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Laboratory Sciences - خون شناسی بیماری های کم خونی

خون شناسی بیماری های کم خونی

Thu 23 Dec 2010

بر اساس کتاب خون شناسی هنری - دیویدسون Dr.Nuriyan Professor Hematology Red Cell Disorders

  Anemia

Erythrocytosis Anemia: Definition Reference Value Of Anemia Gold Standard:Low total red blood cell mass Practical Standard:Low hemoglobin Concentration 6 month to four years Hb < 11 g/dL 5 to 9 years Hb < 11.5 g/dL 10 to 14 years Hb < 12 g/dL Adult Males Hb < 14 g/dL Adult Females Hb < 12 g/dL Pregnant Women Hb < 11 g/dL Pathophysiologic Classification  Decreased production  Nutritional  Marrow suppression  Marrow infiltration  Increased loss  Blood loss  Hemolytic  Immune  Non immune  Acquired:  Decreased production  Increased loss  Congenital:  Increased loss/Hemolytic General Clinical Manifestation Of Anemia  Symptoms  fatigue  dyspnea on exertion  Palpitation’angina  fainting’vertigo’headache  Signs  pallor of skin, nail beds’ buccal mucosa  Rapid bounding pulse’ Systolic murmurs Morphologic Classification  Microcytic  Normocytic  Macrocytic Red Cell Indices  Mean cell volume (MCV)  Mean cell Hb concentration (MCHC)  Red cell distribution width (RDW) Mean Cell Volume (Normal 80 ~ 100 fL)  Low MCV = Microcytic  Normal MCV = Normocytic  High MCV = Macrocytic Mean Cell Hemoglobin Concentration (Normal 32 ~ 36 g/dL)  Low MCHC = Hypochromic  Normal MCHC = Normochromic  High MCHC = Hyperchromic Red Cell Distribution Width (Normal 12 - 15%) High RDW = Anisocytosis Poikilocytosis Any morphologic abnormality in red cell shape Acquired RBC Disorders  Decreased Production:  Aplastic, Hypoplastic anemias  Deficiency anemias Iron, B12, Folate etc.  Lack of erythropoiesis - Kidney disease  Marrow disease, malignancy, radiation  Increased loss/destruction:  Blood loss anemias - parasites, bleeding  Hemolytic anemias - Autoimmune (cold & warm antibody) mechanical, drugs & toxins. Iron Deficiency Anemia  Most common cause of anemia.  Is very common in developing country especially in young girls and child bearing women.  Children between 6 to 24 months are very susceptible (milk anemia of infancy)  Almost all cases of iron deficiency anemia in adult males is due to chronic blood loss. Iron Metabolism  Two thirds of total body iron is in erythrocytes  Each milliliter of red cells contain 1 mg iron  Iron storage is in macrophage as water soluble ferritin and water insoluble hemosiderin  Stored iron is transported to the normoblasts by transferrin( B-globulin).  Each molecule of apotransferrin binds two atoms of iron  Transferrin binds to transferrin receptor on the cell membrane which internalized rapidly. Iron Metabolism  Absorption from duodenum.No excretory mechanism.  Recycling of iron in body(dead cells to new cells)  Requirement is 1mg/day in adult’ 2 mg/day in children.  10% of the 10 to 20 mg of dietary iron absorbs in duodenum  Iron absorption facilitate by lower PH in duodenum  Laboratory tests:  Serum iron:male 60~180 mg/dl-female:40~150 mg/dl  Serum iron binding capacity: 230~ 410 mg/dl  Serum ferritin:Male 20~250 and female 10-120 Mic/dl Iron Deficiency Anemia : Etiology  Blood loss  Acute bleeding,chronic blood loss parasites  Poor diet  Increased need  Pregnancy, children, juvenile  Worm infestation Iron Deficiency  Dietary  Approximately 85% of iron stores in newborn is in Hg  Infants have higher dietary requirement  rapid growth and expanding RBC mass  Rarely encountered before 4 months unless blood loss  Preterm infants are at higher risk of decreased iron stores and more rapid growth  in adolescents experiencing growth spurts  especially adolescent girls both due to rapid growth and menstrual bleeding Clinical Features of IDA  Anemia:  Pallor, Weakness, Lethargy  Breathlessness on exertion  Palpitation’ Heart failure  Edema  Iron Deficiency:  Angular cheilosis, Atrophic glossitis  Dysphagia , koilonychia, Atrophic gastritis. Iron Deficiency Anemia-Pathogenesis  Decreased Iron stores  Decreased Hb Synthesis  Delayed maturation of erythroblasts.  