Complete Blood Count (CBC)

Normals

• WBC - 4.5 - 11.5 x 10³/ul
• RBC - 3.8-5.8 x 10⁶/ul male
• Hemoglobin - 12.5-16.5 gm/dl male
• Platelets - 130-450 x 10³/ul
• Hematocrit - mcv, mch, mchc, RDW

RBC, Hgb and HCT Equations

• RBC x 3 = Hgb
• Hgb x 3 = HCT
• you only need to look at 1, I use hemoglobin 

Red Cell Indicies 

• mcv = (HCT x10)/RBC -> RBC size
• mch = Hgb/RBC 
• mchc = (Hgb x 100)
• RDW gives a numeric estimate of anisocytosis

Types of Microcytic Anemias

• Iron deficiency: TIBC- inc and Ferritin - Dec
• Thalassemia
• Anemia of Chronic Disease: TIBC-dec and Ferritin-inc
• Sideroblastic Anemia - ringed sideroblasts
• Lead poisoning

Types of Macrocytic Anemia

• Megaloblastic Macrocytic - VB12 deficiency, folate deficiency, durg effect, myelodysplastic syndrome
• Non-megaloblastic macrocytic anemia - reticulocytosis, liver dz, hypothyroidism, aplastic anemia

Reticulocyte Count

• measure of 24 hr RBC production by marrow
• Low or (inapropriately) normal reticulocyte count in an anemic pt suggests impaired RBC production
• High Reticulocyte cound suggests blood loss or RBC destruction 

Normocytic Anemia w/ Low Reticulocytes

• hypoproliferative anemia
• Anemia results from inadequate RBC production 
• Caused by awide variety fo systemic and hematologic dz
• Anemia of chronic disease - 1/3 pts are microcytic and 2/3 are normocytic
• Anemia of renal insufficiency - severity of anemia alpha severity of renal failure
• aplastic anemia, or myelophthesic anemia
• anemia elated to endocrine dz

Iron Response Protein-1

(IRP-1)

• derived from aconitase (enzyme in krebs cycle)
• when normal iron status, functions in krebs cycle
• When iron deficienc, undergoes conformational change to IRP-1: this allows binding to iron response elements and inc iron absorption

Hephestin and Ceruloplasmin 

• two ferroxidases found on the basolateral membrane
• allow for conversion of Fe2+ -> Fe3+ to be able to bind to transferrin
• transferrin is produced in liver; needed for iron delivery to cells (must be in Fe3+ form)

TfR - ferritin index

• Ratio of sTfR:Ferritin...... sTRF is the serum transferrin rec
• differentiates b tw iron def anema and the anemia of chronic dz
• ratio < 1 suggests anemia of chronic disease
• ratio >2 suggests iron deficiency anemia

Iron Deficiency Anemia

• Sx - fatigue, headache, dyspnea w/ exertion, pica, restless leg syndrome, beeturia
• Beeturia - excretion of red urine after beet consumption
• Proton pump inhibitors, H2 blockers reduce iron abs
• physical - conjunctival pallor, glossitis, stool guaiac, koilonychias, cheliosis (brown cold sore), dysphagia
• CBC - microcytic anemia, hympchromic (low MCH), high RDW
• inc TIBC, dec ferritin
• causes - blood loss, malabsorption (atrophic/h pylori gastritis, celiac, gastric bypass), erythropoietin response in chronic kidney dz, congenital iron
• chronic intravasc hemolysis (PNH) can cause
• Tx - arrest blood loss and correct inadequate abs
• can give oral iron (ferrous sulfate) or IV (ferrlicit, venofer, infed)

Iron Replacement therapies

Oral Iron - Ferrous Sulfate

• stols turn green-black; abdominal distress and constipation
• take apart from food - interference w/ absorption
• Vit C enhances absorption

IV - Ferrlicit, venofer, Infed

• occasional anaphylactic reaction, especialy w. infed
• use only when cant use oral or need for more rapid correction (weeks compared to months) 

Anemia of Chronic (inflammatory)

Disease (ACD)

• reduction in RBC production - exacerbated by shortened RBC survival (inc macrophages)
• altered iron metabolism and red EPO efficacy and production
• Sx similar to iron def; overshadowed by chronic dz
• common assoc: cancer, diabetes, chornic arthritis, cardiovasc dz, chronic infect
• TIBC dec and ferritn normal or elevated (reflects inflammatory condition)
• TNF alpha, IL-1 and IL-6(stim release of hepcidin)
• Hepcidin - inh of macrophage iron recycling, inh of intestinal iron absorption
• Tx - correct underling dz, EPO (along w/ iron) 
• therapy not indicated for Hgb >11g/dl and asymp

Erythropoietin

• may correct anemia in ACD if serum lvl is less than 500 m/ml (IV/SQ)
• maintain Hgb > 10 g/dl
• procrit(epoietin alpha): toxicities include GI, headache HTN
• Aranesp (darbopoetin oligosacchardie) - toxicity similar to procrit
• must give oral or parenteral iron if erythropoietin is given (neccessary for adequate EPO function

Lead Poisoning 

(borderline anemia but usually normocytic)

• high lvls or long term poisoning can result in irrev dmg to nervous system and kindeys
• severe poisoning w/ blood levels >80mcg/dl
• Sx - colicky abd pain, constipation, muscle aches, headache, short term memory problems, anorexia, dec libdio, nephropathy (Fanconi type syndrome)
• lead line - bluish pigmented line at gum-tooth line
• Basophilic stippling on blood smear
• Tx - reduce exposure, chelation therapy,

Chelation 

(Lead Poisoning

• generally reserved for pts lvls > 100 mcg/dl
• DMSA - oral: common adv effects include abdominal distress, nausea, transient rash, elevated liver transaminase enzymes, neutropenia
• Calcium EDTA (IV or IM) - common adv: hypocalcmeia and kidney dysfunciton
• Absorbic Acid - high doses per day helpful in reducing lead levels

Intra and Extravascular 

Hemolytic Anemia

• intravascular - destruction of RBC in the circulation w/ release of cell content into plasma; mechanical trauma from dmged endothelium; complement system; infectious agents
• Signs of intravascular hemolysis: hemoglobinemia, hemoglobinuria, hemosiderinuria, dec hemopexin
• Extravascular - removal/destruction of RBC by spleen and liver (phaged by macrophages)
• Signs of intra or Extra - inc indirect hyperbilrubin, hemoglobinuria, inc urinary and fecal urobilinogen, dec haptoglobin
• Hx and Px - anemia, dark urine, back pain, jaundice, lmphadenopath, hepatosplenomegaly, leg ulcers  (non-healing)

Hemolytic Anemia Testing

Chemistry

• inc unconjugated bilirubin, inc LDH, dec haptoglobin
• Released Hgb -> unconjugated bilirubin (spleen) -> bound w/ haptoglobin (plasm) -> Hgb-HPT complex cleared by liver
• Haptoglobin attempts to prevent oxidative damage but can be overwhelmed which can lead to renal tubule cells storing iron as hemosiderin (detected by urine prussian blue stain a week later)

