Introduction to Hemolytic Anemias

HEMOLYTIC ANEMIAS Introduction Definition Pathogenesis Classification General clinical features Laboratory evaluation of hemolysis

Hemolytic Anemias Definition A group of disorders leading to anemia caused by a reduction in red cell life span. RBC’s normally survive 60 - 120 days . Bone marrow has the capacity to increase erythropoiesis 6 - 8 times than normal. Anemia is the result of premature destruction of red cells exceeding the erythropoietic capacity of the bone marrow.

Hemolytic Anemias Classification Hemolytic anemias may be classified as I- Hereditary or acquired or II- Intracorpuscular or Extracorpuscular

Hemolysis may occur in two compartments I- Intravascular or II- Extravascular ( eg: spleen )

Unconjugated bilirubin Expired CO Kidney Red cell destruction Extravascular Intravascular Free plasma Hb RES Hpt and Hpx Hb Globin Haem+globin methem Haem Hb- Hpt complex Plasma protein pool Haemopexin-methem Excess Hb methaemalbumin Plasma iron pool Liver Protoporphyrin Unconjugated bilirubin Expired CO Kidney metHb Liver Hb Haemosiderin Conjugated bilirubin GI tract Urine Urobilinogen Faeces

In some types of hemolytic anemias hemolysis occurs particularly as an intravascular hemolysis. eg: Paroxsysmal nocturnal hemoglobinuria Traumatic or microangiopathic hem. anemia (eg:cardiac hemolytic anemia,march hemoglobinuria,TTP) Acute hemolytic transfusion reaction etc

A Simple Classification of Hemolytic Anemias 1- Abnormalities of RBC interior a. Enzyme defects b. Hemoglobinopathies & Thalassemia Maj 2-RBC membrane abnormalities a. Hereditary spherocytosis, elliptocytosis etc b. Paroxysmal nocturnal hemoglobinuria c. Spur cell anemia 3- Extrinsic factors a. Hypersplenism b. Antibody : immune hemolysis c. Traumatic & Microangiopathic hemolysis d. Infections , toxins , etc Hereditary Intracorpuscular Acquired Extracorpuscular

Clinical Manifestations in Summary Onset may be acute or insidious Symptoms and signs of anemia Jaundice Acholuric Without pruritus Symptoms and signs spesific to the type of hemolytic anemia Symptoms related to the underlying disease Splenomegaly Most congenital hem. anemias except sickle cell Some of the acquired hem. anemias Cholelithiasis (gall stones) symptoms Leg ulcers (sickle cell, spherocytosis) Skeletal abnormalities (thalassemia) Crises (chronic hemolytic disease) Aplastic crises (HPV-B19) Hemolytic Megaloblastic Changes in urine color

Laboratory findings I- Increased RBC destruction Decreased RBC life span Increased haem(heme) catabolism Increased serum unconjugated bilirubin* Increased endogenous CO production Increased urobilinogen excretion Increased serum LDH* Absence or decrease of serum haptoglobin* > 1 g /dl /week fall in blood Hb level* Reduced glycosylated Hb Signs of intravascular hemolysis Hemoglobinemia* Hemoglobinuria* Hemosiderinuria* Methemalbuminemia Reduced serum hemopexin level *common practice

Laboratory findings II-Increased bone marrow activity and RBC production Blood Reticulocytosis Macrocytosis Polychromatophilia Erythroblastosis Leukocytosis and thrombocytosis Bone marrow Erythroid hyperplasia Ferrokinetic Increased plasma iron turnover Increased RBC iron turnover Biochemical Increased RBC creatine Increased activity of RBC enzymes eg: hexokinase, etc

Laboratory Evaluation of Hemolysis Extravascular Hematologic Blood film Polychromatophilia Reticulocyte Increased Bone marrow Erythroid hyperplasia Plasma or serum Bilirubin unconjugated Haptoglobin , absent Plasma free Hb N - LDH Urine Bilirubin 0 Hemosiderin 0 Hemoglobin 0 Urobilinogen Intravascular Polychromatophilia Increased Erythroid hyperplasia unconjugated absent + + ( severe cases)

Laboratory tests useful in differential diagnosis Examination of peripheral blood Special Lab. examinations

Morphologic abnormalities in hemolytic anemias Polychromasia Spherocyte : Elliptocytes: Stomatocytes: Acanthocytes: Echinocytes: : Reticulocytes Her. Spherocytosis, immune hem. anemia, burns, chemical injury to RBC Hereditary ovalocytosis, Hereditary stomatocytosis, alcoholism Spur cell anemia with liver disease, abetalipoproteinemia Pyruvate kinase deficiency, uremia

Morphologic abnormalities in hemolytic anemias Sickle cell: Target cels: Schistocytes: Agglutination: Heinz bodies: Sickle cell anemia Thalassemia, HbC disease, liver disease, splenectomy Microangiopathic hem anemia, uremia, DIC, malignant hypertesion, eclampsia, disseminated vasculitis or malignancy, Cold agglutinin disease Unstable Hb, G6PD deficiency and oxidant stress

Bite cells -Blister cells G6PD deficiency Unstable Hemoglobin

RBC fragmentation Helmet Cell, schistocytes Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic uremic syndrome (HUS) Disseminated Intravascular Coagulation Vaskulitis Renal graft rejection Malignant hypertention Burns Artificial cardiac valves March hemoglobinuria

Target cells Liver disease Thalassemia Hb C Splenectomy Sickle cell anemia Iron deficiency

Howell-Jolly bodies (Nuclear remnants) Splenectomy Hyposplenism Megaloblastic anemia Hemolytic anemia (Nuclear remnants)

Ribosomes/RNA/mitochondrial bodies Basophylic stippling Lead poisoning Thalassemia, Unstable hemoglobines MDS Megaloblastic anemia Other hemolytic anemia Eg. 5-Nucleotidase deficiency Ribosomes/RNA/mitochondrial bodies

Heinz Bodies (Denaturated Hemoglobin) RBC Enzyme defects Unstable hemoglobin Thalassemia Sickle cell anemia (Denaturated Hemoglobin)

Special Lab. Examinations Coombs antiglobulin test - immune hemolysis Osmotic fragility test - spherocytosis Autohemolysis- G6PD,PK, spherocytosis Membrane protein analysis- membrane defects Red cell sickling- sickle cell anemia Hemoglobin electrophoresis and HbA2, Hb F , HHb,etc - Hemoglobinopathies and thalassemias Red cell enzyme assays- RBC enzyme defects HAM and sucrose lysis tests and GPI-linked protein analysis by flow cytometry- PNH Oxygen dissociation curve- High oxygen affinity Hb

Diagnostic approach Is there anemia? Detailed history including disease related symptoms, bleeding, drugs,ethnics, occupation , toxic exposure etc. family history Physical exam.: Signs of hemolytic anemia (common and specific ) in addition to anemia and any signs of underlying disease

Diagnostic approach What are the changes in red cell morphology? Smear examination Red cell indexes Are there any changes in other cell lines ? Is there evidence of increased red cell production? Reticulocytes Is there evidence of hemolysis? What is the type/diagn. of hemolysis? Special tests Is there evidence of intravascular hemolysis?