Summary Of All Anemia

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

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 α- thalasemia: 4 genes on ch 16 deletions- 1- silent carries, 4- hydrops fetalis, 3- disease β- thalasemia: 2 genes on ch 11 point mutations on certain regions of gene: in promoter & unsplicing region of intron- β+ (reduced β-chains) In exon & splicing region of intron- β0 (absence of β-chains) G6PD gene on ch X forms G6PD enzyme that regenerates GSH after its oxidation Mutation causes more rapid decay of enzyme (A- variant) Acquired membrane defect secondary to a mutation that involves myeloid stem cells. Mutation in X-linked PIGA (synthesis of intramembranous glycoprotein anchor – PIG) Warm: IgG or (rarely) IgA active at 37 deg. 60% idiopathic and 40 % underlying disease (SLE) or drugs (amethyl dopa, penicillin) Cold: IgM binds to CM below 30 deg. (in distal parts)

Resulting from trauma

Intravascular hemolysis

Valve prostheses and microangiopathic (caused by DIC, malignant HT, SLE or disseminated cancer)

malaria

Intravascular hemolysis

Plasmodium vivax, malariea, ovale & falciparum (most fatal causing cerebral malaria and blackwater fever)

Pathogenesis On deoxygenation-polymerizaton and reversible sickling, continued exposure-ireversible – mononuclear phagocytosis & microvascular obstructions. Particularly predisposed with salmonella osteomyelitis Excessive β- & γ- chains- form stable tetramers (Hb H, Hb bart) low damage, ineffective in O2 delivery Decrease in β-chains – decreased Hb More imp: increase in free α-chains that aggregate, form inclusion in RBC (reduce plasticity of RBC, becomes more susceptible to mononuclear phagocytosis) destruction also of blasts – ineffective erythropoisis - iron overload Exposure to drugs, toxins or infections increases H peroxide so increases oxidation of GSH to GSSG, GSH regeneration is impaired so – accum. of H peroxide which denatures Hb. This ppts causing IVhemolysis and also EVhemolysis in spleen PIGA deficient BM cells are present in normal individuals, when there is immune-mediated destruction or suppression of BM cells by recognition of sp. PIG-tailed antigens the PIGA deficient cells do not express the targets and so escape the attack and replace BM Opsonization by IgG and subsequent phagocytosis by splenic macrophages. Attempts of phagocytosis leads to injured bits of CM – decreased SA:V ratio – spheroidal cells – sequestration Complement most active at 37 deg. so no IVhemolysis, when cells go to warmer regions IgM is not well bound but leaves behind C3b opsonin causing phagocytosis by kupffer cells (EV) Valves cause abnormal pressure gradient and turbulent blood flow, and RBCs are squeezed thru narrowed vessels, results in mechanical damage in both After infecting hepatocytes, merozites infect erythrocytes forming trophozites (characteristic to each specie) which divides giving rise to new merozites that destroy RBCs upon escape

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. Major: Microcytic hypochromic + poikilocytosis Failure of normal development Skeletal deformities, reticulocytosis. Iron overload – leads to cardiac failure (need iron chelators) Minor Mild microcytic hypochromic Normal life expectancy No symptoms unless exposure oxidative injury. In males severe oxidant injury In females asymptomatic Heinz bodies (precipitated Hb) and bite cells (phagocytosis by splenic phagocytes) PIG-tailed proteins (3 that prevent activation of complement on normal RBC’s) cannot be expressed so RBC sensitive to lytic activity of complement, also not expressed on granulocytes and platelets – susceptibility to infections and IVthrombosis +ve direct/ indirect coombs test for both Chronic mild anemia with moderate spleenomegaly Acute during recovery from Mycoplasma pneumonia and infectious mononucleosis or chronic resulting in transient mild anemia with often Raynaud phenomenon Burr, hemlet and triangle cells

Spikes of shaking, chills and fever at intervals which coincide with merozite release from RBC. Brown discoloration of spleen, liver, lymph nodes & BM, massive spleenomegaly (hyperplasia of mononuclear phagocytes)

Anemias of Diminished Erythropoiesis Type Iron Deficiency

Cause Low dietary intake (rare), malabsorption (e.g. gastrectomy), increased demands (pregnancy, infants), chronic blood loss (from GIT – peptic ulcer, hemorrhoids or female genital tract)

Anemia of chronic disease

Occurs in chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abcess), chronic immune disorders (rheumatoid arthritis, regional enteritis) and neoplasms (Hodgkin, lung & breast cancer) Deficiency of folic acid from poor diet or increased metabolic needs. Or inhibition of folate metabolism by methotrexate, acidic foods & beans, phenytoin. pernicious anemia Impaired absorption of vitamin B12 by: *malabsorption (lack of vit B12 uncommon), *autoimmune reaction against parietal cells or IF, *surgery and gut disorders (gastrectomy regional enteritis) or *aging (gastric atrophy & achlohydria)

Megaloblastic anemia

Aplastic

Myelophthisic

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 arising from breast, lung, prostate or thyroid 1ry lesion or with myelofibrosis

Pathogenesis Starts with decline in serum ferretin and stainable amounts of iron in BM. Followed by decrease in circulating iron and rise in transferrin iron-binding capacity – impact on Hb, myoglobin and other iron compounds. When more severe – impaired work performance, brain function and immunocompetence Sequestration of iron from cells from the storage compartment (mononuclear phagocyte storage pool) and suppression of erythropoiesis due to inflammatory mediators (IL-1, TNF, interferon-alpha) that are released from the underlying disease.

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

vit B12 required for regeneration of tetrahydrofolate, Folic acid provides tetrahydrofolate (carrier of a carbon group) so both required for DNA synthesis. Deficiency – delay in nuclear maturation and cell division of erythroid precursors producing megaloblasts (also granulocyte precursors produce giant megakaryocytes) some megaloblasts have very defective DNA that they undergo apoptosis in BM, others give mature RBC’s but output is diminished. The enlarged RBCs are prone to premature destruction by mononuclear phagocyte system leading to accumulation of iron (in mononuclear phagocytes)

Non-specific symptoms relating to pancytopenia (weakness, pallor, easy fatigability, petechia, easy 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, 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 (pancytopenia)

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 replacement of BM by tumors or other lesions

__ Treatment: erythropoietin administration may improve but only treatment of underlying condition is reliable

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 ironbinding 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 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 immature RBCs (teardrops) , slightly elevated WBC count, leukoerythroblastosis