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Immune Haemolytic Anaemia Mechanisms of Immune Red Cell Destruction Cell Mediated Immune Red Cell destruction Human

macrophage & monocyte receptor for Fc portion of IgG & C3 Roles Spleen Liver Plasma Skimming Effect No Plasma Skimming Effect Red cell bound IgG Dependent on cells coated with C3 Extravascular Haemolysis Classification of Haemolytic Anaemias Hereditary Membrane Defects Metabolic Defects Haemoglobin Defects

Acquired Immune y Autoimmune y Alloimmune y Drugs Induced Red cell fragmentation syndromes March Haemoglobinuria Infections Chemical, Physical Agents PMH

Immune Haemolytic Anaemias Autoimmune Alloimmune Warm AIHA HTR Cold AIHA HDN Cold agglutinin syndrome Allografts Paroxysmal cold (BM Transplant) Combine/ Mixed AIHA Complement Mediated Intravascular Haemolysis Complement Activation Classical, Alternative Pathways Usually stops at C3 stage (3b) Extravascular Haemolysis Complement beyond C3 stage MAC formation, Intravascular Haemolysis Autoimmune Haemolytic Anaemia (AIHA)

Drugs Induced Ab against a drug (Red Cell Membrane Complex) Deposition of complement via drugprotein (antigen) True Autoimmune Haemolytic Anaemia

Definition Group of disease Haemolysis occurs because Antibody production by body against its own Red cells Characteristic +ve DAT/ Coombs Test Classification Warm (70%) 1 - Idiopathic 2 Malignancy Lymphoma, CLL Alloallergic disease SLE Infections Mononucleosis syndrome Drugs Methyldopa, Fludarabine

Cold (30%) 1 - Idiopathic 2 Infections Mycoplasma pneumonia, infectious mononucleosis Lymphoma Paroxysmal Cold HbUria

Coombs Test Direct Coombs Test/ Direct Antiglobulin Test (DAT) Detect Abnormal Antibodies attached to surface of patient s RBCs Patient s RBC + Anti-Human IgG Antiserum Agglutination of RBCs Patient s RBC are coated with IgG RBCs covered with complement(C3) & Anti-Human C3 Antiserum Specific (C3 alone) or Broad spectrum DAT (C3, IgG, IgA, IgM) Anti-Sera can be used

Clinical Manifestation of Autoimmune Haemolytic Anaemia (AIHA) Warm AIHA Paroxysmal Cold Cold Agglutinin Haemoglobunuria Syndrome 30-60 y/o Young adult 60-90 y/o Onset F M=F M Sex Variable Acute, Intermittent, Mild, Moderate Severity Massive Anaemia Rare Common Severe cases only HbUria Intermittent Common Spleneomegaly Common Cold Urticaria, Cold Intolerance, Symptoms Treatment
Corticosteroids Splenectomy Immunosuppresive Paresthesis, Rigor, Anaphylactic Treat 1 Disease (Syphilis, Viral infection) Avoid Cold Raynaud s phenomenon Avoid Cold Immunosuppressive

Indirect Coombs Test/ Indirect Antiglobulin Test Detects Antibodies against RBCs found in Patient s Serum Normal RBCs + Patient s Serum DAT

Warm AutoImmune Haemolytic Anaemia Definition AIHA caused by production of Antibody (IgG) against own Red Cell Antigen (strongly at 37C) > 40 y/o Female Half of cases Idiopathic, remaining cases are 2 to predisposing condition Etiology Reactions of Antigens on surface of RBC with circulating Antibody (Mostly does not involve Complement Reaction) Non-Hodgkin s lymphomas, Hodgkin s disease, Autoimmune disorders (RA, SLE), Drugs (Methyl Dopa) Pathogenesis Most common antibody = IgG

