red cell disorders anemia of blood loss hemolytic anemia anemia of decreased erythropoiesis...
TRANSCRIPT
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RED CELL DISORDERS
Anemia of blood lossHemolytic anemiaAnemia of decreased erythropoiesisPolycythemiaBleeding disordersBleeding disorders related to plateletsHemorrhagic diathesis
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AnemiaIt is defined as reduction in the total
circulating RBC mass below the normal limits.
The red cell mass is measured by1. Hematocrit value.( ratio of packed
red cells to the total blood volume)2.Hemoglobin concentration
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Blood LossAcute: trauma
Chronic: lesions of gastrointestinal tract, gynecologic disturbances. The features of chronic blood loss anemia are the same as iron deficiency anemia, and is defined as a situation in which the production cannot keep up with the loss.
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Acute blood loss result in Hypovolemic shockThere is normocytic nromochromic anemiaDecreased in hematocritIncreased erythropoisis and reticulocytosisThere is leuckocytosis due to mobilization by
adrenergic hormones in turn due to hypotension compensatory release of adrenergic hormones, thrombocytosis.
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HEMOLYTICHEREDITARY
MEMBRANE disorders: e.g., spherocytosisENZYME disorders: e.g., G6PD deficciencyHGB disorders (hemoglobinopathies)
ACQUIREDMEMBRANE disorders (PNH)ANTIBODY MEDIATED, transfusion or
autoantibodiesMECHANICAL TRAUMAINFECTIONSDRUGS, TOXINSHYPERSPLENISM
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IMPAIRED PRODUCTIONDisturbance of proliferation and differentiation of stem cells:
Aplastic anemias, Pure RBC aplasia, Renal failure
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Disturbance of proliferation and maturation of erythroblasts
Defective DNA synthesis: (Megaloblastic Anemia), deficiency of folate and Vitamin B12
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Defective heme synthesis: (Fe) Iron deficiency anemia
Deficient globin synthesis: Thalassemias
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Increased Destruction (Hemolytic Anemias) Intrinsic (intracorpuscular) abnormalities.
Hereditary Membrane abnormlities Membrane skeleton proteins: H.Spherocytosis, H.Elliptocytosis
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Enzyme deficiencies Glycolytic enzymes: pyruvate kinase, Hexokinase Enzymes of hexose
monophosphate shunt: glucose-6-phosphate dehydrogenase,
glutathione synthetase
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Disorders of hemoglobin synthesis Deficient globin synthesis: thalassemia
syndromes Structurally abnormal globin synthesis
(hemoglobinopathies): sickle cell anemia, unstable hemoglobins
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Acquired Membrane defect:
paroxysmal nocturnal hemoglobinuria
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Extrinsic(extracorpuscular)abnormalities Antibody mediated Isohemagglutinins:
transfusion reactions, erythroblastosis fetalis (Rh disease of the newborn)
Autoantibodies: idiopathic (primary), drug-associated, systemic lupus erythematosus
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Mechanical trauma to red cells
Microangiopathic hemolytic anemias: thrombotic thrombocytopenic purpura, disseminated intravascular coagulation
Infections: malariaToxins like clostodium toxinMarathon running and drumbeatingChemical injury like lead poisoningHypersplenism and defective cardiac valves.
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Mechanical traumaRed blood cell
fragments, burr cells, and helmet cells are associated with either
microangiopathic hemolytic anemia or mechanical red cell destruction.
In patients with prosthetic valves, red blood cells are exposed to excessive shear and turbulence
in the circulation, causing damage from mechanical trauma
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RED CELL INDICESMCV, MCH MCHC, RDW
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Classification depending on Red cell sizeNormocyticMicrocyticMacrocyticDegree of hemoglobinization the color of the
red cellNormochromicHypochromicHyperchromic
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Mean cell volume(MCV) is average volume of red cell expressed in femtolt(FL)
Normal-82 to96 flDecreased in iron def anemia
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Mean cell hb(MCH) is average mass of the Hb expressed in Picogram
Normal 27 to37 picogramDecreased in iron deficiency anemia
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MCHC(Mean cell Hb concentration) is average concentation of Hb in a given packed red cell.
