IM-Hemolytic Anemia (1)

Embed Size (px)

Text of IM-Hemolytic Anemia (1)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Hemolytic anemia

    HA = decreased levels of erythrocytes in circulating blood (anemia) becauseof their acclerated destruction (hemolysis)

    A red blood cell survives 90 to 120 days (on average) in the circulation,therefore about 1% of human red blood cells break down each day.

    The spleen (part of the reticulo-endothelial system) is the main organ whichremoves old and damaged RBCs from the circulation.

    In health the breakdown and removal of RBCs from the circulation ismatched by the production of new RBCs in the bone marrow.

    When the rate of breakdown increases, the body compensates by producingmore RBCs, but if compensation is inadequate clinical problems can appear.

    Breakdown of RBCs can exceed the rate that the body can make RBCs andso anemia can develop. The breakdown products of hemoglobin willaccumulate in the blood causing jaundice and be excreted in the urinecausing the urine to become dark brown in colour.

  • 8/2/2019 IM-Hemolytic Anemia (1)



    Hemolytic anemia = reduced red-cell lifespan

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Signs of hemolytic anemia: History

    Onset/ duration (hereditary versus acquired) History of fatigue or jaundice Abdomen pain / cholelithiasis (chronic hemolysis) Medications or food /ie fava bean/(may exacerbate enzyme

    deficiencies) Travel (consider infection) and infection Vascular / cardiac surgery Blood loss or sequestration (increases reticulocytes in the absence

    of hemolysis) Discolored urine (intravascular haemolysis) Complete family history (jaundice, gallbladder disease, splenectomy,

    hereditary anaemia or other inherited diseases)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Signs of hemolytic anemia: Physical

    Symptoms of anemia



    Splenomegaly / hepatosplenomegaly

    Increased temperature Rapid pulse

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Laboratory futures (1)

    *Morfology: anemia*Peripheral blood smear microscopy: **fragments of the red blood cells ("schistocytes") can be present **some red blood cells may appear smaller and rounder than usual

    (spherocytes) **reticulocytes are present in elevated numbers. **erytroblasts can be present.*Bone marrow smear microscopy: erytrhroid hyperplasia

    (megaloblasts)*The level of unconjugated bilirubin in the blood is elevated.*The level of lactate dehydrogenase (LDH) in the blood is elevated

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Laboratory futures (2)

    *Haptoglobin, hemopexin levels are decreased*Iron level in the blood is elevated (in NNH is decreased!)*The direct Coombs test is positive, if hemolysis is caused by an

    immune process.

    *Increased excretion of urobilinogen in the urine and stercobilinogen inthe stool.

    *Sometimes abnormal results of the osmotic fragility test

    *Free hemoglobin, methemalbumin elevated level in the blood andhemoglobin,

    hemosiderin in the urine indicates chronic intravascular hemolysis.

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Classification of hemolytic anemias (1)

    Causes of hemolytic anemis can be either

    genetic or acquired.

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Classification of hemolytic anemias (2)===Genetic===

    *Genetic conditions of RBC membrane **Hereditary spherocytosis **Hereditary elliptocytosis

    *Genetic conditions of RBC metabolism (enzymedefects) **Glucose-6-phosphate dehydrogenase deficiency (G6PD

    or favism) **Pyruvate kinase deficiency

    *Genetic conditions of hemoglobin **Sickle cell anemia **Thalassaemia

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Classification of hemolytic anemias (3)===Acquired===

    '''Immune mediated hemolytic anemia''' (direct Coombs test ispositive)

    *Autoimmune hemolytic anemia

    **Warm antibody autoimmune hemolytic anemia ***Idiopathic ***Systemic lupus erythematosus (SLE) ***Evans' syndrome (antiplatelet antibodies and hemolytic antibodies)

    **Cold antibody autoimmune hemolytic anemia ***Idiopathic cold hemagglutinin syndrome ***Infectious mononucleosis and mycoplasma ( atypical) pneumonia ***Paroxysmal cold hemoglobinuria (rare)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Classification of hemolytic anemias (4)===Acquired===

    '''Immune mediated hemolytic anemia''' (direct Coombs test ispositive)

    *Alloimmune hemolytic anemia **Hemolytic disease of the newborn (HDN)

    ***Rh disease (Rh D) ***ABO hemolytic disease of the newborn ***Anti-Kell hemolytic disease of the newborn ***Rhesus c hemolytic disease of the newborn ***Other blood group incompatibility (RhC, Rhe, RhE, Kidd antigen system,

    Duffy antigen, MN, P and others)

    **Alloimmune hemolytic blood transfusion reactions (ie from a non-

    compatible blood type) *Drug induced immune mediated hemolytic anemia **Penicillin (high dose) **Methyldopa

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Classification of hemolytic anemias (5)===Acquired===

    '''Non-immune mediated haemolytic anaemia''' (direct Coombs test isnegative)

