Hemolytic anemia I

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Hemolytic Anemia Membrane and Enzymes Defect Ahmad A. Al-QudahClinical Hematology I LM-753

Hemolytic Anemia - Introduction to Hemolytic Anemia : - Definition - Evidence of Hemolysis - Signs & Symptoms , Lab Findings - Classifications & differential diagnosis - Hemolysis due to Membrane Defect ( Structure , Permeability )

- Hemolysis due to Enzyme Defect

- What is New In Hemolytic Anemia ?

Hemolytic Anemia - Is a form of anemia due to hemolysis, the abnormal breakdown ofred blood cells(RBCs), either in theblood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular) .- Increased red cell destruction (and increased erythropoiesis)- Cells are being produced at the same rate as they are hemolyzed; this can develop into anemia if : - Erythrocyte destruction accelerates beyond the compensatory capacity of the marrow -The B.M suddenly stops producing erythrocytes

Hemolytic Anemia Sites of destruction- Intravascular hemolysis: (within blood vessels)Caused by :-Activation of complement on erythrocyte membrane- Physical or mechanical trauma- Toxic substances

* Hemoglobinemia (free Hb in plasma)* Hemoglobinuria (Hb in urine)* Hemosiderinuria( hemosiderin granules in urine)* Methemoglobinemia

Hemolytic Anemia Sites of destruction-Extravascular hemolysis :

- Erythrocytes removed by tissue phagocytes - More common than intravascular . - increase bilirubin , urobilinogen . - Decrease haptoglobin . - Spleen(slightly damaged RBC),liver( extensively damaged) - Antibodies against RBCs (immune mediated)

Hemolytic Anemia

Hemolytic Anemia Evidence of Hemolysis - Jaundice and hyperbilirubinemia- Reduced plasma haptoglobin* Increased Hb breakdown:- haemoglobinuria- methaemalbuminaemia- haemosiderinuria

Hemolytic Anemia * Damage to red cells: - Spherocytosis & increased fragility - Fragmented RBCs - Heinz bodies - Increased plasma LDH

* Erythroid hyperplasia: - Reticulocytosis - Macrocytosis & polychromasia - BM erythroid hyperplasiaEvidence of Hemolysis

Hemolytic Anemia Signs & Symptoms Jaundice Accumulation of Bilirubin Gallstones / red urine Increased excretion of bilirubin into the biliary tractSplenomegaly Accumulation of damaged RBCs Pulmonary hypertension Increased pressure over the pulmonary arteryPallor , fatigue , cardiac symptoms General Signs of Anemia

Hemolytic Anemia - Testing and Special Approaches :- Reticulocyte Count : Young Cells , Contain RNA . Stained by Supravital Stain , 0.5-2% .

RPI = (%Retics /RMT )*(Hct/45)1 --> 45 1.5 --> 35 2 --> 25 2.5 --> 15 RPI > 2 2.5 , indicate a hemolytic state . - COOMBS ( DAT ) :Detection of Auto Antibody Next Lec.

Hemolytic Anemia - Osmotic Fragility :

Hemolytic Anemia Lab Findings Increased erythrocyte destructionIncreased BM production of erythrocytesAnemiaSpherocytes,schistocytes,poikilocytes+ve DATDecreased haptoglobinDecreased glycosylated HbIncreased urobilinogenIncreased bilirubinHemoglobinemia,hemoglobinuria,hemosiderinuria,methmoglobinemia ( intravascular hemolysis)Reticulocytosis LeukocytosisNucleated erythrocytes in P.BPolychromasia of erythrocytesNormoblastic erythroid hyperplasia in the B.M

Hemolytic Anemia Complications : - Hemolytic crisis : due to accelerated hemolysis.

- Aplastic crisis : due to maturation arrest and associated with megaloblastic changes

- Pigmented gallstones: Increased hemolysis of red blood cells leads to increased bilirubin levels, because bilirubin is a breakdown product of heme. The high levels of bilirubin must be excreted into the bile by the liver, which may cause the formation of a pigmented gallstone, which is composed of calcium bilirubinate. Since these stones contain high levels of calcium carbonates and phosphate, they are visible on x-ray.

- Abnormally lowhemoglobin A1Clevels : the life span of the red blood cells is decreased, providing less time for the non-enzymatic glycosylation of hemoglobin. Thus, even with high overall blood sugar, the A1C will be lower than expected.- Leg ulcer.

- Folate deficiency :caused by increased bone marrow requirement.

Hemolytic Anemia Complications :

Hemolytic Anemia Differential diagnosisPresence of HemolysisIncrease RBC Production Increase RBC destructionCOOMBS ( DAT ) +ve -ve IHAPB Smear RBC MorphologyLab Investigation( LDH , Bili , Retics ..) Definitive Diagnosis

Hemolytic Anemia Classifications- Also it can classify into : INTRACORPUSCULAR HEMOLYSIS-Membrane Abnormalities-Enzyme defectsEXTRACORPUSCULAR HEMOLYSIS-Nonimmune -Immune- Generally , Hemolytic Anemia Classify depends on the causes of Defect into : - Hereditary - Acquired

Hemolytic Anemia Membrane Defects- The membrane protein and lipid interactions associated with abnormal erythrocyte membranes can be divided into two categories:1- Vertical interactions :interactions between the skeletal lattice on the cytoplasmic side and the integral proteins and lipids. Any defect cause uncoupling of the lipid bilayer from the skeletal lattice, selective loss of portions of the lipid bilayer, decrease in the surface area to volume .