Decreased cell size (microcytes)  Decreased Hb content (hypochromia)  Decreased RBC number  Anemia. Iron Deficiency- Evaluation  MCV- Low (microcytosis)  Reticulocyte count- low  RDW:High  Iron: low  Ferritin: low  TIBC: high  FEP (free erythrocyte protoporphyin): high  Blood smear:hypochromia’microcytosis.  Bone marrow:Normoblastic hyperplasia with decreased sideroblasts(< 20%)  Mentzer index: MCV/RBC > 13.5 The anemia is at first normochromic,normocytic gradually becomes microcytic and finally microcytic , hypochromic Blood Film:Anisocytosis’Hypochromia Iron Deficiency Anemia Iron Deficiency Anemia Treatment  Blood transfusion in severe cases (Hg <4)  Also with respiratory or cardiac distress  PRBC’s infused SLOWLY not exceeding 3 ml/kg/hr  Rapid transfusion may result in CHF or hypervolemia  Consider Lasix prior to transfusion  Iron Supplementation  Oral Fe 3-6 mg/kg elemental iron bid-  Give with meals or juice (increased absorption)  Treat underlying cause  Nutrition counseling Anemia with Low MCV and Low Reticulocytes  Differential diagnosis  Iron deficiency  Sideroblastic anemia  Thalassemia trait  Anemia of chronic disease  Laboratory evaluation  Iron, iron-binding capacity, and ferritin  Blood smear - Target cells, stippling, etc.  Hb electrophoresis for Thalassemia  Bone marrow iron stores, ring sideroblasts Differential diagnosis between Iron deficiency anemia and minor thalassemia Iron Deficiency- follow up  Reticulocyte count raises within 7-10 days after treatment (increases earlier than Hb)  Hb may not return to normal until after two months  Further investigation if anemia persists Megaloblastic anemia - Etiology  Inadequate intake(Rare)  Defective production of intrinsic factor:  Pernicious anemia:Antiparietal antibodies (90%) Anti-intrinsic factor antibody( blocking and Binding type)  Congenital pernicious anemia due to lack or defective IF  Gastrectomy,Ileal resection  Inflammatory bowel disease  Malabsorption syndromes  Blind loop syndrome Pathogenesis of Megaloblastic Anemia  Decreased Vit B12 / Folate  Decreased DNA Synthesis and delayed maturation of nucleus due to intermitotic resting and a block early in mitosis  Increased cell size due to large cytoplasmic mass  Normal Hb content (Normochromia)  Decreased RBC numbers  Decreased WBC number (pancytopenia)  Anemia & Pancytopenia. Macrocytic Anemia Megaloblastic Anemia-Morphology  Peripheral Blood:Pancytopenia is the rule.  Elevated MCV(Above 100 fl)  Macroovalocyte,Severe poikilocytosis and anisocytosis, multiple Howell-Jolly bodies, basophilic stippling,and NRBCs show karyorrhexis effect.  Leukopenia’increased numbers of granulocytes lobes (five lobes over 5%-six and seven lobes)  Thrombocytopenia  Bone marrow:  Bone marrow is hyperplastic,The fat is replaced  Erythroid precursors is increased and myeloid/erythroid ratio is decreased.All lineage show megaloblastic changes Diagnosis of Cobalamin Deficiency  Therapeutic Trail: 10 Micg/day.  Serum Cobalamin Assay.  Reference value is 200 ~ 900 ng/L  Methylmalonic Acid and Homocysteine Assay.  Methylmalonic acid is isomerized by B12 to succinate’in B12 deficiency increased amount of homocystein is significant  Deoxyrubidine Suppression test  This measures the ability of marrow cells in vitro to utilize deoxyrubidine in DNA synthesis.The major source of thymidine for DNA is from deoxyrubidine. Folic Acid Deficiency  Inadequate Intake Of Folate  Dietary folate deficiency is common in tropics  Anemia will appear after 3~ 6 months.  Fresh milk contain adequate folate but heated milk’ powdered milk and gout’s milk do not  Defective Absorption Of Folate  Malabsorption Syndromes’Anticonvulcents,OCP.  