Acquired Microangiopathic Hemolytic Anemia

• fragmented hemolysis (shistocytes)
• mechanical disruption of RBC membrane - intravascular hemolysis
• HUS, thrombotic thrombocytopenic purpura, DIC, pre-eclampsia, eclampsia, maligant HTN, scleroderma renal crisis
• prosthetic cardiac valves, transjugular intrahepatic portosystemic shunts, intravascular devices

Warm-Reacting Ab

Hemolytic Anemia

• idiopathic or secondary (autoimmine, immunodef, lmphoproliferative, non-lymphoid cancer, viral inf)
• almost always IgG - destruction by macrophages-spleen for IgG coated cells; liver for C3b
• Tx - withdrawal offending agent, prednisone, splenectomy (w/i 2-3wks if hemolysis remians severe despite therapy)

Cold Reacting Ab

Acquired immune-mediated Hemolytic Anemia

• idiopathic or secondary (inf, lymphoproliferative, Ca)
• Usually IgM - monoclonal disorder, mycoplasma, EBV, lymphoid neoplasia, cold white/blue fingers Sx
• Paroxysmal cold hemoglobemia (PCH) - Donath-Landsteiner Ab) - syphilis, viral inf; IgG mediated
• Exposure to cold leads to intravascular hemolysis; also has complement activity
• Tx - maintain warm env, chlorambucil/cytoxin
• steroids, IVIG, and splenectomy not recommended

Drug Induced Acquired Immune med

Hemolytic Anemia

• Hapten (PCN) - stimulate IgG ab production -> binds to cell membrane by FAB portion -> extravascular (macrophages) and rarely significant (moderate anemia)
• Immune Complex (Quinine) - IgM mainly; binds to RBC membrane and initatiates complement activaiton -> intravascular; can be severe (DIC)
• Autoantibody (alpha-methyldopa) - unknown mech (dec CD8), IgG Ab binds to FAB portion -> extravascular (macrophages); rx occurs proceeding removal of agent; mild anemia

Acquired Paroxysmal Nocturnal Hemoglobinuria

(PNH)

• red urine - urine w/ hemoglobin and hemosiderin
• anemia - tiredness, SOB, palpitations, abd pain, dysphagia, odynophagia, and ED
• thrombosis in 40% - major source of mortality - common sites (legs/lungs) and unusual: hepatic vein (bud chiari), portal vein, superior and inf mesenteric vein, cerebral venous thrombosis
• Intravascular hemolysis - coombs test (DAT) negative
• Flow cytometry for CD55 and CD59 gold standard test
• chronic dz - high risk of thrombosis so use warfarin
• acute attacks - use transfusion therapy (correct anemia but careful w/ iron) and steroids
• eculizumab - protects against complement system (PIGA defect on X chromosome)

Phosphatidylinositol glycan A 

(PIGA)

• required to make GPI which anchors proteins to cell membrane
• gene on X chormosome; mutation leads to defect in anchor
• defective cell membranes fail to protect from desturciton by the complement system resulting in RBC destruction (PNH)
• main proteins are the decay accelerating factor (DAF) (CD55) which disrupts formation of C3 convertase 
• also CD59 which binds the membrane attack complex and prevents C9 from binding to the cell normally

Malaria

• most common infectious etiology
• hemolysis directly from RBC infestation
• VIvax and ovale invade only reticulocytes
• Malariae invades mature RBC
• Falciparum invades all ages of RBC (more parasitism) - binds to sialic acid residues on RBC on glycophorin A
• Tx - chemoprophylaxis (all assoc w/G6PD)

Babesiosis

• nantucket, cape cod, northern california
• Ixodides Tick
• Fever, lethargy, malaise, hemoglobinuria 1-4 wks after bite - intravascular; renal and hepatic lab abnormalities
• Intraerythrocytic parasites on thin blood smear - produces no pigment 
• Rare reports of infection w/ transfusion
• Tx: clindamycin, quinine, atovoquone, atavoquone, z-max

Bartonellosis (oroya Fever)

(carrion disease)

• 2 stages - acute hemolytic anemia and chronic granulomatous phase
• Acute hemolyic anemia - rapid, severe w/ hemoglobinemia/hemoglobinuria; hemolysis caused by flagella of bartonellae
• south american (peruvian andes, brasil)
• Giemsa-Stained blood iflms (red-violet rods)
• Tx - PCN, streptomycin, tetracyclin, chloramphenicol

Other Acquired Infection Hemolytic Anemias

• clostridium (intravascular) - alpha toxin (spherocytic anemia)
• Gram positive cocci (GPC) (direct toxin effect)
• Gram neg Rod - Salmonella - 1-3 wk infection, direct polyagglutination of RBC -> marcophage destruction by liver and spleen
• Atypical - mycoplasma (cold agglutins), EBV (IgM ab), Viral (donath-landsteiner Ab and syphils 

Acquired Chemical and Physical

• oxygen - high conc leads to hemolysis
• Argine Gas - abd pain, nausea, vomiting; treat w/ red cell exchange
• Copper - Wilson's: treat w/ penicillamine or zinc
• lead intoxication - edetate calcium or penicillamine
• spider bites - brown recluse (dmg to band 3 protein; volcain lesions; hemolysis and DIC) and Hobo spider
• bee stings, thermal injury (3rd degree), hypophasphatemia

G6PD Deficiency

• most common enzymopathy causing hemolysis
• chronic hemolytic anemia, acute intermittent hemolytic anemia or no clinical
• vast majority are missense mutations
• clinical enzyme in production of glutathione (used to make new NADPH)
• X linked - G6PD A+ is common in blacks (non-hemolytic); also G6PD A-, G6PD
• RBC has no mitochondria so G6PD is only source of NAPDH
• Hemolysis from stressor
• Heniz bodies are oxidized adn denatured hgb - leads to bite cells
• consider in chronic Coomb's negative hemolysis

Pyruvate Kinase (PK) Deficiency

• most common congential non-spherocytic hemolytic anemia (HA
• Neonatal jaundice, splenomegaly, failure to thrive
• osmotic fragility normal (distingusih from HS)
• Echinocytes (small crenated cells)
• MCV normal/inc; and inc Reticulocyteosis
• Tx - folate, splenectomy

Hereditary Spherocytosis

• 75% AD; 25% AR
• spherocytic, osmotically fragile - susceptible to sodium leakage and loss of lipids leading to dec surface area
• aberrant interactions btw the skeleton and the overlying lipid bilayer
• denisty of skeletal layer reduced: lipid bilayer destabilized -> loss of membrane lipid -> leads to abnormal shape -> splenic loss
• 30-40% defect comprises both anykrin and spectrin
• osmotic fragility test
• pigmented gallstones (adolescence/early adulthood)
• aplastic crisis w/ parvo infection
• acquired folate deficeincy
• coombs test negative

Regulation of Iron Absorption

• mRNA for ferritin and transferrin rec contain iron-response elements (IRE)
• in sates of high Fe, Fe binds to IRE-BP
• for ferritin, this prevents IRE-BP binding to IRE in 5' region, and allows mRNA translation of ferritin
• for transferrin rec, this prevents IRE-BP binding to IREs in 3' region of transferrin rec mRNA, which usually stabilizes that mRNA
• by preventing IRE-BP binding, high iron leads to degradation of mRNA for transferrin rec
• thus high iron inc ferritin levels while dec transferrin rec levels

