Published: 6 December 2019

Publications

Haemolytic anaemia – Sometimes caused by medicines

Prescriber Update 40(4): 83–85
December 2019

What is haemolytic anaemia?

Haemolytic anaemia is characterised by a low number of circulating red blood cells (RBC) due to their premature destruction (haemolysis) and an elevated reticulocyte count¹. There are many causes, including medicines, autoimmune or congenital disorders, infections, transfusions and toxins¹.

Symptoms can include weakness, dizziness, dyspnoea, jaundice, dark urine, mild pallor or splenomegaly². Severe haemolysis can cause hepatosplenomegaly, haemoglobinuria and heart failure². Rarely, immune haemolytic anaemia may be fatal⁴.

How can medicines cause haemolytic anaemia?

Haemolytic anaemia may occur within hours of exposure to a medicine or after several months of exposure³. There are two main mechanisms by which medicines can cause haemolytic anaemia: immune haemolysis and oxidative damage⁵.

Immune haemolysis

Immune haemolysis generally refers to RBC destruction by autoantibodies and/or complement proteins bound to the RBC surface¹. The medicine may alter antigens on the RBC, resulting in the production of autoantibodies that cross-react with the unaltered antigen, or the medicine may associate with structures on the red cell and be part of the antigen in a haptenic reaction⁶.

More than 130 medicines have been associated with immune haemolytic anaemia but the most commonly reported include second- and third-generation cephalosporins, diclofenac, rifampicin, oxaliplatin and fludarabine³.

Transient but clinically significant haemolytic anaemia has been reported following high-dose infusion of intravenous immunoglobulin due to the presence of anti-A, anti-B, and occasionally anti-D or other erythrocyte antibodies in the product⁷. These antibodies coat recipient RBC, producing immune, but not autoimmune haemolysis⁵.

Oxidative damage

Medicines with oxidative potential can cause haemolytic anaemia in all patients, but those with glucose-6-phosphate dehydrogenase (G6PD) deficiency (and other inherited conditions) are at higher risk⁵. G6PD deficiency is an inherited disorder caused by a genetic defect in the RBC enzyme G6PD, which protects RBCs from oxidative injury⁸.

Medicines with oxidative potential that may be unsafe for patients with G6PD include dapsone, methylene blue, nitrofurantoin, primaquine, quinolones, rasburicase and sulphonamides^5,9.

Clinical and laboratory findings

There is no single specific diagnostic test for haemolytic anaemia¹. Patients with haemolytic anaemia usually have an increased reticulocyte count that is not explained by recent bleeding or recent correction of iron deficiency or other nutrient deficiency¹. Patients may also have evidence of RBC destruction, including increased lactate dehydrogenase and bilirubin, decreased haptoglobin, and RBC shape changes on the peripheral blood smear¹.

Immune haemolysis is characterised by a positive direct antiglobulin test (DAT; also called direct Coombs test) and/or a positive indirect antiglobulin test (also called indirect Coombs test)¹.

Management

In cases of unexplained haemolytic anaemia, consider medicines as a possible cause. Check the data sheet to determine whether haemolytic anaemia is a known reaction for that medicine (data sheets are available on the Medsafe website).

Management of haemolytic anaemia is dependent on the cause and severity. Sometimes, discontinuation of the medicine is sufficient. In other cases, interventions, such as transfusion, may be required. Consult a haematologist or transfusion medicine specialist for advice.

New Zealand reports

Since 2010, the Centre for Adverse Reactions Monitoring (CARM) has received 51 reports (with 59 suspected medicines) where the reported reactions included haemolytic anaemia and/or a positive direct Coombs test.

Table 1 shows the medicines most frequently reported to CARM, and the number of positive dechallenges (withdrawal of medicine and cessation of symptoms) and rechallenges (restarting the medicine and recurrence of symptoms).

Table 1: Medicines most frequently reported to CARM for haemolytic anaemia and/or a positive direct Coombs test, 1 January 2010 to 30 September 2019

Medicine	Reports	Positive dechallengea	Positive rechallengeb
Immunoglobulin normal	33	17	2
Amoxicillin/clavulanic acid	4	3
Dapsone	2	1
Sulphasalazine	2	2

Notes:

1. Positive dechallenge: withdrawal of the medicine and cessation of symptoms.
2. Positive rechallenge: restart the medicine and recurrence of symptoms.

References

1. Brodsky R. 2019. Diagnosis of hemolytic anemia in the adult. In: UpToDate 3 October 2019 (Topic 7076 Version 52.0). URL: www.uptodate.com/contents/diagnosis-of-hemolytic-anemia-in-the-adult (accessed 17 October 2019).
2. Hill Q, Stamps R, Massey E, et al. 2017. The diagnosis and management of primary autoimmune haemolytic anaemia. British Journal of Haematology 176(3): 395-411. DOI: 10.1111/bjh.14478 (accessed 18 October 2019).
3. Hill Q, Stamps R, Massey E, et al. 2017. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. British Journal of Haematology 177(2): 208-20. DOI: 10.1111/bjh.14654 (accessed 24 September 2019).
4. Leicht H, Weinig E, Mayer B, et al. 2018. Ceftriaxone-induced hemolytic anemia with severe renal failure: a case report and review of literature. BMC Pharmacology and Toxicology 19(1): 67. DOI: 10.1186/s40360-018-0257-7 (accessed 24 September 2019).
5. Leung L. 2017. Hemolytic anemia due to drugs and toxins. In: UpToDate 2 October 2017 (Topic 7104 Version 28.0). URL: www.uptodate.com/contents/hemolytic-anemia-due-to-drugs-and-toxins (accessed 17 October 2019).
6. Brugnara C. 2018. Pathogenesis of autoimmune hemolytic anemia: Warm agglutinins and drugs. In: UpToDate 19 September 2018 (Topic 7080 Version 29.0). URL: www.uptodate.com/contents/pathogenesis-of-autoimmune-hemolytic-anemia-warm-agglutinins-and-drugs (accessed 14 October 2019).
7. CSL Behring (NZ) Ltd. 2018. Intragam P New Zealand Data Sheet 29 June 2018. URL: www.medsafe.govt.nz/profs/datasheet/i/IntragamPinj.pdf (accessed 20 October 2019).
8. Glader B. 2019. Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency. In: UpToDate 11 June 2019 (Topic 7111 Version 36.0). URL: www.uptodate.com/contents/diagnosis-and-management-of-glucose-6-phosphate-dehydrogenase-g6pd-deficiency (accessed 20 October 2019).
9. New Zealand Formulary. 2019. New Zealand Formulary v. 89: G6PD deficiency 1 November 2019. URL: https://nzf.org.nz/nzf_4994 (accessed 6 November 2019).