Male-33-37g/dl female-33-37g/dl
RDW Red cell distribution width 11.5-14.5
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Hemoglobin- men-13.6-17.2 g/dl women-12.0-15.0 g/dlHematocrit (HCT) Men- -39-49% women- 33-43% Red cell count ×106/mm3 Men4.3-5.9 Women-3.5-5.0 Reticulocyte count 0.5-1.5%
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Hemolytic anemia Hemolytic anemiaAnemia's that are associated with accelerated
destruction of red cells are termed hemolytic anemias.
Destruction can be caused by either inherent (intracorpuscular) red cell defects, which are usually inherited, or
external (extracorpuscular) factors, which are usually acquired
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HEMOLYTIC ANEMIAS
General features of hemolytic anemias.
(1) an increased rate of red cell destruction,
(2) a compensatory increase in erythropoiesis that results in reticulocytosis, and
(3) Accumulation of Hb degradation products
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Intravascular hemolysisDestruction of red cells can occur within the
vascular compartmentExtravascular hemolysis.Red cell destruction within the cells of the
mononuclear phagocyte (reticuloendothelial) system
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Clinical features of extra vascular hemolysisExtravascular hemolysis needs alteration in
RBC shape to less deformable to pass thro the spllenic sinusoids
Features1.Anemia2.Jaundice 3.Splenomegaly.
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Intravascular hemolysis causesMechanical traumaBy defective cardiac valves thrombotic Narrowing of the
microcirculationComplement fixationIntracellualr parasites(Malarial parasite)Toxic injuries
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Clinical features
1.Anemia2.Hbglobinemia3.Hemoglobinuria4.Hemosiderinuria. Massive intravascular hemolysis sometimes
leads to acute tubular necrosis (Free iron damamging the tubular cells)
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HEMOGLOBIONURIALarge amount of Hb is released from the
lysed RBCs bound to heptoglobin cleared by MNPS and depletion of heptoglobin occurs and remaining free Hb oxidizes to methhemoglobin which is brown in color causing when excreted in urine give rise to hemoglobinuria
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JaundiceHb bounded to heptoglobin form complex is
cataboliseed to bilirubin in MNPs leads to jaundice.
The heme converts to conjugated and uncongugated bilirubin and excess of unconjugated bilirubin leads to icterus.
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HemosiderosisSome Hb release iron which accumulates in renal tubular cells cause renal hemosiderosis.(also renal tubular necrosis)
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There is a raise in uncongugated bilirubin in hemolytic anemia
Also formation of gall stones.
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Hereditary Spherocytosis
The inherited disorder is caused by the intrinsic defect in the red cell membrane skeleton that leads RBC to spheroid,and vulnerable to splenic sequestration and destruction.
It is a Autosomal dominant, in ¾ of the cases.Common in Northern Europe25% of patients have a more severe
autosomal recessive form of the disease.
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PATHOGENESISIn HS the primary abnormality resides in one
of a group of proteins.The major protein in this skeleton is spectrin,The mutations is that they weaken the
vertical interactions between the membrane skeleton and the intrinsic membrane proteins
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Hereditary spherocytosisMild to moderate
hemolytic anemia can lead to splenomegaly, jaundice, and pigmented gallstones.
.
common defect involves mutations in the gene that codes for ankyrin
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In all types of HS the red cells have reduced membrane stability and consequently lose membrane fragments after their release into the periphery,
Blood smears showasSpherocytosisReticulocytosisRaised MCHC due to dehydration caused
by loss of H2o and K
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Clinical Course anemia, splenomegaly, and jaundice.Because of their spheroidal shape, HS red
cells show increased osmotic fragility when placed in hypotonic salt solutions, a characteristic that is helpful for diagnosis
Pigment stones 40 to 50% of the cases
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Complications
Complications 1. Aplastic crisis due to Infection by parvovirus2.Hemolytic crisis3.Gall stonesTreatmentSplenectomy
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HEREDITARY SPHEROCYTOSIS
Genetic defects affecting ankyrin, spectrin, usually autosomal dominant
Children, adults
Anemia, hemolysis, jaundice, splenomegaly, gallstones (what kind?)