Iron Toxicity

• Acute - young children (1-2 gm fatal) - necrotizing gastroenteritis, bloody diarrhea, shock - treat w/ iron chelator (deferoxamine)
• activated charcoal is ineffective w/ iron
• Chronic - hemochromatosis, long term blood transufsions - treat w/ phleotomy or deferasirox 

Vitamin B12 (cyanocobalmin)

• required for methylation - B12 is donor and acceptor -> purine and pyrimidine syn; methionine syn
• absorption: req gastric IF; Acid frees B12 -> R binds and takes it to duodenum ->proteolytic degredation seperates from R then IF binds and transports to ileum
• binds transcobalamin II for transport -> storage in liver (5yr)
• deficiencies - pernicious anemia, dietary lack, lack of transcobalamin II, Ileal dz, lack of absorption
• Sx - demyelination, neuronal death -> irreverisble progressive: loss of vision, memory loss, confsion, hallucinations

Folic Acid 

• folacin, pteroyglutamic acid
• moa: involved in the biosn of amino acids, purines and pyrimidines
• indications - diet deficiency, intestinal dz or alcoholism (most common)
• implicated in neural tube defects (spina bifida)
• precautions - potential irreversible nerve damage when used to treat B12 def

Leucovorin (Folinic Acid)

• 5-formyl derivative of tetrahydrofolic acid
• effective as part of chemotherapeutic protocol
• rescure form high dose methotrexate (folic acid antagonist)
• reduce toxicity and counteract folic acid blockers 

Erythropoietin Signaling

• producedi n kidney and levels regulated by tissue oxygenation (mRNA level)
• regulated through transcription facotr HIF-1α and HIF-1β
• in the presence of HIF-1α is ydroxylated which leads to VHL protein targeting it and ubiquitonating it for proteasome degredation
• when there isnt oxygen, HIF-1α binds to HIF-1β to form a HIF-1 complex that binds hypoxia-response enhancer, leading to inc in EPO gene expression
• binds to EPO rec which are JAK-STAT signaling pathways

Recombinant Erythropoietin 

• epoetin-apha, darbepoetin, epoetin
• MOA - sitmulation of differentation and proliferation of progenitor RBCs - also inc reticulocyte release from bone
• indication - RBC anemia, renal disease, bone marrow failure, cancer pts, other anemias w/ dec EPO
• adv - thrombotic effects, HTN (inc hematocrit), iron def, red cell aplasia, risk of cnacer recurrence, inc tumor progression
• Black box warning - shortened survival, risk of tumor progression and recurrence; inc mortality and cardiovasc risk when doses to Hb >12 g/dl; inc rate of DVT

Recombinant G-CSF 

• Filgrastim, pegfilgrastim
• MOA - proliferation/differentation of neutrophil progenitors: inc activity of neutrophils (JAK/STAT rec)
• indications - severe chronic neutropenia, mobilization of hematopoietic stem cells, chemo induced neutropenia
• adm - IV or SC, not adm w/i 24hr of chemo/radiation
• precautions - ARDS, rare splenic rpture, ppt sickle cell crisis 

Recombinant GM-CSF

• sagramostim
• MOA: broader action than G-CSF - proliferation/differentiation of granulocytes, monocyte/macrophages, erythroid and megakaryocyte precursors
• Indications: myeloid reconstitution (bone marrow transplant), neutropenia, febrile peripheral stem cell mobilization
• adm - slow IV or SC, do not adm w/i 24 hr of chemo/radiation
• adv effects - bone pain, edema, malaise, weakness, capillary leak (pleural/pericardial effusion)
• first dose effect - tachycardia, flushing, hypotension, sweating

Recombinant Interleukin-11

• oprelvekin
• MOA - proliferation and maturation of megakaryocyte progenitors to inc platelet production
• indications - prevention of thrombocytopenia w/ chemo
• adv effects: possible anaphylaxis (permanent discontinuation in any pts who develps allergly); edema (HF)

Thrombopoietin Rec Agonist

• Romiplostim (peptide-Ab/peptibody) and eltrombopag (small molc agonist); oral (E) or SC (R)
• MOA - stimulations proliferation and maturation of megakaryocyte progenitors to inc platelet prodcution; activates thrombopoietin rec
• Indicaitons - chronic immune thrombocytopenic purpura, refractory to corticosteroids or other Tx
• Adv effects: rebound thrombocytopenia, Ab formation (R), hepatotoxicity (E), headache, athralgia, fatigue, GI, dyspepsia 

Alpha Thalassemia 

• two alleles on two chromosomes - Ch16 - produce 4 alpha globin chains
• if one alpha is mutated - carrier, asymp
• if two alphas are mutated - alpha -thal minor: asymp - mild microcytic anmiea
• If three alphas are mutated - Hb H disease: symptomatic - hemolytic and microcytic anemia; splenomegaly
• If all four mutated - incompatible w/ life - hydrops fatalis

Beta Thalassemia

• heterozygous beta thalassemia: pts usually asymp; smear w/ target cells and basophilic stippling, electrophoresis w/ elevetaed A2 and found in 1.4% of african americans
• homozygous - sever hpochormic, microcytic anemia, hepatosplenomegaly, thalassemic facies, hair on end appearance on skull films, gallstones, leg ulcers, short stature
• dx - hemoglobin barts, hemoglobin H, inc hemoglobin A2, no adult hemoglobin
• tx - transfusions or bone marrow transplant

Newborn hemoglobinopathy Screening

• all babies screened for sickle cell anemia; normal pattern is FA
• FAS is sickle cell trait
• F-homozyg B⁰thal, FS - homozyg SS dz or S/B^o
• FSA - sickle/B⁺
• FSC - sickle cell/hgb C dz
• FSD - sickle cell/hgb D dz
• FE - homozygous E or HgbE/B^othal

Sickle Cell Disease

• single base substitution of valine for glutamic acid in the beta globin gene on Chr 11
• 8% of african americs cary the Hgb S gene (sickle trait)
• induction of red cell sickling by polymerizaiton of deoxyhemoglobin S
• Dehydration, low oxygen, stress, menses, pregnancy, extremes of temp, infection can cause sickling
• clincal - vaso-occlusive paiful crisis, fever/infection, acute chest pain sndrome, stroke, pulmonary HTN
• other - anaplastic crisis, splenic cirsis, priapism, AVN, leg ulcers, retinopathy
• 11% of children w/ SS dz will have stroke by 20
• Tx - hydroxyurea: promotes HgbF

Combination of Hemoglobinopathies and 

Thalassemia

• sickle/beta thal - african american and mediterranean ancestry; milder course than SS, splenomegaly common
• SS w/ Alpha thal - alpha thal protective w/ elevated Hgb F leading to milder course
• Hgb C/Beta Thal - found in blacks, mild hypochromic anemia w/ target cells
• Hgb E/Beta Thal - common in thailand and SE asia, almost as severe as homozygous beta thal