Increased Requirement For Folate  Pregnancy,Rapid growth,Infections,Hemolytic states’ Liver disease’Alchoholism  Inadequate Utilization Of Folate  Folic acid antagonists:Methotrexate’Alcohole Therapy For Megaloblastic Anemia  Pernicious anemia is treated by intramuscular injection of 1000 Mg of B12 daily’1000 Mg twice weekly after two weeks.  In folate deficiency oral therapy is used as a dosage of 1 ~ 2 mg/day  The maximal reticulocyte response occurs in 5 ~ 7 days.  Within 2 ~ 4 days,the marrow appear normoblstic.  Granulocytic abnormalities return to normal more slowly, hypersegmented neutrophils disappear after 12 ~ 14 days Anemia of Chronic Disease  Anemia is due to chronic inflammation Cancer and autoimmune disease.  Second most common cause of anemia  Cytokines prevent iron release from macrophages and also prevent hematopoiesis  Anemia is normocytic or microcytic.  Diagnostic tests in serum: High ferritin, Low iron, Low transferrin Impaired Production:Anemia Of Chronic Disease  Anemia is usually normocytic and normochromic but occasionally microcytic and hypochromic.  Marrow is normocellular or minimally hypocellular.  Serum iron is characteristically low. TIBC is decreased.  Sideroblasts are decreased’Storage iron is normal.  Erythropoietin level is above normal.  Pathogenesis:Presence of high levels of cytokines ( TNE-a ~ IL-1 ~ IFN-a) resulted to decreased red cell survival’altered iron metabolism’direct inhibition of hematopoiesis by inhibition of BFU-E & CFU-E , and decreased erythropoietin secretion. Impaired Production:Anemia Of Renal Insufficiency  The correlation between anemia and elevated BUN is positive’when creatinine clearance falls below 20ml/min HCT is below 30%Decreased production of erythropoietin.  Inhibitors of Erythropoies  is (PTH and Spermin).  Extracorpuscular Hemolysis:Both due to factors in uremic serum(resulted to Echinocyte,Spiculated RBCs) or change in red cell membrane ATPase.  Bleeding:Both due to thrombocytopenia or platelet dysfunction.  Folic acid deficiency in patients in a dialysis program. Blood Film:Burr Cells Chronic Renal Failure Blood Film:Basophilic Stippling Impaired Production:Anemia In Liver Disease  The anemia is of unknown origin.  The anemia is normocytic or macrocytic’ frequently with target cells’especially in obstructive jundice.  Red cells have increased surface membrane with increased cholesterol and lecithin contant.  Marrow is hypercellular and macronormoblastic without response to B12 or folic acid.  Small proportion of patient with cirrhosis have a hemolytic anemia associated with “Spur Cells”.  Spur Cells are secondary to lipid abnormalities in plasma are prone to destruction in the spleen. Blood Film:Target Cell Chronic Liver Disease Blood Film:Stomatocytosis Severe Liver Disease Blood Film:Acanthocytosis Impaired Production:Anemia In Endocrine Disease  Hypothyroidism:  Normochromic,normocytic to macrocytic anemia due to smaller tissue oxygen requirement resulted to reduced erythropoietin secretion.  Adrenal Cortical Hormone deficiency:  Mild to moderate normocytic normochromic anemia with an unknown etiology.  Deficient Testosterone Secretion:  Decreased red cell production of 1 ~ 2 g Hb/dL due to the effect of androgens on erythropoietin secretion.  Pituitary Deficiency:  Anemia is due to loss of growth hormone. Anemia Associated With Bone Marrow Infiltration (Myelophthisic Anemia)  This anemia is associated with marrow involvement by metastatic carcinoma’multiple myeloma’ leukemia’ lymphoma and storage disease.  Anemia is charactristic leukoerythroblastic anemia.  Anemia is normocytic and normochromic of varying severity with increased reticulocytes and with presence of normoblasts of any stages.  Leukocyte count is reduced or normal(occasionally high) immature neutrophils,even myeloblasts may be found.  Differential dignosis from MMM is by clinic.In MMM splenomegaly and hepatomegaly is the rule. Aplastic Anemia  Clinical Features:  Profound pancytopenia with an acute fulminating course and a rapid progression to death is common feature.  