hereditary/acquired hemolytic anemia. hemolytic anemias hemolytic anemias = reduced red-cell life...

HEREDITARY/ACQUIRED HEREDITARY/ACQUIRED HEMOLYTIC HEMOLYTIC ANEMIAANEMIA

HEMOLYTIC ANEMIASHEMOLYTIC ANEMIAS

HemolyticHemolytic anemiasanemias == reducedreduced red-cellred-cell lifelife spanspan

ClassificationClassification ofof HemolyticHemolytic anemiasanemias

I.I. RedRed cellcell abnormalityabnormality (Intracorpuscular(Intracorpuscular factors)factors) AA. . HereditaryHereditary 1. Membrane defect (spherocytosis, elliptocytosis) 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate- 2. Metabolic defect (Glucoze-6-Phosphate- Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) thalassemias, sickle cell anemia )

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

II.II. Extracorpuscular factorsExtracorpuscular factors

A.A. ImmuneImmune hemolytichemolytic anemiasanemias 1. Autoimmune hemolytic anemia 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by warm-reactive antibodies - caused by cold-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood 2. Transfusion of incompatible blood

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

SOME TYPES OF HHA eg.

• SICKLE CELL DISEASE

• THALASSEMIAS

• G6PD DEFICIENCY

• HEREDITARY SPHEROCYTOSIS

THALASSEMIAS

• MICROCYTIC, HYPOCHROMIC, HEMOLYTIC ANEMIA

• MOST COMMON IN AFRICAN, MEDITERRANEAN, MIDDLE EASTERN, & SOUTHEAST ASIAN DESCENT

• MULTIPLE VARIANTS

THALASSEMIAS

• CHARACTERIZED BY DEFECTIVE SYNTHESIS OF GLOBIN CHAINS, UNABLE TO PRODUCE NORMAL ADULT HEMOGLOBIN

• TRAIT THOUGHT TO BE PROTECTIVE AGAINST MALARIA AS WELL

HEMOGLOBIN

• NORMAL ADULT RBC CONSISTS OF 3 FORMS OF Hb: - HbA - 2 α and 2 β globin chains - HbA2 – 2 α and 2 δ globin chains - HbF - 2 α and 2 γ globin chains

• THALASSEMIAS α and β

THALASSEMIAS

• TYPES OF DZ CHARACTERIZED BY DEFFERING EXTREMES OF ANEMIA

• DEPENDS ON AMOUNT OF INEFFECTIVE ERYTHROPOIESIS AND PREMATURE DESTRUCTION OF CIRCULATING RBC’S

• HYPOXIA IN SEVERE CASES

G6PD DEFICIENCY

• MOST COMMON HUMAN ENZYME DEFECT

• X-LINKED DISORDER

• AFFECTS 15% OF U.S. BLACK MALES

• DECREASE IN GLUTATHIONE LEVELS

G6PD DEFICIENCY

• HEINZ BODIES SEEN ON PERIPHERAL BLOOD SMEAR

• NEONATAL JAUNDICE 1-4 DAYS AFTER BIRTH IN SEVERE VARIANTS

• INCREASE INCIDENCE OF PIDMENTED GALLSTONES AND SPLENOMEGALY

G6PD DEFICIENCY

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

G6PD DEFICIENCY

• DIAGNOSIS – QUANTITATIVE ASSAY DETECTING LOW ENZYME

• TREATMENT – SUPPORTIVE AND PREVENTATIVE

HEREDITARY SPHEROCYTOSIS

• RBS MEMBRANE DEFECT

• MOST COMMON HEREDITARY ANEMIA FROM PTS OF NORTHERN EUROPEAN DESCENT

• AUTOSOMAL DOMINANT

• MUTATIONS IN SPECTRIN AND ANKYRIN (MEMBRANE PROTEINS)

HEREDITARY SPHEROCYTOSIS

• SPHEROCYTES – IN PERIPHERAL BLOOD SMEAR

• SPHEROCYTES UNABLE TO PASS THROUGH THE SPLEEN

• SEVERE CASES REQUIRE A SPLENECTOMY

HEREDITARY SPHEROCYTOSIS

• NEONATAL JAUNDICE IN 1ST WEEK OCCURS IN 30-50% OF HS PTS

• ANEMIA, SPLENOMEGALY, JAUNDICE, AND TRANSFUSIONS NEEDED VARY DEPENDING ON SEVERITY OF DZ

HereditaryHereditary microspherocytosismicrospherocytosis

1.1. PathophysiologyPathophysiology - red cell membrane protein defects (spectrin - red cell membrane protein defects (spectrin deficiency)deficiency) resulting cytoskeleton instabilityresulting cytoskeleton instability2.2. FamillyFamilly historyhistory3.3. ClinicalClinical featuresfeatures - splenomegaly - splenomegaly4.4. LaboratoryLaboratory featuresfeatures - hemolytic anemia - hemolytic anemia - blood smear-microspherocytes - blood smear-microspherocytes - abnormal osmotic fragility test - abnormal osmotic fragility test - positive autohemolysis test - positive autohemolysis test - prevention of increased autohemolysis by - prevention of increased autohemolysis by including glucose in incubation medium including glucose in incubation medium 5.5. TreatmentTreatment - splenectomy - splenectomy

