L-3 Hemolytic Anemia

• Hemolytic Anemia is a form of anemia caused by hemolysis, the abnormal breakdown of red blood cells.
• Hemolysis can occur in the blood vessels or elsewhere in the body.
• It commonly occurs within the spleen but can occur in the reticuloendothelial system or mechanically.
• Hemolytic anemia accounts for 5% of all existing anemias.
• Hemolytic anemia can range from general symptoms to life-threatening systemic effects.
• The general classification of hemolytic anemia is either intrinsic or extrinsic.
• Treatment depends on the type and cause of the hemolytic anemia.

Common Hemolytic Anemias

• Hereditary Spherocytosis: Inherited intrinsic defect in the red blood cell membrane.
• Sickle Cell Anemia: Inherited defect in the hemoglobin molecule B globin chain.
• Thalassmia: Inherited disorders in globin genes that decrease the synthesis of alpha or beta globin.
• Glucose -6 -Phosphate Dehydrogenase Deficiency (G6PD) is caused by exposure to toxins, drugs, and infectious agents.
• Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired mutation in the PIGA gene (phosphatidylinositol glycan).
• Immunohemolytic Anemia is caused by antibodies that bind to determinants on the red cell membranes induced by exogenous agents, drugs, or chemicals.

Hemolytic Anemia Classifications

• Extrinsic causes (Extra corpuscular): -Antibody mediated: Transfusion reaction disease of the newborn. -Autoantibodies: Drug associated. -Mechanical trauma to RBCs, defective cardiac valves. -Disseminated intravascular coagulation (blood clots throughout the body). -Infections: Malaria.
• Intrinsic causes (Intra corpuscular): -Membrane abnormalities (hereditary spherocytosis). -Enzyme deficiencies (glucose 6 phosphate dehydrogenase deficiency). -Disorders of hemoglobin synthesis (sickle cell disease). -Deficient hemoglobin synthesis (thalassemia syndromes). -Acquired intrinsic red cell membrane defect (paroxysmal nocturnal hemoglobinuria PNH).

Intravascular Causes in Red

• Within the red cell: -Membrane defects: -HS -HE -Hereditary pyropoikilocytosis -Hereditary stomatocytosis -Enzyme defects: -G6PD -Pyruvate kinase -Hemoglobin defects: -SCA -Thalassemis -Unstable hemoglobin
• Outside the red cell: -Auto-Immune -Warm -Cold -Transfusion reactions -Drug associated -Non-Immune -Hypersplenism -Fragmentation Syndromes -Grafts/Valves/AS -HTN/Pre-eclampsia -March hemoglobinuria -MAHA -TTP/HUS -DIC -Hemangioma -Infections/Toxins (Malaria, Babeosis,Bartonella, Clostridium welchii, snakes, spiders) -Drugs -Liver dz (spur cell) -PNH

Clinical Approach to Classifying Hemolytic Anemias: Extravascular (spleen)

• Extravascular Hemolysis is caused by defects that increase destruction of RBCs by phagocytes, in the spleen.
• Hyperbilirubinemia and jaundice can result from the degradation of hemoglobin in macrophages. This can result in: -Splenomegaly -Cholelithiasis with bilirubin rich gall stones.

Clinical Approach to Classifying Hemolytic Anemias: Intravascular Hemolysis

• Red blood cells explode within the circulation due to injury to the RBC membrane.
• Causes include turbulence due to defective heart valve defects, bacterial toxins, heat shock, and complement fixation.
• Intravascular hemolysis can be identified from extravascular hemolysis based on: -Hemoglobinemia: elevated levels of hemoglobin in the blood. -Hemoglobinuria: elevated levels of hemoglobin in the urine. -Hemosiderinuria: elevated levels of hemosiderin in the urine.
• The clinical condition also results in a loss of iron.

Clinical Features of Hemolytic Anemia

• Weakness, dizziness
• Fever, weight loss, fatigue
• Pallor
• Jaundice
• Dark Urine
• Gallstones
• Splenomegaly
• Extramedullary hematopoiesis
• Thinning of cortical bone.

Laboratory Features of Extravascular and Intravascular Hemolysis

• Extravascular Hemolysis: -Hyperbilirubinemia> Jaundice -Cholelithiasis with bilirubin-rich gallstones -Splenomegaly -Decreased serum haptoglobin
• Intravascular Hemolysis: -Hemoglobinemia -Hemoglobinuria -Loss of Iron -Hemosiderinuria -Decreased serum haptoglobin

Laboratory Values in Hemolytic Anemia

• Hemoglobin and Hematocrit are usually low.
• Hemoglobin: Iron-rich protein that carries oxygen.
• Hematocrit measures how much space red blood cells (RBCs) take up in the blood.
• Mean Corpuscular Volume (MCV) measures the average size of RBCs.
• Coombs test: Identifies if antibodies are produced to destroy RBCs.
• Haptoglobin combines with hemoglobin, therefore a low level of haptoblobin is a sign of hemolytic anemia.
• When Hemoglobin is broken down to bilirubin, increased levels may signal hemolytic anemia.
• Hemoglobin electrophoresis.
• Osmotic fragility test looks for RBCs that are more fragile than others, as seen in Hereditary spherocytosis and Thalassemia.
• G6PD, (Glucose 6 phosphate dehydrogenase) deficiency
• Urine test for hemoglobin

