HEMATOLOGY

DEFINITIONS o Occur in asplenia, when no spleen or non-

functioning spleen
 CBC: includes hemoglobin, hematocrit, WBC  Pattern for treatment: treating cause, treating
count, platelet count, RBC indices symptoms, life threatening emergency, treating
o Must separately order WBC differential, complications, prevention
reticulocyte count  Hemorrhage: ongoing bleed from vessels
 Lymphadenopathy: any change in lymph o Hemostatic can prevent from smaller
vessels/nodes (e.g. size, distribution, tenderness, vessels
mobility, consistency, course) o Intervention for extensive bleed from larger
o Occurs during infection or malignancy  Serum: blood plasma minus clotting proteins
 Marked pallor: distinct and obvious paleness  Trimethoprim-sulfamethoxazole: antibiotic that
 Ceftriaxone: cephalosporin-antibiotic (beta-lactam) blocks two steps in bacterial folate synthesis, which
 Cytopenia: reduction in # of mature blood cells is required for nucleic acids and proteins
o Anemia, leukopenia, thrombocytopenia,  Platelet clumping: on peripheral blood smear, can
pancytopenia be mistaken as one platelet (pseudo-
 Blood film: part of peripheral smear, look at blood thrombocytopenia)
cells under microscope  RBC fragments: can be mistaken as platelets
 Absolute reticulocyte count:  (pseudo-thrombocythemia)
o Reticulocyte = immature blood cells  Limb weakness: lack of muscle strength
o Males: 16-130 *103/uL or *109/L  Petechiae, purpura, and ecchymosis:
o Females: 16-98 *103/uL or *109/L hemorrhages with size <2mm, 0.2-1cm, and >1cm
 Also presented as a % of usually referring to under skin, causing
hematocrit; normal → 0.5–1.5%; discoloration
o Indicator of what is happening in bone  Hematoma: collection of blood that has more or
marrow less clotted outside blood vessel
 Hypochromic vs. normochromic vs.  Bleeding tendency: prolonged and excessive
hyperchromic: refers hemoglobin content in blood bleeding after minor trauma or spontaneously
cell  HIV or hepatitis: risk of contracting less than 1 in
o Normochromic → normal hemoglobin millions from any blood product
content (N = 26-34 pg/cell) o Can only vaccinate
o Hypochromic → low hemoglobin content  D-dimer: degradation product of cross-linked
of an RBC; eg. iron deficiency fibrin, elevated in acute DVT
o Hyperchromic → elevated hemoglobin  Thrombosis: clotting in unbroken blood vessel
content eg. vit b12 deficiency  (usually vein)
 Icterus: jaundice due to build up of bilirubin  Embolus: blood clot, bubble of air, fat from broken
(product of breakdown of hemoglobin) bones, or piece of debris transported by blood
 Splenohepatomegaly: increases in size  Wells score: risk of DVT/PE based on clinical
(hyperplasia) to do extramedullary erythropoiesis if criteria
bone marrow affected; if none indicates bone  Baby exam: initial examination within 24 hours of
marrow normal birth to determine general well-being
 Most elements of blood last hours, days, weeks o General appearance, skin, head, eyes, ears,
 Some lymphocytes have years of lifetime nose, mouth, neck, clavicles, chest,
 Hb electrophoresis: assess type and relative abdomen, hips, genitalia, extremities, back,
amounts of Hb present in RBCs sacral dimple, anus, neurologic
o HbA composed of both alpha and beta-  Fundus: interior surface of eye opposite lens,
globins typically 95%-98% in adults including retina, blood vessels, optic disc, macula,
o HbA2 normally 2-3% fovea, and posterior pole
o HbF normally <2%  Ophthalmoscopy/fundoscopy: dilate pupils,
visualize fundus to look for conditions such as
 Polychromasia: RBCs stained many colours retinal tear or detachment, glaucoma,
o In practice, means abnormally high # of retinoblastoma, macular degeneration, hypertension
reticulocytes due to premature release from  Strabismus: eyes do not properly align when
bone marrow during erythropoiesis looking at an object, mainly extraocular muscle
o Often shades of grayish blue problem
 Target cells/codocytes: excess of cell membrane o If constant, can lose stereo-vision
relative to cell volume  appear as shooting target o Complication: amblyopia (likely due to
o Macrocytic seen in liver disease, microcytic brain’s preference for one eye over the
seen in thalassemia other, visual acuity not corrected by
 Howell-Jolly body: left-over nuclear remnants prescription)
usually removed when blood cells are in spleen  Red reflex: shine light from ophthalmoscope
through normally transparent parts (tear film,
 cornea, aqueous humor, crystalline lens, vitreous o But may be rejected by host or immune
humor)  reflected off ocular fundus  aperture of cells attack host tissue (graft-versus-host
ophthalmoscope and imaged by examiner disease)
o Any factor that impedes (e.g. tumor) will  ABVD:
affect red reflection o Adriamycin (doxorubicin): inhibits
o Unequal refractive errors and strabismus topoisomerase II, causing DNA damage
may also produce asymmetry of red reflex and inducing apoptosis. When combined
 Leukocoria: abnormal red reflex in which yellow, with iron, also free radical DNA oxidative
pale, or white reflection of light in pupil damage
o Caused by strabismus, anisometropia, o Bleomycin: bind to metal ions (e.g. Fe)
retinoblastoma, congenital cataract forming metallobleomycin complexes that
 Bilateral cervical chains: lower, middle, upper generate ROS  breaks in DNA that
internal jugular (deep cervical) chains produce free base propenals, particularly
 Diffuse: spread widely through tissue thymine  cell cycle arrest at G2 phase
 Adenopathy: disease or inflammation involving o DTIC: bioactivated in liver to alkylating
glandular tissue or lymph nodes (add lymph-) agent (methylated DNA strands stick
 Ki-67: protein in cells that increases as they prepare together and makes cell division
to divide into new cells impossible)
o Staining to see what % of tumor cells have o Vinblastine: binds to tubulin  inhibits
Ki-67; higher % = faster cell proliferation formation of microtubules  mitosis
o 45% is indolent vs. aggressive lymphoma arrested at metaphase. ALSO blocks
 Prednisone: glucocorticoid derived from cortisone glutamic acid utilization in nucleic acid and
with anti-inflammatory and antineoplastic effects protein synthesis
o Converted to active prednisolone in liver  R-CHOP:
o Immune: suppresses migration of o Cyclophosphamide: bioactivated in liver to
polymorphonuclear leukocytes, reverses aldophosphamide, alkylating agent 
increased capillary permeability cross-linkages between adjacent DNA
o Antineoplastic: inhibit glucose transport, strands at gnuanine N-7 position 
phosphorylation apoptosis
o Cell surface receptor  nuclear receptor  o Doxorubicin hydrochloride:
inhibit proinflammatory cytokine o Vincristine sulfate: same as vinblastine but
production  reduces volume of more neurotoxic
lymphocytes and stimulates apoptosis in o Prednisone:
sensitive tumor cells o Rituximab: anti-CD20 chimeric antibody
 Allopurinol: urate-lowering medication  cell death by antibody-dependent cell-
