HEMOLYTIC ANEMIA EXTRACORPUSCULAR DEFECTS DR. SWAMY C.R. Anemia resulting from an increase in the rate of red cell destruction. CAUSES: I.Immune A. B.

c. A. Isoimmune Hemolytic disease of the newborn incompatible blood transfusion B. Autoimmune: lgG only; c3 only; mixed lgG and C3 1. Idiopathic a.Warm antibody b. Cold antibody c. Cold warm (Donath Landsteiner antibody) SECONDARY: a. Infection, viral: Infectious mononucleosis (Epstein Barr virus (EBVI), kcytomegalovius

(CMV), hepatitis, herpes simplex, measles, varicella, influenza A, coxsackie B, human immunodeficiency virus (HIV), bacterial; streptococcal, typhoid fever, Escherichia coli sapticemia; Mycoplasma pneumoniae (atypical pneumonia). b.Drugs and chemicals: quinine, quinidine, phenacetin, p-aminosalicylic acid, Sodium cephalothin (Keflin), penicillin, tetracycline, rifampin,sulfonamides,chlorpromazine,pyramidon, dipyrone, insulin c.Hematologic disorders: leukemias, lymphomas, lymphoproliferative

syndrome, idiopathic thrombocytopenic purpura (Evans syndrome), paroxysmal cold hemoglobinuria, paroxysmal noctumal hemoglobinuria d. Immunopathic disorders: Systemic lupus erythematosus,

perirteritis nodosa, scleroderma, dermatomyositis, rheumatoid arthritis, ulcerative colitis, agammaglobulinemia, Wiskott Aldrich syndrome, dysgammaglobinemai igA deficiency, thyroid disorders e. Tumors : ovarian teratomate, dermods Nonimmune A. Idiopathic B. Secondary

1. Infection, viral; infectious mononucleosis, viral hepatitis; bacterial; streptococcal, E.coli septicemia, clostridium perfringens, Bartonella bacilliformis; parasites; malaria, histoplasmosis. 2. Drugs: phenylhydrazine, vitamin k, benzene, nitrobenzene sulfones, lead phenacetin, acetinalimide 3. Hematologic disorders: leukemia, aplastic anemia, megaloblastic anemia, bypersplenism, pyknocytosis Microangiopathic hemolytic anemia: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chronic relapsing schestocytstic

hemolytic anemia, burns, postcardiac surgery, march hemoglobinuria. Miscellaneous: Wilsons disease, erythropoietic porphyria, osteopetrosis, hypersplenism HEMOLYTIC DISEASE OF THE NEWBORN Immune hemolysis occurring in the fetus as a result of the transplacental passage of maternal antibody directed against a fetal red cell antigen that is not shared by the mother. The antibody is the product of the normal immune response to a foreign substance and is invariably of the lgG type, although hemolytic disease of the newborn caused by ABO incompatibility always has been more common than that caused by Rh incompatibility, ABO

hemolytic disease is usually less severe and has not been associated with fetal and neonatal death or significant sequelae to the extent that Rh hemolytic disease has. The spectrum of pathologic conditions resulting from minimal anemia or hyperbilirubinemia to hydrops fetalis. ETIOLOGY AND PATHOGENESES Rh disease is most significant clinically because of its severity, although ABO hemolytic disease is about twice as common. The passage of fetal red cells across the placenta into the maternal circulation may result in the production of antibodies against fetal red cell antigens

recognized by mother as not self . The introduction of a sensitive acid elution technique for identifying fetal cells by the demonstration of intracellular Hb F enabled the detection of 0.05 ml of fetal blood in the maternal circulation. The gestational are at which fetal maternal transplacental leakage of red cells begins is uncertain, The volume of fetal blood that at any one time enters the maternal circulation during a normal pregnancy is small, probably less than 0.1 ml. It is during delivery that larger boluses, greater than 0.2 ml, enter the maternal circulation.