Cold AutoImmune Haemolytic Anaemia Cold Agglutinin Syndrome Definition Caused by IgM AutoAntibodies exhibit maximal reactivity at 4C Cold environment Exacerbate condition Chronic disease > 50 y/o (peak 70 y/o) 2 Etiology (1 - Idiopathic) Adults Lymphoproliferative Disease (Lymphoma, CLL, Infection) Children Infection (Mycoplasma pneumonia, Mononucleosis, HIV) Epstein Barr Virus, Cytomegalovirus Normally All have Circulating Antibodies directed against RBC but in conc. to trigger disease. In Cold Agglutinin Disease, the concentration is Pathogenesis After Mycoplasma pneumoniea, Mononucleosis cause cold Antibody prod. In B-cell Lymphoma, CLL - cold antibody production by malignant B-cell At body temperature (28-31C) (During winter months) Antibodies (generally IgM) bind to RBC (I, i, Pr antigens) Activate Classical pathway of Complement System (Agglutination Acrocyanosis) If complement response Sufficient, RBC damaged by MAC causing Intravascular haemolysis If complement response Insufficient, RBC damaged by Opsonization & Extravascular haemolysis in RES Clinical Laboratory Chronic Anaemic Symptoms Similar to Warm AIHA (Fatigue, SOB, Weakness) (Except Spherocytosis marked) Dark Urine Red cells agglutination (in the cold) Acrocyanosis DAT reveals complement (C3d) only (Ears, Nose Tips, Fingers, Toes) on Red Cell Surface (Gangrene of digits) (alluted IgM in central circulation) (caused by Autoagglutination causing Urine Hb & Hemosiderin local blood stasis) Haptoglobin or Absent Pallor, Jaundice Treatment Hepatosplenomegaly Keep patient Warm Lymphadenopathy Treat Underlying causes Alkylating agents (chlorambucil) Splenectomy (does not help unless massive) Steroids are not helpful

Clinical Short Period Anaemia Jaundice Remit & Relapse Splenomegaly Associated with ITP (Evan s syndrome) Underlying disease (SLE, Hodgkin s) Treatment Remove all causes Corticosteroids Splenectomy Immunosuppressive drugs Blood Transfusion (least incompatible blood)

Laboratory Findings FBP Spherocytes, Larger Polychromatic & Nucleated RBC Hb, HCT Normal Mild Haemolysis - Severe Haemolysis Reticulocyte Persistently WBC Normal Idiopathic AIHA Varies greatly - 2 AIHA Platelet count Normal Idiopathic warm AIHA - Evan Syndrome LDH Serum Haptoglobin Urine Urobilinogen -ve Hemosiderin, Hb DAT +ve (95% AIHA) Bone Marrow (Erythroid Hyperplasia)

Agglutination of Red Cells Paroxysmal Cold Haemoglobinuria (Donath-Landsteiner Haemolytic Anaemia) Definition Rare syndrome Acute Intravascular Haemolysis after Exposure to Cold environment Caused by D-L autoantibody (cause severe haemolysis even in titer) Conditions Cold Specificity for P antigen on RBC Warm Lysis with complement 2 Etiology (1 - Idiopathic) Late stage or Congenital Syphilis in Chronic cases Viral Upper Respiratory Illness Viral Infections Measles, Mumps, Epstein-Barr Virus (EBV), CytoMegaloVirus(CMV), Varicella zoster virus, Adenovirus, Coxsackie A9, Parvovirus, Influenza A Bacterial Infection Mycoplasma pneumoniae, Haemophilus influenza, Klebsiella pneumoniae, Escherichia coli Pathophysiology

Laboratory

Spleen congested (Spherocytes)

Spherocytes, Nucleated RBC

Spherocytes, Nucleated young RBC, Reticulocyte

Clinical Mild Jaundice Splenomegaly Acrocyanosis Chronic Haemolytic Anaemia aggravated by cold & associated with Intravascular Haemolysis

Investigation Donath Landsteiner test (Agglutinate in cold but reversible after warm) Direct Antiglobulin test Monoclonal IgM antibodies

