HEREDITARY/ACQUIRED HEMOLYTIC ANEMIA

HEMOLYTIC ANEMIAS

Hemolytic anemias = reduced red-cell life span

Classification of Hemolytic anemias

I. Red cell abnormality (Intracorpuscular factors) A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate- Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia )

B. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)

II. Extracorpuscular factors

A. Immune hemolytic anemias 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood

B. Nonimmune hemolytic anemias 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves 4. Hypersplenism

SOME TYPES OF HHA eg.SICKLE CELL DISEASETHALASSEMIASG6PD DEFICIENCYHEREDITARY SPHEROCYTOSIS

THALASSEMIASMICROCYTIC, HYPOCHROMIC, HEMOLYTIC ANEMIAMOST COMMON IN AFRICAN, MEDITERRANEAN, MIDDLE EASTERN, & SOUTHEAST ASIAN DESCENTMULTIPLE VARIANTS

THALASSEMIASCHARACTERIZED BY DEFECTIVE SYNTHESIS OF GLOBIN CHAINS, UNABLE TO PRODUCE NORMAL ADULT HEMOGLOBINTRAIT THOUGHT TO BE PROTECTIVE AGAINST MALARIA AS WELL

HEMOGLOBINNORMAL ADULT RBC CONSISTS OF 3 FORMS OF Hb: - HbA - 2 and 2 globin chains - HbA2 2 and 2 globin chains - HbF - 2 and 2 globin chains

THALASSEMIAS and

THALASSEMIASTYPES OF DZ CHARACTERIZED BY DEFFERING EXTREMES OF ANEMIADEPENDS ON AMOUNT OF INEFFECTIVE ERYTHROPOIESIS AND PREMATURE DESTRUCTION OF CIRCULATING RBCSHYPOXIA IN SEVERE CASES

G6PD DEFICIENCYMOST COMMON HUMAN ENZYME DEFECTX-LINKED DISORDERAFFECTS 15% OF U.S. BLACK MALESDECREASE IN GLUTATHIONE LEVELS

G6PD DEFICIENCYHEINZ BODIES SEEN ON PERIPHERAL BLOOD SMEARNEONATAL JAUNDICE 1-4 DAYS AFTER BIRTH IN SEVERE VARIANTSINCREASE INCIDENCE OF PIDMENTED GALLSTONES AND SPLENOMEGALY

G6PD DEFICIENCYACUTE HEMOLYTIC CRISIS DUE TO: - BACTERIAL/VIRAL INFECTION - OXIDANT DRUGS (SULFAMETHOXAZOLE) - METABOLIC ACIDOSIS (DKA) - RENAL FAILURE - INGESTION OF FAVA BEANS

G6PD DEFICIENCYDIAGNOSIS QUANTITATIVE ASSAY DETECTING LOW ENZYME

TREATMENT SUPPORTIVE AND PREVENTATIVE

HEREDITARY SPHEROCYTOSISRBS MEMBRANE DEFECTMOST COMMON HEREDITARY ANEMIA FROM PTS OF NORTHERN EUROPEAN DESCENTAUTOSOMAL DOMINANTMUTATIONS IN SPECTRIN AND ANKYRIN (MEMBRANE PROTEINS)

HEREDITARY SPHEROCYTOSISSPHEROCYTES IN PERIPHERAL BLOOD SMEARSPHEROCYTES UNABLE TO PASS THROUGH THE SPLEENSEVERE CASES REQUIRE A SPLENECTOMY

HEREDITARY SPHEROCYTOSISNEONATAL JAUNDICE IN 1ST WEEK OCCURS IN 30-50% OF HS PTSANEMIA, SPLENOMEGALY, JAUNDICE, AND TRANSFUSIONS NEEDED VARY DEPENDING ON SEVERITY OF DZ

