Hemolytic Anemias Type Sickle cell anemia
Type of hemolysis
Extravascular hemolysis
Thalasemia
intravascular hemolysis
G6PD deficiency
Intra- & extravascular hemolysis
Paroxysmal nocturnal hemoglobinuria
intravascular hemolysis
Immunohemolytic anemia
Extravascular hemolysis
Resulting from trauma
Intravascular hemolysis
malaria
Intravascular
Mutation/ Cause
Point mutation in beta-globin chain-glu replaced by val- S Hb Can be homozygous- all chains have mutation or heterozygous- abt half chains have mutation
Pathogenesis
On deoxygenation-polymerizaton and reversible sickling, continued exposure-ireversible – mononuclear phagocytosis & microvascular obstructions.
Clinical picture and findings
Homozygous: severe anemia, HCT 18-30%, reticulocytosis, hyper-bilirubinemia, crisis Hetero: asymptomatic until exposure to severe hypoxia Hypospleenism in adults, spleenomegaly in children- infections.
Particularly predisposed with salmonella osteomyelitis α- thalasemia: 4 genes on ch 16 Excessive β- & γ- chains- form stable tetramers Major: deletions- 1- silent carries, 4- hydrops (Hb H, Hb bart) low damage, ineffective in O2 Microcytic hypochromic + poikilocytosis fetalis, 3- disease delivery Failure of normal development Skeletal deformities, reticulocytosis. β- thalasemia: 2 genes on ch 11 Decrease in β-chains – decreased Hb point mutations on certain regions of More imp: increase in free α-chains that aggregate, Iron overload – leads to cardiac failure (need iron chelators) gene: in promoter & unsplicing region form inclusion in RBC (reduce plasticity of RBC, Minor of intron- β+ (reduced β-chains) becomes more susceptible to mononuclear Mild microcytic hypochromic In exon & splicing region of intron- β0 phagocytosis) destruction also of blasts – Normal life expectancy (absence of β-chains) ineffective erythropoisis - iron overload G6PD gene on ch X forms G6PD Exposure to drugs, toxins or infections increases H No symptoms unless exposure oxidative injury. injury. enzyme that regenerates GSH after its peroxide so increases oxidation of GSH to GSSG, In males severe oxidant injury oxidation GSH regeneration is impaired so – accum. of H In females asymptomatic Mutation causes more rapid decay of peroxide which denatures Hb. This ppts causing Heinz bodies (precipitated Hb) and bite cells enzyme (A- variant) IVhemolysis and also EVhemolysis in spleen (phagocytosis by splenic phagocytes) Acquired membrane defect secondary PIGA deficient BM cells are present in normal PIG-tailed proteins (3 that prevent activation of to a mutation that involves myeloid individuals, when there is immune-mediated complement on normal RBC’s) cannot be stem cells. Mutation in X-linked PIGA destruction or suppression of BM cells by expressed so RBC sensitive to lytic activity of (synthesis of intramembranous recognition of sp. PIG-tailed antigens the PIGA complement, also not expressed on granulocytes glycoprotein anchor – PIG) deficient cells do not express the targets and so and platelets – susceptibility to infections and escape the attack and replace BM IVthrombosis Warm: IgG or (rarely) IgA active at 37 Opsonization by IgG and subsequent phagocytosis +ve direct/ indirect coombs test for both deg. 60% idiopathic and 40 % by splenic macrophages. Attempts of phagocytosis Chronic mild anemia with moderate underlying disease (SLE) or drugs (aleads to injured bits of CM – decreased SA:V ratio spleenomegaly methyl dopa, penicillin) – spheroidal cells – sequestration Cold: IgM binds to CM below 30 deg. Complement most active at 37 deg. so no Acute during recovery from Mycoplasma (in distal parts) IVhemolysis, when cells go to warmer regions pneumonia and infectious mononucleosis or IgM is not well bound but leaves behind C3b chronic resulting in transient mild anemia with opsonin causing phagocytosis by kupffer cells often Raynaud phenomenon (EV) Valve prostheses and microangiopathic Valves cause abnormal pressure gradient and Burr, hemlet and triangle cells (caused by DIC, malignant HT, SLE or turbulent blood flow, and RBCs are squeezed thru disseminated cancer) narrowed vessels, results in mechanical damage in both Plasmodium vivax, malariea, ovale & After infecting hepatocytes, merozites infect Spikes of shaking, chills and fever at intervals
Anemias of Diminished Erythropoiesis Type Iron Deficiency
Anemia of chronic disease
Megaloblastic anemia
Aplastic
Myelophthisic
Cause
Pathogenesis
