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71 Cards in this Set

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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.
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
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
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.
Fe Deficiency
Microcytic Anemia

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)
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.
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
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.
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:
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
Acute Fe Overload
Usu toxic ingestion (kids); also ineffective erythropoiesis, transfusional ITx for anemias, bone marrow failure)
Dx: ?

Sx: ?
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!)
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
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-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
Etio: Heterozygous genotype produces mild dz
Mild protection against malaria.

Tx: none needed
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
Etio: Loss of a gene on each xsome (α/- α/-)

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
Etio: Loss of both genes on same xsome (α/α -/-)
Risk of developing more severe α-thal

Tx: none
HbH disease
(HbH = 4 β chains)
Microcytic Anemia

Dx: Hbg electrophoresis shows HbH

Sx: Severe hemolytic anemia
Etio: three α gene deletions (α/- -/-)
Excess β-chain inclusions cause RBC lysis by M0s.

Tx: ?
Hb Bart disease
(Hb Bart = 4 γ chains)
Microcytic Anemia

Dx: Hbg electrophoresis shows Hb Bart

Sx: Ridiculously severe hemolytic anemia
(incompatible with life)
Etio: four α gene deletions

Tx: none (pt dies)
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
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
Anemia due to Chronic Renal Failure
Normocytic Anemia

Features: burr cells (undulating RBC membrane)
Platelet dysfxn - thrombocytopenia; prolonged bleeding time due to defective aggregation
Etio: ↓ EPO synth (usually)

Tx: treat underlying condition
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)
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 Elliptocytosis
Normocytic hemolytic anemia

Dx: Elliptocytes (>25% of RBCs)
↑ RBC osmotic fragility

Sx: often asymptomatic, or mild hemolytic anemia
Splenomegaly
Etio: Auto dom; defective spectrin & band 4.1

Tx: splenectomy (only if symptomatic)
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
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
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
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?
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?)
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: ?
Anemia of Chronic Disease (ACD)
Normocytic anemia (nonhemolytic)

Dx: ↓ Fe, ↓ TIBC, ↑ ferritin
Etio: Inflm → ↑ hepcidin → ↓ Fe release from M0s
Can become microcytic & hypochromic in long-standing dz
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?
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)
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)
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
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
Etio: assoc w/HTLV-1
TAX gene activation inhibits TP53 suppressor gene → monoclonal proliferation of CD4+ T cells
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
Etio: most in middle-aged men, elderly
B-cell proliferation

Tx: good response to purine nucleosides
Follicular Lymphoma
INDOLENT; incurable. B cells derived from germinal center

Dx: Immunochem - CD20+; CD10+; CD5-; CD23-
Marrow involvement

Sx: Generalized lymphadenopathy
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
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.
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)
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)
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 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
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 - 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
Etio: transformation can be slowly (over mos) or explosively (over wks)

Tx: unresponsive to therapy
CML - Blast Crisis
Last Phase

Dx: as defined, 30% blasts or promyelocytes
Large blast clusters in marrow

Sx:
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
Leukemoid reaction

2nd side - similarities to CML
3rd side - differences from CML
NOT CML!

Transient leukocytosis.
Like CML: ↑ myeloid cells, neutrophils, band cells, & metamyelocytes
More mature forms of neutrophils & band cells
LAP (leukocyte alkaline phosphatase) usu high
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
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
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
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
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)
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
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
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%
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
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%
Mantle Cell Lymphoma
AGGRESSIVE

Dx: BCL-1 mutation (cyclin D1)

Sx: general lymphadenopathy, splenomegaly, GI involvement
Etio: more male; ~60 yrs
t11;14 → BCL-1 mutation

Tx: Allogenic SCT or aggressive chemo → long-term survival?
MALT Lymphoma
INDOLENT; usu localized

Dx: API-2 MLT mutation (anti-apoptotic)

Sx: ?
Assoc w/stomach, lung, thyroid, salivary/lacrimal glands
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)
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
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
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
Etio: usu benign/premalignant; in elderly.
can progress to MM

Tx: none. Just observe.
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
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
Smoldering Myeloma
Dx: M protein >3.0 and/or clonal plasma cells in marrow >10%

Sx: asymptomatic
10-20%/yr risk progression to MM

Tx: observe only
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
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
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...
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
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
Etio: progressive degeneration of vessel wall
Lesions ↑ with age (↑ endothelial breakdown)
Ehlers-Danlos Syndrome
Congenital SQ collagen disorder

Sx: skin hyperelasticity
Hypermobile joints
Aortic dissection
Ecchymoses; bleeding into skin
Bad wound healing
Aortic dissection - most common cause of death
Pseudoxanthoma elasticum
Elastic fiber defect
Acquired causes: hypercortisolism or steroid purpura; snile atrophic purpura; scurvy; vasculitis
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
Can also be from non-immune activators - lipid activators of neutrophils
GVHD - Graft vs. Host Disease
Lymphocytes in donor blood attack recipient Ags

