Drug-induced hemolysis

What every physician needs to know:

Drug-induced hemolysis can occur either by an immune-mediated mechanism or a non immune-mediated mechanism. In all cases, anemia is present with an elevated reticulocyte count, serum lactate dehydrogenase (LDH), and indirect bilirubin. A thorough history is necessary to evaluate for possible offending agents, as there are many drugs that can induce hemolysis. Stopping the offending drug early is important to arrest hemolysis and prevent further complications.

What features of the presentation will guide me toward possible causes and next treatment steps:

On history, patients may report nonspecific signs attributable to anemia, such as fatigue and dyspnea on exertion. An important historical clue is that the patient has taken a medication that may be associated with hemolysis.

On examination, the conjunctiva may appear pale or icteric, indicating anemia and hyperbilirubinemia respectively. The patient may appear cyanotic in the setting of a normal arterial PO2, indicating significant methemoglobinemia.

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What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The following studies should be ordered:

  • Reticulocyte count

  • LDH

  • Total and direct bilirubin

  • Haptoglobin

  • Direct and indirect Coombs’ test (direct antiglobulin test, antibody screen)

  • Peripheral blood smear

The reticulocyte count is elevated and the reticulocyte index is >2%, indicating adequate marrow response to the degree of anemia present. Serum LDH is elevated along with indirect bilirubin with a concomitant decrease in haptoglobin.

A special preparation of the peripheral blood smear may show Heinz bodies, which are precipitated hemichromes due to high levels of oxidative stress.

What conditions can underlie drug-induced hemolysis:

Drug-induced non immune hemolysis

Several medications are known to cause non immune-mediated hemolysis through an oxidative mechanism, usually in the setting of some forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

  • Nitrofurantoin

  • Sulfasalazine

  • Dapsone

  • Primaquine

  • Phenazopyridine

  • Rifampin

  • Ribavirin

Drug-induced immune hemolysis
  • Penicillin

  • Alpha-methyldopa

  • Cephalosporins

  • NSAIDs

  • Quinine/Quinidine

When do you need to get more aggressive tests:


What imaging studies (if any) will be helpful?

Ultrasound to assess for splenomegaly.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Stop any possible offending drugs.

If methemoglobinemia is present, methylene blue may be administered to reduce methemoglobin to hemoglobin. Methylene blue should not be administered to individuals with G6PD deficiency, since reduction of methemoglobin requires the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) generated by G6PD.

What other therapies are helpful for reducing complications?

Transfusion of packed red-blood cells may be necessary as a supportive measure until the hemolytic process ends. Testing for compatible blood cells may be complicated by antibody coating of erythrocytes if there is immune-mediated hemolysis.

What should you tell the patient and the family about prognosis?

Prognosis is generally guided by the degree of anemia and comorbidities. If the offending drug is stopped, most cases resolve and patients will do well as long as supportive measures can be initiated. The time course to complete recovery is variable, from several days to several weeks. The patient and their family should be aware of this variable time course and possibility of relapse, should the offending drug be reintroduced in the future.

“What if” scenarios.

Patients undergoing multiple transfusions may develop antibodies, making it more difficult to crossmatch compatible units. Consultation with a transfusion specialist is recommended.

In patients with ongoing hemolysis who have received multiple transfusions, the drug-induced component of hemolysis may be less of a contributing factor and a full transfusion reaction work-up should be considered.

As noted above, it may be difficult to determine a compatible crossmatch for red blood cell transfusion. If this is the case, transfuse O-negative blood should the patient require transfusion (that is, in the setting of hemodynamic instability).


Drug-induced oxidative hemolysis

Erythrocytes undergo substantial oxidative stress during the course of normal reactions involving oxygenation and dexoygenation of hemoglobin. Methemoglobin is formed at a slower rate and reduced back to hemoglobin through a nictinamide adenine dinucleotide (NADH) -dependent cytochrome reductase.

The hexose monophosphate shunt also helps reduce oxidative stress by maintaining high levels of reduced glutathione. Maintaining high levels of reduced glutathione requires NADPH produced by G6PD. Individuals with a deficiency of G6PD cannot reduce oxidized glutathione to reduced glutathione, leading to oxidative damage and eventual hemolysis.

Drug-induced autoimmune hemolysis

See chapter on Autoimmune hemolytic anemia (including Evan’s syndrome) for more information about the pathophysiology of AIHA. In brief, drug-induced immune hemolysis can occur by one of several mechanisms:

  • Patients treated with penicillin may produce antibodies generated against the drug itself.

– As the drug binds to the erythrocyte surface, the entire unit is opsonized and the erythrocyte is destroyed. Withdrawal of the offending drug stops hemolysis since the antibody is only directed against the drug, not the erythrocyte itself.

  • The drug may bind to protein with antibodies forming against this immune complex.

– The antibody-drug-protein immune complex may then bind to erythrocytes and initiate hemolytic destruction.

  • Some medications, such as alpha-methyldopa, induce antibodies targeted against erythrocytes.

– Cyclosporine and cocaine have been associated with microangiopathic hemolytic anemias.

What other clinical manifestations may help me to diagnose drug-induced hemolysis?


What other additional laboratory studies may be ordered?

G6PD deficiency testing.

What’s the evidence?

Carstairs, KC, Breckenridge, A, Dollery, CT, Worlledge, SM. “Incidence of a positive direct Coombs test in patients on alpha-methyldopa”. . vol. 2. 1966. pp. 133-135. [A classic paper describing the association between the hemolytic anemia and alpha-methyldopa.]

Garratty, G. “Drug-induced immune hemolytic anemia”. . vol. 73. 2009. pp. 79[A review of the pathophysiology of immune-mediated drug-induced hemolysis geared toward the general hematologist.]

Garratty, G. “Immune hemolytic anemia associated with drug therapy”. . vol. 24. 2010. pp. 143-150. [A review of of the pathophysiology and management of patients with drug-induced hemolytic anemia with an immune-mediated mechanism.]

Gehrs, BC, Friedberg, RC. “Autoimmune hemolytic anemia”. . vol. 69. 2002. pp. 258-271. [A review on the general principles of hemolytic anemia which includes information about autoimmune hemolytic anemia too.]

Silvilotti, ML. “Oxidant stress and haemolysis of the human erythrocyte”. . vol. 23. 2004. pp. 169-188. [Review of the pathophysiology involved in drug-induced hemolysis by oxidative mechanisms.]

Youngster, I, Arcavi, L, Schechmaster, R. “Medications and glucose-6-phosphate dehydrogenase deficiency; an evidence-based review”. . vol. 33. 2010. pp. 713-726. [A comprehensive review of medications which can be dangerous in patients with G6PD deficiency.]