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Glucose-6-Phosphate Dehydrogenase Deficiency
Red cells are subjected to injuries by exo or endogenous oxidants
Any abnormality in HMP shunt or glutathione metabolism result in deficient in enzyme function and reduces RBC to protect themselvs against oxidants and leads to hemolysis
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G6PD genetic variants are,G6PD AAnd G6PD Mediterranean, most common in Middle east countries and clinically more significant.
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Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
A- and Mediterranean are most significant types
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G6PD is a X linked recessive disorderMost of these cases are harmless.The deficiency is caused by exposure that
generate oxidative stressMainly infectionsViral hepatitisPneumoniaTyphoid fever
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Drugs and certain foods like fava beansDrugs areAntimalarialsSulfonamidesNitrofurantoinIt can cause both intra and extravascular
hemolysis
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G6 PD deficiency anemiaHeinz bodies consist
of denatured HbFava beans
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G6PD
BITE CELL
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G6PD functionsRegenerates NADPH, allowing
regeneration of glutathioneProtects against oxidative stressLack of G6PD leads to hemolysis during
oxidative stressInfectionMedicationsFava beans
Oxidative stress leads to Heinz body formation, extravascular hemolysis
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Presence of Heinz bodies is hall mark of G6Pd deficiency
Oxidants cause cross linking of sulfhydryl groups on globin chain and denature and membrane bound precipitates called as Heinz bodies also responsible for intravascular hemolysis and less deformable leads to extravascular hemolysis.
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The hemoglobinopathiesThe hemoglobinopathies are a group of
hereditary disorders that are defined by the presence of structurally abnormal hemoglobins
Sickle Cell Anemia It is a common herditary Hb nopathy occurs
primarily in individuals of African descent.
On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2).
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SICKLE CELL ANEMIASickle cell anemia is caused by mutations in
globin gene.Substitution of valine for glutamic acid at the
sixth position of the β-chain produces HbS
About 8 to 10% of African American are heterozygous individuals it remain asymptomatic as sickle cell trait.
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Etiology and Pathogenesis
Etiology and Pathogenesis Upon de oxygenation, Hb S molecules undergo polymerization, a process also referred to as gelation or crystallization. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape.
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Sickling of red cells is initially reversible upon reoxygenation;
Membrane damage occurs with each episode of sickling, and eventually the cells accumulate calcium, lose potassium and water, and become irreversibly sickled.
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The presnce of HBS responsible for the clinical manifestations
Chronic hemolysis.Microvascular occlusion,Tissue damage
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sickle cell traitIn Heterozygote ie in sickle cell trait
The HbS is 40% and HbA is 60%.The remaining is HbA which in turn prevent HbS polymerization, so sickling is very unlikely.
Only in profound Hypoxic condition it can cause anemia.
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Why children remain asymptomatic till 5 to 6 months?
Hereditary persistence of HbF in these people the sickle cell disease is less severe.
Another variant Hb C Lysine is substituted for glutamate.
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HbF also prevents the HbS polymerization so they remain asymptomatic
In some children th HbF remain higher level and sickling is very less.
But HbC which causes the increase in the HbS and polymerization
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MCHC levelsIncrease in the MCHC also increase the
sicklingIntracellular PHDecrease in Ph facilitates the sicklingTransit time of red cells through
microvascular beds.
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Major consequences stem from the sickling of red cells
chronic extravascular hemolytic anemiamicrovascular obstructionsresult in ischemic tissue damage and pain
crises
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PATHOGENESIS OF MICROVASCULAR OcclusionMicrovascular occlusion depends on red cell
membrane damage and factors like Inflammation tend to slow or arrest rbcs
movement thr microvaculature.Sickle cells exhibit high adhesion moledules
and are sticky.The stagnation of rbcs causes Obstruction,hypoxia and more sickling.