Bleeding ,and less commonly infection are presentation.  As a rule splenomegaly and lymphadenopathy are absent.  Disorder may have an insidious onset and a chronic course.  Etiology:  In approximately 70% Of cases any specific etiologic agent was not found, such cases are considered idiopathic.  11% ~ 20% of cases are due to drugs and chemical agents.  Infectious hepatitis account for 2% ~ 9% of cases. Aplastic Anemia Associated With Chemical Or Physical Agents  Toxic Aplastic Anemias:  Mustard compounds,Benzene,Busulfan,Urethane  Ionizing Radiation:  Erythroid cells are most sensitive’granulocyte have intermediate sensitivity’megakaryocyte are the least sensitive .Stromal cells are insensitive.  After acute exposure’reticulocyte count falls’but the red cell decline slowly because of their long survival.  A fall in lymphocytes occur after the first day.  Hypersensitive Aplastic Anemia:  A large number of drugs produce marrow damage after single or repeated exposure’antibiotics(Chloramphenicol)’anticonvulsants(mephenytoin)’ analgesics(phenylbutazone)’antithyroid(Cabimazole)’insecticids’etc. Aplastic Anemia And Other Disease  Infection:  Viral infections are frequently associated with marrow suppression.  0.07% of patient with HBV and 2% of Non-A,Non-B infection.  Patients are males and under 20’with a grave prognosis.  Mechanism of disease is due to direct toxicity or immune mediated  Paroxysmal Nocturnal Hemoglobinuria.  Pregnancy.  Thymoma:  Although thymomas are usually associated with pure red cell aplasi in 10%~15% of cases pancytopenia is seen  Immunologic disease:  Aplastic anemia is seen in 10% of eosinophilic fasciitis.  In SLE and rheumatoid arthritis. Constitutional Aplastic Anemia  Constitutional aplastic anemia designate to genetic predisposition to chronic bone marrow failure.  Fanconi’s Anemia:  Pancytopenia (Usually become obvious by eight years) with hypocellular marrow’increased level of fetal hemoglobin also developmental anomalies such as hyperpigmentation’ short stature’hypogonadism and aplasia of radius.  Risk of leukemia is high and median survival is 19 years.  Familial Aplastic Anemia  Patients have pancytopenia and hypocellular marrow without major developmental anomalies. Pure Red Cell Aplasia  Transitory Arrest Of Erythropoiesis:  Occur during the course of a hemolytic anemia which often preceded by parvovirus B19 infection which inhibits CFU-E.  Transient Erythroblastopenia of Childhood:  TEC occurs in healthy children between 1~3 years of age.  Congenital Red Cell Aplasia(Diamond-Blackfan Anemia):  A rare constitutional red cell aplasia appear in the first year of life due to defects in erythroid-commited progenitor cells.  Aquired Pure Red Cell Aplasia:  Most of these anemias appear to be part of a spectrum of autoimmune cytopenia.Half of the cases have thymoma. Hemolytic Anemias  A:Intrinsic abnormalities:  Red cell membrane disorders  Red cell enzyme deficiency  Disorders of hemoglobin synthesis  B:Extrinsic abnormalities:  Antibody mediated  Mechanical trauma  Infections  Chemical injury  Hypersplenism Hemolytic Anemias Immune lysis Warm and Cold Antibodies Mechanical Damage  Microangiopathy (DIC), Prosthesis, Trauma(march) Hereditary Defects  Membrane defect, Hb abnormalities, Enzyme defect Infection induced  Clostridia, malaria, septicemia Clinical Features:  Pallor  Mild and usually mucosal  Jaundice  Mild and usually fluctuating  Splenomegaly  Pigment gall stones  Crisis  Aplastic, Hemolytic,Vascular  Ankle ulcers CBC Analyzer Report Evaluation of Hemolytic Anemia  Red blood cell survival assay  By C51 25 to 32 days instead of 60 days  Plasma Hemoglobin assay  Normal value is 0.5 to 5 mg/dl  Serum LDH  Hemoglobinemia’Hemoglobinuria’Hemosiderinuria  Serum billirubin  Bone marrow biopsy  Peripheral blood smear  Reticulocyte Count Congenital RBC Disorders  Membrane Disorders:  Spherocytosis, Elliptocytosis  Hemoglobin Disorders:  Hemoglobinopathies - Sickle cell, HbC.  