WBC and RBC - WBC PDF

White Blood Cell Diseases Proliferative - expansion of leukocytes Reactive -> infection or inflammatory process Neoplastic -> less frequent, more serious Disease Name Cause of Dx...

White Blood Cell Diseases Proliferative - expansion of leukocytes Reactive -> infection or inflammatory process Neoplastic -> less frequent, more serious Disease Name Cause of Dx MOA Key Features Associated Diseases Tx for Disease Prognosis Picture Acute Nonspecific lymphadenitis Infections B cells make high affinity Abs against specific Ags (in Enlarged follicles Draining from teeth or tonsils -> cervical enlargement germinal centers) Pale staining germinal centers Infection of extremities -> axilla or inguinal enlargement Paracortical T-cell zone undergoes hyperplasia Large reactive germinal centers with mitotic figures Pyogenic infections => neutrophils present => necrosis Chronic nonspecific lymphadenitis Stimuli that cause humoral response = Rheumatoid Stimuli that activate humoral immune responses => follicular Large oblong germinal centers [secondary follicles] surrounded by collar arthritis, toxoplasmosis, early HIV infection -> follicular hyperplasia of small resting naive B cells [mantle zone] hyperplasia TLDR: forms ABs in response to Ags Polarized germinal centers Dark zone: proliferating blast-like B cells [centroblasts] -> Blast-like B cell = bigger, actively dividing B cells in response to antigenic stimuli (infection) Light zone: B cells with irregular or cleaved nuclear contours [centrocytes] Reactive (nonneoplastic) hyperplasia Preservation of lymph node architecture -> Interfollciular T cell zones -> Sinusoids Variation in shape and size of follices Presence of: -> mitotic figures -> phagocytic macrophages = tingible macrophages: have nuclear debris of dead B-cells that fail to produce ABs **indicate reactiveness -> light and dark zones Hemophagocytic Lymphohistiocytosis Trigger = Epstein-Barr virus infection Systemic activation of macrophages and CD8+ Cytotoxic T Hallmark: reactive condition marked by cytopenias and systemic Immunosuppressive Poor without treatment Cells -> marrow: phagocytosis of blood cell progenitors = inflammation related to Mo activation drugs, mild **Histiocytoses = proliferative lesions of Complication of peripheral T cell lymphoma form elements in peripheral tissues chemotherapy, or macrophages and dendritic cells Acute febrile illness, with splenomegaly and hepatomegaly (results antibodies that Macrophages and lymphocytes => release mediators: IFN-y, from systemic inflammation) neutralize the activity TNF-a, IL-6, IL-12 -> suppress hematopoiesis + produce of IFN-y systemic inflammation Sx => acute febrile illness with Hemophagocytosis seen on bone marrow examination splenomegaly and hepatomegaly -> Cytokine storm (cytopenias and shock) or systemic inflammatory response syndrome (SIRS) Neoplastic Proliferations Chromosomal translocations and acquired Nonrandom chromosomal abnormalities mutations Factors that lead to neoplasia Oncoproteins block normal maturation => turn on pro-growth - radiation and chemotherapy signaling pathways or protect cells from apoptotic cell death - smoking -> benzene exposure -> Oncoproteins => cause arrest in differentiation when cells are incidence of AML increases proliferating rapdily (acute leukemia) Other mutations => enhance self-renewal and inhibit apoptosis Inherited genetic factors = genetic disease => promote genomic instability => bloom syndrome, fanconi anemia, ataxia telangiectasia, down syndrome, NF type 1 Lymphoid Neoplasms -> Leukemia: widespread involvement of bone marrow and usually (not always) peripheral blood -> Lymphoma: white cell proliferations that present as discrete tissue masses -> Ag receptor