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1. AşkınK.KaplanM.D.
Hemolytic Anemia
Asst. Prof. Aşkın K. Kaplan M.D.
Maltepe University Maltepe Faculty of Medicine

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RED BLOOD CELL LIFE CYCLE

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Anemia- Clinical History
• Symptoms acute vs chronic
• Duration of symptoms
• Previous blood counts
• Previous diagnosis of anemia
• History of treatment with iron, folate, or
cobalamin
• Familial history of anemia
• Gastrointestinal system symptoms
• Nutrition status
• Medications

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Anemia- Clinical History
• Consumption of alcohol
• Menstruation and pregnancy
• Jaundice and dark urine
• Loss of weight
• Fever, night sweats
• Abdominal discomfort
• Stomatitis, glossitis
• Paresthesia, weakness

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Anemia- Physical Examination
• The major aim on physical examination is
– to find signs of organ or multisystem involvement
– to assess the severity of the patient's condition.
• Pallor
• Jaundice
• The presence or absence of lymphadenopathy, hepatomegaly,
splenomegaly, and bone tenderness, leg ulcers, coilonichia
• Signs of other hematologic abnormalities
– petechiae due to thrombocytopenia
– ecchymoses, and other signs of bleeding due to abnormalities of
coagulation.
– signs and symptoms of recurrent infections secondary to
neutropenia or immune deficiency states.
• The presence of occult blood

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Source: Overview of the Anemias, Pathophysiology of Blood Disorders, 2e
Citation: Aster JC, Bunn H. Pathophysiology of Blood Disorders, 2e; 2017 Available at:
http://accessmedicine.mhmedical.com/content.aspx?bookid=1900&sectionid=137394689 Accessed: March 02, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved

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Classification of Anemia
• Kinetic approach
– Decreased RBC production
– Increased RBC destruction (hemolysis)
– Blood loss; bleeding
• Morphologic
– According to RBC size (MCV)
• Macrocytic anemia
• Microcytic anemia
• Normocytic anemia
– According to reticulocyte count
• Hyporegenerative
• Regenerative

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Kinetic Approach
Increased RBC Destruction- Hemolysis
• Extravascular hemolysis
– Intrinsic red blood cell defects
– Extrinsic red blood cell defects
• Intravascular hemolysis
OR
• Inherited hemolytic anemias
• Acquired hemolytic anemias

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Hemolytic Anemia

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Increased RBC Destruction
Extravascular RBC Destruction
Intrinsic RBC Defects
• Hemoglobinopathies
– Thalassemias
– Sickle cell anemia
– Unstable Hb variants
• RBC membrane disorders
– Hereditary spherocytosis
– Hereditary elliptocytosis
• RBC enzyme deficiencies
– G6PD deficiency
– Pyruvate kinase deficiency
Extrinsic RBC Defects
• Autoimmune hemolytic anemia
(warm or cold reacting, drugs)
• Liver disease
• Hypersplenism
• Infections (malaria, bartonella)
• Oxidant agents (drugs)
• Other agents (lead, copper,
snake and spider bites)
• Large granular lymphocyte
leukemia
• Intravenous immune globulin
infusion

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Glucose-6-Phosphate Dehydrogenase
(G6PD) Deficiency
• G-6-PD: reduces NADP/oxidizes glucose-6-
phosphate
– Detoxifies free radicals and peroxides

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Glucose-6-Phosphate Dehydrogenase
Deficiency
• Sex-linked disorder
• 8% of African-American males
• Hemolytic anemia usually occurs in the
presence of stress (infection or drugs)
– African form - mild hemolysis usually with drugs,
infection, fever
– Mediterranean form - more severe
• Unique sensitivity to fava beans
– Chronic non-spherocytic hemolytic anemia

