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71 Cards in this Set
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Etio: T cell activation against early progenitor cells. (Also poss - defective/deficient stem cells)
Most cases idiopathic. Also: drugs/radiation, chemicals, infxn, thymoma, PNH Telomerase defect - stem cells age faster from chromosomal instability. (Inc. risk of clonal dz) Tx: imm.supp. *dangerous!* since WBCs are already low. If < 20 yrs - allogenic transplant |
Aplastic Anemia (AA)
Normocytic Anemia Dx: exclusion. Marrow histo - aplasia (hypocellular), absence of growth. Fat replaces marrow Pancytopenia with reticulocytopenia Sx: neutropenia → inc. infxn risk, fever Thrombocytopenia → bleeding Anemia → fatigue, pallor, etc. |
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Etio: Absent/defective PIG-A -> absence of RBC membrane proteins.
Dec. CD59/CD55 -> inc. complement binding Loss of CD59 -> thrombosis Tx: Eclizumab - Ab inhibits cleavage of C5, dec. complement cascade. |
Paroxysmal Nocturnal Hemoglobulinuria (PNH)
Dx: ? Sx: "coke-colored" morning urine. Paroxysmal - older RBCs more susceptible to lysis by complement. Nocturnal - 1st morning urine more concentrated, darkened with Hbg Hemoglobinuria - free Hbg from RBC lysis cleared by kidney |
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Etio: in adult male or post-menopausal female, assume pathologic blood loss!
Pregnancy - bleeding at delivery. Most females - menstrual bleeding Malabsorption - aggressive PPI use [HCl needed to convert Fe(3+) -> Fe(2+)]; barosurgery; small bowel dz Tx: Oral Fe - ferrous sulfate (most common). Inc. dose slowly -> better tolerance, better compliance, less adverse fx (black poo) IV Ferric Gluconate - if pt can't absorb. (Blood loss -> dec. absorption) Low allergy risk. |
Microcytic Anemia
Fe Deficiency Dx: serum Fe/TIBC Serum ferritin - ~95% correlation to marrow Fe Marrow Fe Stores - "gold standard" but invasive Blood smear Sx: anemia (dyspnea, pallor, fatigue) |
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Etio: B12 needed for myelin synthesis & DNA metabolism (affects tissues w/rapid turnover).
Immature RBC nuclei can't synthesize DNA needed for apoptosis; can't extrude DNA, RBCs stay in bone marrows & amass Hgb (-> macrocytes!) Schilling test (oral radioactive B12) may find cause - If absorbed -- dietary deficiency If absorbed after IF given -- pernicious anemia If absorbed after Abx given -- bacterial overgrowth is destroying B12-IF complex If absorbed after pancreatic extract given -- chronic pancreatitis (lack of enzymes) Gastritis - autoimm attack against parietal cells ("pernicious anemia") Dz of terminal ileum - Celiac Sprue, enteritis, tropical sprue, etc. Diphyllabothrium (rare!) Tx: Parenteral VitB12 - easy, inexpensive, low toxicity SubQ B12 - can regularly self-administer Oral B12 - ONLY if absorption not affected (duh) & if high pt compliance Blood should be normal in 8 wks Neurologic Sx - if present < 3 mos before Dx, it's reversible. Recovery can take 6 mos. If present > 6 mos before Dx, probably permanent. |
B12 Deficiency
Macrocytic Anemia Dx: Smear: pancytopenia; oval macrocytes (MCV > 100); hypersegmented neutrophils Serum B12 < 200 mg/L **High homocysteine & MMA confirm true tissue deficiency!! Non helpful assays: Marrow - megaloblastic nucleated cells with primative "lacy" chromatin IF Abs for autoimm deficiency - spec, not sens Serum gastrin - high sens, not spec Antiparietal cell Abs - not specific Sx: anemia (pallor, fatigue, dyspnea...) Neurologic dysfxn - myelopathic. Usu posterior white column & lateral corticospinal tracts affected Lateral CoSp degeneration -> spastic quadraparesis |
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Etio: su HFE gene - homozygous C282Y mutation, variable penetrance. Codes defective regulatory receptor -> long asymptomatic period of inc. Fe absorbed in GI; Sx in mid-life.
Inc. transferrin saturation -> inc. storage in ferritin -> Fe deposits in tissues (parenchymal of liver/heart/endocrine organs) Tx: phlebotomy. Goal: Transferrin SAT <50%, ferritin <100 Screen family; can give early prophylaxis |
Genetic Fe Overload (Hemochromatosis)
Dx: Transferrin sat > 45% Genetic testing - HFE mutation. (Heterozygote - probable dx) Persistently elevated serum ferritin. Liver bx for hepatic Fe index Sx: Liver -> inc. transaminases, cirrhosis, hepatoma Endocrine - pancreas -> DM, hypogonadism Arthritis, joint dysfxn Cardiac - infiltrative cardiomyopathy & CHF. (Usu terminal) Sx: |
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Etio: Fe overload can't be excreted.
Excessive RBC breakdown -> Fe accumulates in resident M0s, then into tissue parenchymal cells Tx: can't phlebotomize Chemical chelation, pulls Fe out in urine. (Renal tox!) |
Acute Fe Overload
Usu toxic ingestion (kids); also ineffective erythropoiesis, transfusional ITx for anemias, bone marrow failure) Dx: ? Sx: ? |
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Etio: Common in Afr Amers, Greek, Italian. Auto rec - nonsense mutation → stop codon.