Sx: fever; skin rash; hepatitis; diarrhea; marrow suppression → pancytopenia; infxn.
Immunocompetent donor lymphocytes recognize HLA of imm.suppressed pt
Prevent by irradiation of cellular blood components

High mortality
Hemophilia A
Deficiency of Factor VIII

Sx: Hemarthrosis → joint destruction
Ecchymoses
Etio: X-linked

Hemophilia B = Factor IX deficiency
Fanconi Syndrome

(NOT Fanconi Anemia!)
Sx: proximal renal tubular acidosis (↓ bicarb in urine)
Aminoaciduria
Phosphaturia
Glucosuria
Etio: nephrotoxic damage to proximal renal tubules by Pb
Fanconi Anemia

(NOT Fanconi Syndrome!)
Sx: bone marrow failure in 90% cases
Risk of progression to AML 9or other cancer)
Etio: X-linked; congenital defect in DNA repair proteins

In cancer Tx, avoid drugs that cross-link DNA
May-Hegglin Anomaly (MHA)
Dx: Dohle bodies - small rods in WBCs
Giant platelets

Sx: renal failure
Hearing loss
Etio: autosomal dom MYH9 mutation → mutated myosin heavy chain (non-muscle)
Congenital Amegakaryocytic Thrombocytopenia
Dx: platelets < 10K

Sx: Thrombocytopenia
Megakaryocytopenia
CNS Sx
Etio: autosomal rec mpl defect
(c-mpl = TPO receptor)

Tx: Usu need platelet transfusions
BMT
Wiskott-Aldrich
Sx: thrombocytopenia → bruising
Small platelet size
Eczema
Severe immunodeficiency
↑ risk autoimm d/o, malignancies
↑ IgA/IgE; ↓ IgM
Etio: X-linked rec mutation; rare.

Tx: symptom-based
Avoid aspirin & NSAIDs; prevent head injury → intracranial bleed
SCT
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
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
TTP - Thrombotic Thrombocytopenic Purpura
Sx: Thrombocytopenia
Microangiopathic hemolytic anemia (small thrombi form → IV hemolysis)
Acute renal failure
Fluctuating neuro Sx, fever
Etio: ↓ ADAMTS13 - metalloprotease that cleaves vWF polymer
Large vWF → ↑ platelet binding → thrombosis in small vessel
Poss - Abs against ADAMST13

Tx: plasma infusion
Plasmapheresis
Steroids
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?
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
Bernard Soulier Syndrome
Dx: absent GpIb platelet receptor (for vWF)

Sx: thrombocytopenia, giant platelets
Bleeding
Etio: autosomal rec
Platelet adhesion defect
Glanzmann's Disease
Dx: no aggregation w/ADP, epi, or ristocentin
Absent GpIIb-IIIa receptors (for fibrinogen)
Absent thrombosthenin

Sx: lifelong bleeding issues
Etio: autosomal rec; platelet aggregation defect
Hewrmansky-Pudlak Syndrome
Dx: Deficit in platelet dense granules + oculocutaneous albinism + nystagmus

Sx: Bleeding, pallor
Neuro Sx (nystagmus)
???

(Not much said about this)
Gray platelet syndrome
Dx: Deficit in platelet α granules
→ Bad clotting, I assume
Scott Syndrome

(no 3rd side)
Sx: excess bleeding

Etio: Platelet membrane defect → coag factors don't bind as well

Tx: platelet transfusion
Antithrombin deficiency
ATIII usu neutralizes activated serine proteases (XII, XI, IX, X, thrombin). Deficiency → hypercoag

Dx: No prolonged PTT after heparin admin
Etio: auto dom; no homozygous state

Tx: infuse ↑ heparin dose - PTT will eventually ↑
Warfarin for outpatient Tx
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
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 S deficiency
Hypercoag

Dx: protein S functional assay

Sx (heterozygotes): DVT, sup TP, PE
poss warfarin-induced skin necrosis
Etio: 60% complexed to C4b-binding protein → inactive
Can't inactivate factors V & VIII

Acquired causes - pregnancy, OCs, liver dz, DIC, acute thromboembolic dz
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
Etio: single point mutation Arg→Gln
Mutant form can't be degraded by proteins C & S
(APC = Activated Protein C)
Prothrombin variant G20210A
Hypercoag

Dx: genetic testing
Family Hx is strong indicator

Sx: VT from ↑ serum prothrombin
Etio: allele assoc w/↑ prothrombin
Risk factor for VT → ↑↑ incidence (3x)
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
Etio: remethylation path: met → homocysteine. Req B12, tetrahydrofolate, B6
Risk of stroke, MI, artery dz
With other risk factors → ↑↑ VTE risk
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
Etio: assoc w/SLE & HIV
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
Etio: mostly in kids
Toxin causes endothelial damage at arteriole-capillary jxn