o Converted to active oxypurinol in liver mediated cytotoxicity (ADCC),
o Xanthine oxidase inhibitor, enzyme in complement-mediated-cytotoxicity
purine catabolism pathway converting (CDC), and direct effects
hypoxanthine to xanthine to uric acid  CD20 Ca channel and role in
 Rasburicase: recombinant uricase oxidizing uric maturation and activation of B cells
acid to allantoin, more water soluble  kidneys  Absolute neutrophil count (ANC): 1500-8000/mL
o Used as prophylaxis against chemo-related o Mild neutropenia: 1000-1500
hyperuricemia o Moderate: 500-1000
 Malignant ascites/malignant peritoneal effusion: o Severe: <500
fluid in peritoneal cavity contains cancer cells  Globular heart: abnormally smooth arcuate
 Primary refractory: progression of disease during contours of the heart on imaging due either to
induction treatment or a partial or transient response disease of the ventricles or to a false cardiac
(< 60 days) to induction therapy appearance produced by excessive pericardial fluid
 Guarded prognosis: non-favorable outcome  Crush syndrome: characterized by shock and
expected but slight chance of better outcomes kidney failure after a crushing injury to skeletal
 Autologous stem cell transplant: healthy muscle
hematopoietic stem cells from own body frozen   Mucositis: inflammation of mucous membranes
chemo/radiation  thawed and replace diseased or lining digestive tract
damaged bone marrow  Alopecia: partial or complete hair loss. Often from
o Compatibility not an issue chemotherapy which disrupts hair cycle
o But cancer cells might be collected  Hemodynamic stability: abnormal BP causing
 Allogeneic SCT: matched related or unrelated inadequate perfusion of tissues/organs
donor
o Donor stem cells make own immune cells HEMATOPOIESIS
which could help kill cancer (graft-versus-
cancer effect)  Hematopoiesis: process of blood elements
developing
  Red bone marrow: highly vascularized connective  **E = erythrocyte, Meg = megakaryocyte, GM =
tissue between trabeculae of spongy bone tissue granulocyte macrophage
o Mostly in bones of 1) axial skeleton, 2) REGULATION
pectoral and pelvic girdles, 3) proximal  Hemopoietic growth factors: hormones regulate
epiphyses of humerus and femur differentiation and proliferation of progenitor cells
 Yellow bone marrow: largely consists of fat cells  Erythropoietin: increases # of RBC precurosrs
 Pluripotent stem cells/hemocytoblasts: make up o Primarily produced in kidney by peritubular
0.05-0.1% of red bone marrow cells interstitial cells in response to adequacy of
o Derived from mesenchyme, tissue from tissue oxygenation relative to metabolism
which almost all connective tissues develop o Kidney failure  EPO release slows 
o Reproduce themselves, proliferate, inadequate RBC production  decreased
differentiate into cells hematocrit
 >3 months before birth: yolk sac of embryo, later in  Thrombopoietin: stimulates formation of platelets
liver, spleen, thymus, lymph nodes from megakaryocytes
 <3 months before birth: red bone marrow becomes o Primarily produced by liver
primary site for rest of life  Cytokines: glycoproteins that regulate development
o In newborns, all bone marrow red and thus of different blood cell types
active in blood cell production o Produced by red bone marrow cells,
 As age: red bone marrow in medullary cavity of leukocytes, macrophages, fibroblasts,
long bones becomes inactive and yellow bone endothelial cells, etc.
marrow replaces  rate of blood cell formation o 1. Generally act as local hormones
decreases (autocrines or paracrines)
o In some conditions such as severe bleeding, o 2. Stimulate proliferation of progenitor cells
yellow bone marrow can revert to red bone in red bone marrow
marrow by blood-forming stem cells o 3. Regulate cell activities in immunity
migration into yellow  repopulation by  Colony-stimulating factors and interleukin: two
pluripotent stem cells families that stimulate WBC formation
CELL LINES PATHWAY
 Pluripotent stem cells can produce blood cells,  Blood enters bone via nutrient and metaphyseal
reticular cells, mast cells, adipocytes, osteoblasts, arteries  passes into sinuses, enlarged and leaky
chondroblasts (cartilage), muscle cells capillaries that surround red bone marrow cells 
o Reticular cells produce reticular fibers newly formed blood cells enter sinuses and other
o Reticular fibers form stroma that supports vessels  leave via nutrient and periosteal veins
red bone marrow cells  All blood cells except lymphocytes do not divide
 For blood cells: 2 types of stem cells, myeloid stem once leave red bone marrow
cells and lymphoid stem cells
o Myeloid completely develop in marrow RBC LIFE CYCLE
o Lymphoid begin development in red bone
marrow but complete in lymphatic tissues  Erythropoiesis influenced by cytokines and EPO
 1st generation: progenitor cells less capacity for  1. EPO enhances growth and differentiation of two
differentiation and self-renewal erythroid progenitors: burst forming unit (BFU-E)
o Some are colony-forming units (CFU) and CFU-E
 2nd generation: precursor cells/blasts develop into  2. Progenitors differentiate into normblasts of
actual elements over several divisions increasing maturity
 Myeloid stem cells:  3. Most mature, orthochromatic normoblast,
o CFU-E  proerythroblast  eventually extrudes nucleus
nucleus ejected, reticulocyte  erythrocyte  4. Now reticulocyte capable of limited amount of
o CFU-Meg  megakaryoblast  Hb and protein synthesis
megakaryocyte  platelets  5. Reticulocyte retains ribosomal network for
o CFU-GM  eosinophilic myeloblast, approximately 4 days: 3 in bone marrow, 1 in
basophilic myeloblast, neutrophilic peripheral blood
myeloblast, monoblast  6. Mature RBC circulates for 11-120 days
 Eosinophil, basophil, neutrophil,  7. Removed by macrophages in spleen, liver, red
monocyte ( macrophage) bone marrow that detect senescent signals primarily
o Mast cell on RBC membrane
 Lymphoid stem cell:
o T lymphoblast  T lymphocyte HEMOGLOBIN
o B lymphoblast  B lymphocyte ( plasma
cell) CHARACTERISTICS
o NK lymphoblast  NK cell  Globular protein of 4 subunits, each containing
 Granular leukocytes: eosinophil, basophil, heme moiety (iron-containing porphyrin) and
neutrophil polypeptide chain (two has alpha, two has beta, so
 Agranular leukocytes: monocyte, T, B, NK cell normal is α2β2)
 o Iron is in ferrous (Fe2+) state o Pulmonary capillary becomes 100 mmHg
 Oxygen-binding process: o R state favored, high affinity Hb binds O2
o Hb combines rapidly and reversibly with O2  minimize free O2 concentration 
to form oxyhemoglobin maintain partial pressure gradient for
o DeoxyHb has tight or tense (T) structure, diffusion
conformation reduces affinity  requires o Affinity of Hb relatively constant between
higher PO2 to bind oxygen 60-100 mmHg, thus can tolerate
o Oxygen binding releases bonds holding atmosphere that changes alveolar PO2 to 60
