Hemolytic anemia

Last updated: July 21, 2023

Summarytoggle arrow icon

Hemolytic anemia is characterized by the breakdown of red blood cells (RBCs). Hemolysis can either be caused by abnormalities in RBCs (hemoglobin, the RBC membrane, or intracellular enzymes), which is called intrinsic hemolytic anemia, or by external causes (immune-mediated or mechanical damage), which is called extrinsic hemolytic anemia. Hemolysis can be further categorized depending on whether it occurs inside the blood vessels (intravascular hemolysis), in the reticuloendothelial system (extravascular hemolysis), or both. Hemolytic anemias cause varying degrees of fatigue, pallor, and weakness, ranging from asymptomatic disease to life-threatening hemolytic crisis; although, some hemolytic anemias have more specific findings (e.g., thrombosis in paroxysmal nocturnal hemoglobinuria). Hemolytic anemia should be suspected in patients with anemia and laboratory findings of hemolysis (e.g., elevated indirect bilirubin and lactate dehydrogenase, reticulocytosis, and decreased haptoglobin levels). The Coombs test helps to distinguish between antibody-mediated (positive direct Coombs test) and nonantibody-mediated (negative direct Coombs test) anemias. Further tests should be performed to investigate the underlying etiology. Treatment involves RBC transfusions as required. Additional treatment is based on the type of hemolytic anemia and its cause.

See also “Sickle cell disease”, “Paroxysmal nocturnal hemoglobinuria”, and “Autoimmune hemolytic anemia.”

Overviewtoggle arrow icon

Types and etiologies of hemolytic anemia

Hemolytic anemias are characterized by an excessive breakdown of red blood cells (RBCs). They can be classified according to the cause of hemolysis (intrinsic or extrinsic) and by the location of hemolysis (intravascular or extravascular).

Type Definition Causes
By RBC pathology
Intrinsic hemolytic anemia
  • Increased destruction of RBCs due to a defect within the RBC
Extrinsic hemolytic anemia
  • Abnormal breakdown of normal RBCs
By location of RBC breakdown
Intravascular hemolytic anemia
Extravascular hemolytic anemia

Clinical featurestoggle arrow icon

References: [3][4]

Diagnosticstoggle arrow icon

Consider hemolysis in patients with acute or chronic anemia in whom an obvious cause (e.g., bleeding) is not apparent. See “Diagnosis of anemia” for details on the general approach for a patient with anemia. [5]

Approach [5][6]

  1. Perform initial laboratory studies to confirm anemia and hemolysis and classify anemia by morphology.
  2. Obtain a direct Coombs test (i.e., DAT) to narrow the differential:
  3. Consider further investigations of the underlying etiology based on clinical suspicion and DAT results.

Rule out hemolysis in any patient with unexplained anemia, even if the urine dipstick test is negative for blood and jaundice is not evident on physical examination.

If the patient has severe symptoms of anemia or a life-threatening cause is suspected (i.e., TTP/HUS, disseminated intravascular coagulation, HELLP syndrome, acute hemolytic transfusion reaction), proceed directly to treatment in parallel with diagnostic evaluation.

Routine laboratory studies [5][6]

Iron studies are usually normal in hemolytic anemia, however, iron deficiency can be seen in chronic intravascular hemolysis [9]

Hemolysis workuptoggle arrow icon

While no single test can be used to confirm hemolysis, the finding of anemia in the presence of accelerated erythropoiesis (i.e., reticulocytosis) in addition to evidence of RBC destruction in serum and/or urine studies is highly suggestive of hemolytic anemia.

Typical biochemical findings in hemolysis include haptoglobin, LDH concentration, indirect bilirubin concentration, peripheral blood smear abnormalities (e.g., reticulocytes, schistocytes, spherocytes, polychromasia), and urinalysis abnormalities (e.g., hemoglobinuria, hemosiderinuria, and urobilinogen).