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Increased RBC Destruction
Intravascular RBC Destruction
• Microangiopathy
– Aortic stenosis, prosthetic valve leak
• Transfusion reactions
– ABO incompatibility
• Infection
– Sepsis, severe malaria
• Paroxysmal cold hemoglobinuria
• Cold agglutinin disease
• Paroxysmal nocturnal hemoglobinuria
• Following infusion of Rho(D) immune globulin
• Snake bites
• Exposure to compounds with high oxidant potential
– Copper in Wilson’s disease

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Increased RBC Destruction
Hereditary Hemolytic Diseases
• Red cell membrane disorders
– Hereditary spherocytosis
– Hereditary elliptocytosis
– Hereditary pyropoikilocytosis
– Hereditary stomatocytosis
• Enzyme deficiencies
– Hexose monophosphate shunt enzyme deficiencies
• G6PD deficiency, glutathione synthetase deficiency
– Glycolytic enzyme deficiencies
• Pyruvate kinase deficiency, hexokinase deficiency
• Globin chain abnormalities
– Deficient globin synthesis; thalassemia
– Structurally abnormal globins; sickle cell disease, unstable
hemoglobins

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Acquired Hemolytic Diseases
• Deficiency of phosphatidylinositol- linked glycoproteins
– Paroxysmal nocturnal hemoglobinuria (PNH)
• Antibody mediated destruction; Coombs positive AIHA
– Warm Ab, Cold Ab, paroxysmal cold hemoglobinuria
• Mechanical trauma
– Microangiopathic hemolytic anemias
– Cardiac traumatic hemolysis
– Repetitive physical trauma
• Infections of red blood cells; Malaria
• Toxic or chemical injury
– Sepsis, snake venom, lead poisoning
• Membrane lipid abnormalities; abetalipoproteinemia
• Sequestration; hypersplenism

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Hemolytic Anemia with Extravascular
Hemolysis
• Extravascular (reticuloendothelial system)
– Hereditary
• Hemoglobinopathies (sickle cell anemia)
• Enzymopathies (G6PD deficiency)
• Membrane defects (hereditary spherocytosis)
– Acquired
• Immune mediated
– Autoimmune hemolytic anemia
• Non-immune mediated
– Spur cell hemolytic anemia
– Paroxysmal nocturnal hemoglobinuria (PNH)

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Acquired Hemolytic Diseases
• Immune mediated hemolytic anemia
• Non-immune mediated

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Autoimmune Hemolytic Anemia
• Warm antibodies (IgG-mediated)
– Primary 45%
– Secondary 40%
• Lymphoproliferative disease
• Connective tissue disease
• Infectious disease
– Drug-induced 15%
• Laboratory testing
– Normocytic/macrocytic anemia
– Peripheral smear: spherocytosis

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Anti-Globulin (Coombs) Testing
Direct antiglobulin testing
Indirect antiglobulin testing
Patients RBCs
Patients serum
Anti-C3d
Anti-IgG
+
RBCs
+
Anti-IgG
+

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Spherocytes: Autoimmune Hemolytic Anemia

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Acquired Hemolytic Anemia
with Intravascular Hemolysis
• Mechanical damage (microangiopathy)
• Chemical damage
• Infection
• ABO incompatibility

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Non-immune hemolytic anemia
Microangiopathic Hemolytic Anemia
• Thrombotic thrombocytopenic purpura (TTP)
• Hemolytic uremic syndrome (HUS)
• Disseminated intravascular coagulation (DIC)
• Vasculitis
• Malignant hypertension
• Metastatic neoplasm with vascular invasion
• Preeclampsia/HELLP syndrome of pregnancy

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Schistocytes: Microangiopathic Hemolytic Anemia

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Hemolytic Anemia- Diagnostic tests
• Reticulocyte count is elevated
• Peripheral blood smear is helpful
• Blood chemistries
– Increase in unconjugated bilirubin
– Increase in lactate dehydrogenase
– Decrease in haptoglobin
• Spesific tests
– Coombs test; immune hemolytic anemia
– Paroxysmal nocturnal hemoglobinuria screening
– Hemoglobin electrophoresis
– Glucose-6-phosphate dehydrogenase levels
– Intravascular hemolysis;hemoglobinuria, hemosiderinuria