Impaired β chain production → ↑ α globin. Microcytic RBCs w/α-chain inclusions undergo apoptosis in marrow or are removed by M0s in spleen. Alpha globin precipitates → multi-organ involvement. Microcytosis, hypochromia Tx: Long-term transfusion - risk of hemosiderosis (Fe overload), infxn, liver/spleen dz. Maximizes growth & development, suppresses ineffective erythropoiesis & excess Fe absorption Chelation - binds free Fe, reduces hemosiderin deposits Splenectomy - indicated if xfusion requirement ↑ by 50% in 6 mos; if severe leukopenia; if severe thrombocytopenia |
β -Thalassemia Major (Cooley's Anemia)
Dx: genetic - both β globin genes defective Hbg < 7 Microcytic RBCs with α-chain inclusions. ↑ reticulocytes Hbg electrophoresis - No HbA synthesized;↑ HbA2 & ↑↑ HbF Sx: Presents in first year of life (or dx prenatally) - severe hemolytic anemia. CV - CHF, arrhythmia, pulm HTN Hypercoag, thrombophilia - from inc. platelets & inc. peptide activation Osteopenia/osteoporosis |
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Etio: Heterozygous genotype produces mild dz
Mild protection against malaria. Tx: none needed |
β-Thal minor (β/β°)
Microcytic anemia (mild) Dx (Characteristics): ↓ MCV, Hbg, & Hct ↑ RBC count ↓ RBC life span No fx on RDW & serum ferritin Hbg electrophoresis: ↓ HbA (2α/2β) ↑ HbA2 (2α/2δ) & ↑ HbF (2α/2γ) Sx: asymptomatic |
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Etio: Loss of a gene on each xsome (α/- α/-)
Tx: none |
α-thal trait - Black American type
Microcytic Anemia Dx: ↓ HbA, HbA2, & HbF. (normal Hbg electrophoresis) Normal RDW & serum ferritin ↑ RBC count ↓ MCV, Hb, & Hct Sx: mild anemia |
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Etio: Loss of both genes on same xsome (α/α -/-)
Risk of developing more severe α-thal Tx: none |
α-thal trait - Southeast Asian type
Microcytic Anemia Dx: ↓ HbA, HbA2, & HbF. (normal Hbg electrophoresis) Normal RDW & serum ferritin ↑ RBC count ↓ MCV, Hb, & Hct Sx: mild anemia |
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Etio: three α gene deletions (α/- -/-)
Excess β-chain inclusions cause RBC lysis by M0s. Tx: ? |
HbH disease
(HbH = 4 β chains) Microcytic Anemia Dx: Hbg electrophoresis shows HbH Sx: Severe hemolytic anemia |
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Etio: four α gene deletions
Tx: none (pt dies) |
Hb Bart disease
(Hb Bart = 4 γ chains) Microcytic Anemia Dx: Hbg electrophoresis shows Hb Bart Sx: Ridiculously severe hemolytic anemia (incompatible with life) |
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Etio: most often from chronic alcoholism; also Vit B6 deficiency, Pb poisoning
Mitochondria unable to make heme; Fe accumulates in mitochondria (makes ringed sideroblasts) Alcohol - mitochondrial toxin; damages heme biosynthesis pathway B6 deficiency - cofactor in rate-limiting step of heme synth; most common from INH Pb poisoning - mostly in kids; denatures enzymes - ferrochelatase (heme synthase), ALA dehydrase, & ribonuclease. Build-up of δ-ALA. Lack of ribonuclease → RBCs retain ribosomes → "coarse basophilic stippling" on peripheral smear. Dx by ↑ whole blood & urine Pb Tx: treat underlying condition |
Sideroblastic anemia
Microcytic Anemia Dx: ↑ serum Fe, Fe Sat, & ferritin ↓ MCV & TIBC Ringed sideroblasts in bome marrow aspirate Sx: Abdominal colic w/diarrhea (Pb seen in GI tract on XR) Encephalopathy in kids: δ-ALA build-up damages neurons; demyelination; ↑ vessel permeability → edema Growth retardation (kids): Pb deposits in bone epiphysis (XR shows ↑ density) Peripheral neuropathy (adults) Nephrotox at proximal renal tubules → Fanconi's syndrome |
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Etio: ↓ EPO synth (usually)
Tx: treat underlying condition |
Anemia due to Chronic Renal Failure
Normocytic Anemia Features: burr cells (undulating RBC membrane) Platelet dysfxn - thrombocytopenia; prolonged bleeding time due to defective aggregation |
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Etio: auto dom membrane protein defect (usu ankyrin, poss spectrin, band 4.1) → abnormal RBC membrane, spherocyte formation
Dysfxn in Na/K/ATPase pump → ↑ Na permeability → rupture in salt solution Tx: splenectomy. Spherocytes stay in peripheral blood & Howell-Jolly bodies are present |
Hereditary Spherocytosis
Normocytic Hemolytic Anemia Dx: Spherocytes in blood smear (no central pallor) ↑ MCHC ↑ RBC osmotic fragility - rupture in mildly hypotonic solution Sx: jaundice (↑ unconjugated bilirubin) ↑ Ca-bilirubinate gallstones (↑ conjugated bili in bile) Splenomegaly Aplastic crisis - esp after viral infxn in kids (parvo B19) |
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Etio: Auto dom; defective spectrin & band 4.1
Tx: splenectomy (only if symptomatic) |
Hereditary Elliptocytosis
Normocytic hemolytic anemia Dx: Elliptocytes (>25% of RBCs) ↑ RBC osmotic fragility Sx: often asymptomatic, or mild hemolytic anemia Splenomegaly |
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Etio: Auto rec, Afr Amers. Heterozygote (HbAS) - no anemia; protective against P. falciparum malaria.