Serum studies

Evidence of hemolysis in serum studies [5][6]
Parameter Description Features of intravascular hemolysis Features of extravascular hemolysis
Haptoglobin [10][11]
Lactate dehydrogenase
  • ↑↑
Indirect (unconjugated) bilirubin
  • Can be normal or slightly elevated

Haptoglobin levels can be low in both intravascular hemolysis and extravascular hemolysis and, therefore, should not be used to differentiate between the two. [10]

Urine studies

Evidence of hemolysis in urine studies [5][6]
Parameter Description Findings
Intravascular hemolysis Extravascular hemolysis [13]
Hemoglobinuria [14]
  • Present
  • Usually absent
Hemosiderinuria [7]
  • Present
  • Usually absent
Urobilinogen [15]
  • Usually absent
  • Present

Coombs testing (Antiglobulin testing)toggle arrow icon

  • Description: A special reagent is added to patients' blood samples: Coombs serum, which contains antihuman globulins (AHGs) that detect and adhere (with 2 binding sites) to immune proteins that mediate hemolysis, i.e., antibodies (IgG) and/or complement
    • If these proteins are coating the RBC surface when the serum is added, AHGs will cause multiple RBCs to adhere to each other in a process called agglutination.
    • If no such proteins are present, AHGs will not bind to anything.
    • RBC agglutination is considered a positive result, while the absence of RBC agglutination is considered a negative result.

Direct Coombs test (DAT) [16]

This is a key test in the workup of hemolytic anemia.

Indirect Coombs test [18]

Differences between the Coombs tests

Key differences between direct and indirect Coombs testing
Direct Coombs test [16] Indirect Coombs test [18]
Clinical applications
Location of antibodies detected
  • Serum
Coombs serum added to:
  • The patient's purified RBCs
  • The patient's purified serum which has been mixed with test RBCs
AHGs in Coombs serum bind to:

The direct Coombs test detects antibodies that are directly attached to the RBC surface. The indirect (or not direct) Coombs test detects serum antibodies that are not bound to RBCs.

Investigation of underlying causestoggle arrow icon

Perform further diagnostic workup according to the suspected etiology; specialist consultation is advised. [17][19]

Antibody-mediated hemolysis (DAT positive)

Laboratory investigations for antibody-mediated hemolysis [5]
Concerning initial features Suggested additional investigations
Laboratory studies PBS
AIHA [20] Warm AIHA
  • RBC agglutination

Hemolytic transfusion reactions [21]

Nonantibody-mediated hemolysis (DAT negative)

Laboratory investigations for nonantibody-mediated hemolysis [5]
Concerning initial features Suggested additional investigations
Laboratory studies PBS
Intrinsic hemolytic anemia Hereditary spherocytosis
Hereditary elliptocytosis
Paroxysmal nocturnal hemoglobinuria [17]
Pyruvate kinase deficiency
G6PD deficiency
Extrinsic hemolytic anemia

Microangiopathic hemolysis

Macroangiopathic hemolysis
Intracellular pathogens
  • Intracellular organisms

Intrinsic hemolytic anemiastoggle arrow icon

Hemolytic anemia that is caused by structural or functional RBC abnormalities can be further classified as one of the following based on pathogenesis:

See respective articles for more detailed information.

Pyruvate kinase deficiencytoggle arrow icon

References [22][23][24]

Hemoglobin C diseasetoggle arrow icon


Pathophysiology [25]

Glutamic acid can also be replaced with a lysine, creating hemoglobin C.

In hemoglobin C disease, lyCine (lysine) replaces the amino acid glutamic acid.

Clinical features [25]


Characteristic findings in hemoglobin C disease compared with hemoglobin C trait [26]
Hemoglobin C disease (HbCC) Hemoglobin C trait (HbAC)
PBS [27]
  • Usually normal
Hemolysis workup
Hb electrophoresis

Treatment [28]

Hemoglobin Zurichtoggle arrow icon

References: [29]

Extrinsic hemolytic anemiatoggle arrow icon

Hemolytic anemia that is caused by the destruction of functionally and structurally normal RBCs can be further classified as one of the following based on the mechanism of RBC destruction:

See respective articles for more detailed information.

Mechanical destruction of RBCstoggle arrow icon

Microangiopathic hemolytic anemia (MAHA) [5][30]


Clinical features

Diagnostics in suspected MAHA

Workup for underlying causes of MAHA
Suspected etiology Supportive clinical features Diagnostic testing and characteristic findings
Primary thrombotic microangiopathy TTP
  • Fever
  • Neurological features
  • Young age
  • Impaired renal function
  • Recent gastrointestinal illness, typically with bloody diarrhea
Atypical HUS
  • Consider the following tests: [32]
    • Extended plasma complement levels
    • Genetic testing for complement mutations
Drug-induced thrombotic microangiopathy [33][34]
  • History of exposure to a typical culprit drug
  • Acute onset when immune mediated (e.g., from quinine exposure)
  • Gradual, dose-dependent onset when caused by a toxic effect (e.g., from cyclosporine or tacrolimus exposure)
  • Improvement after drug discontinuation
  • Test for drug-dependent antibodies.
Malignant hypertension
HELLP syndrome [35]
Disseminated intravascular coagulation
Autoimmune disease (e.g., SLE)
  • History of an autoimmune disease
  • Features of a systemic autoimmune disease
  • Any of the following:
  • Positive findings on infection-specific testing [36]

Management [31][34]

MAHA is a medical emergency. Consult hematology urgently, especially if there is no immediately evident cause (e.g., hypertensive emergency, preeclampsia).

