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hemolytic anemia

Defined as the premature destruction of erythrocytes with resultant anemia. Etiology: 1) acquired a) hypersplenism b) immune-mediated hemolytic anemia - IgG-mediated (extravascular hemolysis) - IgM/complement-mediated (intravascular) - drug-induced (may be IgG or IgM) - fludarabine, bendamustine, quinine, penicillins, alpha-methyldopa - alloimmune - hemolytic transfusion reaction - hemolytic disease of the newborn - blood transfusion of fetal hemoglobin - autoimmune - warm antibody autoimmune hemolytic anemia - cold agglutinin syndrome - paroxysmal cold hemoglobinuria c) paroxysmal nocturnal hemoglobinuria (intravascular) d) toxin & metabolic disorders - arsenic-induced - copper-induced - thermal injury - bacteria-induced - Clostridium perfringens - Escherichia coli - Haemophilus influenzae - Bartonella bacilliformis - protozoan infections: - Babesia microti - Plasmodium (malaria) - snake & spider bite - brown recluse - hypophosphatemia - spur cell hemolytic anemia (Zieve syndrome) e) parasitic infection (intravascular) - Malaria - Babesiosis - Bartonellosis f) erythrocyte trauma (extravascular, microangiopathic, schistocytes) - cardiac valvular disease (no thrombocytopenia) - disseminated intravascular coagulation (DIC) - thrombotic thrombocytopenic purpura (TTP) - hemolytic uremic syndrome - HELLP syndrome [3] - hypotonic solutions [4] - march hemoglobinuria/runner's anemia [3] 2) hereditary hemolytic disorders a) membrane defects (extravascular) - hereditary spherocytosis - hereditary elliptocytosis (noted only with splenomegaly) b) enzyme defects - glycolysis - pyruvate kinase deficiency (extravascular) - hexose monophosphate shunt - glucose-6-phosphate dehydrogenase deficiency (intravascular) - aldolase-A deficiency - adenylate kinase-1 (AK1) deficiency c) thalassemia d) hemoglobinopathy - sickle cell disease & others e) idiopathic hereditary non-spherocytic hemolytic anemia - overexpression of XPO7 f) Wilson's disease Genetics: see hereditary hemolytic disorders above History: - past medical history: - systemic lupus erythematosus - lymphoma - family history: - hemoglobinopathy - congenital anemia Clinical manifestations: 1) symptoms a) symptoms common to all forms of anemia b) worsening of pre-existing angina c) heart failure - high output d) left upper quadrant pain secondary to splenomegaly e) right upper quadrant pain secondary to gallstones 2) signs a) jaundice (intravascular) b) pallor c) cholelithiasis (intravascular) - bilirubin gallstones especially common with chronic hemolysis d) splenomegaly (extravascular) Laboratory: 1) complete blood count (CBC) a) anemia b) leukocyte & platelet count are sometimes elevated, but are usually normal c) MCV generally increased due to reticulocytosis [3] 2) reticulocyte count is generally elevated 3) peripheral smear - erythrocyte morphology a) spherocytes - hereditary spherocytosis - autoimmine hemolytic anemia b) schistocytes*: microangiopathic hemolytic anemia c) target cells - thalassemia - hemoglobin C disease - liver disease d) sickle cells: sickle cell anemia e) bite cells: G6PD deficiency f) erythrocyte agglutination: cold agglutinin syndrome 4) direct antiglobulin test (Coomb's antibody) a) warm antibody autoimmune hemolytic anemia* - IgG-positive direct antiglobulin (DAT) complement-C3 +/- [3] b) complement C3-positive, IgG negative DAT in cold agglutinin syndrome [3] c) complement positive Coomb's antibody in intravascular hemolysis d) IgG-positive direct antiglobulin (DAT) in extravascular hemolysis 5) serum lactate dehydrogenase a) increased in intravascular hemolysis b) normal in extravascular hemolysis 6) serum bilirubin, unconjugated a) increased in intravascular hemolysis b) normal in extravascular hemolysis 7) urinalysis: hemosiderinuria a) positive in intravascular hemolysis b) negative in extravascular hemolysis c) tests for prior or chronic hemolysis of several days 8) serum haptoglobin a) decreased in intravascular hemolysis b) generally normal in extravascular hemolysis c) also an acute phase reactant; levels increased with inflammation 9) elevated serum free hemoglobin in intravascular hemolysis 10) hereditary spherocytosis - osmotic fragility - flow cytometry for eosin-5-maleimide binding to band-3 protein 11) cold agglutinins - cold agglutinin syndrome 12) hemoglobin electrophoresis a) hemoglobinopathy b) thalassemia 13) serum glucose-6-phosphate dehydrogenase (serum G6PD) a) G6PD deficiency b) check 2-3 months after hemolytic episode [3] 14) blood culture - if indicated 15) paroxysmal nocturnal hemoglobinuria (PNH) a) Ham test b) flow cytometery for CD55 & CD59 16) see ARUP consult [5] *schistocytes on peripheral blood smear sufficient to rule out warm autoimmune hemolytic anemia without direct antiglobulin testing (DAT) [1] Special laboratory: - echocardiography if hemolysis is suspected due to mechanical heart valve [3] Differential diagnosis: 1) intravascular hemolysis 2) extravascular hemolysis 3) bleeding diathesis 4) hypoplastic anemia a) primary marrow failure b) chronic renal insufficiency - decreased erythropoietin Management: 1) supportive a) bedrest b) oxygen c) blood transfusion to treat symptoms, not Hgb/Hct d) aggressive treatment of cardiac/end organ hypoperfusion or ischemia 2) treatment of underlying disorder (see underlying disorder) - autoimmune hemolytic anemia - warm autoimmune hemolytic anemia - cold agglutinin syndrome - thrombotic thrombocytopenic purpura - hereditary spherocytosis - thalassemia - paroxysmal nocturnal hemoglobinuria 3) chronic hemolytic anemia (all patients) [3] - folic acid 1 mg/day - pneumococcal vaccine - Haemophilus influenzae B vaccine - meningococcal vaccine [3] 4) chronic hemolytic anemia (strategies) [3] - hydroxyurea - hematopoietic stem cell transplantation - prophylactic transfusions