    *Drugs (i.e., some drugs and other ingested substances lead to hemolysis by direct action onRBCs)

    *Toxins (e.g., snake venom)

    *Trauma **Mechanical (heart valves, extensive vascular surgery, microvascular disease) *Microangiopathic hemolytic anemia (a specific subtype with causes such as TTP, HUS, DIC

    and HELLP syndrome) *Infections **Malaria **Babesiosis **Septicaemia *Membrane disorders **Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder of red blood cell surface

    proteins) **Liver disease *Hypersplenism

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Mechanisms of hemolysis:

    - intravascular

    - extravascular

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Intravascular hemolysis (1):

    - red cells destruction occurs in vascular space

    - clinical states associated with Intravascular hemolysis:

    acute hemolytic transfusion reactions

    severe and extensive burns

    paroxysmal nocturnal hemoglobinuria

    severe microangiopathic hemolysis

    physical trauma

    bacterial infections and parasitic infections (sepsis)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Intravascular hemolysis (2):

    - laboratory signs of intravascular hemolysis:tests for hemolysis and aditionally:


  • 8/2/2019 IM-Hemolytic Anemia (1)


    Extravascular hemolysis :

    - red cells destruction occurs in reticuloendothelialsystem

    - clinical states associated with extravascular hemolysis :

    autoimmune hemolysis

    delayed hemolytic transfusion reactions


    hereditary spherocytosis


    hemolysis with liver disease

    - laboratory signs of extravascular hemolysis:tests for hemolysis

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Hemolytic anemia




  • 8/2/2019 IM-Hemolytic Anemia (1)


    Differential diagnosis

    * ''Ineffective hematopoiesis'' is sometimesmisdiagnosed as hemolysis.

    ** Clinically these conditions may share manyfeatures of hemolysis

    ** Red cell breakdown occurs before a fully

    developed red cell is released into the circulation. ** Examples: myelodysplastic syndrome,

    megaloblastic anemia.

  • 8/2/2019 IM-Hemolytic Anemia (1)



    Compensated hemolysis observation (clinical evaluation) and folicacid at an oral dose 1mg/day

    Decompensated hemolysis (definitive therapy depends on the cause):

    *Symptomatic treatment -blood transfusion: if there is markedanemia. *In immune-related hemolytic anemia: steroid therapy ,

    immunosupressive agents, immunoglobulins *Sometimes splenectomy can be helpful where extravascular

    heamolysis is predominant (ie most of the red blood cells are being

    removed by the spleen). Folic acid

    Hemochromatosis chelatic agents (Desferal)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Hereditary microspherocytosis (HS)1. Epidemiology: usually inherited as an autosomal dominanttrait; affects about 220 per million people worldwide2. Pathophysiology: red cell membrane protein defects

    (spectrin, spectrin-ankyrin, bad3 and 4.2 (palladin)deficiency) caused by mutations in he spectrin and ankyringenes, resulting cytoskeleton instability3. Familly history (at least half of new diagosed patients)4. Clinical features: jaundice, gallstones, splenomegaly,constitutional skeleton changes (ie tower cranium, gothic

    palate)5. Laboratory features

    - hemolytic anemia- blood smear-microspherocytes- abnormal osmotic fragility test, cryohemolysis test,acidified glycerol lysis time

    - negative direct Coombs test- increased MCHC

    6. Treatment- splenectomy (patients >6 yrs old) eradicates clinical

    manifestations of the disorder, including aplastic crises

    aroxysma nocturna emog o nur a PNH

  • 8/2/2019 IM-Hemolytic Anemia (1)


    aroxysma nocturna emog o nur a PNH

    1. Pathogenesis- an acquired clonal disease, arising from a somaticmutation in a single abnormal stem cell. PNH involves

    the PIG-A gene (short arm of the X chromsome). Themutation results of glycosyl-phosphatidyl-inositol (GPI)anchor abnormality

    - deficiency of the GPI anchored membrane proteins(DAF=decay-accelerating factor CD55, MIRL=amembrane inhibitor of reactive lysis, C8BP=C8

    binding protein)- the defective synthesis of GPI affects all hematopoietic

    cells (anemia, neutropenia end thrombocythopenia, orthey may have complete BM failure)

    - red cells are more sensitive to the lytic effect ofcomplement

    - intravascular hemolysis2. Symptoms: passage of dark brown urine in themorning, severe pain in he abdomen and recurrentthromboembolism (ie vena cava inf., portal mesentericsystem)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    3. PNHlaboratory features:- pancytopenia

    - chronic urinary iron loss- serum iron concentration decreased- hemoglobinuria- hemosiderinuria- positive Hams test (acid hemolysis test)

    - positive sugar-water test- specific immunophenotype of erytrocytes (CD59,CD55)

    4. Treatment:- washed RBC transfusion

    - iron therapy- allogenic bone marrow transplantation(streoids may reduce transfusion requirements;splenectomy very questionable benefit)

  • 8/2/2019 IM-Hemolytic Anemia (1)



    Definition: chronic hemolytic anemiaoccuring almost exclusively in blacksand characterized by sickle-shaped redcells(RBCs) caused by homozygousinheritance of Hemoglobin S

  • 8/2/2019 IM-Hemolytic Anemia (1)


    SICKLE CELL ANEMIA-pathogenesis

    - In HbS, valine is substituted for glutamic acid inthe sixth amino acid of the chain.