Consider urgent initiation of plasma exchange for suspected TTP while waiting for ADAMTS13 test results.

Macroangiopathic hemolytic anemia

Referencestoggle arrow icon

  1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014; 124 (18): p.2804-2811.doi: 10.1182/blood-2014-02-522128 . | Open in Read by QxMD
  2. Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol. 2016; 91 (3): p.330-340.doi: 10.1002/ajh.24282 . | Open in Read by QxMD
  3. Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential Diagnosis. Am Fam Physician. 2018; 98 (6): p.354-361.
  4. Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology. 2018; 2018 (1): p.382-389.doi: 10.1182/asheducation-2018.1.382 . | Open in Read by QxMD
  5. Delaney M, Wendel S, Bercovitz RS, et al. Transfusion reactions: prevention, diagnosis, and treatment. The Lancet. 2016; 388 (10061): p.2825-2836.doi: 10.1016/s0140-6736(15)01313-6 . | Open in Read by QxMD
  6. Microangiopathic Hemolytic Anemia (MAHA). . Accessed: May 21, 2019.
  7. Arnold DM, Patriquin CJ, Nazy I. Thrombotic microangiopathies: a general approach to diagnosis and management. Can Med Assoc J. 2016; 189 (4): p.E153-E159.doi: 10.1503/cmaj.160142 . | Open in Read by QxMD
  8. Raina R, Krishnappa V, Blaha T, et al. Atypical Hemolytic-Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment. Therapeutic Apheresis and Dialysis. 2018; 23 (1): p.4-21.doi: 10.1111/1744-9987.12763 . | Open in Read by QxMD
  9. 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): p.616-618.doi: 10.1182/blood-2014-11-611335 . | Open in Read by QxMD
  10. Kottke-Marchant K. Diagnostic approach to microangiopathic hemolytic disorders. Int J Lab Hematol. 2017; 39: p.69-75.doi: 10.1111/ijlh.12671 . | Open in Read by QxMD
  11. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth. 2009; 9: p.8.doi: 10.1186/1471-2393-9-8 . | Open in Read by QxMD
  12. Booth KK, Terrell DR, Vesely SK, George JN. Systemic infections mimicking thrombotic thrombocytopenic purpura. Am J Hematol. 2011; 86 (9): p.743-751.doi: 10.1002/ajh.22091 . | Open in Read by QxMD
  13. Westphal RG, Azen EA.. Macroangiopathic hemolytic anemia due to congenital cardiovascular anomalies.. The Journal of the American Medical Association. 1971.
  14. Ismeno G, Renzulli A, Carozza A, et al. Intravascular hemolysis after mitral and aortic valve replacement with different types of mechanical prostheses.. Int J Cardiol. 1999; 69 (2): p.179-83.doi: 10.1016/s0167-5273(99)00024-8 . | Open in Read by QxMD
  15. Lam B-K, Cosgrove DM, Bhudia SK, Gillinov AM. Hemolysis after mitral valve repair: mechanisms and treatment. Ann Thorac Surg. 2004; 77 (1): p.191-195.doi: 10.1016/s0003-4975(03)01455-3 . | Open in Read by QxMD
  16. Hemoglobin C Disease. Updated: November 10, 2016. Accessed: October 22, 2018.
  17. Kohne E. Hemoglobinopathies: Clinical Manifestations, Diagnosis, and Treatment. Dtsch Arztebl Int. 2011.doi: 10.3238/arztebl.2011.0532 . | Open in Read by QxMD
  18. Fairhurst RM, Casella JF. Homozygous Hemoglobin C Disease. N Engl J Med. 2004; 350 (26): p.e24.doi: 10.1056/nejmicm030486 . | Open in Read by QxMD
  19. Caligiuri M, Levi MM, Kaushansky K, et al. Williams Hematology, 9E. McGraw-Hill Education / Medical ; 2015
  20. Prchal JT. Pyruvate kinase deficiency. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: June 9, 2016. Accessed: February 8, 2017.
  21. Zanella A, Bianchi P, Fermo E. Pyruvate kinase deficiency. Haematologica. 2007; 92 (6): p.721-723.doi: 10.3324/haematol.11469 . | Open in Read by QxMD
