SICKLE CELL ANEMIA Most common structural hemoglobinopathy Mutation in -globin gene: AA substitution of valine for glutamine@ 6th

position Abn -chain: S Tetramer of 2 S2: HbS Onset during 1st yr of life: HbF levels fall Heterogenous Asymptomatic throughout adult life; freq hospitalizations during childhood (chronic) Hemolytic anemia Reticulocytosis; granulocytosis; thrombocytosis Hemolytic crises o Splenic sequestration crises Aplastic crises o Ischemia = septic necrosis o Femoral & humeral heads o Bones: osteomyelitis Vaso-occlusion o = protean manifestations Acute painful crises o Most common clinical manifestation o Long bones of back&chest Painful crises Occlusion of retinal vessels Infarction: renal papillary, leg o Widespread renal necrosis common late cause of death o Chronic lower leg ulcers over lower tibia Hand&foot syndromes Priaprism o Painful complication in males Acute chest syndrome o Distinctive manifestation o Most freq underlying concomitant conditions: pulmonary infarction, pneumonia o = pulmonary htn & cor pulmonale common COD Jaundice Hepatomegaly Spleen non-palpable in adult life Enlarged heart Confirmed by Hb electrophoresis; if in childhood Sickle solubility test: functional assays for Hb sickling No specific tx for primary disease Aplastic/hemolytic crises: blood transfusion Cytotoxic agents: HbF BM transplant: definitive cure

SICKLE CELL TRAIT Heterozygous genotype: AS Clinically normal Hematologically normal: no anemia; normal RBCs Renal tubule defect: can t concentrate urine; gross hematuria (+) screening 40% HbS No tx needed THALASSEMIA Microcytosis (+) family hx/lifelong personal hx of microcytic anemia Abn RBC morphology: microcytes, acanthocytes, target cells Hb prod Imbalanced/ biosynthesis of one of the 2 globin chains ( or ) o Ineffective erhytropoiesis Very little functional Hb RBCs prone to rupture = hypochromic, microcytic anemia Hypoproliferative anemia Hemolytic anemia o Hepatosplenomegaly o Leg ulcers o Gallstones o Stillbirths Hemoglobinopathies Chipmunk facie Hemosiderosis: transfusional Fe overload Bizarre peripheral smear Fe stores usu. elevated

-THALASSEMIA Asian Gene deletion Mild anemia -thalassemia-2-trait o loss of single (1) -globin gene loci o asymptomatic o Africans -thalassemia-1-trait o loss of a pair (2) -globin-gene loci o resembles -thalassemia minor HbH disease

o Loss of 3 -globin-gene loci o Doubly heterozygous: -thalasemia 1 & 2 traits o Asymptomatic hypochromic & microcytic anemia o -globin chains accumulate; in adults: form tetramers called HbH o more marked hemolytic anemia Hydrops fetalis o Loss of all 4 -globin-gene loci o No physiologically useful Hb produced o Hb Bart s: tetramer formed by excess -globin -THALASSEMIA HbA2 or HbF levels Mediterranean (Italian, Greek) Deficiency of one/both -globin genes 0 absent globin chain expression + - reduced globin chain synthesis Thalassemia minor o Defect in 1 chain o Mild hypochromic, microcytic anemia o Homozygous chain o Normal life expectancy o Modest anemia Thalassemia intermedia o Homozygous for milder -thalassemia Thalassemia major o Homozygous for -thalassemia o Defect in both -globin chains o or no prod HbA o Normal at birth til 6 mos. o Severe hemolytic anemia o Frontal bossing, osteopenia, stunted growth o Thinning of bones, hepatosplenomegaly o Severe anemia SIDEROBLASTIC ANEMIA Presence of ringed sideroblasts in BM (cells w/ Fe depostits encircling RBC nucleus) Hb synthesis: failure to incorporate protoporphyrin Fe accumulates in mitochondria Prussian blue stain of BM Myelodysplasia Chronic alcoholism Lead poisning Moderate anemia

NEUTROPENIA granulocytes /defective granulopoiesis BM disorders o Aplastic anemia o Pure white cell aplasia o Cyclic neutropenia Peripheral disorders o Hypersplenism o Sepsis o HIV o Felty s syndrome immune neutropenia assoc w/ seropositive nodular rheumatoid arthritis & splenomegaly Infections o Gram-positive/negative bacteria o Septicaemia o Pneumonia Ulcerative necrotizing lesions o Stomatitis o Cellulitis o Ulcerative colitis REACTIVE LEUKOCYTOSIS WBC Common rxn to inflammatory states by microbial/antimicrobial stimuli Non-specific PMN leukocytosis o Acute bacterial infections Eosinophilic leukocytosis o Allergic disorders Monocytosis o Chronic infections Lymphocytosis o Chronic immunologic disease LEUKEMIA Cancerous condition inv. WBCs Malignant neoplasm of hemotopoietic stem cells Immature WBCs in bloodstream Severe anemia: excess WBCs WBCs prod not functional Most common cancer in pediatric age Leading COD in 3-14y/o Lymphocytic