Homozygote (HbSS) - missense point mutation (Glu→Val at 6th position in β chain) causes Hbg to polymerize in needle-like shape. RBCs sickle if HbS > 60%. ↑ deoxy-Hbg ↑ sickling risk -- acidosis, hypovolemia, hypoxemia Irreversible sickled cell have ↑ adherence to endothelium → vaso-occlusive crisis & ischemic damage Tx: O2 (reverses initial sickling, but not recurrent sickling) Hydroxyurea - ↑ HbF BMT |
Sickle Cell Anemia
Severe hemolytic anemia with vaso-occlusive crises Dx: Hbg electrophoresis - HbS 90-95%; HbF 5-10%, no HbA. (for carrier: HbA 55-60%; HbS 40-45%) Smear - sickle cell; Howell-Jolly bodies (dark inclusions are RBC nuclear remnants) Prenatal DNA screening for mutation Sx: Asymptomatic at birth due to high HbF Dactylitis - painful swelling of hands/feet in infants, due to bone infarcts Acute Chest Syndrome - vaso-occ of pulm capillaries; chest pain, lung infiltrates, hypox. Poss fatal. Aplastic crisis - reticulocytopenia; assoc w/parvo Sequestration crisis - splenic enlargment due to RBC entrapment → hypovoluemia; reticulocytosis Autosplenectomy - enlarged & dysfxnal spleen early in life. (H-J bodies indicate loss of splenic M0 fxn. Later in life, spleen fibrosed & small. ↑ infxn risk - from spleen dysfxn, ↓ opsonization. Strep pneumoniae - most common death in kids; Salmonella → osteomyelitis Microhematuria - low O2 tension in renal medulla → infarction & sickling Renal papillary necrosis (low O2 in papilla) Aseptic necrosis of femoral head |
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Etio: X-linked rec; Mediterranean & Afr Amer variants. Protective against P. falciparum malaria
↓ NADPH synth ↓ glutathione synth → excess H2O2 oxidizes Hbg → Heinz bodies precipitate Heinz bodies damage RBCs → intravas lysis Heinz bodies removed by M0s in spleen (extravas lysis) → RBCs become bite cells Infxn - ↓ NADPH impaires WBC bacterial killing (myeloperoxidase system) Drugs - sulfas, primaquine, chloroquine Fava beans can induce (esp. Med variant) Tx: ? Antioxidants? |
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Severe chronic normocytic hemolytic anemia - Mediterranean variant Episodic normocytic hemolytic anemia (after oxidant stress) - Afr Amer variant Dx: Heinz bodies IDed with supravital stain - best screen during active hemolysis RBC enzyme analysis - after hemolysis subsided, for confirmation Bite cells in peripheral smear Sx: sudden onset back pain w/hemoglobinuria following oxidant stress |
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Etio: Auto rec; usu enzyme deficiency in Embden-Meyerhof pathway.
PK makes phosphoenolpyruvate to pyruvate - makes 2 ATP ↓ ATP → membrane damage → RBC dehydration, rigid RBCs Tx: ? |
Pyruvate Kinase (PK) deficiency
Normocytic extravascular hemolytic anemia Dx: Echinocytes (RBCs w/thorny projecytions) RBC enzyme assay - confirmatory Sx: Anemia w/jaundice at birth ↑ 2,3-BPG synth (proximal to enzyme block) → ↑ O2 release (remember the OBC curve?) |
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Etio: Inflm → ↑ hepcidin → ↓ Fe release from M0s
Can become microcytic & hypochromic in long-standing dz |
Anemia of Chronic Disease (ACD)
Normocytic anemia (nonhemolytic) Dx: ↓ Fe, ↓ TIBC, ↑ ferritin |
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Etio: clonal lymphoid stem cell dz
in kids - marrow involvement if young; mediastinal mass in adolescent males Bone marrow replaced with ↑↑↑ lymphoblasts Tx: highly treatable (>90% remission) |
ALL - Acute Lymphoblastic Leukemia
Dx: TdT+ (for pre-T & pre-B cells) B-cell type (most common): CALLA+, CD10+. t(12;21) - indicates better prognosis WBC count 10K-100K - >20% lymphoblasts Normocytic anemia & thrombocytopenia Marrow - totally replaced by lymphoblasts Sx: B-cell types have common mets to CNS & testes T-cell types - anterior mediastinal mass, acute leukemia mets - chest/spine/renal? |
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Etio: elderly (>60 yrs); most common leukemia, most common cause of elderly generalized lymphadenopathy
Virgin B cell neoplasm (NOT plasma cell) Assoc w/some deletions: 13q - good prog; 11q - bad prog; 17p - v. bad prog Richter's transformation → Large-Cell Lymphoma Tx: If stage 0 w/o Sx - watch & wait Any Sx is indication for Tx: B Sx (fever/wt loss/night sweats), mass dz, organ impingement Note: Small LL - same as CLL but less peripheral blood lymphocytosis |