Macrocytic Anemia

Non-Megaloblastic

• alcoholism - direct toxic effect of alcohol on erythroid precursors (secondary liver dz and folate deficiency)
• liver dz - reticulocytosis w/ stim erythropoiesis; inc RBC membrane lipids
• Hemolysis or posthemorrhagic anemia
• hypothyroidism and anaplastic anemia causes of macrocytic anemia
• artifactual - cold agglutinin dz; severe hyperglycemia; RBC clumping or swelling

Megaloblastic Anemia

• nuclear maturation defect leads to giant erythroid precursors (megaloblasts)
• 95% caused by vitB12 or Folate deficiency -> both are coenzymes for nucleic acid synthesis
• clinical - anemia sx, glossitis, atrophy of the gastric mucosa, neurologic (only B12)
• peripheral blood - oval macrocytes, howell-jolly bodies, RBC anisocytosis and poikilocytosis and hypersegmented neutrophils (highly sensitive)
• bone marrow - hypercellular and dec M:E ratio, giant band forms (PMNs), irr nuc ocntours/segmentation (megakaryocytes)
• lab findings- serum and RBC folate, serum vB12, LDH, MMA, homocysteine
• FIGLU (urine folate) and schilling test
• Tx remove cause and replace deficient vitamin; ?folate can correct somewhat a vB12 deficiency but not vice versa?

Folate Deficiency

• small reserve in body - deficiency can come from inc requirement (pregnancy or hemolysis), malabsorption  (in jejunum) or drug inhibition
• phenytoin induces malabsorption and methotrexate and antimicribials interfere w/ metabolism
• all rapidly dividing cells are affected; marked slowing of DNA syn
• absorbed into intestinal epithelial cells and circulates as M-THF - normally gives M to vitB12 but can be trapped as M-THF if vB12 deficiency

Vitamin B12 Deficiency

• large stores in liver, heart and kidneys
• caused by malabsorption (pernicious anemia), abnormalities of the ileum, or nutritional deficiency
• leads to defect in thymidylate syn and ultimately a defect in DNA syn (dUMP to dTMP)

Pernicious Anemia

• absence of IF secondary to gastric atrophy
• women > men; Northern European
• Autoimmune stigmata- thyroid, gastritis, addison's disease
• Ab produciton - 90% ab to parietal cells (not specific) and 56% Ab to intrinsic facctor (specifc)
• IF specific can prefent IF-B12 complex formation or complex absorption in ileum
• Schilling Test can be used to determine (low B12 does not determine btw pernicious or other causes of B12 deficiency)

Schilling Test

• used in B12 deficiency testing
• adm of labeled vB12 followed by flushing dose
• normal absorption would show Co57 vB12 in kidney
• impaired absorption would have no Co57 vB12 in kidney
• Pernicious anemia - Co57 vB12 and IF given orally - Co57 vB12 found in kidney
• Malabsorption due to other causes - Co57vB12 and IF given orally and no Co57vB12 in urine - shows that IF is not the cause of malabsorption

WBC Differential

Normal Ranges

• neutrophils: 43-80% - 1.8 - 7.3 x 10³/ul
• lymphocytes: 20-42% - 1.5-4.00
• Monocytes: 2-12% - 0.1-1.00
• eosinophils: 0-6% - 0.05-0.5
• Basophils: 0-2% 0.00 - 0.2

Neutrophila

• inc in circulating neutrophils to more than 7,300 ul
• mech: inc mobilization from bone marrow storage, enhanced release from marginal pool, inc bone marrow production
• Causes: infections (esp bacterial), immune/inflam, tissue necrosis, neoplasia, hemolysis, endrocrine disorders, drugs, physical stimuli, pregnancy
• Left shift - an inc in band neutrophils above 2,100/ul in the presence of neutrophila
• leukemoid reaction - reactive neutrophilic leukocytosis so severe that it resembles CML

Lymphocytosis

• inc in peripheral blood lymphcytes above 4,000/ul: >7,000 in children and >9,000 in infants
• causes infections, lymphoid neoplasms (esp CLL)
• infections - viral, pertusis, chronic bacterial infection (TB, brucellosis)

Monocytosis

• inc in peirpheral blood monocytes above 1,000/ul
• causes: chronic infectinos, hematologic disorders, nonhematologic cancers, immunologic and inflam disease
• Hematologic disorders - acute and chronic myeloid leukemias, myelodysplastic syndrome, hodgkin's and nonhodgkins lymphoma, neutropenia

Eosinophilia

• inc in peripheral blood eosinophils above 500/ul
• causes: allergy, skin dz, parasitic infections, malignant neopasms, collagen-vascular diseae, drgus, hypereosinophilic syndrome
• malignant neoplasms - lymphoma, leukemia, MPD, carcinomas

Basophilia

• inc in peripheral blood basophils above 200/ul
• causes: allergy, hypersensitivity, inflammatory bowel, viral infection (pox) and myxedema
• also caused by neoplasia (chronic myeloproliferative syndromes, hodgkins disease, carcinomas)

Neutropenia

• dec absolute neutrophil count below 1,080/ul
• susceptible to infeciton, esp <500/ul
• inadequate granulopoiesis can cause: aplastic anemia, marrow replacement, drugs
• accelerated destruction can also cause: autoimmune dz, drugs, overwhelming infection, hypersplenism

Acute Myeloid Leukemia 

(AML)

• bone marrow > 20% blasts; MPO positive
• incidence inc w/ age (avg 64); younger pts occur de novo and elderly pts evolve from myelodysplasia
• signs of marrow failure: fatigue, fever, bleeding
• presents in sudden (weeks) in de novo state and less suden (wks to months) in transformation from MDS
• bone pain from marrow expansion - sternal tenderness; also gingivitis/stomatitis
• favorable prognosis: <45 age, de novo, low relative WBC, M2, M3, M4
• poor prognosis: age <2 or >60, prior MDS/MPN, infection present, high WBC, M0, M6, M7
• treatment - full support, remission induction-cytotoxic chemo, bone marrow transplant
• cytotoxic chemo - Ara-C, antracyclines (aunorubicin, idarubicin), growth factor support (G-CSF, GM-CSF)

Acute Myeloid Leukemia

FAB Classification

• M0: Acute myeloid Leukemia w/ minimal differentiate
• M1: Acute Myeloid Leukemia w/o maturation
• M2: Acute Myeloid Leukemia w/ maturation: > 20% blasts w/ >10% neutrophilic forms; t(8;21)
• M3: acute promyelocytic Leukemia (APL)
• M4: Acute myelomonocytic Leukemia (most common)
• M5: acute monocytic/monoblastic leukemia(AMoL)
• M6: Erytrholeukemia: >20% blasts w/ >50% erytrhoid precursors, agressive clinical course all negative cytochemical stains
• M7: Acute megakaryocytic leukemia

Acute Promyelocytic Leukemia (APL)

• FAB class M3 of Acute Myeloid Leukemia
• pancytopenia and circulating promyelocytes
• predominance of abnormal promyelocytes in bone marrow
• cytogenic abnormality: t(15;17)- retinoic acid receptor gene on 17 fuses w/ PML gene on 15 - seen in 100% of pts
• cytochemic stains: positive MPO, SBB and SpEST
• Only AML where maintenance therapy is beneficial - combo of cytotoxic chemo and all-trans Retinoic Acid
• arsenic trioxide for relapse
• Results - 80% of complete remisssion pts alive at 5 yrs

