Handout # 9 Normocytic anemias: Non Hemolytic with corrected reticulocyte count <2% Pathogenesis Causes Clinical findings Normal

Hb/Hct with initial acute blood loss. Plasma deficit replaced first and uncovers RBC deficit Infusion of 0.9% normal saline uncovers RBC deficit immediately GI Bleed: MCC Upper GI MC site Duodenal Ulcer > gastriculcer Lower GI: diverticulosis, angiodysplasia, colon cancer (>50 yrs age) Miscellaneous: splenic rupture, Trauma, ruptured aortic aneurysm, Blleding Meckel's diverticulum Positive tilt test Lower left rib tederness: splenic rupture Fractures: Pelvic and femoral

Anemia Acute/Chronic blood loss MCV: normocytic (80-100) Reticulocyte count: <2% (>3% if bleed is over 5-7 days) PS: normal findings until reticulocyte response (presence of Reticulocytes and Shift cells)

Aplastic Anemia MCV: normocytic Reticulocyte count: <2% Key findings: Pancytopenia due to hypocellular BM

Stem cell disease: Idiopathic: MCC Suppression of trilineage stem Genetic: Fanconi's syndrome cell in the BM Chemical: Benzene (increased risk of acute leukemmia) Drugs: Chloramphenicol Infection: NANB hepatitis Radiation Anemia: aplastic crisis due to hemolytic anemia (SCD and HS) Often associated with Pavovirus B19 infection Pure Red cell aplasia: No BM RBC precursor Parvovirus infection of erythroid cells Thymoma Decreased erythropoietin DM is MCC of chronic renal renal disease

Bleeding: thrombocytopenia Infection associated with neutropenia Fatigue: anemia

Renal disease MCV: normocytic Reticulocyte count: <2% Key findings: Burr cells

Anemia not present until creatinine clearacen is <40 mL/min

Leukoerythroblastic smear: Metastasis of cancer to BM causes spilling of immature MCV: normocytic cells in peripheral blood Reticulocyte count: <2% Key findings: immature neutrophil precursors and nucleated RBC's

Prostate cencer in men: tends to metastasize to Bone pain Pathlogical fractures vertebral column. Breast cancer: metastasizes to vertebral colunm Other cancers that metastasize to bone: lung, kidney

Handout # 9

Laboratory tests No specific lab tests General: Stool guaiac, dipstick of urine for blood

CBC: pancytopenia Bone marrow : hypocellular Lymphoid cells still present*

Serum BUN/Creatinine: increased PS: leukoerythroblastic picture BM biopsy: to confirm metastasis

Handout # 10 Anemia Characteristics Congenital Spherocytosis MCV: normocytic Reticulocyte count: >3% Key findings: Spherocytes (no central pallor; since not biconcave disc) Shift cells

Paroxysmal Nocturnal Hemoglobinuria (PNH) MCV: normocytic Reticulocyte count:> 3% Key findings: Pancytopenia, iron deficiency in chronic stages

Normocytic Anemias: Hemolytic with corrected Reticulocyte Count >3% Pathogenesis Causes Clinical findings Hemolytic Anemia: macrophage Northern European people Triad of findings: phagocytosis maximum prevalance anemia Intrinsic abnormality of RBC with Autosomal dominant disease splenomegaly jaundice ( unconjugated extravascular hemolysis hyperbilirubinemia) Defect in spectrin in cell membrane Consider HS if family history of --> decreased amount of RBC splenectomy or increased membrane --> spherocytes --> incidence of gallstones (jet black trpped in splenic macrophages --> calcium bilurubinate stones) at hemolysis early age. Hemoglobinuria noted Hemolytic anemia: Intravascular Episodic hemolysis Intrinsic abnormality of RBC Acquired deficiency of Decay Accelerating factor (DAF) on trilineage myeloid stem cell membrane. Affects RBC's, WBC's and platelets in the first morning void. Platelet destruction predisposes to vessel thrombosis (release of TxA2)--> Hepatic vein thrombosis (Budd Chiari syndrome). Abdominal pain Iron deficiency in chronic cases due to loss of hemoglobin in urine. Possible leukemia as a terminal event

Autoimmune Hemolytic Anemia (AIHA) MCV: normocytic Reticulocyte count: >3% Key findings: Spherocytes, Shift cells

Hemolytic anemia: Warm (IgG) type: Extravascular hemolysis: SLE: MCC Macrophage Removal of RBCs Drugs: Penicillin and methyldopa coated with IgG (Warm ab type) Intravascular hemolysis: IgM Cold (IgM) type: mediated hemolysis due to activation Infections: Mycoplasma of complement (Cold ab type) pneumoniae with anti I ab, Infectious mononucleosis with anti-i-ab Chronic lymphocytic leukemia (CLL) Drugs: quinidine, INH Hemolytic anemia: Intravascular hemolysis. RBCs damaged by: Calcified valeves Fibrin clots in DIC Platelet plugs in TTP/HUS

Fever, Jaundice (extravascular hemolysis) Hepatosplenomegaly and generalized lymphadenopathy: both in cold and warm type

Microangiopathic hemolytic anemia (MAHA) MCV: normocytic Reticulocyte count: >3% Key findings: Schistiocytes (fragmented RBCs)

Varies with the underlying disease state Aortic Stenosis: MCC Prosthetic heart valves TTP/HUS Runner's anemia in long distance runners

Handout # 10 Laboratory findings Osmotic fragility: increased Spherocytes begin to hemolyse at 0.65%, whearas normal RBC begin to hemolyse at 0.50%. Total bilirubin: increased (primarily unconjugated bilirubin