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THROMBOSIS
Depletion of NO occurs as released Hb from sickled rbcs bind to the NO and NO level decreases causes more narrowing of vessels platelet aggregation, red cell stasis and thrombosis.
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Clinical findings
Clinical findings Dactylitis (hand-foot syndrome)Painful swelling of hands and feet2. Acute chest syndromeBy chest infections esp sterp pneumonia and Fat emboli3. central nervous system stroke,
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Dactilitis
Dactylitis Hand Foot Syndrome Images - Image Results
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Sickle cell anemia
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Acute chest syndrome and stroke are the two leading causes of ischemia-related death
4. aplastic crisisThere is transient decrease in erythropoisisDue to infection by parvovirus and leads to
anemia5.Spenic sequestration crisisThere is massive entrapment of sickled cells
into spleen leading splenic enlargement.
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Hypovolemia and shock and sometime to death.
6.AutospleneetomySpleen enlarges to certain extent in
childhood Spleen is fibrosed and diminish in size called
auto spenectomy7,Vasoocclusive crisis also called pain crisis
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Due to hypoxia and infarction cause severe pain
AcidosisInfections and dehydration can trigger the
pain crisis
More susceptible to infections by Salmonella,Strp pneumonia and H influenza.
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Laboratory findingsHb electrophoresisDemonstrate HbSFetal DNA analysis by amniocentesisPeripheral blood findingsthere are sickle cells and targel cells.Hb concentration decreased.
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Treatment and PrognosisHydroxyurea has beneficiary effectIt increases the HbF levelIt has anti-inflammatory effectAlso long term use of folic acidVaccination against H influenza and
Sterptococcal. P
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IMMUNE HEMOLYTIC ANEMIA General principalsAll require antigen-antibody reactionsTypes of reactions dependent on:
Class of AntibodyNumber & Spacing of antigenic sites on cellAvailability of complementEnvironmental TemperatureFunctional status of reticuloendothelial system
ManifestationsIntravascular hemolysisExtravascular hemolysis
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Antibodies combine with RBC, & either1. Activate complement cascade, &/or2. Opsonize RBC for immune system
If 1, if all of complement cascade is fixed to red cell, intravascular cell lysis occurs
If 2, &/or if complement is only partially fixed, macrophages recognize Fc receptor of Ig &/or C3b of complement & phagocytize RBC, causing extravascular RBC destruction.
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Immune Hemolytic anemiaImmune Hemolytic anemiaCaused by antibodies that bind to RBC
leading to premature destructionCalled autoimmune hemolytic anemiaBut it triggered by ingestion of drugs so
called Immune Hemolytic Anemia.
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Two types of IHAWarm antibody type Cold antibody (agglutinin) type
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Warm IHAIt is more common in women than men
Also in patients with SLEDrug induced methyldopa, penicillin,
quinidine
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Warm antibody type is more common (48% to 70%)and are of primary or idiopathic(50%)
Secondary to SLE, Lymphomas,leukemias and other malignancy.
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Most causative antibody is IgG IgG and sometime IgA antibodies are present
The IgG coated red cell binds to fc receptors of phagocytes which remove red cell membrane causing spherocytosis cause splenomegaly.
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Immune Complex MechanismQuinidine, Quinine, Isoniazid
“Haptenic” Immune MechanismPenicillins, Cephalosporins
True Autoimmune MechanismMethyldopa, L-DOPA, Procaineamide,
Ibuprofen
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Warm antibody IHAUsually IgG antibodiesFix complement only to level of C3,if at allImmunoglobulin binding occurs at all tempsFc receptors/C3b recognized by
macrophages; Hemolysis primarily extravascular70% associated with other illnessesResponsive to steroids/splenectomy
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HAPTEN MECHANSIMDrug binds to & reacts with red cell surface
proteinsAntibodies recognize altered protein, ± drug,
as foreignAntibodies bind to altered protein & initiate
process leading to hemolysis
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Auto antibody modelAlpha Methyl dopa an antihypertensive drug.