Sickle-Cell AnemiaSickle-Cell Anemia

HemoglobinComposed of:

1 Heme and 4 Globin Chains

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

Sickle Cell Disease• Cannot make Beta Chains

• Valine substituted for glutamate in 6th position of beta chain

Sickle Cell Disease

• Affects people of African

descent

• Affects 72,000 people in the US

• 2 million people are carriers

• Occurs 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 hemoglobin

The 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 protein

Lungs Tissues

O2

CO2

HbO2

deoxy Hb (CO2)

Hemoglobin changes structure for efficient oxygen uptake and delivery

HbO2

deoxy Hb (CO2)

Strong binding state

R stateWeak binding state

T state

The small change in hemoglobin structure leads to aggregation

Normal hemoglobin (Hb A) Sickle cell hemoglobin (Hb S)

Subunits

Genetic Inheritance

Symptoms in Children

• Start to appear at 6 months

• Dactylitis (swelling of hands and

feet)

• Heart Enlargement

• Growth Retardation

• Delayed Sexual Development

Dactylitis

Sickle Cell Crisis• Severe pain caused by blocked

blood flow

• Triggered by Infection,

Dehydration, Fatigue, or Emotional

Stress

• Can last up to 5 days

Splenic Sequestration

• Spleen tried to remove abnormal cells

• Becomes enlarged and causes pain

• Autosplenectomy occurs

• Usually not seen in adults

Symptoms of Anemia

• Tiredness

• Headaches

• Dizziness

• Faintness

• Shortness of breath

Other Symptoms• Chronic, low-level pain in joints

and bones

• Abdominal pain

• Retina Damage

• Gallstones

• Leg Ulcers (adults)

• Chest pain

Leg Ulcers

Blood Picture

• Sickle, Target and/or nRBCs

• Decreased Hemoglobin

• Increased retic count

• White cell count increased

• WBC shift to the left

Hgb Electrophoresis

• Amino acids in globin chains

have different charges

• Separates hemoglobin according

to charge

• 90% Hgb S, 10% Hgb F, small

fraction of Hgb A2

Prognosis• No cure• Life expectancy:

42 years men48 years women

• 85% reach the age of 20• 50% reach age 50• Causes of death:

Infection, heart failure

Treatment

• Pain Medication

• Increase fluids

• Blood Transfusion

• Bone Marrow Transplant

Acquired Hemolytic Anemia

Introduction

• Increased RBC Destruction –

• Short RBC life span <120 days.

• Normocytic normochromic, reticulocytosis

• Anemia, Jaundice, marrow hyperplasia

• Splenomegaly, bilirubin gall stones

• Unconjugated “acholuric” (pale urine)

• Common types - AIHA, MAHA

Types of acquired HA

• AutoImmune Haemolytic Anemias (+ve DAT)• Alloimmune haemolytic anemias• Drug-induced immune haemolytic anemias• Red cell fragmentation syndromes• Infections• Chemical & physical agents• Secondary Haemolytic anemias• Paroxysmal Nocturnal Haemoglobinuria (PNH)

Pathogenesis of Jaundice:

• Hb Globin-Iron-Haem Bilirubin • Glucoronide–Conjugation Bile Gut

• Stercobilinogen & Stercobilin (ex.in stool)

• Urobilinogen & Urobilin (ex. In urine)

Ketabolism of Hb:

Classification :• Auto Immune AIHA -

– Warm antibody type– Cold antibody type

• Alloimmune– Transfusion reactions– Hemolytic disease of new born

• Non-Immune– Microangiopathic hemolytic anemia– Infections – Malaria, clostridia, – Burns, Toxins, snake & spider bites.