Acute Myelomonocytic Leukemia 

• Fab classificaiton M4 Acute myeloid leukemia
• commonest type of acute leukemia in adults
• both myeloid and monocytic differentiatino
• tissue infovlement is common
• cytogenic abnorm: inv(16) in M4E (M4 w/ eosinophilia)
• 11q23 abnormlaity assoc w/ DIC
• cytochemical stains - positive for MP, SBB, 

Acute Lymphoblastic Leukemia

(ALL)

• peaks < 10yr and >50 yrs; most common malignancy in children <15
• Sx of bone marrow failure, acute onset and severe illness (all similar to AML)
• lymphadenopathy and splenomegaly found in ALL
• all are TdT positive; T-ALL is CD2-7 and B-ALL is CD10-19
• FAB-L3 is also Burkett Lymphoma
• unusual Sx: testicular swellingm mediastinal mass, retinal infiltration, polyuria
• female, low WBC, white, asian no CNS good signs
• male, black/native, CNS, WBC >30k bad signs
• remission induction: prednisone, vincristine, asparaginase, daunorubicn, Ara-C, cyclophosphamide
• watch for tumor lysis syndrome
• maintenance agents methotrexate and 6-mercaptopurine

Chronic Myeloid Leukemia

(CML)

• median age 50; 1/3 of pts >60
• untreated progression from chronic stable phase, to accelerated phase to blast crisis
• Leukocytosis: immature neutrophils in peripheral blood, eosinophila, monocytosis, basophilia
• leukocte alkaline phosphate (LAP) - dec in CML, inc in reactive neutrophila and infection
• philadelphia chromosome: t(9;22) - bcr/abl gene - tyrosine kinase activity
• Imatinib first line therapy in chronic stage; alpha interferon 3rd line hterapy
• accelerated phase - myeloblasts 10-19%, basophils >20%, persistent thrombocytopenia and thromboctosis, inc WBC or spleen size
• Blast crisis - transform to acute leukemia - 2/3 AML, 1/3 ALL
• bome marrow transplantation best results in chronic phase

Tyrosine Kinase Inhibitors (TKI)

• used to treat Chronic myeloid Leukemia (CML) - phladelphia chromosome leads to bcr/abl that has tyrosine kinase activity
• Imatinib
• nilotinib and dasatinib are new agents
• oral agents w/ few side effects

Polycythemia vera

• erythrocytosis predominates
• chronic headaches, malaise, fatigue if Hb > 18 g/dl
• hyperviscosity complications when 20 g/dl - venosu and/or arterial thrombosis; blood flow to major organs compromised
• splenomegaly
• JAK2 mutation (transducer for erythropoeitin rec)

Essential Thrombocytosis

(ET)

• thrombocytosis predominates
• usually asymptomatic- found on routine CBC
• thrombosis or bleading
• headaches, dizziness, visual abnormlaities, paresthesias, acrocyanosis
• mild splenomegaly in 50%
• JAK2 positive
• Tx - aspirin for X; 
• if platelet cound > 1mil and one thrombotic event or age > 60; treat w/ hydroxyurea, anagrelide, alpha interferon

Chronic Idiopathic Myelofibrosis

• pancytopenia in peripheral blood
• bone marrow shows granulocytic and megakaryocytic hyperplasia w/ progressive marrow fibrosis (secondary)
• splenomegaly
• JAK2 positive
• prognosis: median survival 3-5 yrs, death from cytopenias, occasional transformation to acute

Chronic Lymphocytic Leukemia

• most common adult leukemia -90% older than 40
• males > females (2:1);1st degreerelative inc risk x30
• accumulation of mature lmphocytes due to inhibition of apoptosis
• signs: 50% have lymphadenopathy, hepatosplenomegaly or both
• signs infections: staph, strep, herpes, shingles, hemolytic anemia
• elevated WBC: matue lymphocytes, smudge cells
• anemia, thrombocytopenia, neutropenia occur as dz duration inc
• B cell neoplasm so CD19 and CD20; also CD5 and 23
• no cure; intensitivy of therapy should match clinical severity
• chemo - chlorambucil, fludarabine, vincristine, prednisone
• monoclonal Ab - rituxan, campath
• transfromation - 10% progress to more aggressive disorder - Richter's transformation into diffuse large B cell Lymphoma; can also go to prolymphocytic leukemia or ALL

Chronic Lymphocytic Leukemia

Rai Staging

• 0-finding of lymphocytosis - mean survival 150 months - 35% of pts present
• I - lymphadenopathy - mean survival 101 months - 20% of patents present
• II - enlarged liver or spleen - 71 months - 25% pts present
• III - Anemia (< 11gm/dl) - 19 months - 10%
• IV - thrombocytopenia (< 100k/ul) - 17 months - 10%

Myelodysplastic Syndrome

• more common than AML; median age > 60
• males > females; can lead to progression to AML
• clonal disorder of hematopoietic cells - marked by peripheral blood cytopenias, dyspalstic bone marrow precursors and cytogenic abnormalities
• primary (unknown cause) and secondary 9radiation, chemo, benzene, tobacco, pesticide exposure)
• presentation - insidious onset; fatigue most cmmon Sx; bruising, bleeding from gums, nose, weight loss
• IPSS 0 - 5-7yr survival; IPSS >2 - 0.4yr survivl w/ 45% progressing to AML in 0.2 yrs
• full supportive care used
• EPO -50% response rate if endogenous lvls < 500mU; del(5q)
• chemotherapy - hypomethylating agents
• revlamid - response in 5q syndrome utpo 75%
• cause of death suually complicaiton of cytopenias - infection or hemorrhage

Plasma Donation

• AB is the common donator and O is the common acceptor of plasma - this is opposite of RBCs
• O (anti A, B,, Anti A and Anti B): transfuse to O
• A (anti B): transfusion to A, O
• B (anti A): transfusion to B, O
• AB(none): transfusion to O, A, B, AB

Cross Match

• includes type and screen and continues testing (RBC adm only) by testing pts serum against donor RBCs from the unit to be adm to the pt
• Cells= cells from the unit of blood to be adm to the pt
• serum/plasma - from the pt who is to receive the RBCs
• ONLY component cross-matched is RBCs
• all other are on "paper" only (eg plasma)
• compatible = no agglutination; incompatable=agglutination

Component - Red Blood Cells

• AS=1 adenine-saline preservative; ATP) 
• RBCs; very little (reduced) plasma; WBCs
• for symptomatic deficit of oxygen - carrying capacity: chronic anemia or acute anemia at higher lvls
• also for exhcange transfusions (infants;neonates) or to restore rBC mass in symptomatic anemia
• just give one unit at a time; can test post hgb as early as 15 mins after transfusion - 10gm/l good lvl
• HMHP - Hgb < 7g/dl or HCT < 21%
• Hgb < 8g/dl or HCT < 24% in pt w/ CAD, unstable angina, MI or cardiogenic shock

