- Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD more...
Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if bone marrow activity cannot compensate for the erythrocyte loss. The severity of the anemia depends on whether the onset of hemolysis is gradual or abrupt and on the extent of erythrocyte destruction. Mild hemolysis can be asymptomatic while the anemia in severe hemolysis can be life threatening and cause angina and cardiopulmonary decompensation.
Hemolytic anemia has multiple causes, and the clinical presentation can differ depending on the etiology. An array of laboratory tests are available for detecting hemolysis, and specialized tests may be indicated to diagnose the cause for hemolysis (see Workup). There are differences in the management of various types of hemolytic anemias (see Treatment).
Hemolysis can be due to hereditary and acquired disorders. The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as intrinsic membrane defects, abnormal hemoglobins, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism.
Hemolysis may be an extravascular or an intravascular phenomenon. Autoimmune hemolytic anemia and hereditary spherocytosis are examples of extravascular hemolysis because the red blood cells are destroyed in the spleen and other reticuloendothelial tissues. Intravascular hemolysis occurs in hemolytic anemia due to the following:
Prosthetic cardiac valves
Transfusion of ABO incompatible blood
Hemolysis may also be intramedullary, when fragile red blood cell (RBC) precursors are destroyed in the bone marrow prior to release into the circulation. Intramedullary hemolysis occurs in pernicious anemia and thalassemia major.
Hemolysis is associated with a release of RBC lactate dehydrogenase (LDH). Hemoglobin released from damaged RBCs leads to an increase in indirect bilirubin and urobilinogen levels.
A patient with mild hemolysis may have normal hemoglobin levels if increased RBC production matches the rate of RBC destruction. However, patients with mild hemolysis may develop marked anemia if their bone marrow erythrocyte production is transiently shut off by viral (parvovirus B-19) or other infections. This scenario would be an aplastic crisis since the bone marrow can no longer compensate for ongoing hemolysis.
Skull and skeletal deformities can occur in childhood due to a marked increase in hematopoiesis and resultant bone marrow expansion in disorders such as thalassemia.
A wide range of causes of hemolytic anemia have been documented.[2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12] Only the more commonly encountered hemolytic disorders are discussed in this article.
Hereditary disorders may cause hemolysis as a result of erythrocyte membrane abnormalities, enzymatic defects, and hemoglobin abnormalities. Hereditary disorders include the following:
Acquired causes of hemolysis include the following:
Toxic chemicals and drugs [3, 16]
Antiviral agents (eg, ribavirin  )
Autoimmune hemolytic anemia (AIHA) can be due to warm or cold autoantibody types and, rarely, mixed types.[12, 19, 20] Most warm autoantibodies belong to the immunoglobulin IgG class. These antibodies can be detected by a direct Coombs test, which also is known as a direct antiglobulin test (DAT). AIHA may occur after allogeneic hematopoietic stem cell transplantation. The 3-year cumulative incidence in this population has been reported at 4.44%.
Microangiopathic hemolytic anemia, which results in the production of fragmented erythrocytes (schistocytes), may be caused by any of the following[22, 23] :
Defective prosthetic cardiac valves
Disseminated intravascular coagulation (DIC)
Hemolytic uremic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP)
In paroxysmal nocturnal hemoglobinuria, hemolysis is due to intravascular complement-mediated destruction of erythrocytes.
Hemolytic anemia represents approximately 5% of all anemias. Acute AIHA is relatively rare, with an incidence of one to three cases per 100,000 population per year.
Hemolytic anemias are not specific to any race. However, sickle cell disorders are found primarily in Africans, African Americans, some Arabic peoples, and Aborigines in southern India.
Several variants of G6PD deficiency exist. The A(-) variant is found in West Africans and African Americans. Approximately 10% of African Americans carry at least 1 copy of the gene for this variant. The Mediterranean variant occurs in individuals of Mediterranean descent and in some Asians.
Most cases of hemolytic anemia are not sex specific. However, AIHA is slightly more likely to occur in females than in males. G6PD deficiency is an X-linked recessive disorder. Therefore, males are usually affected, and females are carriers.
Although hemolytic anemia can occur in persons of any age, hereditary disorders are usually evident early in life. AIHA is more likely to occur in middle-aged and older individuals.
The prognosis for patients with hemolytic anemia depends on the underlying cause.
Overall, mortality rates are low in hemolytic anemias. However, the risk is greater in older patients and patients with cardiovascular impairment.