Chronic Lymphocytic Leukemia (CLL)
INDOLENT. >95% have B cell origin Dx: smudge cells in blood smear WBC count 15K-200K - lymphoblasts <10%, neutropenia Marrow - CRAZY lymphocytosis (neoplastic B cells) Hypo-γ-globulinema common (normal B cells crowded out) Sx: generalized lymphadenopathy metastases - chest/spine/renal? Normocytic anemia (50% cases) Thrombocytopenia (40% cases) ↑ incidence of immune hemolytic anemia - both warm (IgG) or cold (IgM) Infxn-prone (immune compromised) |
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Etio: assoc w/HTLV-1
TAX gene activation inhibits TP53 suppressor gene → monoclonal proliferation of CD4+ T cells |
Adult T-Cell Leukemia
Dx: WBC count 10K-50K - >20% lymphoblasts; CD4+, TdT-neg Marrow - replaced by CD4 lymphoblasts Sx: Hematosplenomegaly, generalized lymphadenopathy Skin infiltration (common to T-cell malignancy) Normocytic anemia & thrombocytopenia Lytic bone lesions - lymphoblast release osteoclast-activating factor; assoc w/hyperCa |
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Etio: most in middle-aged men, elderly
B-cell proliferation Tx: good response to purine nucleosides |
Hairy Cell Leukemia
Dx: Pancytopenia - leukemic cells w/hairlike projections TRAP+ -- stain with tartrate-resistant acid phosphatase Sx: splenomegaly (common - in 90% cases) NO lymphadenopathy (the only leukemia without it) Hepatomegaly - 20% cases Autoimm vasculitis & arthritis |
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Etio: t14;18 → BCL-2 (anti-apoptotic) - accumulation of small cleaved B cells
Age ~60; adv stage at presentation. Survival ~8-12 yrs Tx: Stages I/II - watch & wait, or radiation Stages III/IV - watch & wait if no Sx; single or combo chemo if Sx Rituximab - targeted to CD20 → induce apoptosis |
Follicular Lymphoma
INDOLENT; incurable. B cells derived from germinal center Dx: Immunochem - CD20+; CD10+; CD5-; CD23- Marrow involvement Sx: Generalized lymphadenopathy |
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Etio: usu only in adults (< 60)
Cytogenic mutations possible - t(15;17) - acute promyelocytic leukemia Tx: APL responds well to VitA (ATRA) - induces myeloblast differentiatiohn Originally used FAB classification (M0 thru M7) |
Acute myelogenous leukemia (AML)
Dx: ↑↑↑ myeloblasts in blood smear Auer rods - splenter-shaped, peroxidase-+ inclusions in myeloblast/granulocyte cytosol. Often in APL. NOT found in CML! Sx: DIC is common. Also - Tx of APL can release Auer rods & cause DIC. |
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Etio: ↑ incidence in elderly, ionizing radiation or benzene exposure
Ph chromosome - t9;22 → Bcr-Abl gene fusion. Mutant RNA → TK activity → pro-survival (↓ marrow stromal adherence, ↓ apoptosis). Clonal expansion of pluripotent stem cell → potential for various differention Tx: TKIs (Tyrosine Kinase Inhibitors) Imatinib - standard for newly diagnosed CML, at all phases. Also good for Ph+ ALL. Inhibition of Bcr-Abl TK → apoptosis of Ph+ cells. Multiple P450 interactions. Nilotinib - chronic or accel'd phase; use if resistant or intolerant to imatinib Dasatinib - if resistant to imatinib Stem Cell Txplt - curative. IFN-α - selectively promotes Ph- cells; suppress Ph+ clones & thrombocytosis Hydroxyurea - oral for acute cytoreduction. ↓ clones & Sx, but DOES NOT ↑ SURVIVAL |
CML - Chronic Myelogenous Leukemia
(Just the basics - details on the 3 phases are on separate cards) Dx: Phila xsome & Bcr-Abl fusion oncogene - DIAGNOSTIC. ~95% CML are Ph+, but ALL have Bcr-Abl gene (Goljan). Most sens & spec test! Diagnose by cytogenetics, FISH, Southern Blot, or PCR. Other lab signs: low LAP (leukocyte alkaline phosphatase); ↑ urate (in blood/pee); ↑ B12 & B12 binding capacity; WBC count 50K-200K (all stages of development) - ↑ neutrophils, metamyelocytes, basophils Sx: Anemia Sx Hyperhistaminemia (itching, urticaria) Hepatosplenomegaly, generalized lymphadenopathy (mets) Sternal tenderness (due to marrow production, ↑ intramedullary cell growth) Sx from ↑ metabolic rate - ↑ urate, gout, heat intolerance, fever, wt loss Bleeding or thrombosis (40-50% cases of thrombocytosis; the rest have thrombocytopenia) |
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Etio: Lasts 3-5 yrs w/o tx or with cytoreduction only.
