Pathology Exam 3 PDF - Blood Disorders, Hemoglobinopathies

BLOOD Overview ​ Blood disorders affect 3 main components: RBC, WBC, and clotting (platelets and factors) Red cell disease ​ 3 ways to have an issue ○​ Lose RBC-> bleeding ○​ RBC destruction -> hemolysis ○​ Decreased production ​ Anemia: ○​...

BLOOD Overview ​ Blood disorders affect 3 main components: RBC, WBC, and clotting (platelets and factors) Red cell disease ​ 3 ways to have an issue ○​ Lose RBC-> bleeding ○​ RBC destruction -> hemolysis ○​ Decreased production ​ Anemia: ○​ Acute: SOB, organ failure, shock ○​ Chronic: pallor, fatigue, presyncope ​ Severe (colon cancer) & congenital (bone deformities): due to reactive marrow hyperplasia ​ RBC morphology: ○​ Made by erythropoietin (EPO) from kidneys to bone marrow ○​ Measure RBC: Hgb, Htc, MCV (size), retic count (young cells- hemolytic or generative anemia) ○​ Measure iron: serum, iron binding capacity, ferritin ○​ Bilirubin: conjugated (processed by liver so water-soluble) & unconjugated (not processed in liver so not water soluble) ○​ Folate & B12: macrocytic anemia ○​ Hgb electrophoresis: distinguish type of hgb abnormality ○​ Coombs test: anti-body mediated hemolytic anemia ○​ Hemoglobin specifics: ​ Measure change not number (abrupt change is what matters) ​ When onset of anemia is slow: O2 deficit increases CO & Resp rate. Red cell 2,3-diphosphoglycerate (DPG) enhances releases of O2 from hgb (adaptive change to help compensate for chronic anemia) ○​ During blood loss: ​ hgb will not read as low because the concentration is technically normal, but over days dilution will begin and anemia symptoms start ​ Iron will be gradually depleted (iron needed for hgb) so chronic anemia occurs ​ Tests will show: low serum iron (low iron), high TIBC (body iron hungry), low ferritin (no more storage) ​ Note: high ferritin= anemia of chronic disease Hemolysis ​ RBC live 120 days and are lysed when they die ○​ Cells release unconjugated bili (byproduct of hgb breakdown) ​ hemolysis-> low O2 -> increased EPO -> increased reticulocytes (check retic count, high= hemolysis) ​ Extravascular hemolysis: ○​ Cause: destruction of RBCs by phagocytes (often in spleen)  ○​ How: hgb breaks down inside RBC (release unconjugated bili as byproduct) + disease makes RBC not be able to change shape which must happen to move in spleen and if they can't they get sequestered/stuck and fed to macrophages ○​ clinical: hyperbilirubinemia & jaundice, gallstones, splenomegaly ○​ Labs: increased unconjugated bili, decreased haptoglobin (plasma protein which binds to free hgb) ​ Intravascular: ○​ Cause: direct destruction of RBC in bloodstream (often from turbulence from defective heart valve, completement destruction, or some toxins) ​ Hgb released into blood and excreted in urine, some will turn into hemosiderin which is also excreted in urine ○​ Labs: increased unconjugated bili, decreased haptoglobin (plasma protein which binds to free hgb) (same as extravascular) Hereditary spherocytosis (extravascular hemolytic disease) ​ Autosomal dominant condition ​ Defect in RBC membrane proteins (ankyrin or spectrin) ​ creates spherical, non-deformable cells (overtime surface to vol ratio is decreased which cause the sphere shape) ​ Cells are sequestered and destroyed in spleen by macrophages ​ Clinical: anemia (pt prone to infection of parvovirus 19 which causes aplastic crisis), splenomegaly, and jaundice ​ Treated with splenectomy to improve anemia Hemoglobinopathies ​ Sickle cell disease ○​ Normally: hgb composed of 2 beta and 2 alpha globins (though a fetus (HgF) has gamma-globin instead of beta but by 6 months old the gamma is replaced by beta) ○​ Single amino acid mutation in beta hemoglobin (get valine instead of glutamate) ​ Homozygotes: all adult hgb (HgA) turns to sickled hgb (HgS) ​ Heterozygotes: only ½ proteins are mutated ○​ Under hypoxic condition, cells undergo sickled structural change (irreversible)- but does not happen until 6 months old (when gamma goblin turns to beta globin) ​ Cells will have an influx of calcium -> K and H2O loss -> damage membrane skeleton ​ Sickle cells hemolyze ealy and become stuck in microvasculature ○​ Clinically: ​ Splenomegaly (RBC get stuck here) ​ pain (bc of vasoocclusive) (tx with narcotics) ​ hand-foot syndrome (infarct in bones where occlusion is) ​ acute chest syndrome (sluggish blood flow in inflamed lung -> hypoxia) ​ Stroke (due to occlusion) ​ Proliferative retinopathy (due to occlusions-> vision loss)  ​ Thalassemias ○​ Imbalance in production of alpha or beta globin -> hgb with abnormal amount of globin -> do not bind to O2 efficiently -> can