Hemolytic Anemia Lecture Notes PDF

PAT Hemolytic Anemia ADRIAN...

PAT Hemolytic Anemia ADRIANA 1. describe classifications of haemolytic anaemia (hereditary vs. acquired; intravascular vs. extravascular). 2. describe causes (intravascular and extravascular) and clinical manifestations / complications of haemolytic anaemia. 3. describe laboratory findings in haemolytic anaemia according to: i) features of increased red cell breakdown; ii) features of increased red cell production; iii) damaged red cells. 4. describe pathogenesis, clinical features and diagnosis of disorders that cause haemolytic anaemia (glucose-6-phosphate dehydrogenase [G6PD] deficiency, autoimmune haemolytic anaemia [AIHA], hereditary spherocytosis [HS]). HEMOLYTIC ANEMIA High rate of RBC destruction (hemolysis) RBC lifespan is I matured into erythrocytes Hallmarks: reticulocytosis & erythroid hyperplasia CLASSIFICATION HEREDITARY ACQUIRED Membrane defects Immune haemolytic anaemia Hereditary spherocytosis Autoimmune Hereditary elliptocytoses o Warm AIHA, Cold AIHA South-East Asian ovalocytosis Alloimmune o Haemolytic transfusion o Haemolytic disease of newborn o Allografts (esp marrow transplant) Drug associated RBC metabolism defects Red cell fragmentation syndrome G6PD deficiency Infections Chemical/ physical agents synthesis Secondary hemolytic anaemia in hemoglobin ( t ) Detect - thalassemia sickle-cell anaemia Paroxysmal nocturnal - haemoglobinuria ( intravascular ) > anaerobic glycolysis > EPO release from kidney > brown urine EXTRAVASCULAR HEMOLYSIS INTRAVASCULAR HEMOLYSIS DEFINITION Defects that increase the RBC destruction by macrophages in spleen RBC burst/ lyse in the circulation d/t mechanical forces, biochemical/ physical agents that damage the RBC membrane FINDING Hyperbilirubinemia & jaundice – d/r degradation of Hb in Hemoglobinemia macrophages Hemoglobinuria Splenomegaly Hemosiderinuria Bilirubin-rich gallstones (pigment stones) Loss of iron High risk of cholelithiasis Low haptoglobin – binds to free Hb à removed from the circulation Low haptoglobin LABORATORY FINDING CLASSIFICATION FEATURES OF ↑ RBC BREAKDOWN FEATURES OF ↑ RBC PRODUCTION DAMAGED RBC ↑ serum bilirubin Reticulocytosis Morphology ↑ urine urobilinogen Bone marrow erythroid hyperplasia Osmotic fragility ↑ faecal stercobilinogen Specific enzyme, protein & DNA test Absence of serum haptoglobin Heme biting uwbilin stereo y 4 Bilivetdin stercobilinogen d Urobilinogen ^ Bilirubin I t liver BDA t I conjugated bilirubin - → BMG by UDP - gluuuronate  HEREDITARY HEMOLYTIC ANEMIA FEATURES INVESTIGATION LAB FINDINGS TREATMENT Autosomal Osmotic fragility test: curved shifted to Spherocytes are dark red & lack of Blood transfusion dominant (minor: right central pallor Folate TDMA ? autosomal o In hypotonic salt solutions à Hyperchromic spherocytes Splenectomy – recessive) spherocytosis show increase in Compensatory hyperplasia of RBC principal. Try to avoid Anemia osmotic fragility progenitors in marrow d/t risk of post- Reticulocytosis Direct antiglobulin (Coomb’s) test – Howell-Jolly bodies (small nuclear splenectomy infection Jaundice negative remnants) o Improve anemia Splenomegaly Eosin-5-maleimide (EMA) binding test – low bcs of removal *common fluorescent of major RBC Cholelithiasis o EMA binds to band 3 à flow destruction cytometry measure the fluorescent HEREDITARY SPHEROCYTOSIS intensity ↑ unconjugated bilirubin & LDH Inherited Inherited defects in the membrane skeleton which stabilized the phospholipid bilayer of RBC (intrinsic) defects Spectrin is the major membrane skeleton protein – long, flexible heterodimer that self-associates at one end, & in RBC à binds with actin at its other end spherocytes o This interaction allows connection to the transmembrane protein band 3 & glycophorin thru linker proteins formation, ankyrin, band 4.2 & band 4.1 nondeformable cells, which is G- lycophorih highly vulnerable to sequestration (removal) & destruction in spleen Vertical interaction b/w membrane Destabilized the lipid shed membrane Little cytoplasm is lost Mutation in ankyrin, skeleton & RBC bilayer --> loss of RBC vesicles into the --> decrease surface Cells become spherical band 3, spectrin membrane proteins is membrane circulation area:volume ratio ( ASB ) weaken Similar to HS, usually milder Failure of spectrin heterodimers to self- PBF – elliptocytosis Homozygous/ doubly heterozygous associate into heterotetramers ELLIPTOCYTOSES present w/ severe hemolytic anemia !