Worse prognosis if - >60 yrs, male, persistent anemia, thrombocytopenia or thrombocytosis, ↑ basophils & circulating blasts Tx: most responsive phase! Imatinib - >90% complete hematologic response; >50% major cytogenic response |
CML -- Chronic Phase
First phase of disease Dx: Blood - nucleated RBCs; anisocytosis [size variation]; poikylocytosis [shape variation]; thrombocytosis. ↑ myeloid cells, more immature forms; ↑ eosinophils, basophilia Marrow - hypercellular; ↑ myeloid:erythroid ratio; more immature cells; megakaryocytic hyperplasia/dysplasia; fibrosis Sx: often asymptomatic |
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Etio: transformation can be slowly (over mos) or explosively (over wks)
Tx: unresponsive to therapy |
CML - Accelerated Phase
Second Phase - Acute Transformation Dx: worsening of clonal defect or maturation block; 10-19% myeloblasts Sx: resembles acute leukemia - anemia, neutropenia, thrombocytopenia, ↑ blast cells |
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Etio: rapid progression; short survival
Tx: try to reinduce chronic phase > 90% end in acute leukemia w/o therapy 20-30% progress to ALL. Tx with vincristine prednisone, CNS prophylaxis If AML - usu refractive to all Tx |
CML - Blast Crisis
Last Phase Dx: as defined, 30% blasts or promyelocytes Large blast clusters in marrow Sx: |
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More mature forms of neutrophils & band cells
LAP (leukocyte alkaline phosphatase) usu high |
Leukemoid reaction
2nd side - similarities to CML 3rd side - differences from CML NOT CML! Transient leukocytosis. Like CML: ↑ myeloid cells, neutrophils, band cells, & metamyelocytes |
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Etio: mean survival ~10 yrs. Most deaths from complications (e.g., thrombosis)
4 phases: Erythrocytic; Spent; Myelofibrotic; Terminal Tx: Phlebotomy - won't prevent thrombosis or relieve pruritis, splenomegaly Hydroxyurea - for cytoreduction; if Hx of thrombosis INF-α - control myeloproliferation, splenomegaly. Use for preg. women Myelofibrotic phase - supportive Tx, transfusion (b/c of marrow fibrosis) Terminal phase - Tx to reduce thrombotic/hemorrhagic complications If >60 w/thrombosis Hx - hydroxyurea & low dose ASA |
PV - Polycythemia Vera
↑ # of blood cells made (RBCs) Dx: Rule out 2° causes - dehydration, hypoxia, inappropriate EPO secretion, cardiopulm dz (low arterial O2 sat), CO in blood Sustained ↑ in Hbg, Hct, & RBC count JAK2 mutation If absolute (1° PV) - EPO titers are normal/low Marrow - hypercellular, panmyelosis w/trilineage proliferation Endogenous erythroid colony forms in vitro Sx: from ↑ viscosity - H/A, dizziness, vertigo, vision disturbance, tinnitus from ↑ basophils & histamine - plethora, pruritus GI hemorrhage, splenomegaly, thrombosis |
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Etio: Onset - late 50s; survival < 5 yrs
Imbalanced fibrogenesis regulation; clonal abnormality in blood cells (NOT in fibroblasts) Abnormal megakaryocyte/monocyte proliferation → fibrogenic growth factors (e.g. TGF-β) Extramedullary hematopoiesis, ↓ erythropoiesis Tx: Allogenic marrow txplt - curative, but limited (pt's marrow is bad environment for cell growth) Supportive care - xfusion; androgens/steroids for anemia; radiation/splenectomy for splenomegaly Experimental Tx - try to target JAK2, TGF-β, histone deacetylase |
PMF - Primary Myelofibrosis
Differential for marrow fibrosis: myelosclerosis; infxn (TB, osteomyelitis); lymphoma; metastatic carcinoma; radiation; benzene poisoning; Paget's dz; osteopetrosis Dx: Blood - Nucleated RBCs, tear drop RBCs, immature myeloid/erythroid forms Marrow - "dry tap" on aspiration indicates extreme fibrosis Sx: insidious onset Usu pt's CC is bone pain Splenomegaly, anemia Sx, thrombocytopenia or thrombocytosis, leukopenia Space-occupying Sx |
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Etio: ↑ cytokines (e.g., inflm, infxn) → ↑ platelets
Tx: varied response, b/c varied molecular base Usu no Tx unless pt is symptomatic or at high risk for thrombosis High risk: if >60 or thrombotic Hx - Hydroxyurea or anagrelide, plus aspirin For pre-op - acute cytoreduction (plateletpheresis) Low risk: if CV risk factor or JAK2 - aspirin Alternately, IFN-α |
ET - Essential Thrombocytosis
(Most common MPD) Dx: exclusion! Reactive thrombocytosis - ↑ in platelets, driven by cytokines Rule out all other MPDs (myeloproliferative disorders), b/c all can have high platelets Marrow - ↑ #/size of megakaryocytes; proliferation of megakaryocytic lineage w/o ↑ in any other myeloid lineages Sustained high platelets (>450K) Sx: often asymptomatic Splenomegaly Thrombotic events - microvascular vaso-occlusive Sx Hemorrhagic events due to impaired platelet aggregation (response to epi and/or ADP) |
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Etio: bimodal peak - ages 15-34, then >60. More in adults, ↑ incidence in men (hormonal response?) - except nodular sclerosing type. ↑ risk in higher SES & clean environments.
