Hemolytic Anemias: Lecture Notes PDF

6/28/2024 Chapter 16 Hemolytic Anemias  PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY.  PowerPoints DO NOT cover the details needed for the Unit exam...

6/28/2024 Chapter 16 Hemolytic Anemias  PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY.  PowerPoints DO NOT cover the details needed for the Unit exam  Each student is responsible for READING the TEXTBOOK for Preamble details to answer the UNIT OBJECTIVES  Unit Objectives are your study guide (not this PowerPoint)  Test questions cover the details of UNIT OBJECTIVES found only in your Textbook! 1  6/28/2024  Common denominator in hemolytic anemias is premature erythrocyte destruction initiated primarily by trapping of cells in the sinuses of the spleen or liver (extravascular) or in the blood vessel (intravascular)  Intrinsic causes of hemolytic anemia:  Hemoglobin composition (hemoglobinopathy) Hemolytic  RBC membrane defects Anemia  RBC enzyme defects (HA) #1  Extrinsic causes of hemolytic anemia:  Vascular defects  Antibodies and/or complement  Infectious agents, such as bacteria or parasites  Toxins or mechanical devices  Other ways of organizing hemolytic anemia themes are as follows:  Inherited versus acquired Hemolytic  Intravascular versus extravascular Anemia  Immune versus nonimmune (HA) #2  Increased BM activity may compensate for RBC reduction, but if the BM fails to increase production, anemia develops.  Most anemias have a hemolytic component, and in anemias of marrow failure, the RBC is defective.  Hemolysis ranges from asymptomatic to life threatening. 2  6/28/2024 The Role of Complement in HA  Various mechanisms:  Classic pathway triggered by immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies coevolved with active immunity.  Mannose-binding lectin pathway triggered by carbohydrates found on bacteria associated with pathogen recognition receptors.  Alternative pathway constitutively activated by the slow spontaneous hydrolysis of the complement component, C3.  Thrombin that directly cleaves C3 and acts as a C5 convertase  Plasmin and kallikrein directly cleave C3 and its activation fragments.  Normally, complement proteins circulate in an inactive form.  Activation is tightly regulated by several membrane-bound and soluble complement regulatory proteins. Activation of  Conditions such as PNH and aHUS are caused by mutations and/or Complement autoantibodies that inactivate these regulatory proteins and activate complement via the alternative pathway.  Activation of complement via any pathway amplifies as it progresses and terminates with the formation of MAC. 3  6/28/2024 Classic Pathway  Classic pathway is one of the major effector mechanisms of antibody- mediated immunity.  Components included are C1 through C9:  Not in sequential order  C3 has the largest quantity  Three major stages:  Recognition  Amplification  Membrane attack complex (MAC)  C5bC6C7C8 complex polymerizes C9 to form a pore and accelerate the osmotic cytolytic reaction. Alternative Pathway  Shows similarity with the classic sequence.  In contrast to the classic pathway, which is initiated by the formation of antigen-antibody reactions, the alternate pathway is predominantly a non–antibody-initiated pathway. 4  6/28/2024 Mannose-Binding Lectin Pathway  Member of the calcium depending lectins, the collectins  Homologous in structure to C1q  Pattern recognition molecule of the innate immune system  Binds to arrays of terminal mannose groups in a variety of bacteria  Can be divided into:  Inherited disorders (intrinsic hemolytic anemia)  Acquired disorders (extrinsic hemolytic anemia)  Further subdivisions are based on the causative mechanism: Hemolytic  Site of destruction  Intravascular Anemia:  Extravascular Membrane Disruption 5  6/28/2024  Etiology  Inherited hemolytic disorders may affect the basic membrane structure, the erythrocytic enzymes, or the hemoglobin molecules within the red cell.  