/ $-spectrin mutants leads to defects in HEREDITARY w/ microspherocytes, poikilocytes, o Spectrin dimer formation splenomegaly o Spectrin-ankyrin interaction o Protein 4.1 deficiency/ abnormality OVALOCYTOSI SOUTH-EAST Malaysia, Indonesia, Philippines Deletion of 9 AA at the junction of PBF – ovalocytosis ASIAN Rigid & resist malarial infection the cytoplasmic & S Mostly not anaemic transmembrane domains of band Asymptomatic 3 protein X – chromosome – affects male, Between crises the blood count is normal Stop the underlying carried by female During haemolytic crises causes of oxidant Resistance to Falciparum malaria o Blood film: bite cell, blister cell, fragmented cell, Heinz stress (drugs/ treat Acute hemolytic anemia d/t oxidant bodies in reticulocyte preparation infection) G6PD DEFICIENCY stress (drugs, fava beans o Intravascular hemolysis features Blood transfusion Neonatal jaundice o G6PD level during acute haemolysis may give false positive Phototherapy for Congenital non-spherocytic d/t high enzyme in young RBC baby hemolytic anemia (rare)  ACQUIRED HAEMOLYTIC ANAEMIA FEATURES PATHOGENESIS LAB FINDINGS TREATMENT AUTOIMMUNE HAEMOLYTIC ANAEMIA Due to antibodies that bind to RBC determinants The AB arise spontaneously/ induced by exogenous agents such as drugs, chemicals Uncommon Chronic mild anemia Haemolysis results from the Extravascular hemolytic Remove underlying cause Moderate binding of high-affinity anaemia features Corticosteroids splenomegaly autoAB to RBC à removed PBF – spherocytosis Monoclonal AB – anti CD20 (rituximab) WARM AIHA Tends to remit & from the circulation by DAT – positive Splenectomy relapse phagocytes Immunosuppression therapy When occur with Part of the coated membrane Folate idiopathic is lost à cell become more Blood transfusion thrombocytopenic spherical to maintain the purpura (ITP) à Evan’s same volume à prematurely Syndrome destroyed in spleen Caused by IgG – active at 37C  AIHA PRIMARY SECONDARY WARM Idiopathic SLE Drugs (! – methyldopa) o Induce autoAB against RBC particularly Rh antigens COLD Idiopathic Infections – Mycoplasma pneumonia, Lymphoma Paroxysmal cold haemoglobinuria IgM autoAB attaches to RBC in peripheral Primary cold agglutinin Paroxysmal cold haemoglobinuria circulation where blood temperature is Chronic haemolytic anaemia Rare cooled Often with intravascular haemolysis Acute intravascular haemolysis IgM autoAB: monoclonal (e.g primary Mild jaundice, splenomegaly, acrocyanosis d/t after exposure to cold cold agglutinin)/ polyclonal (e.g infection) agglutination of RBC in small vessel Caused by IgG (Donald-Lansteiner COLD AIHA PBF: RBC agglutinate IgM best at 4C – high efficient at fixing AB) against P blood group antigen DAT: complement +ve complement à both intra/ extravascular Predisposing factor: viral infection Similar to warm AIHA hemolysis may occur Indolent. May transform to aggressive lymphoma Usually self-limiting Only complement factors can be detected TREATMENT on RBC in lab test as IgM eluted off (cair) as Keep patient warm RBC flow thru warmer parts of circulation Alkylating agents Rituximab Splenectomy Corticosteroid DRUG Penicillin – AB directed against a drug-red cell membrane complex INDUCED Quinidine – Deposition of complement via a drug-protein (antigen)-AB complex into RBC surface IMMUNE HA Methyldopa – autoimmune AB binds to RBC RED CELL FRAGMENTATION SYNDROMES INFECTIONS Precipitate acute haemolytic crisis in G6PD deficiency Meningococcal septicaemia Malaria – intra & extravascular haemolysis Clostridium perfringes – intravascular haemolysis CHEMICAL & PHYSICAL Drugs (sulfasalazine, dapsone) à oxidative intravascular haemolysis w/ Heinz body AGENTS High copper in blood in Wilson’s disease à acute haemolytic anaemia Chemical poisoning (lead, chlorate, arsine) à severe haemolysis Burns à spherocytosis/ acanthocytosis SECONDARY HAEMOLYTIC In liver disease, haemolysis occur: ANAEMIA o Zieve’s syndrome – alcohol intoxification o Wilson’s disease – copper oxidation of RBC membrane o Some chronic immune hepatitis – AIHA o End-stage liver disease – d/t abnormal RBC membranes resulting from lipid changes in kidney disease, haemolysis occur due to HUS/ TTP PAROXYSMAL NORCTURNAL HAEMOGLOBINURIA X -linked Mutation in PIGA – gene required for PIP Flowcytometry loss of Eculizumab Chronic intravascular synthesis expression of CD55 & Iron therapy haemolysis – PIP acts as a membrane anchor for many CD59 Stem cell transplant - definite haemosidenuria, free Hb proteins damage the kidney RBC is sensitive to lysis by the complement Venous thrombosis C5b-C9 membrane attack complex Complication: thrombosis  PIP – phosphatidylinositol glycan - Cleave C3 → C3a,C3b 1 1 chemoattractant trigger phagocytosis ( Pubmed ncbi) -