gene rearrangement = all daughter cells from malignant progenitor share the same ag receptor gene configuration and make identical ag receptor proteins (Monoclonality) => transformation of lymphoid cells -> Normal immune responses = comprised of polyclonal populations of lymphocytes that express many different ag receptors -> 90% lymphoid neoplasms are B-cell origin **Incld: B-cell, T-cell, and NK-cell tumors Disease Name Cause of Dx MOA Key Features Associated Diseases Tx for Disease Prognosis Picture Precursor B-cell/T Cell neoplasms Acute lymphoblastic leukemia/lymphoma (ALL) B-ALLs -> childhood leukemia (~3 y/o) T-ALLs: NOTCH1 mutation, CD1, CD2, CD5, CD7 Lymphoblasts = neoplasms composed of immature B (pre-B) or T (pre- t(9,22) encodes Better prognosis: T) cells active BCR-ABL -> Between 2-10 y/o -> B-cell markers = CD19+, CD20+ **Most common cancer of children T-ALLs -> adolescent males = thymic lymphomas Pre-B-ALL = CD19, PAX5, CD15 tyrosine kinase -> -> Low WBC count -> T-cell markers = CD3, CD4, CD5, CD8 B-ALLs: hyper-diploidy and hypo-diploidy Tx with kinase -> Hyperdiploidy B-ALLs: PAX5, TCF3, ETV6, RUNX1 mutations inhibitor + CTX -> Trisomy Chromosome T-ALLs: mediastinal thymic masses 4, 7, 10 -> T (12,21) Bone marrow: hypercellular, full of blasts Worse prognosis: Tumor Cells: scant basophilic cytoplasm and larger than normal nuclei -> Younger than 2 y/o -> Presents in Hallmark: high mitotic rate -> starry sky appearance adolescene/adulthood -> Peripheral blood blast TdT (histochemical stain) is positive -> shows lymphoblasts that are count > 100,000 myeloperoxidase-negative and contain periodic acid-Schiff-positive -> Hypodiploidy (PAS positive) cytoplasmic material Sx: Onset within days or weeks, neoplastic infiltration leads to: Marrow depression = fatigue, anemia, fever, bleeding, CNS = headache, vomiting, nerve palsy Peripheral B-Cell Neoplasms Chronic lymphocytic leukemia (CLL)/SLL Deletion of 13q14.3, 11q, 17p Bruton tyrosine kinase (BTK) pathway activation Diagnostic requirement: Absolute lymphocyte count >5000/mm^3 Involves: bone marrow, spleen, BTK inhibitors -> Survival: 4-6 years, more liver produce sustained than 10 years with **Most common 60 y/o male adult leukemia in Trisomy 12q Tumor cell markers: CD19, CD20, CD23, CD5 Lymph node architure is diffusely effaced by small lymphocytes with therapeutic response minimal tumor burden at western world High amount of BCL2 expressed round nuclei, condensed chromatin, and scant cytoplasm Richter Syndrome = diffuse large Dx B-cell lymphoma (DLBCL) -> Sx patients: gentle +5, +23 Blood: small round lymphocytes with scant cytoplasm development of rapidly enlarging chemotherapy, mass within lymph node or spleen - immunotherapy with Sx: Easy fatigue, weight loss, anorexia, generalized lymphadenopathy > gain of TP53 or MYC = poor ABs against surface and hepatosplenomegaly prognostic factor proteins of CLL/SLL cells => CD20 Hypogammaglobulinemia => leads to bacterial infections BCL2 Inhibitor Nonneoplastic B-cells => autoAbs => hemolytic anemia or thrombocyopenia NHL! Follicular Lymphoma t(14,18) -> BCL2 overexpression -> antagonizes Express CD19, CD20, CD10, BCL-6, BCL-2 (resemble HALLMARK: t(14,18) -> juxtaposes IGH locus on chromosome 14 and Involves: bone marrow Incurable apoptosis (prevents apoptosis) normal germinal center B-cells, normal are BCL-2 negative) BCL2 locus on chromosome 18 **Most common form of indolent Non Hodgkin's Lymphoma (NHL) in USA NO CD5 Nodular/diffuse growth pattern in lymph nodes -5 Increased MYC expression Principal cell types: -> Centrocytes (small cleaved cells): irregular or cleaved nuclear contours with scant cytoplasm **usually majority** -> Centroblasts (larger cells): open nuclear chromatin, several