This drug initiates the formation of anitbody against the intrinsic red cell antigen, in particular Rh antigens,
10% patients taking alpha methyldopa develop auto antibodies.
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Warm antibody immune hemolytic anemiaA 32-year-old woman who has recently
started taking α-methyldopa develops dark, tea-colored urine. Physical examination reveals mild scleral icterus, a low-grade fever, and mild hepatosplenomegaly. Examination of her peripheral blood reveals many microspherocytes, while laboratory examination finds a positive Coombs’ test
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Immune Complex Mechanism
Drug & antibody bind in the plasmaImmune complexes either
Activate complement in the plasma, orSit on red blood cell
Antigen-antibody complex recognized by RE system
Red cells lysed as “innocent bystander” of destruction of immune complex
REQUIRES DRUG IN SYSTEM
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Hemolytic transfusion reactionCaused by recognition of foreign antigens
on transfused blood cellsSeveral types
Immediate Intravascular Hemolysis (Minutes) - Due to preformed antibodies; life-threatening
Slow extravascular hemolysis (Days) - Usually due to repeat exposure to a foreign antigen to which there was a previous exposure; usually only mild symptoms
Delayed sensitization - (Weeks) - Usually due to 1st exposure to foreign antigen; asymptomatic
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Cold antibody IHAMost commonly IgM mediatedAntibodies bind best at 0 to 4 degree C.Fix entire complement cascadeLeads to formation of membrane attack
complex, which leads to RBC lysis in vasculature
Typically only complement found on cells90% associated with other illnessesPoorly responsive to steroids, splenectomy;
responsive to plasmapheresis
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Cold antibody IHAMost commonly IgM mediatedAntibodies bind best at 30º or lowerFix entire complement cascadeLeads to formation of membrane attack
complex, which leads to RBC lysis in vasculature
Typically only complement found on cells90% associated with other illnessesPoorly responsive to steroids, splenectomy;
responsive to plasmapheresis
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Cold aglutinin present in 15 to 30% of cases,Antibody is IgMBy IgM antibodies that bind red cells at low
temp.Also seen following infection like Mycoplasma pneumonieEB virusCMV and H, inflenza and HIVB cell lymphomas
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Ig M antibody binds to RBCs in the body site where the temp is at low level like 30degree C. hands, toes and ear.
As the blood recirculate these Immunoglobulins detach before the complement mainly the C3b which is a opsosin and the RBCS caught by the phagocytes and hemolysisis occur
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CFJaundiceHepatosplenomegalyRaynauds phenomenon
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DiagnosisDirect coombs testIndirect coombs testTreatmentRemoval of offending drugImmunosuppressive therapy Splenectomy
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Direct Coombs antiglobulin test.Patients RBCs are mixed with
heterogenous antisera specific for human immunoglobulins.If positive they form antibodies and cause agglutination.
Indirect Coombs antiglobulin testPatients sera taken and mixed with
commercially available RBC and the test is positive if clumping or agglutination occurs
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ThalassemiaThalassemia The thalassemias are a heterogeneous group of inherited disorders caused by mutations that decrease the rate of synthesis of α- or β-globin chains. deficiency of hemoglobin, with additional secondary red cell abnormalities.
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BETA THALASSEMIAS Molecular pathogenesisCaused by mutations that decreases the
synthesis of beta globin chainThe β-globin mutations associated with β-
thalassemia fall into two categories: (1) β0, in which no β-globin chains are produced; and (2) β+, in which there is reduced (but detectable) β-globin synthesis.
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Splicing mutations common cause for beta + Thalassemia
Chain terminator mutations cause for beta 0 thalassemia
Promoter region mutations some normal beta globin synthesized so beta + Thalassemia.
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Unpaired α chains form insoluble aggregates that precipitate within the red cells and cause membrane damage that is severe enough to provoke extravascular hemolysis
In severe Thalassemia leads to ineffective erythropoisis
In turn leads to excessive iron reabsorption in the gut leads to hemochromatosis, cardiac failure and death.
