hemolytic anemia

Hemolytic anemiasDefinition:Anemias that result from shortening of RBC life span,RBC destruction could be extravascular or intravascular Etiology
Congenital1- Membrane abnormalities • Hereditary spherocytosis • Hereditary elliptocytosis2-Haemoglobinopathies • Lack of haemoglobin chain synthesis Thalassaemias • Amino acid substitution on the haemoglobin chain Haemoglobin S. C, D3- Red cell enzyme detects • Glucose-B-phosphate dehydrogenase deficiency Acquired1- Immune• Autoimmune Warm antibody Cold antibody • Alloimmune2- Non-immune • Mechanical - Artificial cardiac valves - Burns - Microangiopattlic - March haemoglobinuria• Infections Clostridium perfringens, malaria• Drugs, chemicals3- Paroxysmal nocturnal haemoglobinuria (PNH).

Approach To Hemolytic anemia

A- Prove The Presence of Hemolysis (Evidence of hemolysis): Clinical Features: anemia +jaundice. Laboratory Tests Low Hb Increased reticulocyte count and percentage. Indirect hyperbilirubinemia raised s.LDH, increased urinary urobilinogen. Low serum haptoglobin. Hemosiderinurea, hemoglobinurea in cases of intravascular hemolysis.

B-Find The Cause Of hemolysis

: 1- Blood Film Morphology: Target Cells,Sickle Cells,Heinz Bodies, Blister Cells, Fragmented RBC, Spherocytes. 2-Hemoglobin Electrophoresis: for Hemoglobinopathies. 3- Osmotic Fragility test for Spherocytosis 4- Enzyme assay for Enzymopathies. 5- Coomb,s test for immune hemolysis. 6- Ham,s test for PNH.

25 years old female accidentally discover she had splenomegally while she had biliary colicy pain ,patient has no symptomes apart her new biliary colic no history of transfusion, and she has family history of early cholecystectomyCBC:showed spherocytosis, increase corrected retic 5% ,T.S.B 2mgldl,coombs was negative

Hereditary spherocytosis

This is an autosornal dominant disorder in which the principal abnormality appears in red cell membrane protein. Approximately 25% of patients have no family history. The erythrocyte envelope is abnormally permeable and the sodium pumps are overworked.

The exact nature of the red blood cell defect may vary from family to family.The severity of the disorder is very variable even within an affected family.  The erythrocytes lose their biconcave shape, become spherical and are more susceptible to osmotic lysis. These spherocytes are destroyed almost exclusively by the spleen.Haemolysis is mainly extravascular.



Diagnosis &Treatment
Clinical Features:The severity of anemia is variable from asymptomatic to transfusion dependent anemia.Jaundice is also variable,as well as splenomegaly.Complications include 1- Crises (hemolytic, megaloblastic, and aplastic(. 2- Pigment Gall stones.Lab Tests:Evidence of Hemolysis: Anemia, Reticulocytosis, raised S.LDH…Spherocytes on blood film.+ve Osmotic Fragility Test.-ve Coombs Test.Treatment : 1-Blood Transfusion. 2-Folic acid. 3-Splenectomy for moderate to severe cases.

20 years old male presented with abdominal pain followed by dark color urine .he had history of flu-like illness with history of ingestion of trimethprim.family noticed that he become pale within few hours ago.
CBP:Hb 7 gm/l ,retic 15%,with presence of Heinz body,and blister cell,and spherocytes

Glucose 6 Phosphate Dehydrogenase Deficiency

G6PD Enzyme is the first one in the hexosmonophosphate shunt, the function of this shunt is to service the enzymes glutathione reductase and glutathione peroxidase, which protect the red cells against damage due to oxidation.

G6PD deficiency

The deficiency is inherited as an X-linked disorder Oxidant damage of RBC followed by intavascular hemolysis is induced by: 1- Infections . 2- Ingestion of Fava Beans. 3-Oxidant drugs like: sulfa, dapsone, antimalarial, chloramphenicol….., 4- Surgery.Clinical manifestations: 1- Most cases present with episodic intravascular hemolysis with fever, rapid anemia, jaundice and deep colored urine. 2- Rarely the hemolysis is chronic. 3- Neonatal jaundice.

G6PD deficiency

Lab Tests:1- Anemia, reticulocytosis, indirect hyperbilirubinemia…2- Blister RBC on blood film, and Heinz bodies.3- Hemoglobinurea and later hemosideriurea.4- Enzyme assay is useful after recovery.Treatment:1- Avoid fava beans and oxidant drugs.2- For the hemolytic episode: stop the offending factor, blood transfusion, folic acid.