Laboratory Diagnosis:• RBC Breakdown:

– Hyperbilirubinemia– Urobilinogen, stercobilinogen– serum haptoglobins

• RBC Production:– Reticulocytosis, *MCV– Marrow hyperplasia*

• Damaged RBC– Morphology, fragility, survival

Laboratory Diagnosis:

• Additional features of Intravascular Hemolysis:– Hb-naemia and Hb-nuria– Haemosiderinuria– Methaemoglobinemia

DRUG RELATED HA

• ALPHA-METHYLDOPA

• LEVODOPA• PROCAINAMIDE• SULFA DRUGS

• PENICILLIN• CEFTRIAXONE• CEFOTETAN• QUINIDINE

MICROANGIOPATHIC SYNDROMES

• THROMBOCYTOPENIC PURPURA

• HEMOLYTIC UREMIC SYNDROME

TTP & HUS - PATHOPHYS

• PLATELET AGGREGATION IN THE MICROVASCULATURE CIRCULATION VIA MEDIATION OF von WILLEBRAND’S FACTOR LEADS TO THROMBOCYTOPENIA AND FRAGMENTATION OF RBC’S AS THEY PASS THROUGH THESE OCCLUDED ARTERIOLES AND CAPILLARIES

THROMBOCYTOPENIC PURPURA (TTP)

• PLATLET COUNTS < 20,000

• MORE COMMON IN WOMEN AGES 10-60

• FEVER, NEUROLOGIC DEFICITS, HEMORRAGE, AND RENAL INSUFFICIENCY

• UNTREATED – 80-90% MORTALITY

TTP

• SCHISTOCYTES OR HELMET CELLS SEEN OF PERIPHERAL SMEAR

• INCREASED BUN/Cr LEVELS

TTP

• PREGNANCY IS THE MOST COMMON PRECIPITATING EVENT FOR TTP

• PREECLAMPSIA SIMILAR TO TTP; DELIVERY TX FOR PREECLAMPSIA, NOT CURE TTP

TTP – ER TREATMENT

• PREDNISONE 1-2mg/kg/day INITIALLY

• PLASMA EXCHANGE TRANSFUSION IS FOUNDATION FOR TX (INFUSE FRESH FROZEN PLASMA IF TRANSFUSION UNAVAILABLE

• AVOID PLATELET TRANSFUSION

• NEVER USE ASPIRIN

TTP – ER TREATMENT

• PT MAY NEED SPLENECTOMY

• AZATHIOPRINE AND CYCLOPHOSPHAMIDE FOR THOSE WHO FAIL OR CANNOT TOLERATE STEROIDS

HUS

• DZ OF EARLY CHILDHOOD

• PEAK INCIDENCE BETWEEN 6mo-4yr

• OFTEN FOLLOWS BACTERIAL/VIRAL ILLNESS

• MORTALILY 5-15%, WORSE IN OLDER CHILDREN & ADULTS

HUS

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

HUS

• THE MOST COMMON CAUSE OF ACUTE RENAL FAILURE IN CHILDHOOD

• E.Coli O157:H7 COMMON CAUSE

• MICROTHORMBI ARE CONFINED MAINLY TO KIDENYS, WHERE TTP MORE WIDESPREAD

HUS – ER TREATMENT

• MILD HUS < 24hr OF URINARY SX NEELS ONLY FLUID/ELECTROLYTE CORRECTION AND SUPPORT CARE

• STEROID THERAPY• HEMODIAYLSIS IF ACUTE RENAL FAILURE

PRESENT• ABX TX CONTROVERSIAL WHEN E.Coli

PRESNENT; DO NOT USE ANTIMOLITY DRUG, INCREASE RISK OF DEVELOP HUS

HELLP SYNDROME

• HEMOLYSIS

• ELEVATED LIVER ENZYMES

• LOW PLATLET COUNTS

HELLP SYNDROME

• 1 IN 1OOO PREGNANCIES

• SEEN IN PRESENCE OF ECLAMPSIA, PREECLAMPSIA, AND PLACENTAL ABRUPTION

• MAY EXTEND UP TO 6 DAYS POSTPARTUM

HELLP SYNDROME

• RUQ AND EPIGASTRIC PAIN – SEEN IN 90% OF PTS (POSSIBLE HEPATIC RUPTURE)

• DX BASED ON LAB DATA

• DECREASED SERUM HAPTOGLOBIN LEVEL MOST SENSITIVE

HELLP SYNDROME - TX

• PROMPT DELIVERY OF INFANT

• SUPPORTIVE CARE FOR SEIZURES AND HTN CRISIS

• STEROIDS MAY HELP FETAL LUNGS, BUT NO BENEFIT TO HELLP SYNDROME

Warm AIHA Cold

• Idiopathic• Secondary

– Autoimmune lymphoma, drugs

• Spherocytes• IgG antibody, C3d• Direct Coombs - 37°• Anti c / anti e

• Idiopathic• Secondary

– Infections– Lymphoma

• RBC clumps• IgM antibody• Cold Ag. Titre 4°• DAT +ve compl*• Anti I / i

Warm AIHA Cold

• Idiopathic• Secondary

– SLE, Autoimmune disorders.