nucleoli, and modest cytoplasm Painless generalized lymphadenopathy Indolent waxing and waning course with histologic transformation (~DLBCL) NHL! Diffuse Large B-Cell Lymphomas (DLBCL) MYC Translocation Express CD19, CD20, variable CD10, BCL-6 Large cell size, diffuse growth pattern Primary or secondary involvement MYC translocations - BAD prognosis with MYC of liver, spleen -> large destructive > Tx: Burkitt translocations **Most common form of NHL BCL-6 dysregulation Subtype: Large multilobated/irregular nuclei, with 2-3 nucleoli mass lymphoma -> Normal: DNA binding zinc-finger transcriptional -> Immunodeficiency-associated large B-cell lymphoma chemotherapy Aggressive, rapidly fatal repressor = needed for normal germinal center formation occurs Presents with: rapidly enlarging mass at nodal or extra-nodal sites Immunodeficiency-associated regimen without treatment => factor expression that promotes differentiation, growth (GI tract, skin, bone, brain), present anywhere in body large B-cell lymphoma: T-cell arrest, and apoptosis immunodeficiency = advanced HIV **TLDR: BCL-6 dysregulation => improper germinal Waldeyer ring: oropharyngeal lymphoid tissue, incld adenoids and infection, organ/HSC transplants center formation/differentation and growth tonsils -> Neoplastic B cells: infected with EBV -> Tx: T cell immunity restoration Primary effusion lymphoma: Malignant pleural or ascitic effusion = advanced HIV infection or older adults -> Aplastic tumor cells, no B or T- cell surface markers -> Clonal IGH gene arrangements -> Infected with HHV8 NHL! Burkitt Lymphoma MYC translocation on Chromosome 8 -> increased MYC MYC: Transcription regulator -> increases expression of High mitotic index and apoptotic cells -> nuclear remnants African Burkitt Lymphoma protein levels genes required for aerobic glycolysis [Warburg effect] phagocytosed via benign macrophages = Starry sky appearance =(Mo Endemic -> latently infected with eats up apoptotic cells to create lacunae) EBV IGH Locus t(8,14) OR Ig k t(2;8) OR Ig λ t(8;22) light Express: IgM, CD19, CD20, CD10, BCL6 (~B cell germinal Children and young adults chain loci center origin) Tissue effaced with diffuse infiltrate of intermediate-sized lymphoid -> Sx: mandible mass, abdomnial cells with round/oval nuclei, coarse thromatin, nucleoli, moderate viscera involvement (kidneys, FAILS to express BCL2 cytoplasm ovaries, adrenal glands) Children and young adults Sporadic (nonendemic) Burkitt Lymphoma Children and young adults -> involves ileocecum and peritoneum Aggressive Burkitt lymphoma -> Occuring in individuals with HIV NHL! Mantle Cell Lymphoma t(11,14) -> IGH locus on Chromosome 14 and Cyclin D1 T(11,14) -> overexpression of Cyclin D1 Painless generalized lymphadenopathy Extranodal sites: bone marrow, Moderately aggressive locus on Chromosome 11 -> overexpression of Cyclin spleen, liver, gut and incurable +5, -23 D1 High CD1, CD19, CD20, moderate surface Ig (IgM and IgD, with Peripheral kappa orblood lambda involvement light chains) CD5+, CD23- Proliferation: homogenous population of small lymphocutes with **different from CLL/SLL** irregular to ddeply clefted (cleaved) nuclear contours NHL! Marginal Zone Lymphoma Polyclonal immune reaction --> later: malignant Additional translocations: T(11,18), T(14,18), or T(1, 14) -> Arise within lymph nodes, spleen, or extranodal tissues Extranodal at mucosa sites = antigen-independent tumor growth and survival MALTs (mucosa-associated -> up-regulate expression and function of BCL10 or MALT1 Can spread to distant sites and transfomration to DLBCL lymphoma tumors) (protein components of signaling complex that promotes B -> Arise within tissues involved with cell growth and survival) chronic inflammatory disorders (autoimmune, infectious) -> Sjogren disease + salivary glands -> Hashimoto Thyroiditis + thyroid gland -> Helicobacter gastritis + stomach -> chronic inflammation -> Localized for prolonged periods - > spread systemically late in course -> Regress if inciting agent is eradicated (ex- get rid of H. pylori) NHL! Hairy Cell Leukemia 90% of cases = activating point mutations in Specific mutation = valine to glutamate at residue 600 Round, oblong, nuclei and moderate amounts of pale blue cytoplasm Infiltrate bone marrow, liver, spleen Tx: "gentle" serine/threonine kinase BRAF -> found at high frequencies in melanoma and Langerhans with thread-like or bleb-like extensions chemotherapy -> **Middle aged white males cell histiocytosis long-lasting Marrow = diffuse interstitial infiltrate of cells with oblong or reniform remissions Express: nuclei, condensed chromatin, and pale cytoplasm - pan B-cell markers -> CD19, CD20 Relapse after 5+ - surface Ig -> IgG Only seen in marrow biopsies due to -> enmeshed in extracellular years - CD11c, CD25, CD103, and annexin A1 matrix -> made of reticulin fibrils and in-aspirable (dry tap) Failed chemo -> Tx: splenic red pulp = infiltrated -> obliteration of white pulp + beefy red BRAF inhibitors gross apperance of spleen Sx due to- bone marrow, liver, spleen infiltrations Massive splenomegaly, hepatomegaly (less common), and lymphadenopathy (rare) Infections -> pancytopenia Excellent prognosis NHL! Peripheral T- and NK-cell Neoplasms Express: CD2, CD3, CD5, and either aB or γδ T cell Lymph nodes -> diffusely effaced Harder to treat and receptors worse prognosis than **Hardest to treat vs aggressive mature B-cell Prominent infiltrate of reactive cells aggressive mature B- neoplasms cell neoplasms Sx: generalized lymphadenopathy + eosinophilia, pruiritis, fever, weight loss Dx: DNA analysis confirms clonal T-cell receptor gene rearrangements NHL! Anaplastic large cell lymphomas (ALK positive) Rearrangements in ALK gene on Chromsome 2p23 ALK+ and ALK- = express CD30 (TNF receptor family) Large anaplastic cells, with horseshaped nuclei and abundant cytoplasm Good prognosis, cure rate with CTX **T-cell lymphomas that lack ALK Children, young adults -> soft tissue (chemotherapy?) is high rearrangements occur in older adults with a worse prognosis NHL! Adult T-Cell Leukemia/Lymphoma Adult infected by HTLV-1 -> neoplasm of CD4+ T cell Skin lesions, generalized lymphadenopathy, hepatosplenomegaly, Rapidly progressive -> peripheral blood lymphocytosis, and hypercalcemia fatal **HTLV-1 is endemic in: southern Japan, West Africa, Caribbean basin Progressive demyelinating disease of CNS and SC CElls with multilobated nuclei = cloverleaf, flower cells Rapidly progressive NHL! Mycosis Fungoides/Sezary Syndrome Tumor of CD4+ T helper cells -> skin Cutaneous lesions: Inflammatory premycotic phase -> plaque Neoplastic T cells infiltrate -> epidermis and upper dermis = marked Survival ~10 years phase -> tumor phase infolding of nuclear membrane -> cerebriform appearance **Rash that never goes away Sezary -> generalized exfoliative erythroderma [skin] Indolent Plasma Cell Neoplasms B cell proliferations with neoplastic plasma cells -> secrete monoclonal Ig or Ig fragments (=tumor markers with pathologic consequences) AND synthesize excess light chains --> exception: sometimes only light chains are produced, and rare tumors secrete only heavy chains M component = monoclonal Ig in blood Complete M component = TOO large therefore restricted to plasma/ECF, excluded from urine in absence of glomerular damage Elevated free light chains -> skewed to one light chain at the expense of the other Bence Jones Proteins: free light chains (small), excreted in urine Multiple Myeloma IGH Locus