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Reticulocytosis
• Reticulocyte count is elevated
– Anemia + reticulocytosis ≥ 5% strongly suggests
the presence of hemolysis
– Other causes of reticulocytosis
• During the first 2 weeks of replacement therapy with
vitamin B12 or folic acid
• Acute hypoxia
• Infiltrative bone marrow disorders

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Autoimmune Hemolytic Anemia
• Autoantibodies reacts with erythrocytes.
– Warm antibody AIHA (≥ 370 C), Ig G antibodies
– Cold antibody AIHA (< 370 C), Ig M and
compleman antibodies
– Paroxysmal cold hemoglobinuria, Donath
Landsteiner autoantibody

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Microangiopathic Hemolytic Anemia
• Disseminated intravascular coagulation (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
• Hemolytic uremic syndrome (HUS)
Schistocyte

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Morphologic Approach
Red Blood Cell Size
• Microcytic; MCV < 80 fl
• Normocytic; MCV 80- 96 fl
• Macrocytic; MCV > 100 fl

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Morphologic Classification of Anemia
Microcytic
• Reduced iron
availability
• Iron deficiency
anemia
• Copper deficiency
• Anemia of chronic
disease
• Reduced globin
production
• Thalassemia
• Hemoglobinopathies
• Reduced heme
synthesis
• Sideroblastic anemia
• Lead poisining
Normocytic
• Acute post hemorrhagic
anemia
• Aplastic anemia
• Pure red cell aplasia
• Bone marrow
infiltration
• Bone marrow
suppression
• Hemolytic anemia
• Systemic diseases
Macrocytic
• Megaloblastic
• Cobalamin deficiency
• Folic acid deficiency
• Drug induced
(hydroxyurea,
methotrexate)
• Non-megaloblastic
• Hemolytic anemia
• Liver disease
• Hypothyroidism
• Myelodysplastic
syndrome

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Morphologic Classification
Anisocytosis Microcytosis
Macrocytosis Normocytosis

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Hemolytic Anemia
General examination Jaundice, pallor
Physical examination Spleen may be enlarged
Liver may be enlarged
Gallstones
Discoloration of the urine
Skeletal changes in congenital forms
Reticulocytes Increased
Bilirubin Increased (unconjugated)
LDH Increased
Haptoglobulin Decreased
Hemoglobinuria
Hemosiderinuria
Increased in intravascular hemolysis
Aşkın K. KAPLAN M.D.

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Symptoms and Signs- PNH
• Hemolysis
– Intravascular hemolysis of variable severity
• Hypercoagulable state
– increase in venous thrombosis in the hepatic,
other intra-abdominal, and peripheral veins
• Impaired hematopoiesis
• Predisposition to infections
Aşkın K. KAPLAN M.D.
PNH:Paroxysmal nocturnal hemoglobinuria

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Microangiopathic Hemolytic Anemia
TTP/ HUS
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Renal function abnormality
• Neurologic abnormalities, usually fluctuating
• Fever
• Normal PT, aPTT, fibrinogen
• Markedly increased LDH
• Direct Coomb’s test negative
• Increased serum indirect bilirubin
Easy to diagnose and treat if you think of it
Untreated TTP is deadly

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Disseminated Intravascular Coagulation

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Thank You

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Algorithm for the evaluation of hemolytic anemia
Algorithm for the evaluation of hemolytic anemia. (CBC = complete blood count; LDH = lactate dehydrogenase; DAT = direct antiglobulin test;
G6PD = glucose-6-phosphate dehydrogenase; PT/PTT = prothrombin time/partial thromboplastin time; TTP = thrombotic thrombocytopenic
purpura; HUS = hemolytic uremic syndrome; DIC = disseminated intravascular coagulation)
https://www.aafp.org/afp/2004/0601/p2599.pdf

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Anaemia