Hemolytic Anemia

Hemolytic Anemia 2- Horizontal interactions :Parallel to the plane of the membrane and provide mechanical stability to the membrane .any defect lead to disruption of the skeletal lattice and membrane destabilization which lead to cell fragmentation and formation of poikilocytes .Membrane Defects

Hemolytic Anemia Hereditary spherocytosis- Autosomal-dominant, most common disorder of the red cell membrane (1:2000).- Deficiency of spectrin , combined deficiency of spectrin and ankyrin , mutations of ( ankyrin , or -spectrin , protein 4.2,band 3)- Influx of Na+ 10 times the normal rate- Increased cytoplasmic viscosity

GeneLocusANK18p11.2SPTB14q22-q23SPTA1q21SLC4A117q21-q22EPB4215q15

Hemolytic Anemia

Hemolytic Anemia

Hemolytic Anemia Normal or decreasedHb> 8%Retics60-87 flMCVnormalMCH> 36g/dlMCHCNormoblastic erythroid hyperplasia, increased iron storageBMincreasedOsmotic fragilityincreasedIndirect bilirubinincreasedLDdecreasedhaptoglobinRBCs small and lack the central pallorPB Smear

Laboratory findings

Hemolytic Anemia Hereditary elliptocytosis- Autosomal dominant- Defect in the horizontal membran protein interaction:*Decreased association of spectrin dimers to form tetramers*Defect in band 4.1*Abnormalities in glycophorin C, abnormal anion transport(band 3) with increased affinity to ankyrin-The cells are abnormally permeable to Na+- For Diagnosis : >25% of PB smear --> Elliptocyte

Hemolytic Anemia

Hemolytic Anemia Hereditary Pyropoikilocytosis- Autosomal recessive , closely related to HE- Presents in infancy as severe HA with extreme poikilocytosis- HPP cell membranes fragment when heated to 45-46 C

- Two defects :Related to a deficiency in -spectrin The presence of mutant spectrin that prevents association of heterodimers to tetradimers

Hemolytic Anemia Hereditary PyropoikilocytosisPB Smear : - Fragments, Microspherocytes , Elliptocyte .- Decreased MCV 22-55 fl- Autohemolysis increased - Osmotic fragility is abnormal

Hemolytic Anemia

Hemolytic Anemia Hereditary Stomatocytosis Syndromes- Autosomal dominant HA ,erythrocytes exhibit abnormalities in Na+ and K+ permeability.

- Osmosis leads to the red blood cell having a constant tendency to swell and burst.

- In the hereditary stomatocytosis, the passive leak is increased and the cell becomes swamped with salt and water.

Hemolytic Anemia Hereditary Stomatocytosis SyndromesOHS : the RBC membrane is abnormally permeable to Na+ , K+ ( the net gain of Na+ > the net loss of K+) ,the capacity of cation pump is exceeded Water enters the cell ------> Stomatocyte

DHS :The net loss of intracellular K+ exceeds the passive Na+ influx decreased water and cation content ----> Xerocyte * Variants :

Hemolytic Anemia

Hemolytic Anemia

Hemolytic Anemia

Hemolytic Anemia Abnormal lipid composition Acanthocytosis- Acquired or inherited abnormalities of the membrane lipids- Liver disease, abetalipoproteinemia- lipid of the membrane exchange with plasma lipids- Acquiring excess lipids cause abnormal shapes.- Sequestered in spleen

Hemolytic Anemia Spur cell anemia- Acquired hemolytic condition associated with severe hepatocellular diseaseIncreased cholesterol and phospholipid leads to :1- Decreased membrane fluidity and deformability2- Membrane fragments are lost during splenic passage( spur cells)*Moderate to severe normocytic normochromic anemiaHb 5-10 g/dLReticulocyte 5-15%Acanthocytes 20-80%Increased bilirubin, liver enzymes.

Hemolytic Anemia

Hemolytic Anemia

Hemolytic Anemia Rare forms- Lecithin-cholesterol acyl transferase deficiency- Autosomal recessive affects metabolism of HDL- LACT catalyzes the formation of cholesterol esters from cholesterol.- Low HDL & LDL, high VLDL & lipoprotein X- Mild HA, target cellsOther Forms : - McLeod phenotype with Kx & K antigen deficiency, Acanthocytosis with band 3 abnormalities

Hemolytic Anemia Enzyme deficiencies- RBCs require constant energy to maintain biconcave disc shape and hemoglobin in reduced form. - Without adequate energy, red cells lyse and/or deform. - Energy from glucose is derived from metabolism- An inherited deficiency