Component - Platelets

• platelets, plasma and citrate (ACD; storage for 5 days (bacterial issues)
• 300 ml of platelet rich plasma and WBCs; NO RBCs are given
• thrombocytopenic bleeding
• thormbocytopathic bleeding (normal #)  see plavix
• Prophylaxis is largest use - 50k trigger (operative), 20k trigger (prophylaxis) and 5k trigger
• 10 min, 15 min, or 1 hour post platelent count - if not inc worry aboute HLA/platelet Ab as seen in the chronically transfused;hematology/oncology
• Storage lesion - WBC degranulation and cytokine mediator release (FEBRILE reaction) 
• also role of ACEi in degradatio of bradykinin in pt on ACE inhibitors -acucm of BK in platelet concentrations and plasma

Component - Plasma

• plasma (coagulation proteins), citrate, no cells given; yellow component
• volume - variable; variable Hct in donors
• storage for 1 year
• Tx of stable clotting facotr deficiencs for whicn no conc are available, warfarin/coumadin reversal (emergent) - must monitor prothormbin time/NR
• 10-30 mins after adm - peak drug lvl
• factor VII - shortest 1/2 life (6hr) of the vitK procoagulant factors
• FFP is for immediate therapy for bleeding/surgery in the face of abnormal coagulation state (prolonged PT)
• HMHP - if INR <1.8, specify reasion, if INR >1.8 w/ active bleeding/surgery/trauma or TTP/HUS

Component - Cryoprecipitate

• made form FFP - thawed to 1-6C; cryoprecipitate gel is seen
• rich in Factor XIII, vWF, factor VIII adn fibrinogen (concentrates these out of plasma)
• mostly for fibrinogen content; fibrinogen deficiency (DIC)
• can also be given for fActor XIII def states but not usually given for vWF or VIII because better out there
• monitor fibrinogen level
• HMHP - fibrinogen < 100 mg/dl or <150 w/ active hemorrhage
• can give for renal or hepatic dz - assoc platelet dysfunciton or pre-procedural dosing

Component - Manipulations

• leukocyte - reduced - dec WBC content (RBC, PLT) - dec febrile reacitons, CMV risk and HLA ag sensitization)
• Irradiated - inactivates T lymphocytes/lymphocytes - prevents TAGVHD in recipient; cellular components (RBC, PLT)
• deglycerolized - RBCS - rare donor type sfrozen away for 7-10 yrs in glycerol
• Washed components - RBC, PLT - washed of protein (allergy) or other substances (Ab in plasma - eg mom donates for baby against whom she has Ab)

Transufsion related Acute Lung Disease

• due to DONOR antibodies to recipient WBCs
• Ab sequester WBCs in pulmonary circulation, looks lke CHF w/ inc venous pressures
• looks like ARDS
• supportive hterpay, will resolve
• ANY component but most often FFP

Bacterial Transfusion Contamination

• Platelets - usually Gram +
• RBCs - usually Gram - (Yersinia)
• beware the autologous unit (this is pt blood NOT donor blood)

Bernard - Soulier Syndrome

• autosomal recessive
• inherited defect of GP1B complex, various mutations
• platelet binding to vWF is impaired
• presents in childhood - bruising/bleeding/epistaxis
• large platelets "macrothrombocytopenia
• low normal/low platelet number

Glanzmann thrombasthenia

• rare autosomal recessive defect of GPIIB/IIIa complex, various mutaitons
• impaired platelet aggregation via ligands (fibrinogen,etc)
• presents in childhood - "mucocutaneous bleeding"

Immune Thrombocytopenia

(ITP)

• low platelet count (under 20, clinical relevance)
• exact mechanism unclear - mAB to GPIIb/IIIa often present 
• clearance of platelets by MACS/reticuloendothelial system
• mucocutaneous bleeding; petichiae 
• Tx - steroids, IVIG, splenectomy (50% cure rate)

Thrombotic Thrombocytopenic Purpura

(TTP)

• classic pentad - low platelet count, hemolytic anemia, mental status change/neuro sx, renal failure and fever
• fatal if untreated
• mechanism: ADAMTS13 - protease cleaves vWF  multimers, multimers adhere to platelets -> thrombi develops
• Rx - plasma exchange, plasma, steroids, rituximab

Disseminated Intravascular (DIC)

• systemic activation of pathways leading to and regulating coagulation, which can result in the generation of fibrin clots that may cause organ failure w/ concomitant consumption of platelets and coagulation factors that may result in clinical bleeding
• microvascular thrombosis -> organ failure
• thrombocytopenia and coagulation factor deficiency -> bleeding
• Presents as: low plateelet count, elevated PTT/PT
• causes: sepsis and severe infection, trauma, organ destruction (pancreatitis), malignancy, solid tumors, leukemia, severe liver failure
• obstetric - amniotic fluid embolism, placental abruption, pre-eclampsia
• Rx - treat underlying illness, plasma, and other supportive measure

Acute Intermittent Porphyria

(AIP)

• sx: abdominal pain, unclear etiology
• CNS: neurologic/psychologic disturbance (insomnia, paresis, restlessness)
• provocations: diet/starvation, drugs, EtOH - episodic/provoked
• Dx: PBG in urine 
• Rx: heme, glucose (inhibits ALA dehydratase)
• Hereditary coproporphyria (HCP)
• Variegate Porphyria (VP)

Porphyria Cutanea Tarda (PCT)

• autosmal dominant or acquired (sporadic) def URO-decarboxylase
• Sx: blistering skin lesions and photosensitivity; back of hands/forearms, etc - derm manifestations
• Provocations: HCV, EtOH, iron excess, HIV - HFE mutations (H63D, c28Y)
• excess iron effects uroporpho-methane -> UROX -> uroporphyrin III
• uroporphor-methan blocks UROD in the normal pathway: normal pathway is uroporphyrinogen III -UROD -> coproporphyrinogen III -> Heme
• Dx: uroporphyrin/other porphyrins in urine plasma; metabolites also in liver
• Rx: phlebotomy (remove excess iron); treat provocations;?chloroquine

Congentical Erythropoietic Porphyria

(CEP)

• autosomal recessive defect of URO-synthase
• presents in infancy, childhood
• Dx: inc porphyrisn in erythrocytes, bone marrow (uroporphyrin, coproporphyrin); DNA testing
• Sx: hemolytic anemia, crippling scarring/photosensitivity of skin
• Dx: supportive (abx for infections, transfusions for anemia, stem cell transplant)
• Rx: avoid sun exposure; supportive

Erythropoietic Protoporphyria (EPP)

and

Xlinked protorphyria (XLP)

• EPP: autosomal recessive defect of ferrochelatase
• XLP: X linked, gain of function, mutation ALAS2
• PResents in early childhood
• Dx: inc protoporphryins in erytrhocytes; (red fluorescence on fluorescence microscopy) DNA analysis
• Sx: photosensitivity of skin; chronic changes - protoporphyrins can cause hepatic damage
• Rx: avoid sun exposure; supportive