HAEMOGLOBINOPATHIES

The haemoglobinopathies can be classified into two subgroups: 1- Where there is an alteration in the amino acid structure of the polypeptide chains of the glohin fraction of haemoglohin, commonly called the abnormal haemoglohins: the best-known example is haemoglobin S found in sickle-cell anaemia. 2- Where the polypeptide chain production is impaired or absent for a variety of reasons: these are the Thalassemias.

Hemoglobin Structure and Production

Fetal hemoglobin, HbF (α2γ2) switches to adult forms HbA (α2Я2) and HbA2 (α2δ2) at 3-6 months of life.HbA constitutes 97% of adult hemoglobin.HbA2 constitutes 3% of adult hemoglobin.4 α genes are located on chromosome 16.2 Я genes are located on chromosome 11.There is the possibility of mixed defectse.g. Я-thalassemia minor and sickle cell (HbS) trait.


15years old child presented with ascitis and leg oedemea .he referred by surgeon planning for splenectomy due to huge spleen.Pateint transfusion dependent since childhood and his brother dead on his second decade.On examination: anemic, with slate grey skin and puffy face, leg oedema,Ascitis,hepatosplenomegally
CBC:Hb:7.8,retic 7%,NRBC10/50cell,MCV 56,hypochromic microcytic WBC :3.5x109 Platelet 40x109


Pregnant lady with 24wks gestation referred by her gynecologist as history of increasing anemia and and needs of transfusion. Patient denied any previous history of transfusion and her hemoglobin level since childhood around 10gm/l with family history of anemiaex.patient pale ,not jaundice ,no organomegaly
CBC:Hb 8gm/l,retic 5%,MCV 60 Hypochromic microcytic S.Ferritin was normal

THALASSEMIAS

HETEROZYGOU Я THALASSEMIA : Я-Thalassemia MinorCommon condition in Mediterranean Basin ,Africa,AsiaClinical PresentationMild or no anemia.Spleen sometimes is palpable.May be masked by Fe deficiency and sometimes confused with iron deficiency anemia.Diagnosis 1- Hb 9-12 g/dL, MCV < 70 2- Microcytosis +/– hypochromia,target cells present,basophilic stippling usually present. 3- Hb electrophoresis: Hb A2 increased to 3.5-5% (normal 1.5 - 3.5%), 50% of individuals have slight increase in HbF.ManagementAdd folic acid.Patient and family should receive genetic counseling.

Pathophysiology Ineffective beta chain synthesis due to point mutation in the beta gene promoter or enhancer on chromosome 11, excess alpha chains relative to beta chain leading to ineffective erythropoiesis and hemolysis of RBC, compensatory increase in HbFClinical PresentationStart presenting at 3-6 months because of replacement of HbF by HbASevere anemia developing in the first year of lifeJaundiceStunted growth and development (hypogonadal dwarf)Gross hepatosplenomegaly (extramedullary hematopoiesis)Skeletal changes (expanded marrow cavity) • Skull x-ray has “hair-on-end” appearance • Pathological fractures commonEvidence of increased Hb catabolism (e.g. gallstones)Death from • Untreated anemia . • Infection (early). • Iron overload (late, secondary to transfusions), usually20-30 years old.

PATHOPHYSIOLOGY OF B-THALASSEMIA MAJOR

Diagnosis1- Hemoglobin 4-6 g/dL.2- Peripheral blood: hypochromic microcytosic, increased reticulocytes, basophilic stippling, target cells. - Postsplenectomy blood film shows Howell Jolly bodies, Nuleated RBC, and thrombocytosis.3- Hb electrophoresis • Hb A: 0-10% ( normal > 95%) • Hb F: 90-100%4-DNA analysis.

Management 1- Blood transfusions to ensure growth and decrease skeletal deformities ,try to keep Hb > 10 gm/dL, add folic acid. 2- Fe chelators to prevent iron overload like desferrioxamine, deferiprone.defrasirox.