globin units  relaxed (R) formation mmHg without compromising O2 carrying
increases affinity  requires lower PO2 to  In peripheral tissues (steep portion),
bind oxygen o Aerobic metabolism consumes O2 
 Positive cooperativity minimize tissue O2 concentration 
o Facilitates loading of O2 in lungs and maintain gradient for perfusion
unloading of O2 at tissues o T state favored, lower affinity of Hb
 Oxygen-binding capacity: facilitates unloading
o Max. amount of O2 that can be bound Hb in SHIFTS
units of mL O2 / g Hb  Right shift = reduced Hb affinity, favors unloading
o Measured at 100% saturation o Increased CO2, decreased pH, increased
o Limits amount of O2 that blood can carry temperature, increased DPG
 % saturation of Hb measured by pulse oximetry: o In exercise muscles produce more CO2
o Dual-wavelength spectrophotometry leading to decreased pH
 Adult hemoglobin (HbA and HbA2): o 2,3-DPG is glycolytic intermediate
o HbA has two alpha, two beta produced in higher amounts in low ATP
o HbA2 has two alpha, two delta and high acid state; binds directly to
 Fetal hemoglobin (FHb): deoxyhemoglobin and favors unloading of
o β chains replaced by γ (α2γ2) remaining O2
o O2 affinity higher than adult Hb because o At higher temperatures, unloading favored
because increased thermal energy favors
2,3-DPG binds less avidly to γ than β previously unfavorable reactions
chains
 Left shift in Hb curve o In placenta, muscles
o After 6 months should be <5% o Adaptation to chronic hypoxemia (living at
high altitude) includes increased synthesis
 Methemoglobin: of 2,3-DPG which facilitates unloading
o Iron is Fe state, does not bind O2
3+
 Left shift = increased Hb affinity, favors loading
 Hemoglobin C (HbC): o Reduced CO2, higher pH, reduced
o Alpha normal and beta Glu6Lys temperature, reduced DPG
 Hemoglobin S (HbS): o Fetal Hg allows fetus to pull O2 from
o Alpha normal and beta Glu6Val maternal circulation
 Hemoglobin E (HbE): o CO poisoning: CO 240-fold greater affinity
o Alpha normal and beta Glu26Lys for Hb and will keep in R state, O2 stays on
HEMOGLOBIN-O2 DISSOCIATION CURVE Hb and total O2 content decreased
o In lungs
LYMPHOCYTES
 Primary lymphoid organs: lymphocyte
development
o Bone marrow and thymus
 Secondary lymphoid organs: immune response
o Lymph nodes, spleen, and lymphoid tissues
of alimentary and respiratory tracts
 Spleen: part of reticuloendothelial system,
sequesters aged RBCs, removes opsonized cells,
site of Ab production
 Lymph nodes: sites of B and T-cell activation
B LYMPHOCYTES
 Plot of percent saturation of Hb vs. PO2  Mature in bone marrow
o PO2 100 mmHg (arterial), all four heme  BCR is membrane-bound immunoglobulin  binds
groups bound to specific antigen  activation of phosphoinositide
o PO2 40 mmHg (mixed venous), ~75% 3-kinase (PI3K)  secondary messenger PIP3 
saturated meaning avg. 3/4 heme bound phosphorylation cascade ---> expression of AKT
o PO2 25 mmHg, 50% saturated = P50 o AKT is anti-apoptotic pro-survival kinase
 In lungs (flat portion),
  B cell then matures into memory B cell (persists in  Subclasses:
secondary lymphoid organs) or plasma cell o IgG (most common): IgG1, IgG2, IgG3, IgG4
T LYMPHOCYTES o IgA: IgA1, IgA2
 Mature in thymus as pass from cortex to medulla  Functions:
o Negative selection: destroy self-reactive o IgG: produced for prolonged period,
o Positive selection: select w/ specificity for involved in delayed hypersensitivity
human leucocyte antigen (HLA) reactions
 TCR is heterodimer of α and β chains o IgA: main Ig in secretions, particularly GI
 Mature helper cells express CD4 o IgM: produced first in response to antigen
 Cytotoxic cells express CD8 o Cells can switch from IgM to IgG, IgA, or
 Mature B and T cells migrate to lymph nodes IgE synthesis
NK CELLS
 CD8+ cells lacking T-cell receptor ANTIGEN-RECEPTOR GENE REARRANGEMENTS
 Typically express CD16, CD56, and CD57
 1) Several surface receptors for HLA molecules  IMMUNOGLOBULIN/B-CELL RECEPTOR
if high HLA expression then inhibitory signal  if  Heavy-chain: chromosome 14 | kappa: 2 | lambda:
low expression or abnormal HLA class I molecules 22
(e.g. viral infection or malignant cell)  Structure both light and heavy:
 2) antibody-dependent cell-mediated cytotoxicity o Heavy-chain gene has variable, diversity,
(NK cell binds to Fc portion of bound antibody) joining, and constant regions (V, D, J, C)
LYMPHOCYTE CIRCULATION o Each V, D, and J region contains n different
 Naïve/virgin B and T cells leaving bone marrow gene segments
and thymus are resting cells  Time course both light and heavy:
 Lymphocytes in peripheral blood  post-capillary o B cell early differentiation: one of V
venules  substance of lymph nodes OR into segments combines with a D segment
spleen or bone marrow  efferent lymphatic which has already combined with a J
stream AND thoracic duct  return to peripheral  C region remains separate
blood o Terminal deoxynucleotidyl transferase
 B cells accumulate in follicles of lymph nodes and (TDT) inserts variable number of new bases
spleen into DNA of D region
 T cells accumulate in 1) paracortical areas of lymph o Transcription: intervening RNA spliced
nodes (perifollicular zones) and 2) periarteriolar from mRNA of C region before joining
sheaths surrounding central arterioles of spleen VDJ
o Throughout: mutation of V region genes in
IMMUNOGLOBULINS germinal centres of secondary lymphoids
T-CELL RECEPTOR
 Proteins produced by B cells, bind to antigen  Genes also have V, D, J, C regions AND TdT
 Five isotypes: IgG, IgA, IgM, IgD, IgF  Recombinases need in B and T cells to join DNA
 Structure: segments after excision of intervening sequences
o Two heavy chains: IgG γ, IgA α, IgM μ,  Mistakes in activity contribute to chromosome
IgD δ, IgE ε translocations of B- or T-cell malignancy
o Two light chains: kappa (κ) or lambda (λ)
o Constant regions: same aa sequence within THE IMMUNE RESPONSE
isotype or subclass
o Variable regions: give Ig specificity  Antigens bind to BCR (clonal selection) OR
dendritic cells and APCs present on HLA class 1
o Constant in Fc fragment but variable and (CD8) or HLA class 2 (helper)  proliferate into
constant in Fab fragment many identical copies (clonal expansion) 
differentiate into 1) effector cells (plasma or
cytotoxic/helper T cells) OR 2) memory cells
 Location: antigen carried into lymph node on
dendritic cells  immune responses commence in
secondary lymphoid organs
 Plasma cells
o Antibody production typically requires help
from antigen-specific T cells
 Th1
o Produce IL-2, TNF-β, IFN-γ
o Boost cell-mediated immunity and
granuloma formation
 Th2
o Produce IL-4 and IL-10
o IgG 1 subunit, IgM 5 subunits
 o Boost humoral immunity and antibody endothelial cells, smooth muscle fibers,
production fibroblasts to repair damaged vessel walls
o Lysosomes, some mitochondria, membrane
LYMPHATIC SYSTEM systems that take up, store calcium &
provide channels for release of granular
Consists of lymph (interstitial fluid), lymphatic contents