  22. Bianchi P, Fermo E, Glader B, et al. Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency. Am J Hematol. 2018; 94 (1): p.149-161.doi: 10.1002/ajh.25325 . | Open in Read by QxMD
  23. Hemoglobin Zurich. Updated: March 4, 2014. Accessed: August 3, 2020.
  24. Muneeba Malik, Abeera Mansur. Copper sulphate poisoning and exchange transfusion. Saudi Journal of Kidney Disease and Transplantation. 2011.
  25. SR Mehta, VSM and VK Sashindran. Clinical Features And Management Of Snake Bite. Medical Journal Armed Forces India. 2011.
  26. Barcellini W, Fattizzo B. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015; 2015: p.1-7.doi: 10.1155/2015/635670 . | Open in Read by QxMD
  27. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Stroke. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.$Harrisons Manual of Medicine, 20th Edition. McGraw Hill Professional; 2019.
  28. Riley RS, Ben-Ezra JM, Goel R, Tidwell A. Reticulocytes and reticulocyte enumeration.. J Clin Lab Anal. 2001; 15 (5): p.267-94.doi: 10.1002/jcla.1039 . | Open in Read by QxMD
  29. SEARS DA, ANDERSON PR, FOY AL, WILLIAMS HL, CROSBY WH. Urinary Iron Excretion and Renal Metabolism of Hemoglobin in Hemolytic Diseases. Blood. 1966; 28 (5): p.708-725.doi: 10.1182/blood.v28.5.708.708 . | Open in Read by QxMD
  30. Parker V, Tormey CA. The Direct Antiglobulin Test: Indications, Interpretation, and Pitfalls. Arch Pathol Lab Med. 2017; 141 (2): p.305-310.doi: 10.5858/arpa.2015-0444-rs . | Open in Read by QxMD
  31. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical ; 2018
  32. Shih AWY, McFarlane A, Verhovse M. Haptoglobin testing in hemolysis: Measurementand interpretation. Am J Hematol. 2014; 89 (4): p.443-447.doi: 10.1002/ajh.23623 . | Open in Read by QxMD
  33. Kormoczi GF, Saemann MD, Buchta C, et al. Influence of clinical factors on the haemolysis marker haptoglobin. Eur J Clin Invest. 2006; 36 (3): p.202-209.doi: 10.1111/j.1365-2362.2006.01617.x . | Open in Read by QxMD
  34. Berlin NI, Berk PD. Quantitative aspects of bilirubin metabolism for hematologists. Blood. 1981; 57 (6): p.983-99.
  35. Bensinger TA. Hemolysis in Sickle Cell Disease. Arch Intern Med. 1974; 133 (4): p.624.doi: 10.1001/archinte.1974.00320160118010 . | Open in Read by QxMD
  36. Tabbara IA. Hemolytic anemias: Diagnosis and Management. Med Clin North Am. 1992; 76 (3): p.649-668.doi: 10.1016/s0025-7125(16)30345-5 . | Open in Read by QxMD
  37. Goldman L, Schafer AI. Goldman's Cecil Medicine. Elsevier ; 2012: p. 2461-2469
  38. Vivian C. Ejindu, Andrew L. Hine, Mohammad Mashayekhi, Philip J. Shorvon, Rakesh R. Misra. Musculoskeletal Manifestations of Sickle Cell Disease. Radiology. 2007.
  39. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
  40. Brodsky RA. Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: April 25, 2016. Accessed: February 8, 2017.
  41. Parker CJ. Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy. Hematology Am Soc Hematol Educ Program. 2011; 2011: p.21-29.doi: 10.1182/asheducation-2011.1.21 . | Open in Read by QxMD
  42. Schrier SL. Cold agglutinin disease. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: October 5, 2016. Accessed: February 8, 2017.
  43. Brodsky RA, Schrier SL, Rosmarin AG. Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: June 2, 2016. Accessed: August 30, 2017.
  44. Steinberg MH and Quinn CT. Unstable hemoglobin variants. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: July 23, 2020. Accessed: August 3, 2020.

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