It is these larger fetal maternal hemorrhages that stimulate the production of antibody Immunology fetal maternal bleeds may occur in spontaneous or induced abortions. Entopic pregnancy, cesarean section and manual removal of the placenta. The risk of sensitization is related to the volume of the fetal maternal bleed ing. In general the larger the fetal maternal hemorrhage, the greater the incidence of demonstrable sensitization. Since sensitization occurs most frequently during birth, the most accurate indicator for sensitization is the demonstration of maternal antibodies during the succeeding pregnancy, The incidence of sensitization at the end of the second pregnancy is about 17% in ABO compatible mothers.

CLINICAL FEATURES Jaundice Noted with in the first 24 hrs after birth and in untreated infants reaches maximal levels Immune hemolysis and anemia Encephalopathy (kernicterus) Caused by the effects of unconjugated bilirubin on the central nervous system. Purpura associated with thrombocyutopenia Hypoglycemia -is frequently noted in severally affected infants.

INVESTIGATOINS Peripheral blood Evidence for increased red cell destruction is the degree of anemia, reticulocytosis, and normoblasas, polychromasia and anisocytosis, intense leukocytosis may be seen in severely affected infants. Bone marrow Erythroid hyperplasia is invariably present. Immunologic evaluation The diagnosis is established if red cells from an Rh positive infant born to an Rh negative mother give a positive direct antiglobulin test.

Serum bilirubin - Cord bilirubin levels are not high and levels in excess of 4 mg/dl are evidence of severe disease. THERAPY Prevention of Rh isosensitization - Routine administration of Rh immune globulin to all unsensitized Rh-negative mothers who have

given birth to an Rh-positive infant or who have had a spjontaneous or induced abortion. Administration of 300 micro grams of Rh immune globulin intramuscularly to all unsensitized Rh-negative women within 72 hours of the delivery of an Rh-positive infant. In cases in which Rh immune globulin has not been given within 72 hours, it should be administered late rather than withheld. After abortion less than 12 weeks gestation, 50 micro grams more than 12 weeks gestation, 100 micro grams After amniocentesis 50 micro grams (depending on amount of fetomaternal hemorrhage) After ruptured ectopic pregnancy or manual version, 10 to 15 micro grams ml fetal blood. TREATEMENT OF THE AFFECTED INFANT Major objectives : 1). Prevention of intrauterine fetal death

2) prevention of bilirubin encepkjhalopathy in the live born infant. Prevention of intrauterine fetal death : The developing fetus s at risk from severe anemia, not from hyperbilirubinemia, since the placenta effectively clears this substance. Therapy of the severely affected fetus is directed therefore solely toward correcting the severe anemia. Prevention of bilirubin encephalopathy Exchange transfusion : The volume of an exchange

transfusion is usually calculated at two times the blood volume of the exchanged infant. Or about 160 ml/kg. Phototherapy : ABO HEMOLYTIC DISEASE OF THE NEWBORN A reported to Cause of about two thirds of the cases of hemolytic disease of the newborn. It differs from Rh hemolytic disease primarily in the degree of severity. Severe hyperbilirubinemia is unusual and hyudrops fetalis extremely rare. The pathophysiology of ABO hemolytic disease is identical to that to Rh disease. The antibody causing the immune destruction is of the lgG class. Since igM anti A or anti-B cannot cross the placenta. ABO hemolytic disease is restricted almost to tally to group A or B infants born to group O mothers.

The reason for the lack of clinical disease are not completely known. However, certain factors may affect the interaction of anti A with A cells in the fetus and newborn. A weakly Positive direct antiglobulin test on cord blood or newborn blood may be found. 3. free anti A or anti B may be demonstrated in the serum of the newborn. 4. Confirmatory evidence is the presence of lgG anti A or and B in the maternal serum. 2. TREATMENT

Therapy of severe ABO hemolytic disease is similar to that of Rh hemolytic disease. In the frequently occurring mild cases phototherapy or phenobarbital therapy can be given. WARM AUTOIMMUNE HEMOLYTIC ANEMIA Antibodies of the lgG class arWARe most commonly responsible for AIHA in children. The antigen to which the lgG antbody is directed is one of the Rh erythrocyle antigens in more than 70% of cases. The antibody usually has its maximal activity at 37%C, and resultant hemolysis is called warm antibody-induced hemolytic anemial. Rarely, warm reacting lgM antibodies may be responsible. Clinical Features