– CLL– Lymphoma– Drugs – Mdopa.

• Idiopathic• Secondary

– Infections– Lymphoma

• PCH (anti-P)

Warm AIHA

• IgG, C3d, rarely other Ab.

• Destruction in Spleen & RES

• Loss of partial membrane – spherocytes

• Clinical Features:– Spleenomegaly

AutoimmuneAutoimmune hemolytichemolytic anemiaanemia causedcaused byby warm-reactivewarm-reactive antibodies:antibodies:

I.I. PrimaryPrimary II.II. SecondarySecondary 1.1. acuteacute - viral infections - viral infections - drugs ( - drugs ( -Methyldopa, Penicillin, -Methyldopa, Penicillin, Quinine,Quinidine)Quinine,Quinidine) 2.2. chronicchronic - rheumatoid arthritis, systemic lupus - rheumatoid arthritis, systemic lupus erythemat. erythemat. - lymphoproliferative disorders - lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, (chronic lymphocytic leukemia, lymphomas, Waldenstr WaldenstrÖÖm’s macroglobulinemia)m’s macroglobulinemia) - miscellaneous (thyroid disease, malignancy ) - miscellaneous (thyroid disease, malignancy )

AutoimmuneAutoimmune hemolytichemolytic anemiaanemia causedcaused byby cold-reactivecold-reactive antibodies:antibodies:

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

Alloimmune Haemolysis:

• Antibody from another person.

• Transfusion reactions

• Haemolytic 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.

ParoxysmalParoxysmal nocturnalnocturnal hemoglobinuriahemoglobinuria

1.1. PathogenesisPathogenesis - an acquired clonal disease, arising from a somatic - an acquired clonal disease, arising from a somatic mutation in a single abnormal stem cellmutation in a single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - deficiency of the GPI anchored membrane proteins - deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD55 and a membrane (decay-accelerating factor =CD55 and a membrane inhibitor of reactive lysis =CD59)inhibitor of reactive lysis =CD59) - red cells are more sensitive to the lytic effect of - red cells are more sensitive to the lytic effect of complement complement - intravascular hemolysis - intravascular hemolysis 2.2. SymptomsSymptoms - passage of dark brown urine in the morning - passage of dark brown urine in the morning

3.3. PNHPNH –laboratory–laboratory features:features: - pancytopenia - pancytopenia - chronic urinary iron loss - chronic urinary iron loss - serum iron concentration decreased - serum iron concentration decreased - hemoglobinuria - hemoglobinuria - hemosiderinuria - hemosiderinuria - positive Ham’s test (acid hemolysis test) - positive Ham’s test (acid hemolysis test) - positive sugar-water test - positive sugar-water test - specific immunophenotype of erytrocytes (CD59, - specific immunophenotype of erytrocytes (CD59, CD55)CD55)

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

Microangiopathy:

Spherocytes:

AIHA Cold ab type: Clumping.

Assesment of Assesment of HHA A C Clinicallinical features:features: -- pallorpallor -- jaundicejaundice -- splenomegalysplenomegaly

LaboratoryLaboratory features:features:

1.1. LaboratoryLaboratory featuresfeatures - - normocytic/macrocytic, hyperchromic anemianormocytic/macrocytic, hyperchromic anemia - reticulocytosis - reticulocytosis - increased serum iron - increased serum iron - antiglobulin Coombs’ test is positive - antiglobulin Coombs’ test is positive

2.2. BloodBlood smearsmear - anisopoikilocytosis, spherocytes - anisopoikilocytosis, spherocytes - erythroblasts - erythroblasts - schistocytes - schistocytes

3.3. BoneBone marrowmarrow smearsmear - erythroid hyperplasia - erythroid hyperplasia

DiagnosisDiagnosis ofof hemolytichemolytic syndrome:syndrome:

1. Anemia1. Anemia 2. Reticulocytosis 2. Reticulocytosis 3. Indirect hyperbilirubinemia 3. Indirect hyperbilirubinemia

Autoimmune hemolytic anemia - Autoimmune hemolytic anemia - diagnosis diagnosis

-- positivepositive Coombs’Coombs’ testtest

Treatment:Treatment:

-- steroidssteroids -- splenectomysplenectomy - - immunosupressiveimmunosupressive agentsagents -- transfusiontransfusion