Strategies in Managing Cold Agglutinin Disease - Episode 5

Cold Agglutinin Disease: A Differential Diagnosis

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Diagnostic criteria used by health care professionals who manage patients with autoimmune hemolytic anemias to help distinguish cold agglutinin disease from other medical conditions.

Jeremy Lorber, MD: I have 1 other point to touch on.

Neil Minkoff, MD: Please.

Jeremy Lorber, MD: Dr [Jeremy] Gleeson said that [cold agglutin disease] is a rare disease in which pathways aren’t established, which is true. But my feeling is that as newer drugs get FDA approval, specifically for CAD [cold agglutinin disease], the recognition and awareness of CAD will likely increase, and we’ll see the prevalence increase because of awareness in testing.

Neil Minkoff, MD: Yes, that’s a common thing. Once there’s a clearer pathway to diagnosis and treatment, all of a sudden disease prevalence seems to go up pretty much across disease states.

Jeremy Lorber, MD: Even though the disease was there the whole time.

Neil Minkoff, MD: Of course. Let me push on you a little more, Dr Lorber, on what we haven’t gotten into. We’ve talked on a macro level about what you’re seeing in these patients, but if a patient comes to you where you’re suspecting this, what do you do? This sounds remedial, but what are the basic steps in the work-up? What are you starting with as a differential diagnosis, and how do you weed through that?

Jeremy Lorber, MD: Usually by the time they come to me, some of the basic work-up has been done. In case it hasn’t, we don’t want to forget the basics, so things like a CBC [complete blood count] will obviously confirm that they’re anemic and make sure that they don’t have abnormalities in their other counts—white blood cell count and platelet, which are not typical of CAD. If you see increase or decrease in white blood cell count or platelets, you may want to look outside CAD and work them up for something else.

After that, you want to make sure they have hemolysis, so the typical hemolytic markers: LDH [lactate dehydrogenase], bilirubin, and Coombs testing, also called the direct antiglobulin test. If they’re hemolyzing, anemic, and complaining of cold symptoms, you look at the Coombs test. The typical result from somebody with CAD will be positive Coombs test for C3b but negative for IgG. That should lead you to a high suspicion for CAD.

The next step would be to get a titer of the cold agglutinins. The usually accepted cutoff for CAD is a titer of 64 or greater. Once you get to that point, if the symptoms and the above labs are consistent, you can label the patient with CAD. Keep in mind, is this truly primary or idiopathic CAD? Or does the patient have signs or symptoms of some secondary cause like a lymphoma, which would be more typical in an older patient? Or are there signs or symptoms of an autoimmune disease outside CAD that would be more typical in a younger patient? Do they have a recent antecedent infection, which is also an etiology of secondary cold agglutinin syndrome? If those things are negative, then you can confidently label them as CAD.

Neil Minkoff, MD: Let me back up a second and ask, what is the typical clinical manifestation of the patient who’s referred to you for that work-up? What is it that somebody like me as a primary care physician is cueing in on that leads to the referral to even start that process?

Jeremy Lorber, MD: It’s a patient who is anemic who may not have had various common treatments for anemia. As we mentioned, giving a patient iron without a response. Sometimes, even hematologist-oncologists will have seen a patient and called them an autoimmune hemolytic anemia and treat them with steroids but with no response. Then patients who may have cold symptoms that are not limited to Raynaud phenomenon, might have the acrocyanosis symptoms: discoloration beyond the fingertips to places like the ears and the nose. They will have an associated anemia that’s not clear. Anything that doesn’t fit a classic picture where you can pinpoint why they’re anemic typically leads to a referral to somebody like me.

Mihir Raval, MD, MPH: To expand on that, sometimes I get consulted when a patient is hospitalized for cardiothoracic surgery or something like that and they’re just doing a basic work-up. They find that they’re slightly anemic and doing type and cross for potential transfusion, and now the blood bank detects that they have cold agglutinin titer.

Neil Minkoff, MD: Interesting.

Mihir Raval, MD, MPH: That could be a trigger for a hematologist too: “Blood bank told us that there’s a cold agglutinin titer.” You’ll be surprised how many times I get called directly like that from the blood bank or from the cardiothoracic surgery floor without the patient knowing that they have any such disease.

Transcript edited for clarity.