Thalassemia Syndromes - , ,   Enzyme disorders:  G6PD, PK deficiency Hereditary Spherocytosis  Anemia ‘Splenomegalia’ Jundice  75% cases are autosomal dominant’remaining are autosomal recessive  Deficiency of spectrin is the most common abnormality  Spectrin deficiency lead to reduced membrane stability  Spherocyte are trapped in the spleen  Spherocytosis is distinctive but is not pathognomonic  Moderate spelenomegalia  MCH is elevated in most cases  Hemolytic and Aplastic crisis Hereditory Spherocytosis  1-Osmotic Fragility Test  2-Autohemolysis Test Hereditary Eliptocytosis  Autosomal Dominant  Is due to loss or lack of Spectrin and decreasing of glycophorine C  Variants:  Hereditary(autosomal recessive) piropoeikilocytosis with rod shape eliptocytes’severe hemolytic anemia’ microcytosis and red blood cell fragmentation.  Spherocytic hereditary eliptocytosis: both spherocytes and eliptocytes’mild anemia’splenomegalia  Far east ovalocytosis: mild hemolysis’  Hereditary stomatocytosis: lack of stomatin’ mild anemia’ increased intrance Na and K (H2O)to red cell Paroxismal Nocturnal Hemoglobinuria  Is a rare disease  Clonal Stem cell disease  Intravascular red cell hemolytic by complement  Red blood cells are more sensitive to hemolysis  Decreased amount of anti-complement proteins  Loss or lack of glycosyl-phosphatidyl-inositol in plasma membrane of red cells Paroxismal Nocturnal Hemoglobinuria  Intravascular hemolysis with or without heglobinuria but with persistent hemosiderinuria  Infection’surgery’ blood transfusion and exercise may cause hemolysis.  Neutropenia and thrombocytopenia may be seen  Erythroid hyperplasia in bone marrow  Crisis of bone marrow hypoplasia or aplasia  Direct antiglobulin test is negative  Thrombosis is the most common cause of death  Hemolysis sucrose test:  Sucrose increase affinity of complement system to RBCs membrane  Ham test (Aciditic serum test):  Acidic serum active complement from alternative pass way Erytrocyte metabolism  RBCs have no mitochondria so have no oxidative phosphorylation  Glucose uptake is not insulin dependent in RBCs  ATP production is by glycolytic pathway in 90% and 10 % by pentose phosphate shant  G6PD and 6-phosphogluconate produce NADPH  NADPH reduces glutathione which conserve Hb form oxidation  Oxidized Hemoglobin chains precipitate as Heins body in RBC wall and cause suseptibility to lysis G6PD Deficiency  Recessive X-linked trait  G6PD reduces NADP to NADPH  Acute intravascular hemolysis 2-3 days after exposure of individuals to oxidants  Enzyme activity in reticulocytes is four times more than of old RBCs  G6pd also cause episodic intravascular hemolysis  In G6PD hemoglobin become denatured and precipitate as Heinz bodies G6PD deficiency Assay  Heins bodies (methyl Violet staining)  Cyanide ascorbate test:  Washed RBCs are incubate by ascorbate cyanide and natrium cyanide which produces H2O2  The test is positive in G6PD’ PK’ PNH  Fluorescent spot test  NADP is not fluorescent but NADPH is fluorescent  Quantitative G6PD assay Pyrovate Kinase Defeciency  The most common enzyme defeciency of Embden-Mirhoff pathway  Is an autosomal recessive disease  RBCs contain high level of 2.3DPG because of glycolyse pathway blockage  Mild to moderate hemolytic anemia with splenomegaly  No heins bodies  Flourcent Spot test: Lack of NADPH flourcens  Quantitative PK assay Normal Hemoglobins  HbA(α2 β2 ):  Main Hb of adults’at birth is 15-40% of total Hb. Is an elliptoid molecule with four Heme molecule in surface.  HbF(α2γ2 ):  Fetal hemoglobin  High affinity to O2 because low affinity to 2.3DPG’  Two type of HbF Gδ and Aδ  HbF is < 8% in 6 month, < 2% after 2 years.  