Hereditary microspherocytosis

1. Pathophysiology - red cell membrane protein defects (spectrin deficiency) resulting cytoskeleton instability2. Familly history3. Clinical features - splenomegaly4. Laboratory features - hemolytic anemia - blood smear-microspherocytes - abnormal osmotic fragility test - positive autohemolysis test - prevention of increased autohemolysis by including glucose in incubation medium 5. Treatment - splenectomy

Sickle-Cell Anemia

HemoglobinComposed of:1 Heme and 4 Globin Chains

4 Types of Globin Chains:Alpha, Beta, Delta, Gamma

Sickle Cell DiseaseCannot make Beta Chains

Valine substituted for glutamate in 6th position of beta chain

Sickle Cell DiseaseAffects people of African descentAffects 72,000 people in the US2 million people are carriersOccurs once in every 375 African American births

Sickle Cell AnemiaSickle Cell anemia is an inherited red blood cell disorder. Normal red blood cells are round like doughnuts, and they move through small blood tubes in the body to deliver oxygen.

Sickle red blood cells become hard, sticky and shaped like sickles used to cut wheat. When these hard and pointed red cells go through the small blood tube, they clog the flow and break apart. This can cause pain, damage and a low blood count, or anemia.

The origin of the disease is a small change in the protein hemoglobinThe change in cell structure arises from a change inthe structure of hemoglobin.

A single change in an amino acid causes hemoglobinto aggregate.

Hemoglobin is a carrier proteinLungsTissuesO2CO2HbO2 deoxy Hb (CO2)

Hemoglobin changes structure for efficient oxygen uptake and deliveryHbO2 deoxy Hb (CO2)Strong binding state R stateWeak binding state T state

The small change in hemoglobin structure leads to aggregationNormal hemoglobin (Hb A)Sickle cell hemoglobin (Hb S)abSubunits

Genetic Inheritance

Symptoms in ChildrenStart to appear at 6 monthsDactylitis (swelling of hands and feet)Heart EnlargementGrowth RetardationDelayed Sexual Development

Dactylitis

Sickle Cell CrisisSevere pain caused by blocked blood flowTriggered by Infection, Dehydration, Fatigue, or Emotional StressCan last up to 5 days

Splenic SequestrationSpleen tried to remove abnormal cells

Becomes enlarged and causes pain

Autosplenectomy occurs

Usually not seen in adults

Symptoms of AnemiaTirednessHeadaches Dizziness FaintnessShortness of breath

Other SymptomsChronic, low-level pain in joints and bonesAbdominal painRetina DamageGallstonesLeg Ulcers (adults)Chest pain

Leg Ulcers

Blood PictureSickle, Target and/or nRBCsDecreased HemoglobinIncreased retic countWhite cell count increasedWBC shift to the left

Hgb ElectrophoresisAmino acids in globin chains have different chargesSeparates hemoglobin according to charge90% Hgb S, 10% Hgb F, small fraction of Hgb A2

PrognosisNo cureLife expectancy:42 years men48 years women85% reach the age of 2050% reach age 50Causes of death: Infection, heart failure

TreatmentPain MedicationIncrease fluidsBlood TransfusionBone Marrow Transplant

Acquired Hemolytic Anemia

IntroductionIncreased RBC Destruction Short RBC life span

Types of acquired HAAutoImmune Haemolytic Anemias (+ve DAT)Alloimmune haemolytic anemiasDrug-induced immune haemolytic anemiasRed cell fragmentation syndromesInfectionsChemical & physical agentsSecondary Haemolytic anemiasParoxysmal Nocturnal Haemoglobinuria (PNH)

Pathogenesis of Jaundice:Hb Globin-Iron-Haem Bilirubin GlucoronideConjugation Bile GutStercobilinogen & Stercobilin (ex.in stool)Urobilinogen & Urobilin (ex. In urine)

Ketabolism of Hb:

Classification :Auto Immune AIHA -Warm antibody typeCold antibody typeAlloimmuneTransfusion reactionsHemolytic disease of new bornNon-ImmuneMicroangiopathic hemolytic anemiaInfections Malaria, clostridia, Burns, Toxins, snake & spider bites.