o Immature lympochytes & their progenitors Myelocytic o Pluripotent myeloid stem cells o Interferes w/ maturation of granulocytes, RBCs & platelets Acute o Immature/blast-type cells Chronic o Well-differentiated leukocytes Death: internal hemorrhage & overwhelming infections MYELOID LEUKEMIA Infiltration of blood, BM & other tissues by neoplastic cells of hematopoietic system ACUTE LEUKEMIA Short duration of sx (fatigue, fever & bleeding) Cytopenia, pancytopenia Chromosomal translocation t(15;17) = PML-RAR (retinoic acid) Acute leukemia curable Acute lymphoblastic leukemia/acute lympocytic leukemia (ALL) o Most common leukemia in children o Peak incidence 3-7y/o o Treatable/potentially curable o Mediastinal mass on cxray: esp Tcell o Classified acc to lymphocytes&state of maturation  Early B cell  Pre-B cell  Mature B cell  Early T cell  Mature T cell Acute myelogenous leukemia/acute myelocytic leukemia (AML)/Acute Non-lymphocytic leukemia (ANLL) o Primarily adult disease o Median AOP: >50-60y/o o Incidence increases w/ age o Auer rod pathognomonic of AML Sudden onset Bleeding from thrombocytopenia Epistaxis Menorrhagia Hyperleukocytosis most dramatic presentation Purpura, petecchiae Stomatitis, gum hypertrophy Rectal fissures Bone pain& tenderness sternum, tibia, femur Gen. lymphadenopathy Splenomegaly, hepatomegaly

Pancytopenia + circulating blast: hallmark of acute leukemia Aleukemic leukemia absence of blasts in peripheral smear Hypercellular BM w/ predominance of blast cells Hyperuricemia DIC - fibrinogen Meningeal leukemia blasts in spinal fluid

ACUTE MYELOID LEUKEMIA Cancer of blood-forming tissue (BM) Too many immature WBCs (blast cells) produced Normal blood cell prod suppressed = anemia, leucopenia, thrombocytopenia Primarily adults & <1 y/o Genetic damage to a single cell in BM Petecchiae Bleeding/easy bruising Loss of appetite; weight loss Older adults likely to develop CHRONIC LYMPHOCYTIC LEUKEMIA Proliferation & accumulation of mature lymphocytes w/c are immunologically incompetent Hairy cell leukemia Bcell: US Tcell: Asia Most common lymphoid leukemia Asymptomatic at presentation Splenomegaly typical; hepatomealy Lymphocytosis >5000mcL; lymphocytosis hallmark Mature appearance of lymphocytes B-cell clonal expansion More common in men Peak incidence: 60-80y/o; median AOP: 65y/o Chronic persistent lymphocytosis infiltrate diff. organs Immunosuppression BM failure Organ infiltration w/ lymphocytes Symmetrical enlargement of superficial lymph nodes most frequent clinical sign Multiple bruises Bleeding gingivae Normocytic, normochromic anemia @ later stages = autoimmune hemolysis Smudge/smear cells Hypogammaglobulinemia Lymphocytic replacement of normal BM 4 most common abnormalities o Deletion of 13q14

o o o

Deletion of 11q23 Trisomy12 Structural abnormality of 17p involving p53 gene

CHRONIC MYELOCYTIC LEUKEMIA Chromosomal abnormality: Ph1 Most Bcell disease CHRONIC MYELOD LEUKEMIA Clonal disorder of pluripotent stem cell Myeloproliferative disorder char. by overproduction of myeloid cells Myeloid cells retain capacity for differentiation Normal BM function retained during early phases Asymptomatic @ presentation Strikingly elevated WBC count; WBC (leukocytosis) hallmark Philadelphia chromosome (bcr/abl gene) hallmark o 22q & 9q o Tyrosine kinase L-shifted myeloid series Low percentage of promyelocytes & blasts Splenomegaly typical Lymphocytosis Men>women Occur @ any age Most AOP 40-60 y/o; 40y/o or older Biphasic; sometimes triphasic Abn platelet fxn o Thrombocytosis thrombocytopenia Gout/renal impairment: hyperuricemia Hyperleukocytosis (rare) abdominal girth signs of organ infiltration Sternal tenderness Blast crisis RBC morphology: normochromic, normocytic Chronic phase o Doesn t behave like a malignant disease o Occur @ any age o Normal BM fxn; neutrophils combat infection normally o Unstable, may progress to next phase Accelerated phase o 3.5-5 yrs before evolving to aggressive phases o splenomegaly refractory to chemo o chemo requirement o WBC count o Thrombocytopenia

Blastic phase o Added chromosomal defects o Resembles acute leukemia o Dx requires >30% blast in BM o 2/3 = myeloid blastic  3mos survival o 1/3 = lymphoid blastic  9mos survival