Sugar Water Test: screening test. Sugar Water enhances complement attachemnt to RBCs leading to hemolysis. Acidified serum test (Ham's test): confirmatory test Urine hemosiderin: positive

Direct Coombs test: positive in majority of cases; detects IgG, IgM on surface of RBC's. Indirect Coombs test: often positive; detects antibodies in patients serum (IgG or IgM)

Serum Haptoglobin: low Urine hemosiderin: positive Iron studies: iron deficiency may be present owing to loss of Hb in urine

Handout # 11

Normocytic Anemias: Hemolytic with corrected Reticulocyte Count >3%

Anemia Characteristics Pathogenesis
G6PD deficiency Hemolytic anemia: Macrophage removal of RBCs Key findings: Heinz bodies: Intravascular hemolysis from clumps of denatured Hb identified with supravital stain ; damaged RBC membrane Lack of G6PD Best marker in Acute hemolytic states Reduction in glutathione Bite cells: macrophage removal (GSH) of portion of membarane GSH neutralizes peroxides Infections and drugs precipitate hemolysis

Causes
SXR disease Weak variant occurs in African Americans: Defective enyme with decreasd half life present in older RBCs Less severe hemolysis Mediterranean variant: Decreased sythesis and defective enzymes present in all RBCs (young and old) More severe hemolysis Infection is the most common precipitating event for hemolytic crisis Oxidant drugs precipitate hemolytic episodes Lag phase of 3-4 days Antibiotics: sulfa drugs, Dapsone in Rx of leprosy) Nitro Drugs Antimalarial : primaquine and not choloroquine Antipyretics: acetanilid, not aspirin or acetaminophen Fava beans: Precipitate hemplysis on Mediterranean variant

Clinical findings
Acute Hemolytic episode: hemoglobinuria Back pain Protection against falciparum malaria

Laboratory findings
Acitve hemolysis: Heinz bosy preparation is used Enzyme assay may be normal owing to hemolysis of RBCs lacking the enzyme while remaining RBCs have the enzyme Asymptmatic (non hemolytic) state : enzyme assay is used.

Anemia Characteristics Pathogenesis

Sickle cell Trait and Disease Key findings: Sickle cells (in sickle cell disease only) Howell Jolly bodies: Remnants of nucleus when spleen becomes nonfunctional Trait has a normal peripheral smear MCV: normocytic Reticulocyte count: >3% Hemolytic anemia: extravascular macrophage destruction of RBCs Mutation: point mutation with substitution of valine for glutamic acid in 6th position of beta globin chain Factors nducing sickeling: Concentration of HbS in RBC >60% most important Reduced oxygen tension: high altitude, renal medulla Presence of other Hb: e.g. HbC Dehydration: increased HbS concentration Acidosis: right shifts oxygen dissociation curve --> oxygen released to tissues --> increased amount of deoxygenated Hb--> sickling HbF: inhibits sickeling (high oxygen affinity prevents deoxygenation) Prevalence: -HBSS afflicts 1:600 African Americans -8% of African Americans have HbAS trait

Clinical findings
Two main problems: -Chronic hemolytic anemia -Vasoocclusive disease --> organ damage Newborns with HbSS do not sickle:High HbF levels in RBCs prevents sickleing -Sickeling occurs by 6-9 months as HbF declines and HbA increases Vasoocclusive disease: Due to blockage of microvasculature by sickled cells, and sticking of non sickled cells to endothelium Vasoocclusive Crises: MC clinical manifestation and cause of organ damage Crises may occur at the following sites: Hands and Feet (dactylitis): occurs in 6-9 months old infnats; bone infarcts with painful swelling of hands and feet Lungs: Acute chest syndrome characterized by fever, lung infiltrates, chest pain and hypoxemia. Brain: causes stroke ; Liver: liver cell necrosis RBC aplastic crisis: triggered by Parvovirus B19 infection ; anemia without reticulocytosis; no RBCs produced; no marrow RBC precursors Complications: Aseptic necrosis femoral head and Bone infarction Pigmented gall stones Autosplenectomy: nonfunctioning spleen by 2-3 years of age Osteomyelitis: Salmonella most common cause Increased susceptibility to infections: S.pneumoniae. Priapism: sustained painful erection Micro Hematuria: due to microinfarctions occuring in renal medulla because of occlusion (African American with microhematuria should be screened for Sickle Hb) Sickle cell trait offers protection against P.falciparum malaria

Laboratory
Sickle cell Screen: findings Positive: Sodium metabisulfite reduces oxygen tension--> induces sickleing Hb Electrophoresis: Gold standard test; documents amount of HbS, HbF and other Hb Sickle cell disease: HbS: 90%, HbA: 0%, HbF:5-10% Sickle cell trait: HbS: 40-50%, HbA: 5560%

Myelodysplastic syndrome (MDS)

Definoition Myelodysplastic syndrome (MDS) Stem cell disease Frequently progresses to leukemia = Preleukemia Pathogenesis Neoplastic Stem cells proliferate in BM causing hypercellularity. The noplastic cells retain the capacity to mature and form mature cells but maturation is defective casuing ineffective hematopoiesis. This results in peripheral blood cytopenia. Pancytopenia in the PB is the rule Clinical Two types: Primary: occurs in older people Therapy related (tMDS): occurs in people undergoing chemotherapy. Typical Profile: Elederly person with severe cytopenias. Severe anemia with constant transfusion requirement. 10-40% patients with MDS end up developing acute myelogenous leukemia Laboratory findings Anemia Leukopenia Thrombocytopenia = Pancytopenia Myeloblast < 30% (may have Auer rods). Abnormal morphology of blood cells: Ringed siderblasts Dyspoietic erythroid cells Pseudo Pelger Huet cells Multilobated megakaryocytes