vessels, organs with lymphatic tissue, RBM  Short life span, normally 5-9 days
o Lymphatic tissue is reticular connective  Aged and dead removed by fixed macrophages in
tissue with large # of lymphocytes spleen and liver
 Functions  Normally 150,000-400,000 / µL
o Drain excess interstitial fluid: return to REGULATION
blood  Thrombopoietin produced in liver
o Transport dietary lipids: lipids and lipid-  Binds to stem cells to promote differentiation and
soluble vitamins (A, D, E, K) absorbed by circulating platelets for self-degradation
GI o If less platelets, less degradation, stimulates
o Adaptive immunity platelet production
LYMPHATIC CIRCULATION
 Lymphatic capillary between cells, closed at one COAGULATION FACTORS
end
o Larger in diameter and greater permeability  Protein enzymes produced by liver
(proteins, lipids)  Systemic circulation as zymogens (inactive
o Ends of endothelial cells overlap, forming enzyme), activated by proteolytic cleavage
one-way door based on pressure
o Anchoring filaments attach endothelial cells HEMOSTASIS
to surrounding tissues
 Lacteals are specialized capillaries in small Sequence of responses that stop bleeding
intestine o Quick, localized to region of damage, and
o Carry dietary lipids, which makes lymph carefully controlled
creamy white (referred to as chyle)  Three mechanisms: vascular spasm, platelet plug
 Lymphatic vessels drain capillaries formation, and blood clotting (coagulation)
o Resemble small veins but thinner walls and I. VASCULAR SPASM
more valves  Damage to arteries or arterioles, substances from
 Lymph nodes along lymph vessels activated platelets, reflexes initiated by pain
o Organs consist of masses of B and T cells receptors  circularly arranged smooth muscle
contracts immediately  reduces blood loss for
o In skin, lie in subcutaneous tissue and minutes-hours during which other hemostatic
follow same route as veins mechanisms
o In viscera, form plexuses (networks) II. PLATELET PLUG FORMATION
around arteries  1. Platelet adhesion: adhere to parts of damaged
 Lymphatic trunks drain lymphatic vessels vessel (e.g. collagen fibers of connective tissue
o Lumbar, intestinal, bronchomediastinal, underlying endothelium)  activation
subclavian, and jugular trunks  2. Platelet activation: extend many projections to
 Lymphatic ducts drain lymphatic trunks contact and interact with each other and begin to
o Right lymphatic duct rare, consists of liberate vesicles
right jugular, subclavian, and  3. Secretion and platelet release reaction:
bronchomediastinal o ADP and TA2 activate nearby platelets
o Thoracic duct is main lymphatic vessel o Serotonin and TA2 constrict smooth muscle
 Tissues without lymphatic capillaries: avascular  4. Platelet aggregation: ADP increases ‘stickiness’
tissue, portions of spleen, RBM of activated platelets, promoting recruitment
PLATELETS  Platelet plug: prevents blood loss if small hole
o Initially loose and reversible, tight and
 Megakaryocytes splinter into 2000-3000 fragments irreversible when fibrin reinforced
 Platelet: each fragment enclosed by piece of III. BLOOD CLOTTING
plasma membrane  I. Two pathways, extrinsic or intrinsic, lead to
o Each is irregularly disc-shaped, 2-4 μL, formation of prothrombinase, afterwards common
many vesicles but no nucleus pathway
 Granules contain procoagulant chemicals and other:  II. Prothrombinase in presence of Ca makes
o Clotting factors, ADP, ATP, Ca, serotonin, prothrombin  thrombin
enzymes producing thromboxane A2 (PG),  III. Thrombin in presence of Ca soluble fibrinogen
fibrin-stabilizing factor (strengthen clot)  insoluble fibrin
o Platelet-derived growth factor (PDGF): o Thrombin also activates FXIII (fibrin
hormone can cause proliferation of stabilizing factor) from plasma and platelets
which strengthens and stabilizes fibrin
threads into robust clot
 o Thrombin also activates platelets,  Protein C
reinforces aggregation and release of o Thrombin binds to endothelial cell surface
phospholipids receptor thrombomodulin  complex
 IV. Clot retraction: consolidation or tightening of activates protein C
fibrin clot  pulls edges of damaged vessel closer o Inhibit cofactors FVa and FVIIIa AND
 decreases risk of further damage enhances fibrinolysis by inhibiting plasma
o Some serum can escape between fibrin inhibitors of t-PA
threads but formed elements cannot o Protein S potentiates by binding protein C
o Dependent on adequate # of platelets which to platelet surface
release FXIII and other factors FIBRINOLYTIC SYSTEM
 V. Permanent repair: fibroblasts form connective  Clot contains inactive plasminogen  activated to
tissue and new endothelial cells plasmin (fibrinolysin) by substances in tissues and
 Both prothrombin and fibrinogen are plasma blood (e.g. thrombin, aFXII, t-PA from endothelial)
proteins formed by liver  plasmin 1) digests fibrin threads and 2)
 Coagulation: cascade of enzymatic reactions that inactivates substances such as fibrinogen,
culminates in formation of fibrin threads prothrombin, FV, FXII
 Clot: network of insoluble fibrin  T-PA inactivated by plasminogen activator
 Extrinsic pathway: fewer steps and faster (seconds) inhibitor
o Tissue factor (thromboplastin) leaks into  Plasmin inactivated by inhibitors A2AP and A2M
blood from cells outside blood vessels PROSTACYCLIN
o TF is complex mix of lipoproteins and  Prostacyclin: PG produced by endothelial and
phospholipids released from surface of WBCs that oppose thromboxane A2  inhibits
damaged cells platelet adhesion and release
o Requires presence of Ca
 Intrinsic pathway: more complex and slower (mins) VON WILLEBRAND FACTOR
o Activators contained within blood  Glycoprotein multimer produced by endothelial
o Contact with collagen fibers OR platelet cells (stored in Weibel-Palade bodies) and
phospholipids/Ca activates FXII megakaryocytes (stored in alpha-granules)
ROLE OF VITAMIN K  Synthesis:
 Required for synthesis of 2, 7, 9, 10, C, and S o Begins as 2813 aa  first 22 aa is signal
 Normally produced by bacteria in colon peptide (pre-), leads ribosome to rough ER
 Fat-soluble vitamin that can be absorbed through where cleaved  pro-VWF further folding
lining of intestine if lipid absorption normal and modification in ER (glycosylation,
 Slowed absorption of lipids (e.g. inadequate release dimerization)  more glycosylation in
of bile into gut)  vitamin K deficiency Golgi  mature VWF is 2050 aa
HEMOSTATIC CONTROL MECHANISMS  Structure:
 Several times small clots at site of minor roughness o Multimer formed from basic dimer subunits
or developing atherosclerotic plaque (2-80 subunits in the plasma)
BLOOD FLOW AND SEQUESTRATION o D’D3 domains bind to FVIII, P-selectin,
 Localized clot: vWF
o At periphery, blood flow dilutes and o A1 domain binds to GPIb receptor on
disperses activated factors before fibrin platelets, heparin, and collagen
formation o A2 site is cleavage site by ADAMST13