NON-HODGKIN S LYMPHOMA Heterogenous group of cancers of lymphocytes Mostly B cell Viral/genetic: EBV/AIDS Burkitt s lymphoma: translocation long arms chromosome 8 & 14 (photooncogene c-myc) Follicular lymphoma: translocation chromosome 8 & 14 (oncogene bcl2) Isolated/extranodal lymphadenopathy Normal peripheral smear Paratrabecular lymphoid aggregates Mediastinal mass in CXray (lymphoblastic lymphoma) Serum LDH useful prognostic marker Tissue biopsy definitive dx & staging LN needle aspiration suspicious results HODGKIN S DISEASE (LYMPHOMA) Painless lymphadenopathy Constitutional sx may or may not be present Pathologic dx by LN biopsy Reed-Sternberg cells 60-90% cure rate Peak incidence: 20 & >50y/o Common manifestation: painless progressive enlargement of nodes; spread continuously thoughout lymphatic system Constitional sx: fever, night swears, weight loss, gen. pruritus, fatigue, anemia MULTIPLE MYELOMA Bone pain, usu in lower back Monoclonal paraprotein o IgG, IgA = hyperviscosity Replacement of BM by malignant plasma cells Malignant proliferation of plasma cells derived fr. a single clone Anemia due to BM failure Plasmacytomas = SC compression Bone involvement: osteoporosis, pathologic fractures, hypercalcemia

o bone pain: back/femoral neck o lytic lesions: skull, spine, proximal long bones, ribs o radionuclide bone scan not useful: absent osteoblastic component Older adults; median AOP=65 y/o Most common presenting complaints: anemia, bone pain, infection Hyperviscosity syndrome Lab: proteinuria, hypercalcemia, sedimentation rate, abn serum protein Amyloidosis: enlared tongue, neuropathy, CHF, hepatosplenomegaly Bone tenderness Normal RBC morphology: rouleau formation Normal neutrophil & platelet counts Paraprotein of serum protein electrophoresis hallmark Plasma cells morphologically abnormal Positron emission tomography (PET) scan: staging of myeloma erythrocyte sedimentation rate (ESR) Alkaline phosphatase not elevated Proximal renal tubular acidosis: phosphaturia, glycosuria, uricosuria, aminoaciduria Proteinuria MYELOPROLIFERATIVE DISEASES Myelofibrosis myeloid metaplasia Agnogenic myeloid metaplasia Chronic idiopathic myelofibrosis Primary myelofibrosis Replacement of BM w/ fibrous CT Eponym: Heuck-Assmann/Assman s disease Hematopoietic stem cell disorder: clonal Overproduction of one or more of the formed elements of the blood w/o significant dysplasia Normal maturation Myelodysplastic syndrome: ineffective myeloproliferation Leukocytosis Thrombocytosis megakaryocytes Fibrosis Organomegaly Hepatosplenomegaly Poikilocytosis Disease of adults: peak incidence: 70y/o Insidious onset, develops slowly in older adults >50y/o Median survival: 5yrs Dysregulated proliferation No specific genetic abn Bone fibrosis in all MPD Collagen fibrosis of BM = progressive pancytopenia

Extramedullary hematopoiesis: BM to liver & spleen MYELOFIBROSIS (CHRONIC IDIOPATHIC MYELOFIBROSIS) Striking splenomegaly Teardrop poikilocytosis Leukoerythroblastic blood picture Giant abn platelets Hypercellular BM w/ reticulin or collagen fibrosis Progressive fibrosis of BM & CT element Agnogenic myeloid metaplasia: extramedullary erythropoiesis Abn megakaryocytes PDGF & other cytokines = BM fibrosis= extramedullary hematopoiesis Mesenchymal cells reactivated: resp for fetal hematopoiesis >50% w/ sx of anemia Hypermetabolic syndrome susceptibility to infection Hematopoiesis in liver Anemia Early: platelets; normal Hb & WBC Late: normochromic, normocytic anemia, thrombocytopenia, leukopenia Nucleated RBCs Early granulocytes Bizarre platelet morphology Triad: teardrop poikilocytes, leukoerythroblastic blood, giant abn platelets Dry tap inability to aspirate liquid marrow reticulin fibrosis (Trephine biopsy-silver stain) ESSENTIAL THROMBOCYTOSIS Essential thrombocytopenia Primary thrombocytosis Idiopathic thrombocytosis Elevated platelet count (>2M/mcL) hallmark Normal RBC mass & morphology Absent Philadelphia chromosome WBC mildly elevated (not>30,000/mcL) w/ immature forms Clonal myeloproliferative disease of megakaryocytic lineage Peripheral smear: large platelets w/ absence of giant degranulated forms (MF) BM biopsy: large & megakaryocytes Uncommon myeloproliferative disorder Unknown cause Marked proliferation of megakaryocytes in BM = platelet count Median AOP: 50-60y/o Women Thrombosis st o 1 sign

o Most common clinical prob o Risk w/ age o Venous sites: mesenteric, hepatic, portal vein Erythromelalgia Mucosal bleeding Normal Fe studies Normal sedimentation rate Prolonged bleeding time in 20%