Structural Membrane Defects  The ability of RBCs to deform and return to the their biconcave disc Inherited shape is determined by:  Flexibility of the membrane Hemolytic  Cytoplasmic viscosity Anemia #1  Cell surface–to-volume ratio  Pathology arises by:  Altering the amount or function of the expressed proteins  Compromising the integrity of the membrane  Contribute to abnormal erythrocyte morphology Hereditary Spherocytosis Hereditary Elliptocytosis Most common hereditary HA Defect in membrane skeleton among Northern Europeans Nine clinical forms Loss of erythrocytic membrane Increase in oval and elongated Hereditary surface due to membrane protein defect red cells to greater then 25% Most patients have little to no Spherocytosis Hemolysis is extravascular in spleen hemolysis In symptomatic patients, and Decreased surface area-to- volume ratio changing the shape splenectomy may be indicated. Hereditary from discoid to spherocyte Elliptocytosis 6  6/28/2024  HPP is a rare autosomal recessive disorder, representing a subset of common hereditary elliptocytosis HE, seen primarily in blacks. Hereditary  Manifested in infancy or early childhood as a severe HA with significant poikilocytosis. Pyropoikilocytosis  Bizarre shapes are evident.  MCV range = 55 to 74 fL because of the prevalence of microspherocytes.  Hereditary xerocytosis is a permeability disorder.  In vitro, the thermal instability of spectrin suggests a defect in Hereditary qualitative spectrin abnormality. Xerocytosis  The net loss of intracellular K+ exceeds the passive Na+ influx, yielding a net Na+ gain. This causes the red cell to dehydrate. 7  6/28/2024 Seen in genetic hemoglobin defect, thalassemia and lead poisoning, HS and alcoholic cirrhosis Cation abnormality where rbcs contain increased Na+ and decreased K + Cells are uniconcave MCHC is usually decreased and MCV may be increased Anemia is usually mild to moderate Rhnull disease is also associated with the presence of stomatocytes Hereditary Stomatocytosis  Rh null disease, or Rh deficiency syndrome, is a rare hereditary Rh Null disorder causing mild, compensated chronic hemolytic anemia. Disease  This disorder is associated with stomatocytosis and spherocytosis. 8  6/28/2024 Dense contracted or spheroidal rbcs with multiple thorny projections or spicules Prevalent in two disorders: abetalipoproteinemia and spur cell anemia. Acanthocytes are a manifestation of the profound disturbances in plasma lipoprotein levels found in these disorders Moderate anemia may develop in your children but adults suffer only mild anemia Acanthocytosis All indices and osmotic fragility are normal  Spur cell hemolytic anemia  This form of acanthocyte-associated hemolytic anemia is seen in patients with established alcoholic cirrhosis. Other Forms  Neuroacanthocytosis of Hemolytic  Neuroacanthocytosis (NA) is a heterogeneous group of neurodegenerative disorders associated with acanthocytosis in Anemias peripheral blood. 9  6/28/2024  Disorders of erythrocyte metabolism can be grouped with congenital nonspherocytic hemolytic anemia (CNSHA)  Types:  Glucose-6-phosphate dehydrogenase (G6PD) Erythrocytic  Pyruvate kinase (PK)  Methemoglobin reductase Enzyme  Varying degrees of clinical presentation and severity Defects #1  G6PD enzyme is responsible for protecting the cell from oxidative stress. Glucose-6-  X-linked enzymopathy affects 400 million people worldwide. Phosphate  More than 400 variants of the enzyme have been identified by their biochemical properties. Dehydrogenas  Catalyzes the reaction: G-6-P + NADP  6-PG + NADPH e (G6PD)  Lab findings: Deficiency  Quantitative decrease in G6PD  Positive autohemolysis  Heinz bodies on PB smear 10  6/28/2024  Accounts for 90% of the inherited defects of glycolysis.  Inherited as autosomal recessive.  Pennsylvania Amish have the highest frequency, but it exists worldwide. Pyruvate Kinase  PK is involved in anaerobic glycolysis that generates ATP.  The loss of ATP produces loss of water and results in cell shrinkage and rigidity; this rigidity distorts the RBC causing hemolysis.  Laboratory findings:  Normocytic normochromic  Polychromasia  Elevated 2,3-DPG  Quantitative decrease in PK level  Hemoglobin with oxidized iron (ferric instead of ferrous) is called methemoglobin.  Hereditary deficiency of the enzyme NADH-methemoglobin Methemoglobin reductase (NADH diaphorase) results in increased methemoglobin. Reductase  Clinical presentation involves cyanosis because the methemoglobin Deficiency cannot carry oxygen to the tissues. 