Hemolytic Anemia: Evaluation and Differential Diagnosis

 

Hemolytic anemia is defined by the premature destruction of red blood cells, and can be chronic or life-threatening. It should be part of the differential diagnosis for any normocytic or macrocytic anemia. Hemolysis may occur intravascularly, extravascularly in the reticuloendothelial system, or both. Mechanisms include poor deformability leading to trapping and phagocytosis, antibody-mediated destruction through phagocytosis or direct complement activation, fragmentation due to microthrombi or direct mechanical trauma, oxidation, or direct cellular destruction. Patients with hemolysis may present with acute anemia, jaundice, hematuria, dyspnea, fatigue, tachycardia, and possibly hypotension. Laboratory test results that confirm hemolysis include reticulocytosis, as well as increased lactate dehydrogenase, increased unconjugated bilirubin, and decreased haptoglobin levels. The direct antiglobulin test further differentiates immune causes from nonimmune causes. A peripheral blood smear should be performed when hemolysis is present to identify abnormal red blood cell morphologies. Hemolytic diseases are classified into hemoglobinopathies, membranopathies, enzymopathies, immune-mediated anemias, and extrinsic nonimmune causes. Extrinsic nonimmune causes include the thrombotic microangiopathies, direct trauma, infections, systemic diseases, and oxidative insults. Medications can cause hemolytic anemia through several mechanisms. A rapid onset of anemia or significant hyperbilirubinemia in the neonatal period should prompt consideration of a hemolytic anemia.

Hemolytic anemia is defined as the destruction of red blood cells (RBCs) before their normal 120-day life span. It includes many separate and diverse entities whose common clinical features can aid in the identification of hemolysis. Hemolytic anemia exists on a spectrum from chronic to life-threatening, and warrants consideration in all patients with unexplained normocytic or macrocytic anemia.

 Enlarge     Print

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

After hemolytic anemia is confirmed, a peripheral blood smear should be ordered to determine the etiology.

C

1

Glucocorticoids are the first-line treatment of warm autoimmune hemolytic anemia.

C

4

The PLASMIC score can be used to assess the likelihood of thrombotic thrombocytopenic purpura when ADAMTS13 cannot be easily measured.

C

10

Do not give antibiotics to children with Escherichia coli diarrhea because antibiotics increase the risk of hemolytic uremic syndrome.

B

15

G6PD activity should be measured in infants with jaundice and a family history or geographic background suggestive of possible deficiency.

C

28


G6PD = glucose-6-phosphate dehydrogenase.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingReferences

After hemolytic anemia is confirmed, a peripheral blood smear should be ordered to determine the etiology.

C

1

Glucocorticoids are the first-line treatment of warm autoimmune hemolytic anemia.

C

4

The PLASMIC score can be used to assess the likelihood of thrombotic thrombocytopenic purpura when ADAMTS13 cannot be easily measured.

C

10

Do not give antibiotics to children with Escherichia coli diarrhea because antibiotics increase the risk of hemolytic uremic syndrome.

B

15

G6PD activity should be measured in infants with jaundice and a family history or geographic background suggestive of possible deficiency.

C

28


G6PD = glucose-6-phosphate dehydrogenase.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Pathophysiology

Premature destruction of RBCs can occur intravascularly or extravascularly in the reticuloendothelial system, although the latter is more common. The primary extravascular mechanism is sequestration and phagocytosis due to poor RBC deformability (i.e., the inability to change shape enough to pass through the spleen). Antibody-mediated hemolysis results in phagocytosis or complement-mediated destruction, and can occur intravascularly or extravascularly. The intravascular mechanisms include direct cellular destruction, fragmentation, and oxidation. Direct cellular destruction

The Authors

show all author info

JAMES PHILLIPS, MD, is a hospitalist fellow at Womack Army Medical Center, Fort Bragg, N.C., and an assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences, Bethesda, Md....

ADAM C. HENDERSON, MD, is a third-year resident in the Department of Family Medicine, Womack Army Medical Center.