Increased amount of HbF is seen in Thalassemia’ HPFH, megaloblastic anemia, Aplastic anemia and PNH, leukemias , hidatidiform mole(high level of HbF is seen in CML, Fanconi’s anemia, erythroleukemia up to 30-50%) Normal Hemoglobins  HbA2(α2δ2 ):  1.5 to 3.5 % of normal adult hemoglobin  Increased amount of HbA2 is seen in B-thalasemia up to 6%  Increased amount of HbA2 is seen in hyperthyroidism and megaloblastic anemia’sickle cell trait up to 4.5%  In iron defeciency anemia and α-thalasemia HbA2 decreased  HbA2 increase gradually in the first year of age so in diagnosis of minor B- thalasemia is not valuable  Embryonal Hemoglobins:  Hb Gower-1: (ζ2 ε2)  Hb Gower-2: (α2 ε2)  Hb portland: (ζ2 δ2) Laboratory evaluation of hemoglubins  CBC with cell counter  HPLC  HbA’ HbA2’ HbF’ HbA1C  Hb Electrophoresis  A2’A’C’S’F  Fast Hb: H’I’N’Bart’s J;K  Isoelecteric focusing  Act similar to HPLC  HbF alkaline denaturing test  Acid washing slide for F cells  Microcolumn test for A2  Metabisulfate slide test  Sickle solubility test  DNA analysis by PCR Sickle Cell Disease  Sickle cell anemia’s are hereditary hemoglobinopathy charactrized by production of defective hemoglobin  Point mutation (Subsituation of valin by glutamic acid)  In sickle cell trait the hemoglobin is HbS (α2 βS2 )  In sickle cell anemia the hemoglobin is HbS (α2 SS2 )  Hbs molecule undergo aggregation and polymerization after deoxygenation  Sickle cell trait are asymptomatic but homozygous HbS individuals are symptomatic  HbF inhibits polymerization of HbS  Intracellular dehydration facilitate sickeling  Sickeling cause vascular obstruction Sickle Cell trait (HbAS)  Prevalence is 8% in USA  No clinical symptoms  Resistance to falciparum malaria  Slight target cell in smear  RBC count and RBC indexes are normal  Sickle solubility test is positive  HbA 60%’ Hbs 40%’ HbF and HbA2 normal Sickle Cell Disease  Severe chronic hemolytic aemia  Hbs molecule undergo aggregation and polymerization after deoxygenation  Hand-foot syndrome( dactylitis) in Childs under 4 years of age  In spleen: Sequestration crisis’ Functional asplenia’ penuomococcal and salmonella infections  Vaso-occlusive disease crisis  Acute chest syndrome  Aplastic crisis specially with B19  Neutropenia’thrombocytopenia’High retic count’ polychromasia  No HbA’ HbS 80%’ HbF up to 20%’ HbA2 4.5% Other Hemoglobinopathies  Hb SC hemoglobinopathy  Mild hemolytic anemia’ splenomegalia’ excersional dyspnea’ thromboembolic events specially in pregnancy  Hb B/S thalasemia:  No HbA’ HbS 75-90%’ HbF 5-20%’ HbA2 4-6%  Decreased MCV and MCH  Clinically is similar to sickle cell anemia except splenomegalia which is seen from childhood to adults  Hb -α/SS:  Low MCV& MCH’ mild anemia’ vaso-occlusive disease  Hb SD – Arabic HbO/S Other Hemoglobinopathies  Hemoglobin C disease  Is due to (β 6 glu  lys)’ Anemia without splenomegalia  Many target cell’ Biphasic osmotic fragility test  Hb BO/C  In Mediterranean’ moderate hemolytic anemia.  Hb B+/C  Mild anemia similar to thalassemia trait  Hb D  B121 glu gln’ no hemolysis’ normal RBC indexes’ HbD95%  Hb G Philadelphia  Is due to( 68 asn  lys)’ have no clinical and hematological sign  HbE  The most frequent variant in the world  Is due to (B 26 glu  lys)  Both trait and HbE disease have no anemia and RBCs are normal Thalassemia  Definition  inherited anemia caused by decreased synthetic rate of hemoglobin  or  chains  Classification  Alpha Thalassemia  Beta Thalassemia Beta-Thalassemia  Three levels of clinical severity  Thalassemia minor (trait): Assymptomatic with mild hypochromic anemia  Thalassemia intermedia Mild to moderate anemia, not transfusion dependent  Thalassemia major Severe anemia (Hb 3-4), present in first two years of age with pallor, lethargy and hepatosplenomegaly Beta Thalassemia Clinical Features  Heterozygous  mild anemia  Homozygous  severe anemia in infancy  facial and cranial bone enlargement  splenomegaly  secondary hemochromatosis Anemia with Low MCV and Low Reticulocytes  Differential diagnosis  Iron deficiency  Sideroblastic anemia  Thalassemia trait  Anemia of chronic disease  Laboratory evaluation  Iron, iron-binding capacity, and ferritin  Blood smear - Target cells, stippling, etc.  