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Hemolysis and Hemolytic Anemia

Normal red blood cells have a life span of about 120 days which is shortened when hemolysis occurs. Review the different types of hemolytic anemia.


Hemolytic anemia

There are numerous causes of hemolytic anemia which is caused by hemolysis, the destruction of red blood cells. Normal RBCs have a life span of about 120 days which is shortened when hemolysis occurs.

Red Blood Cell Abnormalities

Hemolysis can be caused by abnormalities in the red blood cell (RBC). It can occur with a hemoglobinopathy when hemoglobin is altered. A membranopathy is where the structure of the red cell membrane may be changed, and the red cell becomes less deformable. In both hemoglobinopathies and membranopathies RBCs may not be flexible enough to pass through the spleen where they are typically sequestered and phagocytized. An enzymopathy, a process which adversely affects an RBC’s metabolic processes, can also cause hemolysis.[1]

Examples of hemoglobinopathies leading to hemolysis include thalassemia and sickle cell disease. Diseases of red cell membranes (membranopathies) include hereditary spherocytosis and hereditary elliptocytosis. RBC enzymopathies include glucose-6-phosphate dehydrogenase deficiency (G6PD) and pyruvate kinase deficiency.[1]

G6PD is an example of oxidative hemolysis. This is where the patient when exposed to certain medications or substances converts reduced state ferrous (2+) iron in hemoglobin, which carries oxygen, to the oxidized ferric (3+) iron, or methemoglobin which does not.[2] This results in methemoglobinemia where the hemoglobin molecule is unable to effectively carry oxygen. The ferric iron is denatured by the body and turns into what are known as Heinz bodies. G6PD is an X chromosome recessive disorder seen mostly in men of Mediterranean and African descent. While methylene blue is used to treat methemoglobinemia from other causes it can worsen G6PD patients and care is supportive and avoiding the offending substance that caused the problem. There is a substantial list of substances that can precipitate oxidative hemolysis in G6PD patients.[3] G6PD is also known as favism due to the fava bean being a common inciting food. A full list of substances to be avoided in G6PD patients can be found at this hyperlink:

Other Causes of Hemolysis

Factors external to the RBC also can cause hemolysis and include mechanical destruction, immune-mediated hemolysis, drug-induced, envenomations and infectious causes.

RBC blood transfusions can cause both acute and delayed hemolytic reactions. Mechanical trauma to RBCs causing hemolysis as can be seen in march hemoglobinuria and with malfunctioning prosthetic cardiac valves. Malaria and babesiosis infections are known to destroy RBC’s. Certain snake bites may cause hemolysis. Paroxysmal nocturnal hemoglobinuria may also result in hemolysis.

RBC fragmentation from thrombotic microangiopathy leading to microangiopathic hemolytic anemia can occur with thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, hemolytic uremic syndrome and the HELLP syndrome in pregnancy (hemolysis, elevated liver enzymes and low platelets).[1] They are all classified as thrombotic microangiopathies, where RBCs are mechanically damaged as they as they pass through small blood vessels that have endothelial damage, microthromboses, platelet aggregations and fibrin deposits.[6,7,8,9]

There are over 150 drugs that have been documented to potentially cause hemolytic anemia. The most common are penicillins, cephalosporins, methyldopa, β-lactamase inhibitors such as clavulanate, nonsteroidal anti-inflammatory drugs and quinidine.[1,3,4,5] Drugs can cause hemolysis either by an immune mechanism or by a direct toxic effect.[10]

In the newborn, onset of hyperbilirubinemia or anemia may be from hemolysis. Hemolytic disease of the newborn is caused by maternal antibodies that lead to destruction of RBCs in the infant. G6PD disease should also be considered as a possible cause of hemolysis in infants.[3]

History and Physical Exam

A careful history should be taken to try to limit diagnostic possibilities as there are so many different etiologies of hemolysis.

The physical exam, depending on the acuity may reveal pallor, jaundice, hematuria, shortness of breath, weakness, fatigue, tachycardia, congestive heart failure if the anemia is severe, or the physical exam may be normal. Specific physical findings will depend on the etiology of the hemolysis.

Laboratory tests

  • Lactate dehydrogenase (LDH) is found inside RBCs, and when they rupture LDH levels typically increase.

  • Haptoglobin binds to free hemoglobin. As RBCs lyse and hemoglobin is released there will be decreased levels of haptoglobin.

  • There typically is an elevated reticulocyte count, as the bone marrow attempts to produce increased amounts of RBCs.

  • A complete blood count will typically reveal a normocytic anemia.

  • There may be hemoglobinuria.