Assoc w/EBV - in 50% mixed cellularity types In germinal centers, B-cell's Ig genes rearrange during maturation Tx: MOPP combo chemo - non-cross resistant mechanisms, non-overlapping tox Stage I/II w/good features - 2-4 cycles ABVD + radiation. 95% long-term, event-free survival Stage I/II w/bad features - 4 cycles ABVD + radiation; 85% l-t, e-f survival Stage III/IV - 6 cycles ABVD + radiation; 60% l-t, e-f survival (better if follow-up sooner) Relapsed/Refractory - switch to another combo chemo. Auto BMT can cure only ~40% |
Hodgkin Lymphoma
Hint: 5 subcategories! Dx: Reed-Sternberg cells - large, binucleate, prominent eosinophilic nucleoli Take entire node bx - preferably a palpable one Nodular Lymphocytic Predominant subcategory - few interspersed malignant R-S varients (L&H - large, pale-staining, multilobed cell); mostly normal lymphocytic background. Best prognosis Lymphocyte Rich subcategory - mostly benign lymphocytes interspersed with classic R-S cells (w/abnormal cell surface proteins) Nodular Sclerosis subcategory - most common in adults; nodular areas separated by collagen/fibrous bands. Infrequent malignant R-S cells with benign WBCs (not just lymphocytes). Lacunar cells - pale cell w/multilobed nucleus & many small nucleoli; lie in clear space More aggressive Mixed cellularity subtype - higher % of R-S cells, less dense cellularity. Lymphocyte-Depleted subcategory - HIGH % of R-S cells; most aggressive, often systemic B Sx. More common in elderly Sx: B Sx → worse prognosis! Fevers, wt loss, night sweats Usu painless swelling in neck (poss in axilla or groin). Non-tender, rubbery Cough - from enlarged nodes in mediastinum Pain after EtOH Pel-Ebstein fever - lasts 1-2 wks, alternate w/afebrile periods Usu present in stages: IA, IIA, IIIB, or IVB I - one lymph node region II - 2+ node regions, same side of diaphragm III - node regions on both sides of diaphragm IV - extranodal organs involved A - no B Sx at Dx; B - B Sx at Dx Ann Arbor: X - bulky mediastinal lymphadenopathy; E - extension from node into single continuous extranodal site |
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Etio: both childhood & elderly; age ~64, slightly more males.
No clear cytogenic abnormality: maybe BCL2, BC6 EBV is risk factor Tx: Rituxan-based combo chemo is standard (R-CHOP) Curability ~50% |
Diffuse Large Cell Lymphoma
AGGRESSIVE; w/o Tx, survival <1 yr Dx: B cells derived from germinal center Localized dz with extranodal involvement Sx: ~1/3 present in stage I/II involvement of GI tract, brain |
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Etio: more male; ~60 yrs
t11;14 → BCL-1 mutation Tx: Allogenic SCT or aggressive chemo → long-term survival? |
Mantle Cell Lymphoma
AGGRESSIVE Dx: BCL-1 mutation (cyclin D1) Sx: general lymphadenopathy, splenomegaly, GI involvement |
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Etio: risk factors - H. pylori, Autoimm (Sjogren's, Hashimoto's)
t11;18 - only in 50% cases Tx: PPIs + Abx → 2/3 regression in gastric MALT lymphoma Non-gastric - radiation for localized; chemo + rituximab for disseminated. (Rituximab blocks CD20 → apoptosis) |
MALT Lymphoma
INDOLENT; usu localized Dx: API-2 MLT mutation (anti-apoptotic) Sx: ? Assoc w/stomach, lung, thyroid, salivary/lacrimal glands |
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Etio: 3 settings - endemic (Africa - jaw); sporadic (kids/young adults); imm. deficient. American type - GI, para-aortic nodes
Assoc w/EBV? **t8;14 → c-MYC oncogene Tx: intensive chemo → high cure rate |
Burkitt's Lymphoma
AGGRESSIVE; acute onset, rapid progression Dx: c-MYC mutation CD20+; CD10+; BCL2- Marrow involvement; leukemic phase common Histo: starry sky appearance (from histiocytes phagocytosing dead cells) Sx: extranodal sites - usu in abdm, CNS dissemination |
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Etio: usu benign/premalignant; in elderly.
can progress to MM Tx: none. Just observe. |
MGUS
- Monoclonal Gammopathy of Undetermined Significance Dx: exclusion. No end-organ damage (no lytic bone lesions, hyperCa, renal failure, etc.) Serum M protein bands shouldn't > 3.0 gm/dL Sx: asymptomatic |
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Etio: ~65 yrs; ↑ incidence in excessive radiation
13q deletion - loss of Rb gene! B cells from Ag-stimulated germinal center Cytokines/growth factors activate myeloma cells → ↑ osteoclast & ↓ osteoblast activity → bone resorption M proteins usu IgG > IgA > light chain dz > IgD (rly rare) Tx: Stage I - observe Chemo: 1. Melphalan & prednisone 2. Thalidomide/Lenalidomide 3. Velcade (bortezomib) - protozoan inhibitor Radiation - for painful bone lesions, solitary plasmacytomas Bisphosphonates - help prevent frx Stem cell xplnt - if <70 w/few comorbidities |
MM - Multiple Myeloma