Morbidity depends on the etiology of the hemolysis and the underlying disorder, such as sickle cell anemia or malaria.
Patients should be able to identify symptoms and signs of the recurrence of hemolysis. They should seek prompt medical attention if symptoms reoccur.
Patients with G6PD deficiency should know which medications to avoid.
Gallagher PG. The Red Blood Cell Membrane and Its Disorders: Hereditary Spherocytosis, Elliptocytosis, and Related Diseases. Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT, eds. Williams Hematology. 8th ed. New York, NY: McGraw Hill; 2010. 617-46.
Lichtman MA. Hemolytic anemia due to infections with microorganisms. Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT, eds. Williams Hematology. 8th ed. New York, NY: McGraw Hill; 2010. 769-76.
Beutler E, Bull BS, Herrmann PC. Hemolytic Anemia Resulting from Chemical and Physical Agents. Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT, eds. Williams Hematology. 8th ed. New York, NY: McGraw Hill; 2010. 763-68.
Glader BE. Hemolytic anemia in children. Clin Lab Med. 1999 Mar. 19(1):87-111, vi. [Medline].
Kong JT, Schmiesing C. Concealed mothball abuse prior to anesthesia: mothballs, inhalants, and their management. Acta Anaesthesiol Scand. 2005 Jan. 49(1):113-6. [Medline].
Lane DR, Youse JS. Coombs-positive hemolytic anemia secondary to brown recluse spider bite: a review of the literature and discussion of treatment. Cutis. 2004 Dec. 74(6):341-7. [Medline].
Packman CH, Leddy JP. Acquired hemolytic anemia due to warm-reacting autoantibodies. Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw Hill; 1995. 667-84.
Gallagher PG. Red cell membrane disorders. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. New York, NY: Churchill Livingstone; 2013. 592-613.
Price EA, Schrier SL. Extrinsic nonimmune hemolytic anemias. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. New York, NY: Churchill Livingstone; 2013. 628-38.
Jager U, Lechner K. Autoimmune hemolytic anemia. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. New York, NY: Churchill Livingstone; 2013. 614-17.
Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015 Jun. 29 (3):455-71. [Medline].
Rink BD, Gonik B, Chmait RH, O'Shaughnessy R. Maternal hemolysis after intravenous immunoglobulin treatment in fetal and neonatal alloimmune thrombocytopenia. Obstet Gynecol. 2013 Feb. 121(2 Pt 2 Suppl 1):471-3. [Medline].
Mayer B, Leo A, Herziger A, Houben P, Schemmer P, Salama A. Intravascular immune hemolysis caused by the contrast medium iomeprol. Transfusion. 2013 Jan 24. [Medline].
Acharya D, McGiffin DC. Hemolysis after Mitral Valve Repair. J Card Surg. 2013 Jan 13. 1-4. [Medline].
Petz LD. Drug-induced autoimmune hemolytic anemia. Transfus Med Rev. 1993 Oct. 7(4):242-54. [Medline].
Chiao EY, Engels EA, Kramer JR, Pietz K, Henderson L, Giordano TP, et al. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection. Arch Intern Med. 2009 Feb 23. 169(4):357-63. [Medline]. [Full Text].
Zamvar V, McClean P, Odeka E, Richards M, Davison S. Hepatitis E virus infection with nonimmune hemolytic anemia. J Pediatr Gastroenterol Nutr. 2005 Feb. 40(2):223-5. [Medline].
Naik R. Warm autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015 Jun. 29 (3):445-53. [Medline].
Mayer B, Yürek S, Kiesewetter H, Salama A. Mixed-type autoimmune hemolytic anemia: differential diagnosis and a critical review of reported cases. Transfusion. 2008 Oct. 48(10):2229-34. [Medline].
Sanz J, Arriaga F, Montesinos P, Ortí G, Lorenzo I, Cantero S, et al. Autoimmune hemolytic anemia following allogeneic hematopoietic stem cell transplantation in adult patients. Bone Marrow Transplant. 2007 May. 39(9):555-61. [Medline].
George JN. The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (Experience of The Oklahoma TTP-HUS Registry, 1989-2007). Kidney Int Suppl. 2009 Feb. S8-S10. [Medline].
Lechner K, Obermeier HL. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012 Jul. 91 (4):195-205. [Medline].
Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. 2002 Apr. 69(4):258-71. [Medline].