Hb electrophoresis for Thalassemia  Bone marrow iron stores, ring sideroblasts Differential diagnosis between Iron deficiency anemia and minor thalassemia Beta Thalassemia  Pathogenesis  point mutations in 1 or 2 beta genes  decreased hemoglobin production  hemolysis of red cells in marrow and blood Thalassemia Syndromes  Definition:  Thalassemia is a genetic lesion leading to decrease synthesis of a- or B-globin chain of Hb  Variants:  B0-thalassemia and B+-thalassemia Evaluation  Low MCV (<75)  Increased RBC mass (sometimes)  RDW is <15% in trait and is >15% in patients  Normal reticulocyte count(trait) or high (syndrome)  Normal RDW in traits versus increased in patients Ferritin is normal to increased in traits  Ferritin is very high in patient who are treated by Packed cell transfusions  Mentzer index: MCV/RBC mass < 13.5  Patient and parents should be evaluate for HbA2 Alpha Thalassemia  Four clinical classifications  One gene mutation: silent carriers(normal Hb)  Two gene mutation: trait  mild microcytic anemia  Three gene mutation (Hg H disease)  Mod to severe anemia ‘ Gamma chains in neonates  Hb range from 3 to 4 g/dl ‘ Hemolytic episodes  Four gene mutation  Hydrops fetalis - Produce alpha globin in utero  Develop CHF, Severe anemia, Stillborn Acquired hemolysis with extrinsic factors  Chemical agents:  Hemolytic agents for normal RBCs: Distilled water plumb’ others  Hemolytic agents for abnormal RBCs: Oxidant in G6PD’  Physical agents:  Heat  Traumatic hemolysis  Cardiac valvular disease & prostheses Microangiopathic Thrombotic Anemia  Small vascular obstructive lesion  Systemic or renal platelet aggregation  Fragmentation of RBCs (schistocyte)  Idiopathic’ Mitomycin C’ Malignancy’ Graft’ Malignancy’ Pregnancy’ Collagen vascular disease  TTP for adult  HUS for childrens Hemolytic Uremic Syndrome  Children below 2 years  After diarrhea (shigella’ verotoxin E.Coli)  Attachment of toxin to endothelium of glomerules  Focal necrotic and thrombotic glomerulonephritis  Hemolytic anemia’ thrombocytopenia’ Uremia  Death rate is 50% of pateint Thrombotic Thrombocytopenic Purpura  More common in third decade  More common in women  Lack or decreased vWF cleaving protease cause production of very large vWF molecule cause platelet aggregation  Anti-endothelial cell antibodies and anti CD36  Hemolytic anemia’ neurologic disturbances’ Thrombocytopenia’ fever’ renal disease  Endothelial cell proliferation with hyalin clot formation Eclampsia and Pre-eclampsia  Microangiopathic disorder  In 40% of patient with eclampsia HELP syndrome is seen  HELP syndrome:  Hemolysis  Low platelet count(thrombocytopenia)  Elevated liver enzyme Infectious Agents  Malaria  Oroya fever: Barthonella baciliformis  Babesiosis  Viral induced hemolytic anemia Auto-immune Hemolytic Anemia  Up to 30 in 1000,000 population  Cause of autoantibody formation is unknown  Cold antibodies are sometimes produce after mycoplasma infections (anti-I and anti-i)  Auto antibodies after lymphoproliferative disorders or after autoimmune disease  Warm antibodies have high affinity at 370 C react with IgG and RBCs destroyed in spleen  Cold antibodies have high affinity at 40 C react with IgM and RBCs are destroyed in veins by complement fixation  7% 0f patient have both (warm and cold) pattern Warm antibody associated AIHA  Is slightly more in women  Pregnant women are susceptible four times  Normoblastic hyperplasia in bone marrow  Mild to moderate anemia’Reticulocytosis’ polychromasia  Increases in serum billirubin and LDH with decreased serum haptoglobulins.  