1. Severe, life-threatening condition 2. Sudden onset of pallor, jaundice, dark urine 3. Splenomegaly 4. Laboratory findings. a. Hemoglobin level: may be very low b. Marked reticulocytosis is very common c. Smear: prominent spherocytes, polychromasia, macrocytes, autoagglutination d. Neutropenia and thrombocytopenia (occasionally) e. Increased osmotic fragility and autohemolysis proportional to sphero cytes

Direct coombs test positive b. Hyperbilirubinemia c. Haptoglobin level is usually markedly decreased d. Hemoglobinuria, increased urinary urobilinogen a.

MANAGEMENT Because this is a life-theatening condition, the following parameters must be monitored carefully. 1. Hemoglobin level (q4h) 2. Reticulocyte count (daily) 3. Splenic size (daily) 4. Hemoglobinuria (daily) 5. Haptoglobin level (weekly) 6. Coombs test (weekly

TREATMENT 1. Blood transfusion a. If specific antibody is identified, compatible donor may be selected. b. Washed packed red cells should be used c. The volume of transfused blood should only be of sufficient quantity to relieve any cardiopulmonary embarrassment from the anemia. 2. Corticosteriod therapy. a.

Hydrocortisone 8-40 mg/day IV in divided doses (q8h) or prednisone 2-10 mg/day PO is administered. a. High dosage corticosteroid therapy should be maintained for several days. Threafter, corticosteroid therapy in the form of prednisone should be slowly tapered off over a 3 to 4 week period. 3.Plasmapheresis has been successful in slowing the rate of hemosysis in patients with severe IgG- induced immune hemolytic anemia. Success is limited, possibly because more than half of the IgG is extravascular and the plasma contains only small amounts of the antibody ; most of the antibody is on the red cell surface.

4.Intravenous gamma globulin (IVGG) in a dose of 5 gm/kg, 5.splenectomy: Indicated if the hemolytic process continues to be brisk despite highdosage corticosteroid therapy and intravenous gamma globulin for 3-4 weeks. Cytoxic Agents a. Antimetabolites : azathioprine, 6mercaptopurine, and thiroguanine b. Alkylating agents: chlorambucil and cyclophosphamide. c.

Mitotic inhibitos: vincristine and vinblastine 6. 7. Immunosuppressive therapy: Cyclosporine 8. Hormonal therapy : danazol, (synthetic androgen). which has a masculinizing effect. Appears to be due to decreased expression of macrophage Fcy receptor activity; COLD AUTOIMMUNE HEMOLYTIC ANEMIA IgM antibodies are found less often in association with hemolysis in the pediatric age group. The destruction

of red blood cells is usually triggered by cold exposure. Cold hemagglutinin disease usually occurs during 1. Mycoplasma pneumoniae infection 2. Infectious mononucleosis, 3. cytomegalovirus 4. mumps.. CLINICAL FEATURES Similar to those in warm autoimmune hemolytic anemia but are less marked. TREATMENT Treatment consists of control of the underlying disorder. 1. Blood Transfusions may be necessary ; warming the blood to 370 C during administration by means of a heating coil or water bath is indicated to avoid further

temperature activation of antibody. If the anemia is severe, a trial of cytotoxic drug therapy is appropriate. Alkylating agents such as cyclophosphamide and chlorambucil. Treatment with corticosteroids or splenectomy is generally not effective. Plasmapheresis is a valuable approach to reducing the level of cold agglutinins. DONATH LANDSTEINER COLD HEMOLYSIS An unusual igG antibody with anti P specificity, is responsible. This antibody, although uncommon, is most frequently found in children with viral infections. Hemolysis in this syndrome is most commonly intravascular as a result of the unusual complement activating efficiency of this IgG antibody. Hemolysis, which is usually mild, may

occasionally be severe but resolves as the infection clears. MICROASGIOGRAPHIC HEMOLYTIC ANEMIA The blood smear is characterized by the presence of buu erythrocytes, schistocytes, helmet cells, and microspheocytes. THANK YOU

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