o Fibrin absorbs some thrombin into clot o A3 domain binds to collagen
 Activated factors removed by liver parenchyma o C1-C6 domains bind ADAMTS13, fibrin,
 Particulate matter removed by liver Kupffer cells platelet integrins, insulin-like growth
and other reticuloendothelial cells factors
COAGULATION FACTOR INHIBITORS  Release:
 Tissue factor pathway inhibitor (TFPI) first to o Weibel-Palade: vasopressin V2 induces
act secretion after proteolyzed into small
o Synthesized in endothelial, present in multimers by ADAMTS13
plasma and platelets (thus accumulates o Alpha-granules: arachidonic acid, EN,
locally) collagen induce during platelet aggregation
o Inhibits Xa, VIIa, and TF  More resistant to ADAMTS13
 Antithrombin along with other circulating cleavage
inhibitors o Stress, exercise, desmopressin all stimulate
o AT most potent direct inactivation of  Functions:
thrombin and other serine proteases o Platelet adhesion: exposed VWF bound to
o Unfractionated heparin significantly collagen from endothelial damage binds to
potentiates action on Xa and IIa, whereas platelet GPIb receptor and activates, aids in
LMWH only on Xa primary hemostasis
 Heparin cofactor II inhibits
thrombin in presence
 o FVIII stabilization: VWF-FVIII is Most vulnerable: children <5, women of
nonconvalent complex circulating in reproductive age, and pregnant women
plasma, aids in intrinsic pathway ETIOLOGY AND PATHOPHYSIOLOGY
 Increases FVIII half-life  Kinetic approach: categorize by mechanisms
significantly via structure responsible for fall in hemoglobin concentration
stabilization, protection against  Morphologic approach: categorize by alterations in
proteolysis and removal from indices and reticulocyte response
circulation, change cellular  Kinetic: anemia can be caused independently by 1)
interactions decreased RBC production, 2) increased RBC
o Bigger multimers are more active, partly destruction, or 3) blood loss
because more binding sites  1) decreased RBC production
 Clearance: o A) Reduced effective production of RBCs
o Main contributor is macrophage uptake,  Lack of nutrients (e.g. vit B12 and
which is mediated by several receptors, iron): dietary lack, malabsorption
including CLEC4M and LRP1  Bone marrow disorders leading to
reduced # RBC precurosrs
COAGULATION TESTS  Bone marrow suppression such as
drugs, chemotherapy, radiation
 Typically citrated plasma derived from whole blood  Low levels of trophic hormones,
o Citrate removes Ca ions essential for chronic renal failure (EPO), thyroid
coagul. hormone (hypothyroidism),
 Prothrombin time (PT): add thromboplastin androgens (hypogonadism)
reagent containing TF, calcium, and phospholipids  Reduced availability of iron:
 extrinsic inflammation causes decreased
 INR: standardized PT result for patients taking absorption from GI tract, decreased
warfarin to assess how well it is inhibiting release from macrophages, relative
coagulation reduction in EPO
o <1.1 is normal o B) Destruction of RBC precursors within
 Activated partial thromboplastin time (aPTT): bone marrow (ineffective erythropoiesis) 
add (-) charged surface sch as silica as well as erythroid precursors not maturing and
phospholipid extract free of tissue factor  dying
intrinsic pathway  Megaloblastic anemia, alpha and
 1:1 mixing study: mix equal volumes of patient beta thalassemia, myelodysplastic
citrated plasma with normal pooled plasma syndromes, sideroblastic anemias,
o Repeat PT/aPTT will become normal if congenital dyserythropoietic
clotting factor deficiency, but uncorrected anemia in children
if excess inhibitor present (e.g. auto-ab to  2) Increased destruction of circulating RBCs
FVIII and APS) o A) Extravascular hemolysis
 Thrombin time (TT): add exogenous thrombin to o Inherited hemolytic anemias (e.g. sickle
pre-warmed plasma  fibrin formation cell disease, PK deficiency), acquired
 Bleeding time (BT): standardized incision (IVY in hemolytic anemias (e.g. malaria,
volar forearm, Duke in finger or earlobe) thrombotic thrombocytopenic purpura),
 PT: 10.7-15.3s | INR: <1.1 for normal, 2-3 for increased destruction of RBCs by
warfarin users | aPTT: 26.8-41.2s | TT: 12.8-21.7s | hypersplenism
Duke: <3 mins; IVY: <8 mins o B) Intravascular hemolysis
o Microangiopathic hemolytic anemia,
ANEMIA clostridial sepsis, paroxysmal nocturnal or
cold hemoglobinuria, cold agglutinin
DEFINITION disease
 Reduction in one or more of major RBC  3) Blood loss
measurements obtained as part of CBC: o Most common cause
hemoglobin, hematocrit, RBC count o Obvious bleeding (e.g. trauma,melena),
o Usually all components decrease in parallel, occult bleeding (e.g. slow bleeding ulcer or
but RBC count may be increased in cases of carcinoma), induced bleeding (e.g.
extreme microcytosis hemodialysis losses, excess donation)
o Normal ranges may not apply to: athletes,  Morphologic : classified based on mean corpuscular
living at high altitude, smokers, African- volume into microcytic (MCV<80 fl), normocytic
Americans, chronic disease, older adults (80-100 fl), macrocytic (>100 fl)
 Not a disease but a sign of disease o Microcytic: insufficient hemoglobin
EPIDEMIOLOGY production
 In 2010, estimated 1/3 of world’s population has o Normocytic: decreased blood volume
anemia and/or erythropoiesis
o Macrocytic: insufficient nucleus maturation
relative to cytoplasm expansion due to
  Defective DNA synthesis  M: 13.6-16.9 g/dL
 Defective DNA repair  F: 11.9-14.8 g/dL
CLINICAL COURSE o Hematocrit, packed spun volume of blood
 Dependent on degree of anemia and rate of that consists of intact RBCs
evolution  M: 40-50%
 Symptoms less likely if evolves slowly because  F: 35-43%
multiple homeostatic factors compensate for o RBC count, # of RBCs in V of whole
reduced oxygen carrying capacity to maintain blood
oxygen delivery:  M: 4.2-5.7 *106/uL
o Increased HR, SV, and decreased TPR by  F: 3.8-5.9 *106/uL
decreasing blood viscosity and cross- o WBC count
sectional area of vascular beds (overall CO)  3.8-10.4 *103/uL in M and F
o Increased plasma volume, helps decrease o WBC differential
viscosity o Platelet count
o Increased 2,3-DPG, shifts oxy-hemoglobin  M: 152-325 *103/uL
dissociation curve to right and facilitates  M: 153-361 *103/uL
oxygen unloading o Reticulocyte count
 Decreased oxygen delivery:  M: 16-130 *103/uL or *109/L
o Manifest below 5-10 g/dL hemoglobin at  F: 16-98 *103/uL or *109/L
rest or at higher concentrations in context o Serum iron (bound to transferrin), serum
of increased O2 demand or heart disease iron capacity (transferrin saturation), serum
o Primary: dyspnea, fatigue, bounding pulses, ferritin (measure of iron storage)
palpitations, roaring pulsatile sound in ears  In iron-deficient, serum iron and
o Severe: lethargy, confusion, congestive HF, ferritin low, iron capacity high
angina, arrhythmia, and/or MI (liver producing lots of transferrin)
 Hypovolemia:  2. RBC indices
o In patients with acute and marked bleeding, o Mean corpuscular volume (MCV) is avg.