Management Keep patient Warm Treat underlying cause Rutiximab & Campath Splenectomy (does not help unless massive) Steroid does not help

Alloimmune Haemolytic Disease Definition Body gains Immunity from Another individual (same species) against own cells Alloimmunity can occur After Transfusion of Fluids (blood, plasma) After Allografts (grafts) Fetus after Maternal Antibodies have passed through placenta in fetus (Hemolytic disease of newborn, Fetomaternal Alloimmune Thrombocytopenia) Haemolytic Transfusion Reaction (HTR) Definition RBC Transfused to patient is Destroyed by patient s own immune system Classification
Type Antibody detected initially Yes Yes No No Primary Antibody Type IgM IgG IgG IgG Degree of Complement Binding Full (C1-9) None/ Partial Full (C1-9) None/ Partial Example

Haemolysis Disease of Newborn (HDN) Definition Destruction of RBC of Fetus & Neonate by Antibodies from Mother Red Cell Life Span of Fetal/ Neonate (maternal Allo-Antibodies against Red Cell Antigens acquired from father) Causes Destruction of RBCs of Fetus by Antibodies produced by mother (Fetal Red Cell contain corresponding Antigen, binding of Antibody will occur) Coated RBCs are removed by Mononuclear Phagocytic System Pathophysiology

Acute Intravascular Acute Extravascular Delayed Intravascular Delayed Extravascular

ABO Rh Kidd Duff

Immune Mediated HTR caused by IgM (ABO antibodies)(Anti-A,B,AB) results in Severe, Intravascular Haemolysis IgG (Rh, Kell, Duffy) results in Mild, Extravascular Haemolysis Types Acute HTR Delayed HTR Occur within minutes At least 24h after post-transfusion Incompatible Red Cells transfused 2 Immune response into patient who has corresponding Previously immunized by Transfusion, antibodies Pregnancy Clinical Clinical Fever HCT Chills +ve DAT (Coombs test) Heat in vein when blood transfused Haemoglobinuria Pain in Lumbar region Mild Serum Bilirubin Constricting Chest Pain Tachycardia Hb to pretransfusion level after 1-2 Hypotension weeks posttransfusion Haemoglobinemia Pathophysiology Mechanism of Alloimmunization
ABO Incompatible HTR Fixation of C5b9 complexs MAC occurs Release C3a, C5a (anaphylatoxins) Formation of pores in red cell membrane Intravascular Haemolysis Hemoglobinuria Hemoglobinemia Donor APCs (macrophages, dendritic cells, B cells) Present Donor Antigens to Recipient T cells Recognition of MHC Class I alloantigens by CD4+ recipient T cells Activation, Development of 1 Immune Response Formation of Memory Cells (from T cells)

Clinical Less Severe Mild Anaemia

Severe Icterus Gravis Neonatorum (Kernicterus) Brain damage (infant) caused by unconjugatedindirect bilirubin

Intrauterine Death Hydrops Fetalis Edematous, Ascites, Bulky Swollen, Friable Placenta Pathophysiology Extravascular haemolysis, Extramedullary Erythropoiesis Hepatic, Cardiac Failure

Bronchospasm Mast cell degranulation Hypotension Pulmonary dysfunction V/Q abnormality

After Birth Anaemia (Destruction of Red Cells) Heart Failure Bilirubin Kernicterus Severe Growth Retardation Rh Haemolytic Disease of Newborn (Rh HDN) Antibodies against Anti-D ( common Anti-c, Anti-E) Mother is cause of Anti-D Rh ve Firstborn infant is Unaffected Sensitization of Mother occurs (during Gestation, at Birth) All subsequent offspring inhering D-antigen will be affected (Anti-D HDN) Pathogenesis
Fetomaternal Hemorrhage Maternal Antibodies formed against Paternally derived antigens During subsequent pregnancy, placental passage of maternal IgG antibodies Maternal antibody attaches to Fetal Red Blood Cells Fetal Red Blood Cell Hemolysis

