the underlying cause, if there is one (i.e., treat the infection), and keep the patient warm! The pallor/cyanosis in distal body parts is usually not severe enough to cause infarction – but it is annoying,  and patients should be kept warm so they don’t have to suffer from those symptoms, on top of everything else they are dealing with.