intracellular and extracellular V depletion size of patients’ RBCs
o Hemolysis: blood but not plasma volume o Mean corpuscular hemoglobin (MCH) is
affected | chronic blood loss: compensatory avg. hemoglobin content in RBC
fluid compartment exchange and RAAS o Mean corpuscular hemoglobin
o Early: easy fatigability, lassitude, muscle concentration (MCHC) is avg. Hb
cramps concentration per RBC
o Late: postural dizziness, lethargy, syncope, o Red cell distribution width (RDW) is
persistent hypotension, shock, death measure of variation in RBC size
 Aplastic anemia: thrombocytopenia and petechiae  3. Corrected reticulocyte count = % reticulocytes *
(minor bleeding under skin that is unclotted) patient’s HCT/normal HCT
EVALUATION o Normal HCT = 45% men, 40% women
 History: o If >2, suggests hyperproliferative
o Constitutional symptoms might be (hemolysis or acute blood loss)
indicative of infection or malignancy o If <2, suggests hypoproliferative
o Symptoms of conditions that cause anemia  4. If hyperproliferative:
o Recent (almost always acquired disorder) o A. Confirm hemolysis by elevated LDH,
vs. lifelong (likely to be inherited) elevated indirect bilirubin, decreased or low
o Use of medications, specifically alcohol, haptoglobin
aspirin, NSAIDs o B. Determine if extravascular or
o Past history of blood transfusions, liver intravascular
disease, occupational exposures  Extra: spherocytes present, urine
o Nutritional status hemosiderin and hemoglobin (-)
 Physical exam:  Intra: urine hemosiderin and
o Systolic ejection murmur due to hemoglobin elevated
compensatory SV and plasma volume o C. Examine peripheral blood smear
o Find signs of multisystem involvement and o D. If spherocytes +, check DAT
assess severity  5. If hypoproliferative, use MCV to classify into
o Presence or absence of tachycardia, microcytic, normocytic, macrocytic
dyspnea, fever, or postural hypotension  6. Other
o Pallor and jaundice not reliable indicators o Colonoscopy for lower GI bleed
as once thought o Imaging for malignancy or internal
o Other: lymphadenopathy, hemorrhage
hepatosplenomegaly, bone tenderness (e.g.
infiltrative disease such as leukemia, MM)
 1. Complete blood count
o Hemoglobin concentration
 o BM generates B cells and T cells

Secondary lymphoid tissue:
o Lymph nodes, spleen, Waldeyer’s ring,
lymphoid tissue in GI and respiratory
o B cells mainly localize to follicles, T cells
localize to interfollicular areas
B CELLS
 Humoral immunity (antibodies)
 Mature B cells migrate from BM to lymph nodes
and lymphatic tissue, where encounter pathogens
 BCR-antigen complex endocytosed and processed
 presented on MHC II  helper T become
activated, releasing cytokines that induce B cell to
replicate  differentiate into memory (quick
anamnestic ab response to re-exposure) AND
plasma (effector cells produce antibodies)
T CELLS
 Cell-mediated immunity
 TCR recognizes antigens bound to:
o Class I MHCs on nucleated cells and
TREATMENT platelets (i.e. all but RBCs), identify ‘self’
 Depends on underlying cause o Class II MHCs expressed on professional
 1) Blood loss: treat with IV fluids, crossmatched APCs (macrophages, dendritic, B cells)
RBCs and oxygen  Cytotoxic, through perforin and proteases
o Hemoglobin >7g/dL in majority, >8g/dL release:
may be required in CVD o Kill target cells by apoptosis or cell lysis
 2) Nutritional deficiencies: oral/IV iron, B12, folate  Helper, through cytokines:
o Ferrous fumarate good to go with orange o Activate macrophages, stimulate Ab
juice, low pH + vit. C helps absorption production, tissue inflammation
o Oral most common method for iron  Also memory T cells
depletion; IV may be beneficial when MONOCYTE
require rapid increase in levels  After migrating into tissue, differentiate into
 3) Defects in bone marrow and stem cells: may macrophages, dendritic cells, or osteoclasts
require bone marrow transplantation  Macrophage: phagocytosis and stimulate response
 4) Chronic disease: renal failure responds to EPO, of other immune cells
other requires specific treatment  Dendritic cell: present in epithelial tissue 
 5) Increased RBC destruction: migrates to lymph nodes upon activation 
o Remove medication, blood transfusion in presents antigens on surface, bridging to adaptive
hemoglobinopathies e.g. sickle, immunity
splenectomy if necessary NEUTROPHIL
 50-65% all leukocytes in blood
IMMUNE CELLS  Migration (chemotaxis) to sites of inflammation
(first responder)  identification and phagocytosis
PRODUCTION of extracellular infectious agents AND recruitment
 Hematopoietic stem cell  myeloid stem cell and  Against bacteria, fungi
lymphoid stem cell EOSINOPHIL
 Lymphoid stem cell  NK cell or small  Chemotaxis to site of inflammation (esp. histamine)
lymphocyte  release of Ig (esp. IgE), proteolytic enzymes,
o Small lymphocyte  T cell or B cell cytokines
 Myeloid stem cell  megakaryocytes, erythrocyte,  Against bacteria and parasites
mast cell, myeloblast BASOPHIL
o Myeloblast  basophil, eosinophil,  Migrates into tissue (not found in healthy like mast)
neutrophil, monocyte  release of histamine, heparin AND production of
o Monocyte  macrophage, dendritic leukotrienes  inflammation and allergic reaction
 Agranulocytes: lymphocytes, monocytes MAST CELL
 Granulocytes: neutrophils, eosinophils, basophils,  In interstitial connective tissue  IgE antibodies
mast cells, NK cells bound to Fc receptors (sensitization) crosslinked by
o Make up largest portion of leukocytes allergen (reaction)  degranulates  release of
o Usually account for histamine and heparin  inflammation and allergic
leukocytosis/leukopenia  Both basophils and mast cells  recruits
LYMPH SYSTEM macrophages and neutrophils, wound healing
 Primary lymphoid tissue: NK CELL
o Bone marrow and thymus
  Detection and destruction of cells that do not CKD or cirrhosis common, bronze skin,
express MHC-I receptors (viruses, tumor cells) arrhythmias, hepatosplenomegaly,
 Kill via induction of apoptosis (granzymes, endocrine depending on location (DM,
perforin) OR ADCC (binding of CD16) hypothyroidism or hypoparathyroidism,
arthropathy, early-onset Parkinson’s disease
THALASSEMIA due to nigra)
 Alpha:
DEFINITION o One-two allele deletion is mostly silent
 Heterogeneous group that result from decreased o Four allele deletion most severe form  no