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Clinical Course β-thalassemia major manifests itself
postnatally as HbF synthesis diminishesGrowth retardationAnemia,Repeated blood transfusion leads to iron
overload due to increase absorption.Iron overload on heart cause usually death.
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Diagnosis
Hb electrophoresisReduction in HbAIncreased HbFMicrocytic hypochromic anemiaAnisocytosisPoilkilocytosisTarget cellsReticulocyte count slightly raised
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Beta thalassemia majorThe correct answer isHemoglobin A Hemoglobin A2
Hemoglobin Fa. Increased Increased Increasedb. Increased Increased Decreasedc. Increased Decreased Increasedd. Decreased Increased Increasede. Decreased Decreased Decreased
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Tear drop cells
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ALPHA THALASSEMIASInherited deletions that results in reduced or
absent synthesis of alpha globin chain.So unpaired gamma in fetal life or beta chain
in adultsThese are soluble so hemolysis and
ineffective erythropoiesis is less severe than beta thalassemia.
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Excess of unpaired gamma globin forms tetramers known as Hemoglobin BARTS.
The unpaired beta globins forms tetramers known as HbH.
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Different types of alpha thalassemias1.Silent carrier state(deletion of single alpha globin gene)
2.alpha thalassemia trait(2 Alpha gene deletion)
3.Hb H disease(3 alpha gene deletion)
4.Hydrops fetalis(4 alpha globin gene deletion)
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Hemolytic Anemias Resulting from Mechanical Trauma to Red Cells
cardiac valves like bioprosthetic or mechanical valves.
the narrowing and partial obstruction Traumatic hemolytic anemia physical blows (e.g., marathon racing and
bongo drumming
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Microangiopathic hemolytic anemia1.disseminated intravascular coagulation due
to intravascular deposition of fibrin. 2.malignant hypertension, 3.SLE, 4.thrombotic thrombocytopenic purpura,
5.hemolytic-uremic syndrome, 6.disseminated cancer
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The morphologic alterations in the injured red cells
(schistocytes) "burr cells," "helmet cells," and "triangle cells“.
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Tear drop RBC
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Helmet cells
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Microangiopathic Hemolytic AnemiaCausesVascular abnormalities
Thrombotic thrombocytopenic purpuraRenal lesions
Malignant hypertension Glomerulonephritis Preeclampsia Transplant rejection
Vasculitis Polyarteritis nodosa Rocky mountain spotted fever Wegener’s granulomatosis
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Vascular abnormalities AV Fistula Cavernous hemangioma
Intravascular coagulation predominantAbruptio placentaeDisseminated intravascular coagulation
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PNH(PARAOXYSMAL NOCTURNAL HEMOGLOBINURIA)Clonal cell disorderOngoing Intra- & Extravascular
hemolysis; classically at nightTesting
Acid hemolysis (Ham test)Sucrose hemolysisCD-59 negative (Product of PIG-A gene)
Acquired deficit of GPI-Associated proteins (including Decay Activating Factor)
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GPI links a series of proteins to outer leaf of cell membrane via phosphatidyl inositol bridge, with membrane anchor via diacylglycerol bridge
PIG-A gene, on X-chromosome, codes for synthesis of this bridge; multiple defects known to cause lack of this bridge
Absence of decay accelerating factor leads to failure to inactivate complement & thereby to increased cell lysis
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ANEMIAS OF DIMINISHED ERYTHROPOIESISANEMIAS OF DIMINISHED ERYTHROPOIESIS
Decreased red cell production commonly due to nutritional deficiency
Bone marrow failureInfiltrative disorder leads to marrow replacement
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Megaloblastic anemia
Megaloblastic anemiaImpairment in a DNA synthesis leads to
morphologic changes to erythroid precursor and RBCS.