3-Ensure good nutrition and try to minimize the frequency of infectious episodes .Infections should be treated adequately. 3- Allogeneic Bone marrow transplant (if suitable donor). 4- Splenectomy for mechanical problems and hypersplenism.5- Genetic counseling for prevention

ALPHA THALASSEMIAS

PathophysiologyAutosomal recessiveDeficit of alpha chains4 grades of severity depending on the number of defective alpha genes 1 - silent: αα/ α- 2 - trait: αα/-- or α-/ α- 3 - Hb H Disease (presents in adults) : α-/-- 4 - Hb Bart’s (hydrops fetalis): --/--Hb Bart’s made of 4 gamma chains; not compatible with lifeHb H excess of beta chains, is unstable, and leads to inclusion bodiesDiagnosis 1- Peripheral blood film: microcytes, hypochromia, occasional target cells, screen for Hb H inclusion bodies. 2- Hb electrophoresis not diagnostic. 3- DNA analysis using alpha gene probe.Management: same as beta thalassemia.

PATHOPHYSIOLOGY OF ALPHA THALASSEMIAS

HEMOGLOBIN H INCLUSION BODIES

Sickle Cell anemia

Autosomal recessive Amino acid substitution of valine for glutamate in position 6 of beta globin chain. *It has a wide geographical distribution.

Sickle Cell anemia

Mechanisms of SicklingAt low PO2, deoxy Hb S polymerizes, leading to rigid crystal-like rods that distort membrane = SICKLES The PO2 level at which sickling occurs is related to the % of Hb S present - If the patient is heterozygous (Hb AS), the sickling phenomenon occurs at a PO2 of 40 mmHg - If the patient is homozygous (Hb SS), sickling occurs at 80 mmHgSickling is also aggravated by • Acidosis. • Increased CO2. • Increased 2,3-DPG. • Increased temperature and osmolality.

Clinical Consequences Of SCA

Heterozygous SCA: Hb S TraitClinical presentation:• the patient will appear normal except at times of extreme hypoxia and infection, elderly patients may suffer from loss of renal concentration ability. Diagnosis:1- Hb level is normal2- Peripheral blood: normal except for a few target cells3- Hb electrophoresis (confirmatory test): Hb A fraction of 65% ; Hb S fraction of 35%Treatment: 1- Avoid hypoxia during flying and surgery.2- Folic acid for pregnant.3- Genetic counseling.


HEMOGLOBIN ELECTROPHORESIS IN SCA

Homozygous SCA: Hb SS Disease

Clinical presentation1- Chronic hemolytic anemia with jaundice in the first year of life.2- Retarded growth and development +/– skeletal changes.3- Susceptibility to infections by encapsulated organisms due to hyposplenism.4- Spleen enlarged in children and atrophic in adults.5- Crises:Vaso - occlusive crises (infarction) leading to pain, fever , leukocytosis, acidosis& dehydration. Any organ or tissue can be involved.Hyperhemolytic crises associated malaria.Sequestration crises presenting with anemia and rapidly enlarging spleen or liver.Aplastic crisis due to parvovirus infection or folate deficiency, leading to rapid anemia and reticulocytopenia.Acute Chest Syndrome presenting as fever, chest pain, cough and hypoxia.6- Iron overload due to repeated blood transfusion (less likely compared to Thalassemia).7-Gall stones,leg ulcers.

Homozygous SCA: Hb SS Disease

Diagnosis 1- Peripheral blood: sickled cells,target cells, reticulocytosis. 2- Indirect hyperbilirubinemia, raised s.LDH 3- Screening test: sickle cell preparation searching for sickling phenomenon. 4- Hb electrophoresis (confirmatory test): Hb S fraction > 80%,the rest is Hb F.

Homozygous SCA: Hb SS Disease

Management1- Prevention Of Sickling Attacks: • Avoid conditions that favor sickling (hypoxia, acidosis, dehydration, fever). • Vaccination in childhood e.g. pneumococcus, meningococcus. • Good hygiene and nutrition.2- Genetic counseling.3- Blood transfusion to keep Hb>8 g/dl + Iron chelation for frequent transfusions.4- Folic acid to avoid folate deficiency.5- Hydroxyurea to enhance production of Hb F, presence of Hb F in the SS cells decreases polymerization and precipitation of Hb S. Note: Hydroxyurea is cytotoxic and may cause bone marrow suppression it is indicated in severe cases.6- Experimental anti-sickling agents.7- Allogeneic Bone marrow transplant for selected patients.

Homozygous SCA: Hb SS Disease

Treatment of Vaso-Occlusive Crisis Oxygen. Good Hydration (reduces viscosity). Antimicrobials. Correct acidosis if severe. Analgesics/narcotics (give enough to relieve pain). Exchange transfusion for CNS crisis.


25 years old female presented with one week history feature of anemia.Examination revealed tinge of jaundice and palpable spleen. All the following are true except
Hb:4g/l,WBC 15X109,80% neutrophil,retic corrected 16%,DAT positive for IgG,TSB 4mg/dl peripheral blood film showed spherocytosis.