synthesis of alpha or beta chains of hemoglobin alpha globins produced  incompatible
(Hb) with life AND causes hydrops fetalis
 Clinical manifestations range from mild anemia to  Beta:
lethal hemolytic anemia based on degree of o Minor is asymptomatic or mild symptoms
deficiency o Major  no beta globins produced 
ETIOLOGY severe anemia requiring life-long blood
 All forms are autosomal recessive transfusions
 Alpha thalassemia:  Healthy babies but starts
o Deletion of any 4 alleles of alpha globin manifesting after 6 months, when
gene FHb replaced by adult Hb
o Severity depends on # of deleted: minima, o Coinherited alpha thalassemia: less
minor, intermedia, maxima severe alpha-beta chain imbalance and
 Beta: milder clinical course
o Point mutations in beta-globin gene o Coinherited sickle cell trait:
o Three categories: manifestations of sickle cell disease, but
 Beta+ thalassemia/heterozygous: major Hb (>60%) is HbS rather than HbA
beta thalassemia minor EVALUATION
 Beta0 thalassemia/homozygous:  CBC
beta thalassemia major o Low Hb, low MCV
 Beta thalassemia intermedia: o Mentzer index (MCV / RBC count) < 13
between minor and major suggests thalassemia, >13 suggests iron
PATHOPHYSIOLOGY deficiency
 Lack of one or both alpha and beta chains  RBCs o Iron studies rule out iron deficiency
do not form correctly and cannot carry sufficient  Peripheral blood smear:
oxygen  anemia in early childhood for lifetime o Low MCV, hypochromic, variation in size
 Unpaired alpha (in beta) and beta (in alpha) globin (anisocytosis) and shape (poikilocytosis),
chains  aggregate and precipitate  damage RBC increased % reticulocytes, target cells,
membranes  hemolysis Heinz bodies
o Compensation: premature death of  Hb electrophoresis
erythroid precursors  extramedullary o Beta disturbs balance of beta and alpha
expansion of hematopoiesis formation  larger percentages HbF and
 In beta, compensate with FHb HbA2 and absent or very low HbA
 In alpha, cannot compensate with o HbS in sickle cell disease
as much FHb TREATMENT
EPIDEMIOLOGY  Mild thalassemia (Hb 6-10g/dL)
 Alpha prevalent in Asian and African populations o Little treatment needed
 Beta prevalent in Mediterranean, although relatively o Blood transfusion after surgery, following
common in Southeast Asia and Africa childbirth, manage complications
CLINICAL PRESENTATION  Moderate-severe (Hb < 6g/dL)
 Depends on severity: o Frequent blood transfusions to 9-10g/dL Hb
o Skin: pallor and fatigue from anemia, o Splenectomy to reduce # of required
jaundice from hyperbilirubinemia due to transfusions
hemolysis o Cholecystectomy for cholelithiasis
o Abdominal: precipitation of bilirubin gall o Curative: bone marrow transplant, gene
stones from hyperbilirubinemia, therapy or genome editing
hepatosplenomegaly from extramedullary  To help with iron excretion due to chronic
expansion, splenic infarcts or autophagy transfusions, tea (reduces iron gut absorption), low
from chronic hemolysis quantities vitamin C (increase gut iron excretion),
o Musculoskeletal: deformed facial and iron chelation therapy
other skeletal bones, chipmunk face from
extramedullary expansion SICKLE CELL ANEMIA
o Slow growth rate
o Iron deposition from multiple DEFINITION
transfusions causes hemochromatosis:
  Sickle cell disease is group of chronic hemolytic o Splenic sequestration: sickle-shaped cells
anemias characterized by at least one HbS allele entangled in splenic pulp, severe anemia
(Glu6Val) in HBB gene (normally HbA/HbA) with rapidly enlarging spleen
ETIOLOGY o Stroke, retinal hemorrhages with visual loss
 Autosomal recessive  Aplastic crises:
 Point mutation in beta globin chain o Presence of parovirus B19 challenges
o Single base from A to T in codon at stressed bone marrow  fails to generate
position 6 changes glutamic acid to valine appropriate number of RBCs  severe
 Heterozygous for HbS and normal allele  sickle anemia
cell trait (no anemia)  Other:
 Heterozygous for HbS and pathogenic allele o Hemolysis increases pigment load 
(intermediate) pigmented stone formation in gallbladder
 Homozygous for HbS allele, sickle cell anemia o Isothenuria: kidneys lose ability to
(most severe) concentrate urine appropriately
 Vaso-occlusive crises: hypoxia, cold weather, o Avascular necrosis of the long bones,
infection, acidosis, dehydration, alcohol, stress, particularly the head of the femur
pregnancy  Compensation: same as anemia, overproduce FHb,
 Aplastic crises: folic acid deficiency, parvovirus symptoms and signs of extramedullary expansion
B19 infection, ingestion of toxins like EVALUATION
phenylbutazone  CBC with peripheral blood smear
PATHOPHYSIOLOGY o Reduced Hb and RBC, variable MCV,
 Hemoglobin (Hb) is normally soluble and does not increased reticulocyte and leukocyte,
bind to each other/precipitate in presence of reduced ESR
hypoxia, low pH, dehydration o Platelets could be increased because
 Excess HbS polymerizes and then aggregates when endothelial damage
deoxygenated o Presence of sickle cells in periphery
 Histopathology: o Howell-Jolly bodies indicate functional
o Sickle or holly leaf shape of RBC conforms asplenia
to shape of polymerized Hb  Confirmation with Hb electrophoresis
o Cell membrane thick and usually damaged o If concentration of sickle cell Hb > 90% of
o Some RBCs may have MCV>100 fL total Hb, and FHb comprises rest
because deficiency of folic acid secondary o If ~45%, indicates sickle cell trait rather
to enhanced hematopoiesis than the disease
 Time course:  Screening:
o Initially reversible, reverses when o Prenatal screening
oxygenated  Chronic villus sampling (10-12
o Multiple cycles of sickling  damage to weeks) or amniocentesis (14-16
RBC cell membranes  prone to weeks gestation)
phagocytosis by macrophages  o Newborn screening with Hb electrophoresis
destruction and reduction of RBC count  Isothenuria: urine analysis to rule out UTI as cause
 RBCs are also fragile from cell of hematuria
membrane damage, can lyse due to  Emergency (normally vaso-occlusive): instant
physical forces in circulation sickling test, but cannot differentiate
o Sickle cells have strong adherence to hetero/homozygous
endothelium + leukocytes  endothelial  Respiratory distress: ABGs, CXR
activation  hypercoagulability (increased  Osteomyelitis and avascular necrosis: MRI