be lethal ○​ Alpha: reduced/absent alpha globin ​ Cause: deletion of 1 or both alpha globin genes ​ 2 genes for alpha globin so 4 alleles ○​ If 3+ alpha chains are lost, beta-globin pairs into a tetramer ​ Tetramer beta-4 (adults); gamma-4 (infants) -> have high affinity for O2 (won't let it go) ​ Clinical: ​ 1 active alpha globin: silent carrier ​ 2 active alpha-globins: Mild microcytic anemia ​ Hb H(𝛽4) disease: 3 alpha chains lost-> mod-severe hemolytic anemia ○​ RBC get HgH inclusions which are removed by spleen, but this damages the cells leading to premature destruction ​ Hydrops fetalis, Hb Barts (𝛾4): no alpha-globins-> infants suffer from severe hypoxia and born with massive fluid accumulation-> death of fetus ○​ Beta: reduced/absent beta globin ​ Cause: single-base substitution -> reduced/altered/no activity of the 1 beta gene (2 alleles) ​ Decreased beta leads to excess alpha chains -> formation of Heinz body -> damage of RBC membrane -> iron overload (dietary intake cannot be accommodated for) ​ Clinical: ​ Thalassemia minor: carrier of 1 beta-thalassemia allele ○​ Hypochromic, microcytic RBC (can be misdiagnosed as iron deficiency) ​ Thalassemia major: homozygous recessive or compound heterozygote for 2 different beta-thalassemia alleles ○​ Severe anemia-> lifelong medical management ○​ Symptoms: prominent cheekbones & protrusion of upper jaw from expansion of marrow cavity in bones of skull/face trying to make more RBCs) ○​ usually only seen where malaria is common G6PD deficiency (glucose-6-phosphate dehydrogenase) ​ X-linked recessive mutation in G6PD gene (enzyme that processes glucose which produces NADPH (which protects RBC from harmful reactive O2 species)) ​ No symptoms until 3-5 days after exposure to environmental factors that increase oxidant stress (infxn, certain drugs/food, severe stress) -> hemolytic anemia ○​ Drugs: chlorpropamide (for DM), dapsone (abx), fluoroquinolones (abx), nitrofurantoin (abx), sulfa (abx used a lot), antimalarial  ○​ Food: fava beans ○​ Chemical: henna, naphthalene (moth balls) ​ Who: 1 in 10 black males (relatively common) ​ Labs: peripheral blood smear shows RBC with precipitates of denatured globin (heinz bodies) where splenic macrophages have “plucked out” the inclusions (looks like a bite taken out of cell) Anemias of decreased production (diminished erythropoiesis) ​ Iron deficiency anemia ○​ Most common anemia ○​ Cause: inadequate iron intake or blood loss -> insufficient hgb synthesis ○​ Dx criteria: hypochromic & microcytic RBC, low iron levels, low transferrin saturation, high TIBC, low ferritin ○​ Clinical: asymptomatic mostly ​ Severe cases: weakness, listlessness, pallor ​ Chronic cases: spooning of nails or pica (eat inedible things) ​ Anemia of chronic disease ○​ MC anemia in hospitalized pts (bc of chronic infxns, immune disorders, neoplasms) ○​ Chronic inflammation causes inflammatory cytokines to increase hepatic hepcidin (blocks iron from being added to RBCs), & blunts EPO synthesis -> iron stored ○​ Labs: high ferritin, low TIBC (iron not desired), normal MCV ○​ Tx: administer EPO (helps anemia), but to cure tx underlying disease ​ Megaloblastic anemia ○​ Caused by folate or B12 deficiency ○​ Affects DNA synthesis: to make thiamine (T nucleotide), folate and B12 are needed ​ DNA cannot replicate and will eventually be damaged -> increase in megaloblasts (large RBC precursors) ○​ folate deficiency: inadequate dietary intake (found mainly in veggies but destroyed with 10-15 min of cooking) ​ Those at risk: poor nutrition & pregnant women (increased metabolic demand) ​ Clinically: weakness, fatigue ​ Dx: high MCV, blood smear, low folate level ○​ B12 (cobalamin) deficiency: inadequate dietary intake & pernicious anemia ​ How do we get B12: pepsin releases B12 from food, intrinsic factor (from parietal cells) binds to B12 and is then absorbed by enterocytes in the distal ileum, then transferred to liver and body cells ​ Pernicious anemia: autoimmune attack on gastric mucosa-> suppresses intrinsic factor (no matter what cannot absorb dietary B12) ​ Other causes: GI disorders that effect absorption (chrons), gastric bypass, taking PPIs (suppress pepsin bc of higher pH)  ​ Clinically: fatigue, malaise, beefy red tongue, spinal cord disease (cause neurologic symptoms- numbness/tingling/burning in hands/feet, unsteady gait, diminished proprioception) ​ Need to tx B12 deficiency to improve anemia and neurologic sx (could worsen if just given folate) ​ Aplastic anemia ○​ Suppression of multipotent myeloid stem cells -> bone marrow failure & pancytopenia ○​ Cause: ​ ½ cases are idiopathic (could be caused by autoreactive