Adhesion of Platelets to the Subendothelial cell layer

• GPIa (on platelet membrane) initially binds ot the exposed collagen, which results in changes in the 3D configuration of the complex
• This allows GPIb to bind to vWF (on the subendothelial collagen)
• This second binding event exposes the GPIIb/GPIIIa complex - this can also bind vWF and fibrinogen 

Regulation of Plasmin Activation

• plasminogen can be activated by either tPA or SCU-PA (+)
• PAI-1 can block tPA action on plasminogen
• Streptokinase can bind to plasminogen, forming a complex; allows autocatalysis to form plasmin
• Circulaiton alpha2 antiplasmin blocks the activity of any soluble plasmin that may be in blood - this is found in areas of wounds that still need clotting

Patters of Lymph Node Hyperplasia

• acute lymphadenitis - bacterial infection
• Follicular Hyperplasia - rheumatoid arthritis, syphilis, early HIV infection, castleman's Dz
• Sinus histiocytosis: rosai dorfman disease (SHML), dematopathic lymphadenopathy, whipple's disease
• Paracortical lymphoid hyperplasia - infectius mono, CMV, post vaccine, herpes zoster, dilantin hypersensitivity
• Mixed patterns - cat scratch, toxoplasmosis, sarcoidosis

Cat Scratch Disease

• Bartonella Henselae
• clinical: young patient (<18) - epitrochlear, axillary or cervical adenopathy; 50% w/ history of actual cat scratch, regresses over 2-4 months
• path: follicluar hyperplasia, paracortical necrotizing granulomas
• Warthin-starry stain shows bacillary forms - silver rods
• mixed patter of hyperplasia w/ folicular granulomas

Mantle Cell Lymphoma

• 3-4% of NHL cases; older pts (mean 60) M:F >2:1
• pts present w; diffuse adenopathy; GI tract is most cmmon extra-nodal site - bone marrow and peripheral blood involvement also common
• Mean survival is 3-5 years
• Pathology: arises in mantle zone (ring around germ centers) - proliferation of small lymphocytes
• Phenotype: CD10 and CD20 w/ CD5 coexpression
• also positive for cyclin D1 (BCL1) and negative for CD23
• Genotype: t(11;14) - fuses w/ cyclin D1 gene on chromosme 11 w/ the IgH heavy chain promotor/enahncer region on chromosome 14

Follicular Lymphoma

• 40% of NHL in US, predominantly adults (mean 59)
• M:F 1:1; median survival 7-9 yrs (low grade)-no cure
• most have widespread dz at presentation; 40% w/ bone marrow involvement 
• most cases have pred follicular pattern, comprised of neoplastic follicles
• normal architecture is replaced by little, round nodules (no mantle zone aroudn this) - look like germinal center; they closely spaced, generally round
• unlike hyperplasia, this lacks polarization and tangible body macrophages
• small cleaved cells (centrocytes) (dark and irreg; chicken tract cells) and large transformed cells (centroblasts) (open nuc chromatin and prominent nucleoli)
• CD19, CD20, CD10, BCL2
• t(14;18) leads to overexpression of BCL2 (anti-apoptosis)

Multiple Myeloma

• most common plasma cell neoplasm 
• M:F 1.5:1; twice as common in blacks then whites
• mean age at dx is 65; uncommon before 40
• M component is usually IgG or IgA; light chains 
• char by extensive patchy infiltration of malignant plasma cells through the bone marrow - nuc is round to oval, black faved nuc hromatin, eccentric and distinct nucleoli (not normal for plasma cells)
• bone pain, hypercalcemia, pathologic fractures, recurrent bacterial infections (suppressed Ig), renal insufficiency and amyloidosis (5-10%)
• Dx - plasmacytoma by biopsy, bone marrow plasmacytosis, Monoclonal gammopathy (M spike), suppresed normal IgG

Waldenstrom's Macroglobulinemia

• also called lymphoblastic lymphoma
• plasma cell neoplasm where there is production of mnoclonal IgM
• lymphoplasmacytoid morphology: nuc is eccentric and doesnt have clock face and other normal features; pale cytoplasm
• clinical behavior more like lymphoma: lymphadenopathy, spleno-hepatomegaly
• monoclonal IgM causes: coagulopathy (fibrinogen, and factors II, V, and VIII; platelet agglutination) and hyperviscosity syndrome

Diffuse Large B-Cell Lymphoma

• diffuse proliferation of large B cells, w/ open nuc chromatin - nuc size > normal macrophage nuc
• 50% of NHL in west; median age is 7th decade but found in all age groups
• intermediate grade
• 40% of cases present as extranodal dz; GI most common
• see lymph node w/ architecture completely replaced by larger paler cells - lymphoma cells are larger, dark nuc chromatin, nucleoli 
• pts typically present w/ a single enlarging mass; many will have more extensive dz after staging - agresive tumor that untreated is rapidly fatal but is potentially curable
• B cell markes CD19, CD20, CD79a and surface or cytoplasmic Ig
• t(14;18) involveing BCL2 gene; can also have 3q27 abnormalities involving BCL6 gene

Burkitt Lymphoma

• highly aggressive B cell neoplasm that may present as extranodal sites or as acute lukemia (L3-ALL) - fastest growing neopaslm in humans (intermed grade)
• Endemic in african child; sporadic in children and young adults (<30)
• site of involv varies; all at risk for CNS dz: endemic (jaw) and sporadic (intra-abdom-terminal ileum, ovaries, kidneys, breast)
• endemic: EBV palys role; dz proceded by a period of polyclonal b cell activation (Malaria)
• sporadic: EBV in 30%; assoc w/ low soc-econ class
• histo: med sized cells w/ a diffuse monotonous pattern: nuc show clumped chromatin, multiple basophilic nucleoli, high mitotic rate, apoptosis producint starry sky pattern
• CD19, CD20 and CD10; genetic translocaitons involving the c-MYC gene on chromsome 8 and IgH (14), K gene  (chr2) or delta gene (22)
• growth fraction: Ki67 >95%

Peripheral T Cell Lymphoma

• distinguished from precursor T cell lymphoblastic leukemia/lymphoma (central)
• peripheral T cell lymphoma does not arise in mediastinum
• HIsto: somewhere in btw large and small cell lymphoma - see eosinophils w/ these intermediate sized cells
• 15% of adult lymphomas
• Agressive, widespread - high grade lymphoma
• responds poorly to therapy

Hodgkin Lymphoma

• lymphoid neoplasm arising primarily in lymph nodes
• Reed-sternberg cell, systemic manifestations (fever, night sweats, weight loss), spreads to anatomically contiguous node groups
• bimodal age distr w/ peaks 20s and >50yrs
• inc incidence w/ higher socioeconomic status, hgiher educational level and smaller family size
• inc risk w/ hisotry of infectious mono (EBV)
• classic reed-sternberg cells are CD15 and CD30 pos
• clasic hodgkin lymphoma is nodular sclerosis and mixed cellulary (lymphocyte rich and deplete)
• non-classic hodgkin lymphoma is nodular lymphocyte predominant (no assoc w/ EBV and L&H RS cells)

