Hemolytic Anemia I PDF

Hemolytic Anemia Salah Eldin Khairallah, MD, PhD University of Tobruk, School of Medicine 2021-7-28  Pathophysiologic Classification of Anemia 1. Acute Blood Loss 3. Increased RBCs Destruction...

Hemolytic Anemia Salah Eldin Khairallah, MD, PhD University of Tobruk, School of Medicine 2021-7-28  Pathophysiologic Classification of Anemia 1. Acute Blood Loss 3. Increased RBCs Destruction A. Intracorpuscular 2. Decreased RBCs Production Membrane defect A. Stem cell and progenitor cell defects Enzyme defect Aplastic anemia Hemoglobinopathies Pure red cell aplasia B. Extracorpuscular Paroxysmal nocturnal hemoglobinuria A. Immunologic Leukemia and Myelodysplastic syndromes Autoimmune hemolytic anemia (AIHA) Myelophthisic anemia (Marrow infiltration) B. Nonimmunologic - Mechanical B. Anemia of chronic disease and chronic Macroangiopathies (cardiac renal disease prosthesis, marathon runner, bongo drummer) C. Ineffective Hematopoiesis Thrombotic microangiopathies (DIC, Iron deficiency TTP, HUS) Megaloblastic anemia (Vitamin B12 and - Hypersplenism folic acid deficiency - Infection (malaria) Thalassemia - Chemical Increased RBCs Destruction = H E M O L Y S I S Intra-corpuscular Extra-corpuscular 1. Membrane defect A.Immunologic  Hereditary spherocytosis Autoimmune hemolytic anemia (AIHA)  Hereditary elliptocytosis B. Nonimmunologic  PNH = Paroxysmal Nocturnal 1. Mechanical destruction of RBC Hemoglobinuria Macroangiopathies (cardiac prosthesis 2. Enzymopathy (Enzyme defect) Drillers, marathon runner and  G6PD deficiency bongo drummer  Pyruvate kinase deficiency 2. MAHA and Thrombotic microangiopathies (DIC, TTP, HUS) 3. Hemoglobinopathies 3. Hypersplenism  Sickle cell disease 4. Infection (malaria)  Hb-C disease 5. Chemical  HEMOLYSIS INTRA-vascular (vessels) EXTRA-vascular (spleen) Which one would be more likely to produce hemoglobinuria? ANSWER: INTRA-VASCULAR HEMOLYSIS Autoimmune Hemolytic Anemia “AIHA” This is the most common type of hemolytic anemia. It is an autoimmune destruction of RBC by the host own antibodies It may A. Idiopathic B. Secondary to other diseases C. Drug related It is divided into two main groups according to the temperature at which hemolytic reactions occur 1. Worm antibodies 2. Cold antibodies 1. ‘Warm’ antibody type : IgG autoantibody most reactive at 37°C leads to chronic anemia with microspherocytes RBC destruction and extravascular hemolysis @ the spleen. Clinically manifested as pallor, jaundice, and splenomegaly Autoimmune Hemolytic Anemia “AIHA” 2. ‘Cold’ antibody type Autoantibody is IgM and is most reactive at 4°C but it can still bind complement and agglutinate red cells at 30°C, the temperature of peripheral tissues (hands, feet, nose and ears). There is destruction of red cells by von Kupffer cells of the liver Clinical Features  Disorder is chronic and usually mild  Pallor  Cyanosis (blueness) and coldness of the extremities  Occasionally progressing to ischemia and ulceration  ’Warm’ antibody-type hemolysis: RBC membrane is modified and becomes a microspherocyte with consequences similar to hereditary spherocytosis AND early SPLENIC sequestration ’COLD’ antibody-type The antibody combines with RBC, resulting in agglutination (clinically presenting as painful hands and feet) e.g. Paroxysmal cold Hemoglobinuria Biochemistry of RBC membrane and Membrane Integrity maintenance Hereditary Spherocytosis Hereditary spherocytosis (HS) is a diverse group of inherited disorders of RBC cytoskeletons, in which - Spectrin OR - Another cytoskeletal component (ankyrin, protein 4.2, band 3) is deficient  Hereditary Spherocytosis (HS) Hereditary spherocytosis is an autosomal dominant disorder, some cases are autosomal recessive. Common in Northern Europe HS leads to intrinsic defect with extravascular hemolysis. Spherocytes are extravascularly removed by splenic macrophages, which causes normocytic anemia Laboratory Findings 1. Normocytic anemia with spherocytosis 2. Increased MCHC (Only anemia with an increase in MCHC).  