Dhingra KK, Jain D, Mandal S, Khurana N, Singh T, Gupta N. Evans syndrome: a study of six cases with review of literature. Hematology. 2008 Dec. 13(6):356-60. [Medline].
Garratty G. Immune hemolytic anemia associated with negative routine serology. Semin Hematol. 2005 Jul. 42(3):156-64. [Medline].
Kamesaki T, Oyamada T, Omine M, Ozawa K, Kajii E. Cut-off value of red-blood-cell-bound IgG for the diagnosis of Coombs-negative autoimmune hemolytic anemia. Am J Hematol. 2009 Feb. 84(2):98-101. [Medline]. [Full Text].
Kamesaki T, Toyotsuji T, Kajii E. Characterization of direct antiglobulin test-negative autoimmune hemolytic anemia: A study of 154 cases. Am J Hematol. 2013 Feb. 88(2):93-6. [Medline].
Ferrer G, Navarro A, Hodgson K, et al. MicroRNA expression in chronic lymphocytic leukemia developing autoimmune hemolytic anemia. Leuk Lymphoma. 2013 Jan 29. [Medline].
Jubinsky PT, Rashid N. Successful treatment of a patient with mixed warm and cold antibody mediated Evans syndrome and glucose intolerance. Pediatr Blood Cancer. 2005 Sep. 45(3):347-50. [Medline].
Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013 Nov. 163 (3):393-9. [Medline].
Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012 May. 26(3):107-15. [Medline].
McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technol Assess. 2009 Jan. 13(1):iii-iv, ix-xi, 1-121. [Medline]. [Full Text].
Burke JR. Low-dose subcutaneous recombinant erythropoietin in children with chronic renal failure. Australian and New Zealand Paediatric Nephrology Association. Pediatr Nephrol. 1995 Oct. 9(5):558-61. [Medline].
Arbach O, Funck R, Seibt F, Salama A. Erythropoietin May Improve Anemia in Patients with Autoimmune Hemolytic Anemia Associated with Reticulocytopenia. Transfus Med Hemother. 2012 Jun. 39(3):221-223. [Medline]. [Full Text].
Schettler V, Wieland E. A case report of darbepoetin treatment in a patient with sickle cell disease and chronic renal failure undergoing regular hemodialysis procedures that induce a dose-dependent extension of blood transfusion intervals. Ther Apher Dial. 2009 Feb. 13(1):80-2. [Medline].
Ball AM, Winstead PS. Recombinant human erythropoietin therapy in critically ill Jehovah's Witnesses. Pharmacotherapy. 2008 Nov. 28(11):1383-90. [Medline].
Tchernia G, Delhommeau F, Perrotta S, Cynober T, Bader-Meunier B, Nobili B, et al. Recombinant erythropoietin therapy as an alternative to blood transfusions in infants with hereditary spherocytosis. Hematol J. 2000. 1(3):146-52. [Medline].
Hosono S, Hosono A, Mugishima H, Nakano Y, Minato M, Okada T, et al. Successful recombinant erythropoietin therapy for a developing anemic newborn with hereditary spherocytosis. Pediatr Int. 2006 Apr. 48(2):178-80. [Medline].
Morrison JF, Neufeld EJ, Grace RF. The use of erythropoietin-stimulating agents versus supportive care in newborns with hereditary spherocytosis: a single centre's experience. Eur J Haematol. 2014 Aug. 93(2):161-4. [Medline]. [Full Text].
Balestracci A, Martin SM, Toledo I, Alvarado C, Wainsztein RE. Early erythropoietin in post-diarrheal hemolytic uremic syndrome: a case-control study. Pediatr Nephrol. 2014 Aug 21. [Medline].
Bienvenu AL, Picot S. Cerebral malaria: protection by erythropoietin. Methods Mol Biol. 2013. 982:315-24. [Medline].
Hamilton JW, Jones FG, McMullin MF. Glucose-6-phosphate dehydrogenase Guadalajara--a case of chronic non-spherocytic haemolytic anaemia responding to splenectomy and the role of splenectomy in this disorder. Hematology. 2004 Aug. 9(4):307-9. [Medline].
Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S, Michallet AS, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015 Apr. 14 (4):304-13. [Medline].
Packman CH, Leddy JP. Drug-related immune hemolytic anemia. Beutler E, Lichtman MA, Coller BS, Kipps TJ, eds. Williams Hematology. 5th ed. New York, NY: McGraw Hill; 1995. 691-6.