Nodular Sclerosis Hodgkin Lymphoma

• 65% of HD cases, female predominance, commonly low stage, and young ppl
• Presents w/ mediastinal mass
• path: shows nodules w/ sclerosis in btw (fibrosis)
• Histo: purple nodules w/ pink bands of collagen in btw (bright pink and glassy)
• high power in nodule shows the mixed cells and Reed-Sternburg - can be called lacunar cells (white space around it)

Mixed Cellularity Hodgkin Lymphoma

• middle age (35 to 50), commonly present in intermediate stage
• almost uniformly EBV positive 
• mixed background on histo w/ not a whole lot of Reed-Sternburg cells - also has mummified cells (dead reed-sternbrg cells)
• Lymphocyte Rich - elderly pts, 70% male: predom lymphocytes in background w/ few Neutrophils, E and plasma cells); sometimes confused w/ nodule lymphocyte pred hodgkin
• Lymphocyte Depletion - elderly pts, high, bulky dz: may arise as end stage of other tyeps of HD in relapse; see just reed sternburg cells w/ very few other cells (lymphocytes) in background

Nodular Lymphocyte Predominant 

Hodgkin Lymphoma

• 5% of HD cases, predominantly young males
• can be thought of as B cell lymphoma that occurs in young people(rare) - this is because it is diff rom all the other hodgkin lymphomas
• low stage disease and NO assoc w/ EBV
• Good serivval despite relapses
• HIsto: nodular - nodes of light purple surrounded by darker purple
• L & H cells or popcorn cells because nuc looks like that (fairly infrequent)
• Immunophenotype of LH Reed-Sternberg Cells - CD45, CD20 and EMA postive and CD15 and CD30 negative (this is the opposite of normal RS cells)

Causes of Death in Cancer Survivors

(Mortality of Late Effects)

1. recurrence of original cancer
2. second malignancy
3. cardiac disease
4. Pulmonary Disease

Metabolic Syndrome

• has been linked ot GH deficiency
• Defined by the presence of 3 or more:
• abdominal obestity
• high TG and low HDL
• high blood pressure
• high fasting glucose
• inc irks of premature heart dz and diabetes in young adult cancer survivors

Cardiac Problems

Childhood Cancer Survivors

• Risk facotors: anthracyclines, cytoxan, XRT (mediastinal, mantle, whole lung, spinal)
• risk factors: race, gender, age, trisomy 21, 
• childhood cancer survivors 7x more likely to die from cardiac-related events
• late presentation (10-15 yrs later) and irreversible
• greatest risk if abnormal echo at end of therapy
• cardiac late effects: ischemic heart disease, cardiomyopathy, valvular injury, conduction defects(QTc prolongation)
• high risk pop: pregnant women and weight lifting

Pulmonary Problems

Cancer Survivors

• XRT and chemo: bleomycin, cytoxan, alkylators, busulfan
• survivors 8.8x more likely to die of pulmonary related event (pneumonia, fibrosis, other)
• restrictive lung disease - impaired growth of lung tissue and chest wall; progresses w/ time
• pulmonar fibrosis - insidious onset, stabilizes after 1-2 years; SOB, Exercise intolerance
• Bronchiolitis obliterans - end stage of restrictive lung disease 

Types of Secondary Malignancies

• all but hematologic can be traced to XRT
• 1: Hematologic - risk plateaus after 10 yrs; ANLL most common - etoposide, alkylating agents/doxorubicin (often w/ MDS prodrome)
• Solid tumors as SMNs - median latency of 9.5 to 16 yrs; 2/3 ocurr in XRT field, risk does not plateau
• Breast cancer - 55x inc risk; more risk if older at time ot Tx, begins to inc w/i 8 years following tx
• Thyroid Cancer - most ocmmon 5-10 yrs after XRT; 18 inc incidence; MC after therapy for hodgkin lymphoma

Prevention/Amelioration

• cardioprotection - dexrazoxane, continuous infusion of anthracyclines
• mesna for bladder protection
• cognition - delaying or reduced dose intensity of XRT; chagne in Tx schedules
• risk stratified treatment protocols

Common Chemotoxicities

• cisplatin/carboplatin -> nephrotoxic and acoustic nerve damage
• vincristine -> peripheral neuropathy
• Bleomycin -> pulmonary fibrosis
• Doxorubicin -> cardiotoxicity
• 5-Fu, 6-MP and methotrexate - myelosuppression

Superior Vena Cava Syndrome

• caused by mass in the right peritracheal or mediastinal location which blocks the SVC, impairing venous blood return to the heart
• insidious onset: collaterals can form
• historically due to syphilitic aortic aneurysm or TB; now 95% due to cancer: lung (esp small cell) and lymphoma
• sx: swelling around the eyes, upper body swelling, headache, SOB
• signs: edema of face/eyes/neck, cyanosis/facial plethora, collateral veins on upper chest/arms, paralyzed true focal cord, horners syndrome
• Dx: CXR (right sided mass), or CT of chest w/ dye (shows collateral veins and compressed SVC)
• Tx - high dose steroids, urgent chemo/XRT, stent in SVC
• prognosis - pts w/ lymphoma have a chacne for long term survival or even cure

Hematologic Emergencies

• Hemolytic Uremic Syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
• can occur w/ use of mitomycin, cisplatin, bleomycin and gemcitabine
• dx - signs of HUS and TTP, blood smear shows shistocytes
• HUS - deposition of fibrin in small vessels
• TTP - inc in hmw VW multimers
• Tx - plasmapheresis w/ plasma exchange; immunoperfusion over staph protein A column

Metabolic emergency - Hypercalcemia

• humoral hypercalcemia of malignancy - PTHrP, direct invasion of bone or cytokine release (OAF produciton by myeloma)
• Sx - thirst, excessive urination, constipation, somnolence adn comma
• Tx - acute give saline diuresis, steroids, lasix
• Pamidronate - inhibits osteoclasts

Metabolic Emergencies - Hyponatremia

• most common oncologic cause:SIADH - most commonly seen in small cell lung cancer
• cyclophosphamide and vincristine can cause
• Sx: anorexia, weakness, vomiting, lethargy, confusion, seizure and coma
• Dx - serum Na < 130 meq/L and if less than 115 risk of seizures
• Tx - water restriction, hypertonic saline, chemo, democlocycline (Antibiotic that causes diabetes insipidus)

Tumor Lysis Syndrome

• occurs after tx of rapidly growing chemo-sens neoplasm: leukemia, lymphoma and small cell lung
• risk: bulky tumor, high LDH
• rapid release of intracellular products: DNA - uric acid; PRoteins - phosphates; Cytosol - potassium
• Renal failure, hypocalcemia, arrhythmias can occur 
• pretreat w/ allopurinal
• LV hydration w/ initial alkalination to prevent uric acid nephropathy

Leukostasis and Blast Cells

• etiology in lung and brain - leukothrombin w/ fibrin; leukocyte aggregates
• rate correlated w/ WBC count and type of leukemia
• leukostasis occurs most commonly iin AML due ot larger blast size and less deformability - risk inc when WBC > 1000,000
• Leukostasis Sx - brain (confusion/fever), lungs (tachypnea, consolidaiton, rubs, infiltrates), and heart (angina and acute MI)
• Therapy - alkalinizaiton, hydration, leukapheresis, allopurinol or hydroxyurea