Interactions

disease interactions

Related

pharmaceutical agents associated with G6PD deficiency hemolytic anemia pharmaceutical agents associated with immune hemolytic anemia

Specific

autoimmune hemolytic anemia chronic nonspherocytic hemolytic anemia drug-induced hemolytic anemia Evan's syndrome Heinz body anemia hemoglobin C disease hemoglobin SC disease hemolytic anemia associated with ATPase deficiency hemolytic disease of the newborn hemolytic uremic syndrome (HUS) hereditary spherocytosis march hemoglobinuria; runner's anemia; exercise-induced hemolysis microangiopathic hemolytic anemia paroxysmal nocturnal hemoglobinuria (PNH, Marchiafava-Micheli syndrome) pyrimidine 5' nucleotidase deficiency hemolytic anemia; P5N deficiency regulator type Rh-null hemolytic anemia (Rh-deficiency syndrome) sickle cell (hemoglobin SS) disease thalassemia

General

anemia hemolysis

Database Correlations

OMIM correlations MORBIDMAP 103850

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 579-80
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Schiller G, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  5. ARUP Consult: ARUP Consult: Hemolytic Anemias The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hemolytic-anemias - Hemolytic Anemias Testing Algorithm https://arupconsult.com/algorithm/hemolytic-anemias-testing-algorithm - Hereditary Hemolytic Anemia Panel, Sequencing https://arupconsult.com/ati/Hereditary-Hemolytic-Anemia-Panel
  6. Shapira Y, Vaturi M, Sagie A. Hemolysis associated with prosthetic heart valves: a review. Cardiol Rev. 2009 May-Jun;17(3):121-4 PMID: 19384085
  7. Beris P, Picard V. Non-immune Hemolysis: Diagnostic Considerations. Semin Hematol. 2015 Oct;52(4):287-303. Review. PMID: 26404441