It might be surprising to learn that taking a medication could lead to anemia — but that’s the case with a particular type of autoimmune hemolytic anemia (AIHA).

AIHA occurs when the immune system mistakenly attacks and destroys red blood cells (RBCs). When this condition is caused by a medication, it’s known as drug-induced AIHA or drug-induced immune hemolytic anemia (DIIHA).

DIIHA is rare. Studies estimate that the incidence (number of new cases) of DIIHA is about 1 in 1 million people per year. However, the actual number may be higher because less severe cases may go undetected.

Which Drugs Can Cause AIHA?

DIIHA is most commonly associated with antibiotics, but researchers have found more than 100 medications that can cause AIHA.

Study results have shown that cefotetan (Cefotan), a cephalosporin antibiotic, is responsible for more than half of all cases of DIIHA. Besides cephalosporins, which also include ceftriaxone (Rocephin), antibiotics commonly associated with DIIHA include:

• Penicillins, such as piperacillin (Pipracil) and penicillin (Bicillin)
• Fluoroquinolones, such as levofloxacin (Levaquin) and ciprofloxacin (Cipro)
• Nitrofurantoin (Macrobid)
• Doxycycline (Vibramycin)
• Sulfamethoxazole/trimethoprim (Bactrim)
• Dapsone

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also known to cause DIIHA. The most common are:

• Diclofenac (Cataflam)
• Ibuprofen (Motrin)
• Aspirin

Other medications associated with DIIHA include:

• Chemotherapy drugs, such as oxaliplatin (Eloxatin), fludarabine (Fludara), and immune checkpoint inhibitors
• Blood pressure medications, such as methyldopa (Aldomet), hydrochlorothiazide (Microzide), amlodipine (Norvasc), and ramipril (Altace)
• Levodopa (Sinemet)
• Phenazopyridine (Pyridium)
• Lorazepam (Ativan)
• Quinidine (Cardioquin)

How Do Drugs Induce AIHA?

Some medications can change your immune system so that it mistakes your red blood cells for foreign invaders (like bacteria and viruses) that it usually protects you against.

Your body uses proteins called antibodies to identify foreign invaders. The antibody binds to the foreign invader — called an antigen — and sets off a chain reaction that calls the immune system to destroy it.

In DIIHA, your body makes antibodies that target your RBCs. When your body attacks your RBCs, they break down earlier than usual in a process called hemolysis. Having fewer RBCs means that your blood doesn’t transport oxygen around your body as well as it should.

Medications can induce AIHA by causing your immune system to make one of two types of antibodies — either drug-dependent or drug-independent antibodies.

Drug-Dependent Antibodies

Drug-dependent antibodies are the most common type of antibodies in DIIHA. These antibodies are detected only when the drug is also present in the blood. They are usually immunoglobulin G (IgG) antibodies, which the immune system makes to target foreign invaders.

Penicillin is an example of a medication that can cause drug-dependent antibodies. When penicillin is given in high doses, it coats the surface of red blood cells. In some people, the immune system makes antibodies that mistakenly identify these as foreign invaders, prompting the immune system to seek and destroy RBCs coated in penicillin. High-dose penicillin therapy may increase the risk of DIIHA because there is more drug to bind with RBCs.

Drug-Independent Antibodies

Some drugs can affect the immune system in a way that causes the production of antibodies to RBCs — called autoantibodies — although the drug is not bound to RBCs. Drug-independent antibodies can be found in the blood even without the drug present. However, the reason drugs have this effect is not well understood.

It is believed that methyldopa may cause DIIHA in this way. Methyldopa leads to the development of RBC autoantibodies in about 15 percent of people who take this drug, according to a 2009 review article in Hematology. However, only about 1 percent of people will develop AIHA.

Other Mechanisms

People with a glucose-6-phosphate dehydrogenase (G6PD) deficiency may have a higher risk of developing hemolytic anemia triggered by drugs that cause oxidative stress.

G6PD helps red blood cells work properly by protecting them from the harmful effects of cellular byproducts called reactive oxygen species (ROS). The red blood cells of people with a G6PD deficiency are more prone to damage and destruction from ROS. Medications that increase ROS, such as some antibiotics and aspirin, can increase damage to RBCs.

Symptoms of Drug-Induced AIHA

The symptoms of DIIHA result from RBC hemolysis and your blood’s reduced ability to carry oxygen where it is needed.

Symptoms of DIIHA are similar to those of warm AIHA. In fact, DIIHA is often mistakenly diagnosed as warm AIHA. If you have DIIHA, you may notice the following symptoms:

• Tiredness or fatigue
• Dark urine
• Increased heart rate
• Shortness of breath
• Jaundice (yellowish skin and eyes)
• Paleness

In severe cases, DIIHA can lead to renal (kidney) failure, liver damage, or death.

Diagnosis of Drug-Induced AIHA

If your doctor suspects DIIHA, they will run several laboratory tests to help with the diagnosis:

• Reticulocyte count — Determines whether the bone marrow is making RBCs
• Direct Coombs test — Looks for antibodies to RBCs; also known as a direct antiglobulin test
• Indirect bilirubin — Checks for jaundice
• RBC count — Measures number of red blood cells, which will be low in DIIHA
• Serum haptoglobin — Determines if RBCs are being destroyed too soon
• Lactate dehydrogenase (LDH) — Measures blood level of LDH (an enzyme), which will be elevated if RBCs are destroyed too early
• Urine hemoglobin — Detects presence of hemoglobin (protein in red blood cells), which indicates hemolysis

Management of Drug-Induced AIHA

Discontinuing the offending drug is the most important part of treating DIIHA. Most people improve in one to two weeks after stopping the drug that caused it.

In some cases, simply stopping the drug that caused AIHA will allow recovery. Your doctor will monitor your vital signs while you recuperate. If your anemia is severe, you may need supportive care, such as fluid replacement or a blood transfusion. According to an article in the British Journal of Haematology, about half of the people with DIIHA will need a blood transfusion.

Your doctor may start a corticosteroid medication like prednisone (Deltasone) to decrease inflammation. However, the benefit of corticosteroids is unclear. Other treatments for AIHA, such as targeted therapy and immunosuppressive medications, are usually not necessary for DIIHA.

Outlook for Drug-Induced AIHA

If DIIHA is recognized early and the offending drug is stopped, the outcome is usually good. Studies have found that the majority of people survive AIHA caused by cephalosporins or diclofenac. DIIHA is rare in children but can be serious when it does happen. Between 38 percent and 50 percent of cases of DIIHA are fatal in children, according to the 2009 review article.

People who get DIIHA a second time may have a more severe case than the first one. If you experience DIIHA, you should add the medication that caused it to your drug allergy list and avoid taking it again. In some cases, related medications should also be avoided.

DIIHA is a known complication of certain medications, and health care providers are aware of this risk when prescribing these drugs. Be sure to keep all your health care providers updated about all your medications, along with any side effects you experience, to ensure that you receive the safest, most effective treatments for you.

Talk With Others Who Understand

On myAIHAteam, the social network for people with AIHA and their loved ones, members come together to ask questions, give advice, and share their stories with others who understand life with this condition.

Have you experienced drug-induced AIHA? Share your experience in the comments below, or start a conversation by posting on your Activities page.