11  6/28/2024 Acquired Hemolytic Anemia #1 Acquired Hemolytic Anemia #2 12  6/28/2024 Acquired Hemolytic Anemia Immune Mechanisms (Antibodies)  AIHAs are caused by an altered immune response resulting in production of antibody against the patient’s own erythrocytes, with subsequent hemolysis. The definitive cause of autoantibody production is unknown. Autoimmune  Some unusual aspects of the epidemiology of AIHA are association Hemolytic with the following:  Blood transfusion Anemias  Immune hemolysis with allogeneic hematopoietic cell transplantation  Immune hemolysis with orthotopic solid-organ transplantation 13  6/28/2024 Warm-Type Autoimmune Hemolytic Anemia  Cold-type autoimmune hemolytic anemia  In AIHA, associated with cold-type autoantibody (e.g., cold Other Types of hemagglutinin disease), the erythrocytes are usually coated with IgM. Hemolytic  Warm- and cold-type autoimmune hemolytic anemias  AIHA associated with both warm and cold autoantibodies is mediated Anemia #1 by IgG warm antibodies and complement as well as IgM cold hemagglutinins. 14  6/28/2024  Isoimmune hemolytic anemia Other Types of  Drug-induced immune hemolytic anemia Hemolytic Anemia #2  Physical agents  DIC is one example of a microangiopathic hemolytic anemia.  Other examples of microangiopathies include the following: Microangiopathic  Thrombotic thrombocytopenic purpura (TTP) Red Cell  Hemolytic uremia syndrome (HUS) Destruction #1  HELLP syndrome (Hemolysis, Elevated Liver enzyme levels, Low Platelet count) 15  6/28/2024  Etiology  PNH is a rare, acquired, clonal blood disorder caused by a Paroxysmal nonmalignant clonal expansion of one or more stem cell Nocturnal lines. Hemoglobinuria  Pathophysiology  Mutations occur in a gene termed phosphatidylinositol (PNH) #1 glycan-A (PIGA) and result in the failure to present a large class of G protein–coupled receptors on the hematopoietic cell surface, which most protect the cell against complement binding.  Such markers include CD55 and CD59, among at least 14 others mentioned in the literature.  Epidemiology Paroxysmal  Twenty-five percent of cases will evolve into or from aplastic anemia.  Approximately 5% to 10% of patients will have terminal acute myelogenous Nocturnal leukemia. Hemoglobinuria  The median age of patients at diagnosis is 42 years (range, 16 to 75 years).  Median survival after diagnosis is 10 years. Spontaneous long-term remission (PNH) #2 can occur.  Clinical signs and symptoms  PNH begins insidiously in patients between the age of 30 and 60 years.  Irregular episodes of hemoglobinuria associated with sleep are a startling manifestation of this disorder. 16  6/28/2024  Laboratory findings  Most patients have severe anemia with hemoglobin concentrations less than 6 g/dL.  Peripheral blood smears may reveal hypochromic, microcytic red cells if an iron Paroxysmal deficiency state has developed owing to cell lysis.  Autohemolysis is increased after 48 hours, and hemolysis may increase with the Nocturnal addition of glucose to the test. Both the sucrose hemolysis (sugar-water) test Hemoglobinuria and Ham’s test (acid-serum lysis) are diagnostic procedures.  Hemosiderinuria, the excretion of an iron-containing pigment derived from (PNH) #3 hemoglobin on disintegration of red cells, is a classic manifestation of chronic intravascular hemolysis.  Flow cytometry is becoming more commonly used to detect the absence of pertinent CD markers.  The use of flow cytometry for immunophenotyping erythrocytes for the diagnosis of PNH is increasing.  Paroxysmal cold hemoglobinuria is the least common type of AIHA. Paroxysmal  It is transient and self-limiting but can produce serious hemolysis Cold of erythrocytes. Hemoglobinuria  It occurs almost exclusively in children in association with viral disorders. (PCH)  It is primarily due to a biphasic antibody (anti-P), primarily IgG in nature, that binds to RBCs in cold temperatures and induces hemolysis at body temperature.  Detected using the Donath-Landsteiner test. 17  6/28/2024  In most cases of CAD, the classical pathway does proceed to the Cold formation of the MAC complex, but intravascular hemolysis may occur Agglutinin in a minority of cases. Disease  CAD is classified as either primary or secondary.  Primary CAD: clonal B-cell lymphoproliferative disorder  Secondary CAD: syndrome associated with a variety of infections and neoplastic disorders such as aggressive lymphomas, Hodgkin’s lymphoma, and cancer  Treatment with rituximab (monoclonal antibody therapy) is effective.  READ the TEXTBOOK for the details to answer the UNIT OBJECTIVES. Postamble  USE THE UNIT OBJECTIVES AS A STUDY GUIDE  All test questions come from detailed material found in the TEXTBOOK (Not this PowerPoint) and relate back to the Unit Objectives 18