Autoantibodies against RH system or even U’ kell; JK  Antibodies are of IgG type (IgG1 and IgG3 subtype)  Direct and indirect antiglobulin test is positive Cold Agglutinin Disease  Cause 20% of AIHA  Common in over 50 and is common in women  Is associated with lymphoproliferative disease and infections(mycoplasma’ infectious mononucleosis)  Acrocyanosis and Raynoud’s phenomena  Anitibodies are of IgM type and against I or i antigen  Anemia’spherocytosis’ polychromasia with marked RBCs agglutination Paroxismal Cold Hemoglobinuria  Hemoglobinuria’ fever’ chills’ pain in flanks after exposure to cold weather  Acute form after viral infection  Chronic form after syphilis  An IgG type immunoglobulin which fixes complement to red cells in 40 C resulted to RBCs lysis in 25-370 C (Donnat-Landestiner) Hemolytic disease of Newborn  Caused by fetal RBCs lysis by mother antibodies  Fetal mother ABO or Rh incompatibility  Prior immunization in mother by Rh system  About 1 ml of fetal blood inter to blood of mother in labor or abortion but sometimes its reach to 30 ml  IgG type anti-A and anti-B produce in mother spontaneously  ABO incompatibility occur in 15% of group O mothers but HDN occur only in 3% of newborns  Rh related HDN cause jaundice’ hepatosplenomegalia’ kernicterus and even hydrops fetalis.  Peripheral blood show NRBCs even normoblasts  Antiglobulin tests are positive  ABO related HDN is milder from Rh incompatibility Erythrocytosis (polycytemia)  When Hb and HCT is increased but total RBCs mass is normal the condition called erythrocytosis or relative polycytemia  Relative polycytemia  Deminished plasma volume( dehydration)  Spurious polycytemia (Gaisbock syndrome) which are ( hypertensive’over-weight) males with top normal physiologic range of RBCs and HCT. Absolute Polycytemia  Polycytemia with increased erythropoietin production due to hypoxia:  Hypoxia’ high altitude’ pulmonary disease’ Heart disease  High oxygen affinity hemoglobinopathies  Increased erythropoietin production:  Wilms tumor’ renal cell carcinoma’ cerebellar hemangioma  Localized hypoxia: polycystic kidney ’renal artey stenosis  Genetic polycytemia:  AD-Primary familial congenital polycythemia  Chuvash polycytemia(AR- mutated VHL gene) Polycytemia Vera  Definition:  Charctrized by excessive production of:Erythroid with granulocytic and megakaryocytic elements in the marrow (Panmyelosis).Urine Erythropoietin excretion is decreased.  Clinical features:  Usually it begins in middle ages.  PCV is slightly more frequent in men.  Ruddy cyanosis’Splenomegalia(2/3 of patient)’Thrombotic phemomen as myocardial infarction’cerebral thrombosis’ and hemorrhagic phenomen especially as gastrointestinal bleeding. Polycytemia Vera  Bone Marrow:  Marrow is hypercellular with pan myelosis’Reticulin is increased’Storage iron is decreased.  Peripheral Blood:  RBC count is over 6 mil/Micl~Hb is 18 to 24 g/dl~ MCV’ MCH’ MCHC and RDW are normal.ESR is reduced.Blood viscosity is high.Platelet count is high up to 1000.000/Micl’ Platelet function is abnormal’Moderate leukocytosis up to 30.000/Micl with marked elevated neutrophil alkaline phosphatase.Hyperuricemia’high serum transcobalamins ’ increased serum colony-stimulating activity(GM-CSF).  Normal arterial oxygen saturation. Polycythemia Vera  Diagnosis  1- Increased total erythrocyte volume(> 36ml/kg)  2-Normal arterail oxygen saturation  3-Either splenomegaly or two of the followings: Thrombocytosis’leukocytosis’increased neutrophilic alkaline phosphatase’increased serum B12  Prognosis:  PV is a chronic disease’patients usually live 10-20 years under good control or therapy by chemotherapy.  Progressive anemia’myelofibrosis and myeloid metaplasia and acute leukemia(especially after chlorambucil) are common complications. RBCs and plasma volume detection test  Cr51  EV(ml) = I (cpm/ml)/ C (cpm/ml)  Normal erythrocytes volume:  Male: 20-36 ml/kg  Female: 19-31ml/Kg  Normal plasma volume:  Male: 25-43 ml/kg  Female: 28-45 ml/Kg


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