translocations Neoplastic plasma cells -> produce CCL3 = chemokine that Dx: Clonal plasma cells in marrow, presence of CRAB (hyperCalcemia, Excreted light chains= toxic to renal increases osteoclast formation -> bone destruction (bone Renal dysfunction, Anemia, and Bone lesions) tubular epithelial cells -> Bence **Higher in men (65-70 y/o) and African resorption, hypercalcemia, pathologic fractures) To confirm Dx = Need bone marrow examination and tests assessing Jones proteinuria -> renal failure - American descent calcium levels, renal function, blood counts, and serum and urine > death **major cause Positive for CD138 Igs Certain light chains are prone to Criteria: lytic bone lesions, hypercalcemia, renal failure, acquired cause amyloidisis (AL type) -> immune abnormalities exacerbate renal dysfunction + deposits in other tissues Affected: axial skeleton (vertebral column, ribs, skull, pelvis, femus, clavicle, scapula) Lesions: punched out defect 1-4 cm -> soft gelatinous red tumor masses Marrow: increased # of plasma cells Malignant plasma cells: prominent Golgi apparatus & eccentrically placed nucleus = perinuclear clearing Flame cells: accumulation of intact or partically degraded protein -> fiery red cytoplasm Mott cells: grapelike cytoplastic droplets Russell bodies: globular inclusions in cytoplasm Dutcher bodies: (IG accumulation in nucelus) if they are found, will be in nucleus High levels of M protein in blood -> rouleaux formation = red cells stuck to one another in linear arrays in smears Bone resorption -> pathologic fractures and chronic pain Hypercalcemia -> neurologic manifestations = confusion, weakness, lethargy, constipation, and polyuria, and contributes to renal dysfunction Decreased production of normal IGs -> recurrent bacterial infections Lab tests: - increased Ig levels in blood and/or light chains in urine - monoclonal Igs -> abnormal protein spike in serum or urine electrophoresis - most common monoclonal Ig = IgG, and then IgA - excessive production and aggregation of M proteins -> hyperviscosity Mulitple Myeloma Smoldering Myeloma Serum M protein level > 3g/dL and/or 10% or more clonal plasma cells 75% progress to MM in bone marrow **In between MM and MGUS Criteria: end-organ damage, hypercalcemia, bone-lytic lesions, or myeloma related symptoms Mulitple Myeloma MGUS Asymptomatic patients, serum M protein < 3g/dL No evidence of other B-cell proliferative disorder **Most common plasma cell disorder Bone marrow clonal plasma cells < 10% Features: no lytic bone lesions, no myeloma related organ, and no tissue impairement Mulitple Myeloma Symptomatic Plasma Cell Myeloma Characteristics: CRAB, with related organ and tissue impairment Bone marrow clonal plasma cells or plasmacytoma, spreads first to Hallmark: Presence of neoplastic giant cells = Reed Sternberg Cells DDx: infectious mononuclelosis, Tx is determined via STAGING MOST anatomically contingous lymphoid tissues => release factors = accumulation of reactive lymphocytes, solid tissue cancers, large cell NHL tumor stage (not IMPORTANT FOR macrophages, and granulocytes (negative flow cytometry) histologic type) PROGNOSIS! Germinal center/post germinal center B cells -> create **NEED REED STERNBERG FOR DX! -- LOOK LIKE OWLS neoplastic Reed Sternberg Cells: large cells with multiple nuclei OR single multilobular nuclei, with large inclusions (ex- Lacunar Cells [nodular sclerosis]: delicate, folded, multilobate nuclei, similar to a nucleolus) and pale cytoplasm that is disrupted during cutting of sections -> leaves nucelus in empty space = lacuna Lymphohisiocitis variants = L&H cells [lymphocytic and/or histiocytic cells] -> polypoid nuclei, inconspicous nucleoli, and abundant cytoplasm Spread: Begins as nodal disease -> spleen = splenic disease -> liver = hepatic disease -> bone marrow and other tissues Hodgkin Lymphoma CD15+, CD30+, EBV- Frequent lacunar cells and occasional Dx Reed Sternberg cells Nodular Sclerosis Hodgkin Lymphoma Mixed Cellularity CD15+, CD30+, 70% EBV+ Frequent mononuclear and Dx RS cells Hodgkin Lymphoma Lymphocyte-Rich CD15+, CD30+, 40% EBV+ Frequent mononuclear and Dx RS cells Hodgkin Lymphoma Lymphocyte-Depleted CD15+, CD30+, most EBV+ Frequent Dx RS cells Hodgkin Lymphoma Nodular Lymphocyte Predominant CD15-, CD30-, EB- Frequent L&H cells Myeloid Neoplasms Acute Myeloid Leukemia (AML) Acquired oncogenic mutations that impede differentation Accumulation of immature myeloid forms (blasts) in bone Replacement of marrow with blasts -> marrow failure and complications => accumulation of immature myeloblasts in the marrow - marrow -> suppresses normal hematopoiesis ~ anemia, thrombocytopenia, and neutropenia WHO Classification subtypes: > AML = tumor of hematopoietic progenitors - AML with genetic aberrations = inv16, t(15,17) Dx: - MDS Driver Mutations - At least 20% myeloid blasts in bone marrow - Therapy-related AML Transcription factor mutations => interfere with normal - Myeloblasts have delicate nuclear chromatin, 2-4 nucleoli, voluminous - Wastebasket = any AMLs lacking any other myeloid differentiation cytoplasm specified features - t(18,21) -> disrupt RUNX1 - Auer rods = distinctive, needle-like azurophilic granules -> numerous - inv(16) -> CBFB genes, t(15,17) -> creates fusion gene in AML with t(15,17) = acute promyelocytic leukemia) = encodes chimeric proteins made with RARa and part of - Monoblasts with folded or lobulated nuclei, lack Auer rods PML --> interferes with terminal differentiation of - (Some AMLs) Release of fibrogenic cytokines -> marrow fibrosis = granulocytes [overcome by treatment with all-trans megarkaryocytic differentiation retinoic acid = ATRA, and arsenic trioxide] Clinical features: Mutation of signaling proteins => actiation of pro-growth - Presents within weeks-months with complaints ~anemia, neutropenia, and survival pathways thrombocytopenia, fatigue, fever, and spontanous mucosal and - t(15,17) AMLs -> activating mutations in FLT3 = RTK cutaneous bleeding that transmits signals that mimic normal growth factor - AML t(15,17): Leukemic cells -> procoagulants and fibrinolytic cells => signaling -> increases cellular proliferation and survival exacerbate bleeding tendency - Opportunists = fungi, pseudomonas, commensals -> frequent Mutation of genes that regulate or maintain the infections in oral cavity, skin, lungs, kidneys, urinary bladder, colon epigenome - CNS spread in AML is less than ALL - Presents as myeloblastoma, chlorma, or myelosarcoma = localized Mutation of TP53 or genes that regulate p53 soft tissue mass - complex karyotype - marked dysplasia - poor prognosis Myelodysplastic Syndrome (MDS) Group of clonal stem cell disorders -> maturation defects Defective maturation of myeloid progenitors -> ineffective Patients have peripheral blood associated with ineffective hematopoiesis and high risk of hematopoiesis -> cytopenias cytopenias transformation to AML Bone marrow replaced by clonal progeny of neoplastic Morphology: Genotoxic drug or radiation therapy -> primary or multipotent stem cell, that retains the capacity to differentiate Disordered (dysplastic) secondary MDS in an ineffective and disordered fashion differentiation affects erythroid, granulocytic, monocytic, and Primary and Secondary MDS: recurrent chromsomal megakaryocytic lineages abnormalities = - erythroid: ring sideroblasts, - monosomy 5, monosomy 7 megaloblastoid maturation, nuclear - deletion of: 5q, 7q, 20q budding abnormalities (nuclei with - trisomy 8 misshapen outlines) - neutrophils: have decreased numbers of secondary granules, toxic granulations, and/or Dohle bodies - Pseudo-Pelger-Huet cells: neutrophils with only 2 nuclear lobes - Megakaryocytes with single nuclear lobes or multiple separate nuclei (pawn ball megakaryocytes) - Myeloid blasts -> increased, but make up less than 20% of overall marrow cellularity and less than 10% of leukocytes in blood - blood contains pseudo-Pelger- Huet cells, giant platelets, macrocytes, poikilocytes, and monocytosis  Myeloproliferative Neoplasm Increased production of one or more types of blood cells Common features: - increased proliferative drive in bone marrow [increases proliferation] - group of diseases with common pathogenic - homing of neoplastic stem cells to secondary hematopoietic organs => feature which is the presence of mutated, extramedullary hematopoiesis activated tyrosine kinases - variable transformation to a spent phase = marrow fibrosis and peripheral blood cytopenias - variable transformation to acute leukemia Chronic Myeloid Leukemia (CML) BCR gene on Chromosome 22 and ABL gene on Philadelphia Chromosome = Reciprocal t(9,22)(q34;q11) -> Increased number of granuloyctic precursors = elevated proportion of Increased cell turnover -> mild Chromosome 9 -> presence of chimeric BCR-ABL BCR-ABL eosinophils and basophils -> hypercellular marrow anemia and hypermetabolism -> gene fatigue, weakness, weight loss, Hallmarks: anorexia - Presence of scattered macrophages with abundant wrinkled green- blue = sea-blue histiocytes - Leukocytosis, with blasts make up less than 10% of circulating cells - Extensive extramedullary hematopoiesis -> enlarged spleen Accelerated Phase: has anemia, thrombocytopenia, and increased basophils -> leukemia Blast crises occurs (within few months) Additional Diseases Polycythemia Vera Activating mutations in tyrosine kinase JAK2 -> Increased marrow production of red cells, granulocytes, and Serum EPO is low Transformation to AML in 1% of transformed progenitor cells have decr requirements for platelets patients *polycythemia = a lot of blood** EPO and other hematopoietic growth factors Increase in red cell progenitors with increase in granulocytic precursors Increased red cell mass and hematocrit -> Sx and megakaryocytes -> hypercellular marrow Budd-Chiari Syndrome = **In summary, the activating mutations in JAK2 make the thromboses in hepatic veins, ( progenitor cells less dependent on external signals like High cell turnover -> hyperurecemia and systematic gout Dx: marked increase in reticulin fibers in marrow EPO, leading to uncontrolled blood cell production characteristic of polycythemia vera. Congestion -> Mild organomegaly Peripheral blood = increased number of basophils & abnormally large platlets Progression -> spent phase = extensive marrow fibrosis that displaces hematopoietic cells + extramedullary hematopoiesis in spleen and liver - > organomegaly Stagnation and deoxygenation of blood in peripheral vessels -> plethoric and cyanosis Sx: headaches, dizziness, HTN, GI symptoms, in general: thromboses seen in portal and mesenteric veins, if in hepatic = Budd-Chiari Basophils -> release histamine -> intense pruiritis and peptic ulceration Abnormal blood flow and platelet function -> increased risk of bleeding and thrombotic episodes First indication: DVT, MI, or stroke Platelets: giant and defective in aggregation Primary Myelofibrosis Activating mutations in JAK2, CALR, or MPL TGF-B -> promotes collagen deposition and angiogenesis Hallmarks: - Development of obliterative marrow fibrosis - Fibrous tissue -> replaces marrow -> reduces marrow hematopoiesis - > cytopenia and extensive medullary hematopoiesis - Non-neoplastic fibroblast -> extensive deposition of collagen in marrow