Low dietary intake (rare), Starts with decline in serum ferretin a nd malabsorption (e.g. gastrectomy), stainable amounts of iron in BM. Followed increased demands (pregnancy, (pregnancy, by decrease in circulating iron and rise in infants), chronic blood loss (from transferrin iron-binding capacity – impact GIT – peptic ulcer, hemorrhoids - on Hb, myoglobin and other iron or female genital tract) compounds. When more severe – impaired work performance, brain function and immunocompetence Occurs in chronic microbial Sequestration of iron from cells from the infections (osteomyelitis, storage compartment (mononuclear bacterial endocarditis, lung phagocyte storage pool) and suppression of abcess), chronic immune erythropoiesis due to inflammatory disorders (rheumatoid arthritis, mediators (IL-1, TNF, interferon-alpha) that regional enteritis) and neoplasms are released from the underlying disease. (Hodgkin, lung & breast cancer) Deficiency of folic acid from vit B12 required for regeneration of poor diet or increased metabolic tetrahydrofolate, Folic acid provides needs. Or inhibition of folate tetrahydrofolate (carrier of a carbon group) metabolism by methotrexate, so both required for DNA synthesis. acidic foods & beans, phenytoin. Deficiency – delay in nuclear maturation and cell division of erythroid precursors pernicious anemia Impaired producing megaloblasts (also granulocyte absorption of vitamin B12 by: precursors produce giant megakaryocytes) *malabsorption (lack of vit B12 some megaloblasts have very defective uncommon), *autoimmune DNA that they undergo apoptosis in BM, reaction against parietal cells or others give mature RBC’s but output is IF, diminished. The enlarged RBCs are prone *surgery and gut disorders to premature destruction by mononuclear (gastrectomy regional enteritis) phagocyte system leading to accumulation or *aging (gastric atrophy & of iron (in mononuclear phagocytes) achlohydria) Suppression of multipotent myeloid stem cells caused by: *idiopathic, *myelotoxic agents (irradiation or myelotoxic druds), *drugs and chemicals (antineoplastic drugs, benzene, chloramphenicol, or sensitivity to sulfonamides, phenylbutazone etc.), *viral infection Associated with metastasis
Autoreactive T-cells (patients respond to immunosuppressive therapy aimed at T cells) where viral antigens, drug-drived haptens and genetic damage create neoantigens within stem cells that are targets for autoreactive T cells
Bone marrow failure caused by extensive
Clinical picture
Mostly asymptomatic with weakness and pallor in severe cases. Long-term severs anemia – thinning, flattening and spooning of fingernails, pica, increase in platelet count. Sometimes develops plummer-vinson syndrome
__ Treatment: erythropoietin administration may improve but only treatment of underlying condition is reliable Non-specific symptoms relating to pancytopenia (weakness, pallor, easy fatigability, fatigability, petechia, eas y infection). Alimentary tract related symptoms are common e.g. sore tonge (rapid dividing GIT cells). In vit B12 deficiency only neurological symptoms may take place e.g. symmetric numbness, tingling, burning in feet or hands, unsteadiness of gait, loss of position sense *Cellular morphology: hypercellular BM, nuclear-cytoplasmic asynchrony, asynchrony, megaloblasts – delicate finely reticulated nuclear chromatin, megakaryocytes – bizarre multi-lobed nulei Symptoms relating to pancytopenia (weakness pallor, dyspnea, petechiae,frequent persistant minor infections or sudden onset of chills or fever) Normocytic, normochromic, sometimes slight macrocytic. Reticulocytosis is absent Spleenomegaly is absent Anemia and thrombocytopenia
Diagnosis
Low: Hb, HCT, MCV, serum ferretin, iron levels, transferring saturation, microcytic hypochromic RBCs. HIGH total iron-binding capacity
Normocytic normochromic, or hypocytic hypochromic, low serum iron, (similar to iron deficiency) but: Increased storage iron in marrow macrophages, increased serum ferretin, decreased total iron binding capacity Smear of peripheral blood and bone marrow. To differentiate between vit B12 – serum folate and vit B12 levels and RBC folate levels Low serum vit B12 levels, normal or elevated folate, histamine-fast gastric achlohydria, anti IF antibodies, megaloblastic anemia findings, leucopenia, schilling test (unable to absorb an oral dose of vit B12 but when administered with IF absorption takes place)
Differential diagnosis to differentiate between it and myelophthisic (or other pancytopenias) – hypocellular hypocellular BM owing to stem cell failure *Treatment: BM transplantation v. effective in patients nontransfused and younger than 40. other patients – immunosuppressive therapy Peripheral blood smear shows