AUTOIMMUNE HEMOLYTIC ANEMIA

Types: 1- Warm Antibody type :usually IgG. 2- Cold Antibody type: usually IgM.AUTOIMMUNE HEMOLYTIC ANEMIA (Warm Antibody type) Pathophysiology: RBC are coated with IgG or complement (C3d) or both leading to extravascular hemolysis in RES (mainly spleen).Classification:1- idiopathic2- secondary to • Lymphoproliferative disorders (CLL, Hodgkin’s disease, Non - Hodgkin’s lymphoma) • Autoimmune (SLE)3- Drug induced (penicillin, quinine/quinidine, alpha methyl dopa)Clinical Features:Usually insidious :anemia, jaundice and splenomegaly.


Mechanism of extravascular hemolysis in autoimmune hemolytic anemia. (A) Macrophage encounters an lgG-coated erythrocyte and binds to it via its Fc receptors. Thus entrapped, the RBC loses bits of its membrane as a result of digestion by the macrophage. The discoid erythrocyte transforms into a sphere. (B) RBC lightly coated with lgG (and therefore incapable of activating the complement cascade) is preferentially removed in the sluggish circulation of the spleen. (C) RBC with a heavy coat of lgG; thus, C3b (black circles) can be removed both by the spleen and the liver.

AUTOIMMUNE HEMOLYTIC ANEMIA (Warm Antibody type)

Diagnosis1- Spherocytes in blood film, reticulocytosis.2- Indirect hyperbilirubinemia, raised s.LDH.3- Positive direct antiglobulin test (direct Coombs’) best detected at 37єC (hence “warm-reacting antibodies”)4- Exclude delayed transfusion reaction.ManagementTreat underlying causeCorticosteroids: prednisolone 1mg/Kg until response then taper over 2-3 months.Splenectomy for relapsed and corticosteroid resistant cases .Immunosuppressives like azathioprine for relapses after splenectomyBlood transfusion is used with caution.Add folic acid.

Autoimmune Hemolytic Anemia with Cold-Reacting Antibodies

Pathophysiology Either monoclonal or polyclonal IgM Antibodies attach to RBC surface antigens in peripheral circulation where T < 37єC. Antibodies will detach from the surface antigen if T > thermal amplitude Thermal amplitude is the temperature at which IgM is attached to RBC surface Associated with intravascular hemolysisClassification Idiopathic Secondary to • Lymphoproliferative disorders (CLL, Hodgkin’s disease, non-Hodgkin’s lymphoma) • Infections (Mycoplasma pneumoniae, EBV).Clinical Features:Anemia, acrocyanosis, joint pain, vasculitic rash, Raynaud phenomena, and rarely splenomegaly.

COLD AGGLUTININ

Autoimmune Hemolytic Anemia with Cold-ReactingAntibodies (IgM)
Diagnosis1- Anemia, mild reticulocytosis, RBC agglutination in blood film .2- Positive cold agglutinin test best at 4єC.3- Positive direct Coombs’ for complement at any temperature.ManagementTreat underlying causeWarm the patient above the thermal amplitude of the antibodyPlasmapheresis.Immunosuppressives like chlorambucil.

Non Immune Hemolysis

1- Infections: Bacterial, Malaria, Babesia. 2- Mechanical: Microangiopathic Hemolysis (MAHA): TTP, HUS, DIC. March Hemoglobinurea. Mechanical Cardiac Valves. 3- Snake bite. 4- Burns.

Drug Induced Hemolysis

1- Hapten Mechanism: high dose Penicillin 2- Complement Fixation : quinidine , phenacetin. 3- Autoantibody production: L-dopa, methyldopa. 4- Nonspecific: cephalothin. 5- Metabolic: sulfa drugs.

Hypersplenism

It is a state of sequestration of one or more of blood elements in an enlarged spleen. Causes 1- Portal hypertension 2- Myeloproliferative disorders. 3- Thalassemia major. 4- Others. Diagnosis 1- Reduction of one or more of blood elements. 2- Normal cellularity of bone marrow. Treatment Treat the underlying condition, splenectomy may be indicated for increased transfusion requirements.


in Hypersplenism ,the following are:a-Portal hypertension may be a causeb- there may be a reduction only in platelet c- hypocellularity of bone marrow. d-splenectomy may be indicated for sever cytopeniaE- Howell-jolly body may seen in peripheral blood