Mainly Thymidine synthesis.Two types-1. pernicious anemia due to Vit B12
deficiency2.Folic acid deficiency
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Vitamin B12 deficiency
1.Nutritiomal2.Impaired absorption A. Intrinsic factor deficiency Pernicious anemia B Gastrectomy
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3.Malabsorption syndromeDiffuse intestitinal diseaseLymphomaAnd systemic sclerosisIleal resectionIlelitisParasitic uptake Fish tapeworm
infestation
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Folic acid deficiency
1.Decreased intakeInadequate intakeInfancy and alcoholism2.Impaired absorption AnticonvulsantsOral contraceptive pillsMalabsorption states
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Increased loss HemodialysisIncreased demandPreganancyInfancyDisseminated caFolic acid antagonist
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Metabolic role of Vit B12 and Folate
They are coenzymes for the synthesis
Of Thymidine in turn impair metabolism result in defective nuclear maturation and block cell division and leads to nuclear and cytoplasmic asynchrony.
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MORPHOLOGYPancytopenia(All myeloid lineages are
affected)Change in RBC size and shapes(Macrocyte,
and macroovalocyte)HyperchromicHypersegmented neutrophilsHyperplasia of Bone marrowMild ineffective hematopoiesis.
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Anemia due to Vit B12 deficiency
Pernicious anemiaIt is a autoimmune disorder caused by defect
in intrinsic factor productionChronic gastric atrophy leads to loss of
parietal cells Increased incidence of Pernicious in Blood
Group A
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Methyl cobalamine transfers the methyl group to homocysteine to produce
MethionineDeficiency of Vit B12 traps N5 methyl FH4Deficiency of folate or Vit B12.. increases
plasma homocysteine
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Pernicious anemia
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also found in elderly persons with chronic gastritis
MorphologyPeripheral blood smear showsMacrocytesHyperchromaticAnisocytosisPoilkilocytosis
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Nucleated red cell progenitorNeutrophils hypersegmented bone marrow findings Hyper cellularIncreased hematopoietic precursor
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Clinical features
Smooth, sore tongue, glazy ,shiny and beefy tongue with atrophy of papillae
Atrophic glossitisNeurologic diseasePeripheral neuropathy with sensor motor
dysfunctionb. Sub acute combined degeneration
(demyelination) of the spinal cord
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DiagnosisModerate megaloblastic anemiaLeukopeniaLow serum B12 levelsElevated levels of Homocysteine and
methyl melonic acidLow reticulocyte countSchilling testSeru antibodies to intrinsic factor for
pernecious anemia
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methylmalonic acidVitamin B12 is important in DNA synthesis; therefore
hematological manifestations of B12 deficiency aremegaloblastic anemia and pancytopenia. Vitamin B12 (deoxyadenosyl cobalamin) also serves asa cofactor for methylmalonyl CoA mutase. [This
enzyme catalyzes the conversion of methylmalonyl CoA into succinyl CoA.
Succinyl CoA is the final product of fatty acid oxidation that enters citric acid cycle. Deficiency of B12 leads to an accumulation of methylmalonic acid.
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Elevated levels of methylmalonic acid result in myelin synthesis abnormalities. Neurological damage associated with B12 deficiency includes subacute, combined degeneration of the posterior and lateral spinal columns. Axonal degeneration of peripheral nerves is also seen. Loss of position and vibration sensation, ataxia, and spastic paresis result. Increased serum levels of methylmalonic acid are diagnostic of vitamin B12 deficiency
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Folate deficiency
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Aplastic Anemia
Aplastic anemia is a disorder in which multipotent myeloid stem cells are suppressed, leading to marrow failure and pancytopenia.
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Etiology and Pathogenesis
Most of the cases the cause is unknown65% of the cases are idiopathic.Acquired causes Drugs and chemicals., antineoplastic drugs (e.g., alkylating agents,
antimetabolites), benzene, and chloramphenicol. Sulfonamides
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Chemical agentsBenzene,chloramphenicolAntimetabolitesPenicillamines gold saltsPhysical agentsWhole body irradiationViralHepatitis unknown virusEB virus, Herpes zosterInherited (Fanconi anemia)
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certain viral infections, most often community-acquired viral hepatitis.
CMV infections and EB virus
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PATHOGENESIS1. immunologically mediated suppression(T cells)
2.Intrensic abnormality in the stem cell.