T cells) ​ ½ caused by exposure to myelotoxic agents (toxins, radiation) -> bone marrow hypocellular with fat replacement ○​ Clinically: anemia, thrombocytopenia, neutropenia (all low cell counts) ​ Slowly progressive, weakness, pallor, dyspnea, infxn issues Increased RBC production ​ Polycythemia (erythrocytosis) ○​ Cause: abnormal increase in RBC number ○​ Primary (polycythemia vera): clonal proliferation of myeloid stem cells -> uncontrolled production of RBCs ​ Symptoms: HTN, flushed face, headache, pruritus, neurological symptoms, splenomegaly ​ Risks: DVT, MI, stroke, leukemia ○​ Secondary: prolonged hypoxia (high altitude, chronic lung disease, congenital heart disease, renal carcinoma)-> increase EPO -> erythroid bone marrow hyperplasia -> increased RBC vol Leukocyte disorders ​ Benign (often 2ndary cause): ○​ Leukopenia: WBC count below normal ​ Cause: sepsis, neutropenia (chemo decreases production; drugs, infxn, sequestered in spleen increased destruction) ○​ Leukocytosis: WBC count above normal (usually this) ​ Cause: inflammatory response, infxn, stress (low levels bc of demargination), leukemia (if really high WBC count) ​ Malignant: ○​ Leukemia: from WBC precursors (lymphoid or myeloid) in bone marrow ​ Bone marrow infiltrated with malignant cells: clonal expansion of neoplastic stem cells with genetic changes -> suppress normal hematopoiesis -> peripheral blood contain increased # of immature cells ​ Myeloblasts: precursor of myelocytes which can differentiate into granulocytes (basophils, eosinophils, neutrophils)  ​ Lymphoblasts: precursor of lymphocytes which can differentiate into B & T cells ​ Complications: anemia, recurrent infxns, & uncontrollable bleeding ​ Acute myeloid leukemia (AML): look for “blast crisis” (rapid proliferation of immature cells) ​ Acute lymphocytic anemia (ALL): pediatric cancer tx with chemo ​ Chronic myeloid leukemia (CML): high (mature) WBC count; can see a philadelphia chromosome (translocation of chromosomes 9 & 22 which fuses BCR and ABL regions); also may have “blast crisis” ​ Chronic lymphocytic leukemia (CLL): very high (mature) WBC count see in very elderly; slow growing so don't even treat if over 65 ○​ Lymphoma: from WBC in lymph nodes ​ Hodgkins: contiguous spread (spread to what its next to) but usually localized to single axial group of nodes ​ B symptoms: fever/chills, night sweats, weightloss; nontender LAD ​ Dx: reed sternberg cells (large,abnormal lymphocytes with multiple nuclei) ​ Rarely involved mesenteric nodes, waldeyer ring, or extranodes ​ Non Hodgkin's: hematogenous (blood) spread (so frequently involves multiple peripheral nodes) ​ No B symptoms; nontender LAD; no reed sternberg cells ​ Commonly involved mesenteric nodes, waldeyer ring, and extranodes ○​ Multiple myeloma: malignant plasma cells from bone marrow ​ Others that affect WBC or lymph tissue: ○​ Mono: caused by epstein barr virus -> B cells proliferate -> T cells control proliferation of EBV ​ Some EBV infected B cells escape immune response and can keep proliferating causing lymphoma ○​ Cat-scratch disease: self limiting lymphadenitis caused by bartonella henselae-> lymphadenopathy in axilla & neck Bleeding disorders ​ Disseminated intravascular coagulation (DIC): ○​ Cause: wide-spread clotting in the microcirculation all over the body (consume coagulation factors and platelets) & fibrinolytic mechanisms are activated causing profuse bleeding and tissue hypoxemia ○​ triggers: sepsis, major trauma, certain cancers, OB complications ​ Idiopathic thrombocytopenic purpura (ITP): ○​ Cause: autoantibodies against platelet antigens ○​ Triggers: drugs, infxn, lymphomas, idiopathic ​ Thrombotic thrombocytopenic purpura (TTP): ○​ Cause: acquired or inherited deficiency in ADAMTS 13 (mutation that inhibits platelet function through von willebrand factor) -> large platelet aggregations and micro clots -> over use of platelets (thrombocytopenia) & bleeding (milder than DIC) ○​ Other symptoms: fever and CNS involvement ​ Hemolytic uremic syndrome (HUS): ○​ Cause: deficiency of complement regulatory proteins -> platelet activation & aggregation -> thrombocytopenia & RBC destruction ○​ Triggers: infxn (mainly E coli) ​ Von willebrand disease: ○​ Autosomal dominant disorder caused by mutations in vWF -> decreased platelet aggregation -> mild-mod bleeding disorder ​ Hemophilia A: ○​ MC cause of hereditary bleeding ○​ X-linked disorder (males get) caused by mutation in factor VIII -> severe bleeding into soft tissues and joints (have prolonged PTT) ​ Hemophilia B: ○​ X-linked disorder caused by mutations in factor IX (clinically identical to hemophilia A)