Dx: family Hx; bone pain/tenderness Sk bone survey - multiple "hole punch" lytic lesions Marrow aspiration/biopsy - Moth cell (plasma cells STUFFED with Igs in vesicles) Blood - Rouleux (stacking); + proteins neutralize neg membrane charges LDH/urate - indicate cell turnover Electrolytes - indicate renal fxn β-2 microglobulin - measure of "tumor burden" Sx: CRAP (or CRAB) Ca elevation Renal insufficiency (check serum creatinine) Anemia Pain (Bone) - lytic lesions, osteoporosis, compression frx Other: hyperviscosity, infxn, amyloidosis Myeloma kidney - light chain casts in tubules → obstruction Light Chain Deposition Dz - in glomerular BM |
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10-20%/yr risk progression to MM
Tx: observe only |
Smoldering Myeloma
Dx: M protein >3.0 and/or clonal plasma cells in marrow >10% Sx: asymptomatic |
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Etio: more in male; ~65 yrs
Monoclonal IgM → hyperviscosity Tx: none if asymptomatic Plasmapheresis - for hyperviscosity Chemo Rituxan - alone or in combo chemo; target CD20 |
Waldenstrom's Macroglobulinemia
(Lymphoplasmacytic Lymphoma) IgM!!! Dx: Marrow - >10% LP [lymphoplasmacytic] cells (between lymphocyte & plasma cell) Cryoglobulinemia (cold agglutinin hemolytic anemia) Sx: Hyperviscosity → dilated retinal veins → vision deficit Cytopenias, bleeding (bone marrow crowding → ↓ platelets, ↓ WBCs Lymphadenopathy, splenomegaly, neuropathy |
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Etio: Ig light chains or fragments → systemic fibril deposits (most commonly IgLCs, but can be several other precursors)
More in males; ~60-70 Tx: mostly supportive; similar to MM Tx. Chemo - Melphalan/Decadron; Thalidomide; Velcade Autologous SCT |
Amyloidosis (primary = AL)
Dx: multiple organ damage - liver, heart, kidney, soft tissues, PNS, GI Check serum proteins to ID probably source of fibrils Sx: non-specific! Fatigue, dyspnea, edema, paresthesias, wt loss... |
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Etio: progressive degeneration of vessel wall
Lesions ↑ with age (↑ endothelial breakdown) |
Osler-Weber-Rendu syndrome
(Only mentioned briefly, not a lot of info) Dx: ? Sx: violaceous non-pulsatile telangiectasias that blanch w/pressure Most easily seen over lips, mucous membranes Can involve any organ |
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Aortic dissection - most common cause of death
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Ehlers-Danlos Syndrome
Congenital SQ collagen disorder Sx: skin hyperelasticity Hypermobile joints Aortic dissection Ecchymoses; bleeding into skin Bad wound healing |
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Acquired causes: hypercortisolism or steroid purpura; snile atrophic purpura; scurvy; vasculitis
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Pseudoxanthoma elasticum
Elastic fiber defect |
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Can also be from non-immune activators - lipid activators of neutrophils
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TRALI - Transfusion-Related Acute Lung Injury
1. Allergic rxn - urticaria, pruritis, fever. IgE mediation → immediate hypersensitivity 2. Anaphylactic rxn - shock, hypotension. Rapidly fatal. Sx: severe resp distress, laryngeal edema |
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Immunocompetent donor lymphocytes recognize HLA of imm.suppressed pt
Prevent by irradiation of cellular blood components High mortality |
GVHD - Graft vs. Host Disease
Lymphocytes in donor blood attack recipient Ags Sx: fever; skin rash; hepatitis; diarrhea; marrow suppression → pancytopenia; infxn. |
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Etio: X-linked
Hemophilia |
Hemophilia A
Deficiency of Factor VIII Sx: Hemarthrosis → joint destruction Ecchymoses |
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Etio: nephrotoxic damage to proximal renal tubules by Pb
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Fanconi Syndrome
(NOT Fanconi Anemia!) Sx: proximal renal tubular acidosis (↓ bicarb in urine) Aminoaciduria Phosphaturia Glucosuria |
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Etio: X-linked; congenital defect in DNA repair proteins
In cancer Tx, avoid drugs that cross-link DNA |
Fanconi Anemia
(NOT Fanconi Syndrome!) Sx: bone marrow failure in 90% cases Risk of progression to AML 9or other cancer) |
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Etio: autosomal dom MYH9 mutation → mutated myosin heavy chain (non-muscle)
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May-Hegglin Anomaly (MHA)
Dx: Dohle bodies - small rods in WBCs Giant platelets Sx: renal failure Hearing loss |
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Etio: autosomal rec mpl defect
(c-mpl = TPO receptor) Tx: Usu need platelet transfusions BMT |
Congenital Amegakaryocytic Thrombocytopenia
Dx: platelets < 10K Sx: Thrombocytopenia Megakaryocytopenia CNS Sx |
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Etio: X-linked rec mutation; rare.