  • Indirect bilirubin (unconjugated bilirubin) may be elevated from breakdown of hemoglobin porphyrin.[1]

Autoimmune hemolytic anemia is caused by autoantibody-mediated destruction of RBCs. Autoimmune hemolysis can be idiopathic, from viral or bacterial infections, autoimmune diseases, connective tissue disorders, lymphoproliferative cancers, blood transfusions, or organ transplants.[3]

Autoimmune hemolysis typically causes a positive direct antiglobulin test (DAT) or Coombs test. Depending on the binding temperature, autoimmune hemolysis is subdivided into cold and warm agglutinin types. Warm is more commonly seen than cold and involves immunoglobulin G (IgG) antibodies, typically to the Rh complex, that react with the RBC membrane at normal body temperatures. Cold agglutinins are due to IgM antibodies that react with antigens on the surface of an RBC at low temperatures and can cause RBC lysis by complement fixation. Cold agglutinins may cause more symptoms in cold climates or in the extremities where body temperature is lower. About half of patients with cold agglutination disease will have acrocyanosis or Raynaud’s phenomenon.[4] Mycoplasma pneumonia and mononucleosis are two diseases that can commonly may cause cold agglutinin hemolysis.[3]

Blood Smear Examination

A blood smear can help differentiate the etiology of the hemolysis. Specific findings to look for include spherocytes, elliptocytes, fragmented red cells such as helmet cells or schistocytes, intercellular Babesia or malaria organisms, sickled cells, bite cells (also known as blister cells) and inclusions called Heinz bodies, which are particles of denatured hemoglobin. Bite cells occur when the Heinz bodies are removed by the spleen.[1]

Spherocytes can be seen in hereditary spherocytosis as well as autoimmune and drug induced hemolytic anemia. Elliptocytes indicate hereditary elliptocytosis. When RBCs fragment from direct trauma, such as in march hemoglobinuria and malfunctioning prosthetic cardiac valves, a macroangiopathic hemolytic anemia may result and schistocytes may be seen. Some schistocytes may be seen after recent extracorporeal membrane oxygenation (ECMO) or coronary bypass surgery. Thrombotic microangiopathy can also produce schistocytes and microangiopathic hemolytic anemia in diseases such as the HELLP syndrome, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and drug induced hemolytic anemia. Schistocytes may also be seen in infections such as rickettsia, malaria or HIV. Bite cells and Heinz bodies, although they may be seen in some toxin exposures and with some oxidizing drugs, are more typically seen in G6PD.[3,11]

schistocytes and spherocytes

bite cells and Heinz bodies

babesia and malaria


Treatment of hemolysis and hemolytic anemia depends on the cause and may include blood transfusions, splenectomy, immunosuppressants, erythropoiesis-stimulating agents, bone marrow transplants, CRISPR gene therapy, stopping of an offending medication, or cardiac valve replacement. Since there are so many different etiologies, a full discussion of treatment is beyond the scope of this article.[1,3]

The prognosis for hemolytic anemias varies on the cause of the illness as well as how early it is diagnosed and appropriately managed.

Some Specific Complications

15% to 44% of paroxysmal nocturnal hemoglobinuria patients will have at least one thromboembolic event and it is a common cause of death. Thalassemia and sickle cell disease both can create a hypercoagulable state.[1] In patients with autoimmune hemolytic anemia, 11 to 20% of patients are reported to have thrombotic events.[4]

Chronic hemolysis can produce excess free hemoglobin and iron can lead to iron and hemosiderin deposition in the kidneys that may impair kidney function.[1]

Some people with hereditary spherocytosis are not diagnosed until adulthood when they begin to present with recurrent cholelithiasis.[1]


Hemolysis and hemolytic anemia have numerous etiologies. This includes infections, autoimmune diseases, hereditary diseases, medications, toxins, some envenomations, some cancers and mechanical destruction.

The key to making the correct diagnosis is a complete patient and family history. Physical exam may be helpful in delineating cause in some cases. There are a number of laboratory tests that may be helpful but a blood smear may be particularly useful.

Treatment will depend on the etiology and in most cases hematology consultation will be helpful or required.


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[1] Baldwin C, Pandey J, Olarewaju O. Hemolytic Anemia. [Updated 2022 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

[2] Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. [Updated 2022 Aug 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Retrieved from:

[3] Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential Diagnosis. Am Fam Physician. 2018;98(6):354-361. Retrieved from:

[4] Autoimmune Hemolytic Anemias. N Engl J Med 385:1407-1419. October 7, 2021. Retrieved from:

[5] Sarkar RS, Philip J, Mallhi RS, Jain N. Drug-induced immune hemolytic anemia (Direct Antiglobulin Test positive). Med J Armed Forces India. 2013;69(2):190-192. Retrieved from:

[6] Khalid F, Mahendraker N, Tonismae T. HELLP Syndrome. [Updated 2022 Jun 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Retrieved from:

[7] Stanley M, Killeen RB, Michalski JM. Thrombotic Thrombocytopenic Purpura. [Updated 2022 Nov 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Retrieved from:

[8] Chang JC. Disseminated intravascular coagulation: is it fact or fancy?. Blood Coagul Fibrinolysis. 2018;29(3):330-337. Retrieved from:

[9] Thomas, M.R., Robinson, S. and Scully, M.A. (2016), How we manage thrombotic microangiopathies in pregnancy. Br J Haematol, 173: 821-830. Retrieved from:

[6] Zayd L. Al-Nouri, Jessica A. Reese, Deirdra R. Terrell, Sara K. Vesely, James N. George; Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015; 125 (4): 616–618.

[11] Herman TF, Javaid MU. Heinz Body. [Updated 2022 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Retrieved from:

[12] Blood smear with typical schistocytes in TTP marked in blue. Central Hematology Laboratory Hemostasis Research Laboratory Bern University Hospital & University of Bern. March 5, 2013. Retrieved from:

[13] By Guy Waterval - Own work, Apache License 2.0,

initially published 5/28/2023


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