Laboratory Diagnosis:RBC Breakdown:HyperbilirubinemiaUrobilinogen, stercobilinogenserum haptoglobinsRBC Production:Reticulocytosis, *MCVMarrow hyperplasia*Damaged RBCMorphology, fragility, survival

Laboratory Diagnosis:Additional features of Intravascular Hemolysis:Hb-naemia and Hb-nuriaHaemosiderinuriaMethaemoglobinemia

DRUG RELATED HAALPHA-METHYLDOPALEVODOPAPROCAINAMIDESULFA DRUGSPENICILLINCEFTRIAXONECEFOTETANQUINIDINE

MICROANGIOPATHIC SYNDROMESTHROMBOCYTOPENIC PURPURA

HEMOLYTIC UREMIC SYNDROME

TTP & HUS - PATHOPHYSPLATELET AGGREGATION IN THE MICROVASCULATURE CIRCULATION VIA MEDIATION OF von WILLEBRANDS FACTOR LEADS TO THROMBOCYTOPENIA AND FRAGMENTATION OF RBCS AS THEY PASS THROUGH THESE OCCLUDED ARTERIOLES AND CAPILLARIES

THROMBOCYTOPENIC PURPURA (TTP)PLATLET COUNTS < 20,000MORE COMMON IN WOMEN AGES 10-60FEVER, NEUROLOGIC DEFICITS, HEMORRAGE, AND RENAL INSUFFICIENCYUNTREATED 80-90% MORTALITY

TTPSCHISTOCYTES OR HELMET CELLS SEEN OF PERIPHERAL SMEARINCREASED BUN/Cr LEVELS

TTPPREGNANCY IS THE MOST COMMON PRECIPITATING EVENT FOR TTPPREECLAMPSIA SIMILAR TO TTP; DELIVERY TX FOR PREECLAMPSIA, NOT CURE TTP

TTP ER TREATMENTPREDNISONE 1-2mg/kg/day INITIALLYPLASMA EXCHANGE TRANSFUSION IS FOUNDATION FOR TX (INFUSE FRESH FROZEN PLASMA IF TRANSFUSION UNAVAILABLEAVOID PLATELET TRANSFUSIONNEVER USE ASPIRIN

TTP ER TREATMENTPT MAY NEED SPLENECTOMYAZATHIOPRINE AND CYCLOPHOSPHAMIDE FOR THOSE WHO FAIL OR CANNOT TOLERATE STEROIDS

HUSDZ OF EARLY CHILDHOODPEAK INCIDENCE BETWEEN 6mo-4yrOFTEN FOLLOWS BACTERIAL/VIRAL ILLNESSMORTALILY 5-15%, WORSE IN OLDER CHILDREN & ADULTS

HUSCHARACTERIZED BY -ACUTE RENAL FAILURE -MICROANGIOPATHIC HA -FEVER -THROMBOCYTOPENIA (NOT AS SEVERE AS TTP)

HUSTHE MOST COMMON CAUSE OF ACUTE RENAL FAILURE IN CHILDHOODE.Coli O157:H7 COMMON CAUSEMICROTHORMBI ARE CONFINED MAINLY TO KIDENYS, WHERE TTP MORE WIDESPREAD

HUS ER TREATMENTMILD HUS < 24hr OF URINARY SX NEELS ONLY FLUID/ELECTROLYTE CORRECTION AND SUPPORT CARESTEROID THERAPYHEMODIAYLSIS IF ACUTE RENAL FAILURE PRESENTABX TX CONTROVERSIAL WHEN E.Coli PRESNENT; DO NOT USE ANTIMOLITY DRUG, INCREASE RISK OF DEVELOP HUS