Increased MCHC due to cellular dehydration from the loss of potassium and water Other causes of spherocytosis: warm IHA and ABO hemolytic disease of newborn  Hereditary Spherocytosis, Morphology Peripheral Blood Smear (PBS) Peripheral Blood Smear from a patient with normal morphology AD hererditary Spherocytosis showing spherocytes  Hereditary Spherocytosis (HS), Pathogenesis Membrane protein defect results in the loss of RBC membrane and volume, leading to Spherocytes formation 1. Mutation in spectrin is the most common defect. Mutations in ankyrin, band 3 or band 4, account for other defects 2. Microvesicles that form on the surface of the RBCs in the areas of membrane weakness are lost 3. In addition, this membrane defect will result in potassium and eventually water loss leading to cellular dehydration 4. Combination of microvesicle loss of cell membrane plus cellular dehydration yields spherocytes with a decreased surface to volume ratio  Hereditary Spherocytosis, Morphology Marrow Smear, Hemolytic Anemia Hereditary Spherocytosis, (HS) Bone marrow reveals increased RBC membrane changes numbers of maturing erythroid progenitors (normoblasts)  Hereditary Spherocytosis (HS), Clinical Feature 1. Jaundice commonly occurs because of increased unconjugated bilirubin “UCB” from splenic macrophage destruction of RBCs 2. In newborns, 30% to 50% develop a hemolytic anemia with unconjugated hyperbilirubinemia leading to jaundice 3. Incidence of calcium bilirubinate gallstones is increased (Cholilithiaisis) Increased liver conversion of excess amounts of UCB to conjugated bilirubin (CB), which is excreted in the bile CB is converted back to UCB in the gallbladder and combines with calcium to form the stones 4. Splenomegaly in 75% (due to hypertrophy from RBC hemolysis) 5. Aplastic crisis is uncommon but may occur in children, especially after a viral infection (e.g., parvovirus)  Hereditary Elliptocytosis “HE” Hereditary elliptocytosis (HE) is an inherited disorders affecting the erythrocyte cytoskeleton MOLECULAR PATHOGENESIS HE is characterized by elliptical or oval red blood cells, mainly attributed to defects in self-assembly of:  Spectrin  Spectrin – ankyrin binding  Protein 4.1 and glycophorin C RBCs have an area of central pallor, since there is no loss of the lipid bilayer (as seen in HS) Most forms of HE are autosomal dominant Hereditary elliptocytosis (HE), MORPHOLOGY & CLINICAL FEATURES HE is more common in malaria endemic regions of West Africa HE can be totally asymptomatic Mild normocytic anemia Peripheral Blood Smear “PBS” will reveal many elliptocytes with only minimal reticulocytosis Generally, less hemolysis compared with HS  RBC Enzyme Defects (E r y t h r o c y t e s E n z y m o p a t h i e s) RBC enzyme defects (erythrocytes enzymopathies) include: A. Glucose-6-Phosphate Dehydrogenase Deficiency “GPD Deficiency =G6PD” B. Pyruvate Kinase Deficiency “PKD  Glucose-6-Phosphate Dehydrogenase Deficiency “GPD Deficiency” Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive (XR) disorder Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in human being with highest prevalence is in the Middle East, Greece, Italy, and Asia This intrinsic enzymopathy predominantly escalates to intravascular hemolysis and mild to moderate extravascular hemolysis as well Subtypes of G6PD deficiency A. Mediterranean variant B. Black variant (occurs in 10% of blacks). Protective against P. falciparum malaria Hexose Monophosphate Shunt (HMP) and Hexokinase (Pyruvate Kinase) Pathways  Pathogenesis of G6PD deficiency Decreased synthesis of the reduced form of nicotinamide adenine dinucleotide phosphate (NADP) (NADPH) and glutathione (GSH) in the pentose phosphate pathway “HMP Shunt (Hexose Monophosphate Shunt = Pentose Phosphate Pathway “PPP” GSH normally neutralizes H2O2, an oxidant product in RBC metabolism Heinz bodies In G6PD deficiency, H2O2 oxidizes Hb, which precipitates in the form of Heinz bodies  Pathogenesis of G6PD deficiency Heinz bodies damage the RBC membranes, causing intravascular hemolysis Heinz bodies Heinz bodies are removed from RBC membranes by splenic macrophages, producing bite cells Half-life of G6PD in Mediterranean variant is markedly reduced (80% of the deaths in children are due to malaria. Over 50% of reported cases of deaths are typically due to P. falciparum related to immigrant population or travelers or troops returning from an endemic area Pathogenesis of Malaria Plasmodium falciparum Malaria, Intra-erythrocytic parasite causes intravascular PBS. A characteristic heavy parasite hemolysis. Hemolysis correlates with the fever spikes load which might lead to hemolysis Minor component of extravascular hemolysis  Liver Skin Malaria Life Cycle life cycle of plasmodia in humans RBC Plasmodium falciparum ring forms in RBCs Mature gametocyte of P. falciparum Note there is two ring forms. Multiple The presence of this sausage-shaped infestations of an RBC are characteristic of form is diagnostic of P. falciparum malaria P. falciparum malaria  Malaria, Clinical Findings Clinical findings are mainly fever and splenomegaly Plasmodium vivax Most common cause of Plasmodium malariae Plasmodium falciparum malaria worldwide Duffy (Fy) antigen on (malignant tertian malaria) Association with RBCs is the binding site Most lethal type of nephrotic syndrome for the parasite. malaria Simple quartan fever Fy antigen is often Quotidian (malignant pattern (every 72 absent in blacks (what is tertian) fever pattern hours) the benefit) (daily spikes with no Simple tertian fever pattern pattern (every 48 hours)  Malaria, Fever patterns 1.Simple tertian fever occurs every 48 hours (Plasmodium vivax) 2.Simple quartan fever occurs every 72 hours (Plasmodium malariae) 3.Malignant tertian fever spikes daily but has no pattern (P. falciparum)  Malaria, Laboratory Finding THICK and not THIN smears identify organisms in RBCs Immunologic tests have excellent sensitivity (98%) and specificity (99%) Medications of Malaria A. Prophylaxis (prevention): Chloroquine (safe during pregnancy) B. Prophylaxis for resistant strains of P. falciparum: Atovaquone-proguanil is recommended, Mefloquine is an alternative C. Treatment P. vivax/ovale: Chloroquine plus primaquine D. Treatment P. falciparum: Chloroquine sensitive: chloroquine without primaquine E. Chloroquine resistant: quinine sulfate + doxycycline Pathophysiological Taxonomy of Various Subtypes Of Anemias “A SUMMARY”  Thrombotic Microangiopathy and Macroangiopathic Hemolytic Anemia (MAHA) Microangiopathic 1. Platelet thrombi: Hemolytic Uremic Syndrome Thrombotic Thrombocytopenic Purpura “TTP” 2. Fibrin thrombi Disseminated intravascular coagulation HELLP syndrome: H: Hemolytic anemia; EL: Elevated Transaminases; LP, Low Platelets; associated with preeclampsia Macroangiopathic Thrombotic Microangiopathies Aortic stenosis (most common cause) Fragmented red blood cells, or schistocytes Prosthetic heart valves (arrows), in the peripheral blood. Marathon runner Note their helmet-like appearance Bongo drummer  Hemoglobinopathies and Hemoglobin (Hb) Electrophoresis Hemoglobin Electrophoresis, MWM 1 Hgb A Cellulose Acetate Hgb F Hgb S Lane 1 is an infant with sickle cell anemia Hgb S Hgb S (hemoglobin S [Hgb S]) and significant Hgb F 2 3 production 4 Lane 2 homozygous Hgb C disease Hgb C Lane 3 heterozygous Hgb C disease Lane 4 sickle cell trait Hgb C  Hemoglobin (Hb) Electrophoresis Hb electrophoresis is used to detect hemoglobinopathies, which include: 1. Abnormalities in globin chain structure (e.g., sickle cell disease) 2. Abnormalities in globin chain synthesis (e.g., thalassemia) Types of normal Hb detected in human being: 1. HbA1 has 2α/2β globin chains (97% in adults) 2. HbA2 has 2α/2δ globin chains (2% in adults). 3. HbF has 2α/2γ globin chains (1% in adults). Examples of abnormal Hb detected include: Sickle Hb, HbH, and Hb Bart  Hemoglobinopathies Hemoglobinopathies are hemolytic anemias caused by genetically determined abnormalities of hemoglobin structure Two themes are observed: i. Abnormalities in globin chain structure (e.g., sickle cell disease and Hb C) ii. Abnormalities in globin chain synthesis (e.g., thalassemia) Types of Hemoglobinopathies 1. Hemoglobin S (commonest hemoglobinopathies) 2. Hemoglobin C 3. Hemoglobin E 4. Hemoglobin H (3 genes deletion in α-thalassemia)