Laboratory Tests In Hemolytic Anemia

• Haptoglobin: Decreased Binding of free hemoglobin.
• Lactate dehydrogenase: Elevated - Released from lysis of red blood cells.
• Peripheral blood smear: Abnormal red blood cells - Based on cause of anemia.
• Reticulocyte count: Increased - Marrow response to anemia
• Unconjugated bilirubin: Increased - Increased hemoglobin breakdown
• Urinalysis: Shows Urobilinogen presence, positive for bood, free hemoglobin and its metabolites

Pathogenesis of Hereditary Spherocytosis

• Inherited defects in the RBC cell membrane proteins stabilize the lipid layer (spectrin, ankyrin, and band3).
• These mutations in the membrane result in spherocytosis.
• Splenectomy corrects the anemia, but the spherocytosis persists.
• Clinical findings include splenomegaly, typically between 500-1000 grams. A normal spleen weighs approximately 200 grams.
• Other clinical presentations are Anemia, splenomegaly, and jaundice
• Parvovirus marked tropism for RBCs > increasedosmotic fragility
• Marrow may become depleted of RBCprogenitors increasing the anemia and requiringtransfusions.

Hemolytic Anemias causing Increased Destruction

• Abnormal HgB qualitative: Sickle Cell Anemia.
• Abnormal HgB quantitative: Alpha and Beta Thalassemia.
• Enzyme defects: G6PD and PK deficiency.
• Membrane defects: Elliptocytosis and Hereditary Spherocytosis.
• Acquired hemolytic anemia: PNH.
• TTP, Thrombotic Cytopenia Purpura.

Sickle Cell Anemia

• A hemoglobinopathy, hereditary disorder caused by inherited mutations that lead to structural abnormalities in hemoglobin most commonly seen as a familial hemolytic anemia.
• Occurs in 1 of about 350 African Americans and can affect people of any race or ethnicity.
• Caused by a mutation in B-globin chains that leads to sickle deoxygenated hemoglobin (HbS).
• Pathogenesis: Single amino acid substitution in B globin chains resulting in deoxygenated hemoglobin leading to distortion of red blood cell shape.
• Normal hemoglobin is tetramers composed of 2 pairs of of similar chains, alpha and beta (96%HbA (alpha2beta2) and 1% fetal HbF, and HgA2.
• In patients with HbS, it completely replaces HbA with HbS.
• Heterozygous carriers (trait) only half is replaced by HbS.
• HbC, is another mutant Beta-globin that has a lysine residue instead of the normal glutamic acid residue at position 6. Produces the sickle cell trait but not the disease with only minimal sickling.

Oxyhemoglobin Dissociation Curve

• Left Shift -Decreased unloading of O2 at tissue level -Increased affinity -Increased H+ (alkalosis) -Decreased temperature -Decreased 2,3-diphosphoglycerate: -Stored red blood cells
• Right Shift -Increased unloading of O2 at tissue level -Decreased affinity -Increased H+ (acidosis) -Increased temperature -Increased 2,3-diphosphoglycerate: -Pregnancy -Chronic Anemia -Arterial Hypoxaemia -Hb variants -Fetal haemoglobin -Methaemoglobin -Carboxyhaemoglobin -Carbon monoxide poisoning -HypophosphataemiaSickle Cell Anemia follows this curve

Clinical Manifestations of Sickle Cell Anemia

• Sickle cell: 2 major consequences of red blood cell sickling: -Severe Hemolytic Anemia as a result of red blood cell membrane damage. -Vascular Obstruction resulting in ischemia and pain.
• Clinical Features: Unremitting course with crisis -Hand-foot syndrome as a result of ischemia -Acute chest syndrome as a result of sluggish blood flow -in pulmonary circulation -Stroke: a leading cause of death -Retinopathy -Aplastic crisis (parvovirus infection)

Sickle Cell Trait

• Sickle cell trait, is not considered a genetic disorder or disease.
• Affects 1 million to 3 million Americans.
• The affected typically live normal lives without showing signs or symptoms.
• Affects many races and ethnicities - over 100 million individuals, worldwide.
• Carry one gene, compared to two genes in patients with sickle cell anemia.
• Electrophoresis shows HbA 60% and HbS %.

Basic Laboratory Findings in Sickle Cell Anemia

• 5-50%Sickled red blood cells.
• Low hemoglobin: 5-10 gms/dl (Normal 14-18M, 12-15F)
• HgA 0%, HbS 90%
• Increased reticulocytes, platelets, and leukocytes.
• Routine DNA screening required.
• The substitution of valine by glutamic acid in Beta chains results in decreased mobility of HbS in the electric field, compared to HbA.
• Because of less negative charge of Beta-globin chains.

Basic Treatment Principles of Sickle Cell Anemia

• Hydration
• Oxygenation
• Pain Management
• Blood Transfusions
• Bone Marrow Transplant
• Hydroxyurea
• Herbal remedies
• Nutraceuticals
• Dietary
• Lifestyle