Address correspondence to James Phillips, MD, Womack Army Medical Center, 2817 Reilly Rd., Fort Bragg, NC 28310 (e-mail: james.d.phillips2.mil@mail.mil). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

show all references

1. Mentzer WC, Schrier SL. Extrinsic nonimmune hemolytic anemias. In: Hoffman R, Benz EJ Jr., Silberstein LE, et al., eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, Pa.: Elsevier; 2018:663–672....

2. Bain BJ. Diagnosis from the blood smear. N Engl J Med. 2005;353(5):498–507.

3. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599–2606.

4. Michel M, Jäger U. Autoimmune hemolytic anemia. In: Hoffman R, Benz EJ Jr., Silberstein LE, et al., eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, Pa.: Elsevier; 2018:648–662.

5. Sharma S, Sharma P, Tyler LN. Transfusion of blood and blood products: indications and complications. Am Fam Physician. 2011;83(6):719–724.

6. Garratty G. Drug-induced immune hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2009:73–79.

7. Johnson ST, Fueger JT, Gottschall JL. One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia—a new paradigm. Transfusion. 2007;47(4):697–702.

8. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654–666.

9. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15–23.

10. Bendapudi PK, Li A, Hamdan A, et al. Derivation and prospective validation of a predictive score for the rapid diagnosis of thrombotic thrombocytopenic purpura: the Plasmic Score. Blood. 2014;124(21):231.

11. Rock GA, Shumak KH, Buskard NA, et al.; Canadian Apheresis Study Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991;325(6):393–397.

12. Ardissino G, Salardi S, Colombo E, et al. Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network. Eur J Pediatr. 2016;175(4):465–473.

13. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics. 2002;110(2 pt 1):371–376.

14. Jokiranta TS. HUS and atypical HUS. Blood. 2017;129(21):2847–2856.

15. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342(26):1930–1936.

16. Pourrat O, Coudroy R, Pierre F. Differentiation between severe HELLP syndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators. Eur J Obstet Gynecol Reprod Biol. 2015;189:68–72.

17. Keiser SD, Boyd KW, Rehberg JF, et al. A high LDH to AST ratio helps to differentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome. J Matern Fetal Neonatal Med. 2012;25(7):1059–1063.

18. Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2(1):15.

19. Reese JA, Bougie DW, Curtis BR, et al. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma Registry and the BloodCenter of Wisconsin. Am J Hematol. 2015;90(5):406–410.

20. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616–618.

21. Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher. 2016;31(3):149–162.

22. Beutler E. G6PD deficiency. Blood. 1994;84(11):3613–3636.

23. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277–1282.

24. Gregg XT, Prchal JT. Red blood cell enzymopathies. In: Hoffman R, Benz EJ Jr., Silberstein LE, et al., eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, Pa.: Elsevier; 2018:616–625.

25. Sikka P, Bindra VK, Kapoor S, Jain V, Saxena KK. Blue cures blue but be cautious. J Pharm Bioallied Sci. 2011;3(4):543–545.

26. Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009;29(suppl 1):S25–S45.

27. Kaplan M, Herschel M, Hammerman C, Hoyer JD, Stevenson DK. Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates. Pediatrics. 2004;114(2):e213–e219.

28. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation [published correction appears in Pediatrics. 2004;114(4):1138]. Pediatrics. 2004;114(1):297–316.

29. Christensen RD, Yaish HM, Gallagher PG. A pediatrician's practical guide to diagnosing and treating hereditary spherocytosis in neonates. Pediatrics. 2015;135(6):1107–1114.

30. Yawn BP, John-Sowah J. Management of sickle cell disease: recommendations from the 2014 Expert Panel Report. Am Fam Physician. 2015;92(12):1069–1076.

31. Muncie HL Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician. 2009;80(4):339–344.

 

 

Copyright © 2018 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

CME Quiz

More in AFP


Editor's Collections


Related Content


More in Pubmed

MOST RECENT ISSUE


Nov 15, 2018

Access the latest issue of American Family Physician

Read the Issue


Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article