Before Birth Anaemia (Destruction or Red Cells) Heart Failure Fetal Death

Investigation Recheck Sample, Patient ID Measure y Urinary Hb y Serum LDH, Bilirubin, Haptoglobin
Intravascular Haemolysis Produce Free Hb in circulation Taken by Haptoglobin (saturation) Haemoglobinuria Haemosiderinuria (if severe) Hyperbilirubinemia

Anti-RBC Antibody titers of patients with alloimmunization frequently below detactable levels Allowing incompatible units to be transfused Occur in patients previously developed Antibodies from previous Transfusion, Pregnancy At time of pretransfusion screening, antibody is too weak/ to be detected by standard procedures Management Suspect Transfusion Reaction Stop Transfusion Assess Patient Clinically Verify Patient, Blood Identifiers Blood Bank Investigation

Management Maintain BP, Renal Perfussion IV Dextran, Plasma, Saline, Frusemide Hydrocortisone, Antihistamine (alleviate shock) IV Adrenaline (severe shock) Compatible Transfusion Dialysis (Acute Renal Failure)

Factors affecting Immunization & Severity Antigenic exposure Host factors Antibody specificity Influence of ABO group (ABO Incompatible Rh +ve cells Haemolysed before Rh antigen can be recognized by Mother s immune system) Prevention of Rh-HDN Prevention of Active Immunization (Anti-D)( tittered Rh-Ig (Rhogam)) Calculation of dose (Kleihauer test for Fetal Hb) ABO Haemolytic Disease of New Born Clinical Laboratory Anaemia (mild) Microspherocytes ABO-HDN (1st pregnancy) Bilirubin later (1-3d after birth) Mechanism protecting Fetus Cord Blood collection Relatively Weak A,B antigens RBC (reveal Anti-A, Anti-B) Widespread distribution of antigen

Drug-Induced Immune Haemolytic Anaemia Definition Acquired form of Haemolytic Anaemia caused by Interaction of drugs with Immune System Result is Production of Antibodies against RBC & Premature RBC destruction = Immune Haemolytic Anaemia 2 to Drugs = Anaemia Immune Haemolytic - 2 to Drugs Rare in Children Etiology Drugs Cephalosproins (antibiotic) Levodopa Methyldopa (IgG mediated type II Hypersensitivity) Penicillin & its derivatives ( dose) Quinidine (IgM mediated activation of Classical Complement pathway & MAC) NSAIDs G6PD Deficiency Breakdown of RBC due to stress in cell (not immune system)(rare) Mechanisms Antibody directed against a drug-red cell membrane comples

Penicillin Ampicillin

Deposition of complement via drugprotein (antigen) Antibody complex onto red cell surface Quinidine Rifampicin

True autoimmune haemolytic anaemia (role of drug unclear)

Methyldopa (+ve Coombs w/o hemolysis)

Penicillin

Quinidine

Methyldopa

In each case, coated (opsonised) cells are destroyed in RES In each case, Haemolytic Anaemia disappears when drugs are discontinued (except Methyldopa autoantibody may persist for several months) Clinical Dark Urine Fatigue Pale Skin Colour Tachycardia Shortness of Breath Yellow skin colour (Jaundice) Splenomegaly Investigations DAT/ Coombs Test +ve (usually C3b) Indirect Coombs +ve (if offending drug is added to test) Indirect Bilirubin Serum Haptoglobin Hb present in Urine Haemosiderin present in Urine Urine Urobilinogen Absolute Reticulocyte count FBC shows Red Blood Cell Count & Hb Treatment Cessation of Drug Prednisone, Corticosteroids ( Immune response against RBC) Folic acid supplementation (Treat Folic Acid Deficiency anaemia) Blood Transfusions (Severe Symptomatic Anaemia)

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