HELLP SYNDROMEHEMOLYSISELEVATED LIVER ENZYMESLOW PLATLET COUNTS

HELLP SYNDROME1 IN 1OOO PREGNANCIESSEEN IN PRESENCE OF ECLAMPSIA, PREECLAMPSIA, AND PLACENTAL ABRUPTIONMAY EXTEND UP TO 6 DAYS POSTPARTUM

HELLP SYNDROMERUQ AND EPIGASTRIC PAIN SEEN IN 90% OF PTS (POSSIBLE HEPATIC RUPTURE)DX BASED ON LAB DATADECREASED SERUM HAPTOGLOBIN LEVEL MOST SENSITIVE

HELLP SYNDROME - TXPROMPT DELIVERY OF INFANTSUPPORTIVE CARE FOR SEIZURES AND HTN CRISISSTEROIDS MAY HELP FETAL LUNGS, BUT NO BENEFIT TO HELLP SYNDROME

WarmAIHA ColdIdiopathicSecondaryAutoimmune lymphoma, drugsSpherocytesIgG antibody, C3dDirect Coombs - 37Anti c / anti e

IdiopathicSecondaryInfectionsLymphomaRBC clumpsIgM antibodyCold Ag. Titre 4DAT +ve compl*Anti I / i

WarmAIHA ColdIdiopathicSecondarySLE, Autoimmune disorders.CLLLymphomaDrugs Mdopa.IdiopathicSecondaryInfectionsLymphomaPCH (anti-P)

Warm AIHAIgG, C3d, rarely other Ab.Destruction in Spleen & RESLoss of partial membrane spherocytesClinical Features:Spleenomegaly

Autoimmune hemolytic anemia caused by warm-reactive antibodies:

I. Primary II. Secondary 1. acute - viral infections - drugs ( -Methyldopa, Penicillin, Quinine,Quinidine) 2. chronic - rheumatoid arthritis, systemic lupus erythemat. - lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, Waldenstrms macroglobulinemia) - miscellaneous (thyroid disease, malignancy )

Autoimmune hemolytic anemia caused by cold-reactive antibodies:

I. Primary cold agglutinin disease II. Secondary hemolysis: - mycoplasma infections - viral infections - lymphoproliferative disorders III. Paroxysmal cold hemoglobinuria

Alloimmune Haemolysis:Antibody from another person.Transfusion reactionsHaemolytic disease of Newborn (HDN)RH-D, RH neg mother, + father, 2nd baby Kleihauer test HbF, ABO IgG in O mother, mild*, 1st baby- agglutination & spherocytes, DAT neg/mild +Post transplantation induced.

Paroxysmal nocturnal hemoglobinuria

1. Pathogenesis - an acquired clonal disease, arising from a somatic mutation in a single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD55 and a membrane inhibitor of reactive lysis =CD59) - red cells are more sensitive to the lytic effect of complement - intravascular hemolysis 2. Symptoms - passage of dark brown urine in the morning

3. PNH laboratory features: - pancytopenia - chronic urinary iron loss - serum iron concentration decreased - hemoglobinuria - hemosiderinuria - positive Hams test (acid hemolysis test) - positive sugar-water test - specific immunophenotype of erytrocytes (CD59, CD55)

4. Treatment: - washed RBC transfusion - iron therapy - allogenic bone marrow transplantation

Microangiopathy:

Spherocytes:

AIHA Cold ab type: Clumping.

Assesment of HA Clinical features: - pallor - jaundice - splenomegaly

Laboratory features:

1. Laboratory features - normocytic/macrocytic, hyperchromic anemia - reticulocytosis - increased serum iron - antiglobulin Coombs test is positive

2. Blood smear - anisopoikilocytosis, spherocytes - erythroblasts - schistocytes

3. Bone marrow smear - erythroid hyperplasia

Diagnosis of hemolytic syndrome:

1. Anemia 2. Reticulocytosis 3. Indirect hyperbilirubinemia

Autoimmune hemolytic anemia - diagnosis

- positive Coombs test

Treatment:

- steroids - splenectomy - immunosupressive agents - transfusion