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1.Following exposure to chemicals, or viral infections or drugs, the stem cells are antigenic ally altered that evokes the Immune response and the T lymphocytes stimulate cytokines IF gamma and TNF which in run prevents the proliferation and differentiation of stem cells.
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2.Genetic damage that limits the differentiation and proliferation of the stem cells.
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MorphologyThe bone marrow in aplastic anemia typically is markedly hypocellular,
with greater than 90% of the intertrabecular space being occupied by fat.
Bone marrow biopsy yields dry tap
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Anemia may cause fatty change in the liver, and thrombocytopenia and granulocytopenia may result in hemorrhages and bacterial infections,
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weakness, pallor, and dyspnea. Thrombocytopenia often presents with petechiae and ecchymoses
. Granulocytopenia may be manifested only by frequent and persistent minor infections or by the sudden onset of chills, fever, and prostration.
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Splenomegaly is charestically absent.red cells are normocytic and normochromic,
although slight macrocytosis is occasionally present; reticulocytes are reduced in number.
TreatmentThe idiopathic form has a poor prognosis if
left untreated. Bone marrow transplantation is an extremely effective form of therapy
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The prognosis of marrow aplasia is quite unpredictable.,
withdrawal of toxic drugs may lead to recovery in some cases.
The idiopathic form has a poor prognosis if left untreated.
Bone marrow transplantation is an extremely effective form of therapy,
especially if performed in nontransfused patients younger than 40 years of age . benefit from immunosuppressive therapy
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Myelophthisic Anemia Extensive replacement of the marrow by
tumors or other lesions. It is most commonly associated with
metastatic breast, lung, or prostate cancerAdvanced tuberculosis, lipid storage
disorders, and osteosclerosis can produce a similar clinical picture.
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Iron Deficiency Anemia
Most common form of nutritional deficiencyTotal body Fe content in women 2gm for
men 6gmIt is present in 2 compartments1.Storage compartment as Ferritin stored in liver, spleen and bone
marrow and skeletal muscleHemosiderin
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Functional compartment 80% of the total iron in Hb
Daily requirementsFor men 7 to 10mgWomen7 to 20mgHealthy females have low storage of iron
due to Menstrual loss every month compared to men.
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Causes of iron deficiency anemia1.Decreased dietary intake2.Impaired absorption3.Increased demand in pregnancy and lactation, toddlers and children.
4.Chronic blood loss.
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Pathogenesis
Iron is transported by binding to iron binding protein called transferrin
Transferrin levelIn men 120micogram/dlIn women 100micogram/dlMicrocytic hypochromic anemiaThe serum ferritin level fallsThe hepcidin levels decreases.
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Clinical features
Fatigue,PalpitationsDyspneaPallorKoilonychia spoon shaped nails bedsDepletion of iron from the CNS lead to eating
mud or clay.
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Plummer Vinson syndrome
GlossitisOesophageal webHypochromic microcytic anemia
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Factors enhance the iron absorption are
Ascorbic acid and aminoacidsFactors that inhibit the iron
absorption are,Tannates (present in tea)Phytates,phosphates
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Diagnosis
Increased total iron binding capacityDecreased ferritin levelsDecreased total serum ironIncrease in the transferrin receptorsReticulocytosisThrombocytosisIncreased RDWLow hepcidin levels
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Chronic diseases leading to anemia
Chronic infectionsChronic immune disorders like Rheumatoid arthritis
Neoplasms
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Diagnosis
1.Increased ferritin level2.Decreased total iron binding capacity.
3.Increased hepcidin,4.Normochromic normocytic or microcytic hypochromic
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Hypochromic, microcytic red cells.
The serum iron levels, The total iron-binding
capacity,Transferrin saturation
to be reduced. A bone marrow
biopsy reveals the iron to be present mainly within macrophages.
Anemia of chronic disease
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Koilonychia Fe deficiency
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Serum Iron TIBC serum ferritin transferrin
A) Normal Normal Normal Normal
B) Low High Low High
C) Normal /High Normal/low High Low
D) Low Low Normal to high Low