Tx: symptom-based Avoid aspirin & NSAIDs; prevent head injury → intracranial bleed SCT |
Wiskott-Aldrich
Sx: thrombocytopenia → bruising Small platelet size Eczema Severe immunodeficiency ↑ risk autoimm d/o, malignancies ↑ IgA/IgE; ↓ IgM |
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Etio: Ab-mediated destruction → ↑ opsonization, phagocytosis in liver/spleen
Abs usu against platelet surface glycoproteins Stimulated by T cells? Tx: steroids IV IgG → ↓ platelet destruction 2nd line - splenectomy, TPO, rituximab, cyclosporine, cyclophosphamide, azathioprine, vincristine |
ITP - Idiopathic Thrombocytopenic Purpura
Dx: exclusion Marrow - ↑ megakaryocytes, ↓ platelets ↑ platelet-associated IgG Sx: adult - insidious, chronic, more female kids - acute; 66% spontaneous recovery in 6 mos. Often follows viral infxn. Splenomegaly uncommon - reconsider Dx Bruising, petechiae; usu prolonged bleeding time Internal bleeding → potentially fatal |
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Etio: ↓ ADAMTS13 - metalloprotease that cleaves vWF polymer
Large vWF → ↑ platelet binding → thrombosis in small vessel Poss - Abs against ADAMST13 Tx: plasma infusion Plasmapheresis Steroids |
TTP - Thrombotic Thrombocytopenic Purpura
Sx: Thrombocytopenia Microangiopathic hemolytic anemia (small thrombi form → IV hemolysis) Acute renal failure Fluctuating neuro Sx, fever |
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Etio: autosomal dom, xsome 12
↓ vWF & factor VIII:C activity vWF can exist alone; Factor VIII can't. So in vWD, no vWF → no VIII Tx: ddAVP → release vWF from endothelium Oral contraceptive - estrogen |
Von Willebrand Disease (vWD)
Most common auto-dom d/o Combined platelet & coagulation factor disorder Dx: ↑ PTT, normal PT ↑ bleeding time ↓ vWF Ag ↓ VIII:Ag and VIII:C activity Sx: menorrhagic, epistaxis, easy bruising Angiodysplasia of R colon? |
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Etio: autosomal rec
Platelet adhesion defect |
Bernard Soulier Syndrome
Dx: absent GpIb platelet receptor (for vWF) Sx: thrombocytopenia, giant platelets Bleeding |
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Etio: autosomal rec; platelet aggregation defect
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Glanzmann's Disease
Dx: no aggregation w/ADP, epi, or ristocentin Absent GpIIb-IIIa receptors (for fibrinogen) Absent thrombosthenin Sx: lifelong bleeding issues |
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Hewrmansky-Pudlak Syndrome
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Hewrmansky-Pudlak Syndrome
Dx: Deficit in platelet dense granules + oculocutaneous albinism + nystagmus Sx: Bleeding, pallor Neuro Sx (nystagmus) |
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→ Bad clotting, I assume
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Gray platelet syndrome
Dx: Deficit in platelet α granules |
→ Bad clotting, I assume
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Scott Syndrome
(no 3rd side) |
Scott Syndrome
Sx: excess bleeding Etio: Platelet membrane defect → coag factors don't bind as well Tx: platelet transfusion |
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Etio: auto dom; no homozygous state
Tx: infuse ↑ heparin dose - PTT will eventually ↑ Warfarin for outpatient Tx |
Antithrombin deficiency
ATIII usu neutralizes activated serine proteases (XII, XI, IX, X, thrombin). Deficiency → hypercoag Dx: No prolonged PTT after heparin admin |
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Etio: an't inactivate factors V & VIII
Auto dom; homozygote → purpura fulminas Asymptomatic until ~20yrs Initial episode - 70% spontaneous, 30% w/risk factor Tx: heparin + very low dose warfarin (↓ risk of hemorrhagic skin necrosis) |
Protein C deficiency
Hypercoag Dx: protein C functional assay Sx: DVT, iliofemoral, mesenteric Warfarin-induced skin necrosis in 1/200 Heterozygotes have 50% viable protein C. Protein C has short 1/2-life - after 6 hrs, levels fall → ↑ V & VIII activity → hypercoag state → cutaneous vessel thrombosis, skin necrosis |
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Etio: 60% complexed to C4b-binding protein → inactive
Can't inactivate factors V & VIII Acquired causes - pregnancy, OCs, liver dz, DIC, acute thromboembolic dz |
Protein S deficiency
Hypercoag Dx: protein S functional assay Sx (heterozygotes): DVT, sup TP, PE poss warfarin-induced skin necrosis |
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Etio: single point mutation Arg→Gln
Mutant form can't be degraded by proteins C & S (APC = Activated Protein C) |
Factor V Leiden
(a.k.a. APC Resistance) Hypercoag (most common hereditary thrombosis syndrome) Dx: clotting assay shows resistance to APC Confirm w/genetic testing Sx: ↑ venous thrombosis Not consistent w/MI, CVA |
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Etio: allele assoc w/↑ prothrombin
Risk factor for VT → ↑↑ incidence (3x) |
Prothrombin variant G20210A
Hypercoag Dx: genetic testing Family Hx is strong indicator Sx: VT from ↑ serum prothrombin |
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Etio: remethylation path: met → homocysteine. Req B12, tetrahydrofolate, B6
Risk of stroke, MI, artery dz With other risk factors → ↑↑ VTE risk |
Homohomocysteinemia
Dx: homocysteine levels Sx: recurrent venous thrombosis Toxic to endothelium - desquamation Sm muscle proliferation Intimal thickening Induced TF activity Inhibited TPA → ↓ plasmin Impaired NO & PGI2 generation Interfere w/protein C activation Suppress heparin sulfate expression |
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Etio: assoc w/SLE & HIV
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APLS - Antiphospholipid Syndrome
Dx: Clotting assay, ELISA APAs (antiphospholipid antibodies) - anticardiolipin Ab, lupus anticoagulant Anticardiolipin Ab → false + syphilis test Sx: arterial & venous thrombosis syndromes Repeated abortions (thrombosis of placental vessels) Strokes, thromboembolism |
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Etio: mostly in kids
Toxin causes endothelial damage at arteriole-capillary jxn |
HUS - Hemolytic uremic syndrome
Dx: often from E. coli 0157:H7 Shiga toxin Sx: similar to TTP - fever, thrombocytopenia, renal failure, microangiopathic hemolytic anemia w/schistocytes |
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