    - Deoxy-HbS is much less soluble than deoxy HbA;

    it forms a gelatinous network of fibrous polymers thatcause RBCs to sickle at sites of low pO2.

    - Hemolysis - because sickle RBCs are too fragile towithstand the mechanical trauma of circulation

    - Occlusion in microvascular circulation caused by distorted,inflexible RBCs adhering to vascular endothelium

  • 8/2/2019 IM-Hemolytic Anemia (1)


    SICKLE CELL ANEMIA-incidence

    - Homozygous - about 0.3% of blacks in the USA

    (have sickle cell anemia)

    - Heterozygotes-8-13% of blacks, (are not anemic,but the sickling trait=sicklemia can bedemonstrated in vitro)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    SICKLE CELL ANEMIA-clinicalfeatures

    IN HOMOZYGOTES1. Clinical complications due to severe hemolytic


    - slowed growth and development in children

    - bilirubins stones- aplastic crisis

    - congestive heart failure from chronic anemias andcardiac overload compensation

    2. Consequences of vaso-occlusion of themicrocirculations (tissue ischemia and infarction)

    - infarction of spleen, brain, marrow, kidney, lung,aseptic necrosis, central nervous system andophtalmic vascular lesions

  • 8/2/2019 IM-Hemolytic Anemia (1)


    SICKLE CELL ANEMIA-laboratoryfindinges

    1. Anemia-normocytic or slightly macrocytic

    2. Leukocytosis (chronic neutrophilia)

    3. Thrombocytosis - usually mild

  • 8/2/2019 IM-Hemolytic Anemia (1)



    Preventive measures:

    prevention or remedy of: infections (penicillin prophylaxisand pneumococcal vaccination), fever, dehydratation,acidosis, hypoxemia, cold exposure, pain

    Blood transfusions for very severe anemia

    New approaches to therapy;

    1. Activation of HbF synthesis: hydroxyurea, 5-

    azacytidine, decytabine2. Antisickling agents acting on hemoglobin ormembrane (preclinical testing, clinical trials)

    3. Bone marrow transplantation

    4. Gene therapy

  • 8/2/2019 IM-Hemolytic Anemia (1)



    The regions in which thalasemia occure are contiguouswith regions endemic for malaria (protection againstmalaria)

    Thalasemia result from gene (located on chromosomes11 and 16) deletion, abnormalities in transcription andtranslation and instability of the mRNA directing globinsynthesis or of the globin itself.

    Result: imbalanced synthesis of normal globin chain. The

    unpaired chain accumulates in the developing erythroidprecursor cell, and toxicity results ineffectiveerythropoiesis, hemolysis and anemia of variable degree.

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Different forms of thalassemia

    Alfa thalassemia

    Beta thalasemia: major, minor (trait),

    intermedia Delta/Beta thalassemia

    Hereditary persistentce of fetal

    hemoglobin (HPFH)

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Beta-Thalassemia major(Cooley anemia)

    Usually homozygous condition In the most severe variant no beta-chains are


    Clinical futures: sever anemia that appears in the firstyear of life; jaundice, hepatosplenomegaly (secondaryneutropenia and thrombocytopenia), skin pigmentationand chronic leg ulceration, expansions of the erythroidmarrow with secondary body changes (includingretarded growth, bossing of skull, expanded maxilla,

    widened diploe, gross skeletal deformities, spontaneousfractures, dental problem), increased susceptibility toinfection, symptoms of iron overloading

  • 8/2/2019 IM-Hemolytic Anemia (1)


    Beta-Thalassemia majorlaboratory features

    Severe anemia

    Blood film: anisopoikilocytosis, hypochromia,target cells, basophylic stippling, reticulocytes moderate increased

    Marrow: marked erythroid hyperplasia,increased sideroblasts

    Shortened red cell survival Fetal hemoglobin > 90%, HbA absent, HbA2


  • 8/2/2019 IM-Hemolytic Anemia (1)


    Beta-Thalassemia majortreatment

    - High standard of pediatric care required!!!(early treatment of infections, vaccination, folatesupplemets, dental care), replacement therapy

    and chelation when iron-overloading- Transfusion (Hb must be 10 to 14 g/dL) each 6-

    8 weeks- Splenectomy

    - BMT- Experimental therapy: hydroxyurea, somatic

    gene therapy