platelet produced)  vaso-occlusive TREATMENT
EPIDEMIOLOGY  Seven major goals:
 Prevalent in African (most common), Middle o Management of vaso-occlusive crises,
Eastern, Indian, Mediterranean descent chronic anemia, and chronic pain;
 Common in areas where malaria prevalent prevention of infections, stroke, and
CLINICAL PRESENTATION complications; dx and tx of pulmonary
 Manifests usually after 6 months of age, when FHb hypertension
begins falling  Pharmacologic:
o FHb keeps sickle cell Hb in soluble form o Hydroxyurea is antimetabolite that
 Anemia symptoms and signs: increases FHb levels, keeping Hb in soluble
o Palpitations, fatigue, pallor, tachycardia form and preventing most complications
 Most commonly presents as vaso-occlusive crises: o Vaccines, antibiotics (2 months to 5 years),
o Excruciating pain in abdomen, thorax, folic acid supplementation
joints, long bones, and digits  Curative:
o Acute chest syndrome: chest pain, cough, o Bone marrow transplant
leukocytosis, tachypnea o Blood transfusion, particularly aplastic
crises
LYMPHOMA  Long-term: cardiomyopathy, infertility, secondary
malignancy
DEFINITION HODGKIN LYMPHOMA
 Heterogeneous group of malignancies arising from PATHOGENESIS
malignant clonal proliferation of:  RS cells is thought to be of B-lymphoid lineage
o Hodgkin lymphoma: lymphoid cells with from ‘crippled’ Ig gene after multiple mutations
Reed-Sternberg cells o RS cells and associated abnormal
o Non-HL: lymphoid cells of progenitor or mononuclear cells are neoplastic
mature B, T, or NK cells  Associated with Epstein-Barr virus in up to 50%
EPIDEMIOLOGY CLINICAL COURSE
 Represents ~5% of all malignancies  Starts at single site in lymph node  spreads to
 10% Hodgkin lymphoma, 90% non-Hodgkin adjacent nodes  spreads through lymphatic
 Median age of diagnosis is 63 system
ETIOLOGY  Asymptomatic lymphadenopathy (70%)
 Infectious organisms: H. pylori, chlamydia psittaci, o Non-tender, rubbery, enlarged
persistent infection with Epstein Barr virus and o Majority supradiaphragmatic
cytomegalovirus  Spread: splenomegaly (50%) +- hepatomegaly
 Autoimmune diseases: inflammatory bowel disease,  Systemic symptoms:
rheumatoid arthritis, Sjogren’s syndrome o B symptoms: fever, night sweats, weight
 Immunodeficiency: HIV infection, genetic (severe loss
combined OR common variable immunodeficiency)  Non-specific:
 Drugs: TNF-α inhibitors in T cell lymphoma, o Alcohol-induced pain in affected nodes and
chronic immunosuppression in post-transplant nephrotic syndrome
patients INVESTIGATIONS
 Occupational exposure: herbicides, pesticides  CBC:
PATHOPHYSIOLOGY o Anemia, eosinophilia, lymphopenia,
 Complex interaction between infectious, platelets normal or increased early disease
inflammatory, and toxic factors to induce and decreased in advanced disease
lymphomagenesis  Biochemistry:
 Immunosuppressive therapies prevent innate from o HIV, HepB, HepC serologies
destroying malignant cells and warding off o Liver enzymes and/or LFTs (liver
infections that predispose to cancer involved?)
 Tumor compresses various parts of body o ALP, Ca2+ (bone involved?)
 Immunosuppression due to less or dysfunctional o Renal function tests (prior to initiating
lymphocytes chemotherapy)
COMPLICATIONS OF LYMPHOMA o ESR, LDH (monitor disease progression)
 Organ compromise by location of mass/lymph  Imaging:
node: o CXR, CT chest, CT abdomen/pelvis (liver
o Spinal cord compression, airway and spleen involvement), PET scans
obstruction, SVCS, bowel obstruction, o Cardiac function with MUGA scan or echo
hydronephrosis (treatment can be cardiotoxic for
 High grade tumors can result in tumor lysis individuals at high risk of CVD)
syndrome  Confirmatory lymph node biopsy:
o Large amounts of P, K, nucleic acids o Excisional biopsy is gold standard because
o Hyperkalemia  Vfib and asystole assess whole lymph architecture
o Hyperphosphatemia with calcium  Bone marrow biopsy:
phosphate deposition in renal tubules  o Assess marrow infiltration
AKI o If B-symptoms, PET positive marrow,
o Catabolism of nucleic acids to uric acids  cytopenia
hyperuricemia  uric acid in renal tubules TREATMENT
and subsequent renal failure  Stage I-II: chemotherapy (ABVD) followed by
 TLS develops spontaneously or with cytotoxic tx involved field or involved site radiotherapy (XRT)
 High-grade lymphoma should receive prophylaxis  Stage III-IV: chemotherapy (ABVD) with XRT for
with IV hydration and/or hypouricemic agents bulky disease
o Allopurinol blocks xanthine oxidase,  Monitor response to all treatment with repeat
blocking metabolism of hypoxanthine and PET/CT and bloodwork
xanthine to uric acid  Relapse or resistance: high dose chemotherapy and
o Rasburicase catalyzes oxidation of uric autologous stem cell transplant
acid to allantoin, water-soluble COMPLICATIONS OF TREATMENT
COMPLICATIONS OF CHEMOTHERAPY  Cardiac disease due to XRT or adriamycin
 Acute: cytopenias, infection, alopecia,  Hypothyroidism due to XRT
cardiomyopathy, neuropathy, nausea/vomiting,  Interstitial pneumonitis due to bleomycin
mucositis, diarrhea, constipation
  Secondary malignancy in irradiated field COMPLICATIONS
 Infertility  Hypersplenism, infection, autoimmune hemolytic
NON-HODGKIN LYMPHOMA anemia, vascular obstruction, bowel perforation,
WHO/REAL CLASSIFICATION tumor lysis syndrome (esp. in very aggressive)
 Originate from B (85%) or T or NK (15%)
 B-cell NHL: THROMBOCYTOPENIA
o Indolent (35-40%): follicular, small
lymphocytic, mantle cell lymphomas DEFINITION
o Aggressive (50%): diffuse large B-cell  Platelet count < 150,000 / µL
o Highly aggressive (5%): Burkitt’s ETIOLOGY
lymphoma  Primary immune thrombocytopenia, drug-induced
 T-cell NHL: immune, and autoimmune disorders (e.g. SLE)
o Mycosis fungoides (skin), TCL-NOS, and  Drug-induced non-immune
anaplastic large cell lymphoma  Pregnancy, infections, hypersplenism
CLINICAL COURSE  Chronic alcohol abuse, nutrient deficiencies (folate,
 Usually presents as widespread, with exception of vitamin B12, copper)
aggressive lymphoma  Non-common: myelodysplasia, cancer with marrow
 Painless superficial lymphadenopathy, usually > 1 suppression, thrombotic microangiopathy, aplastic
lymph node region anemia, inherited (e.g. VWD type 2)
 Constitutional symptoms not as common as HL EPIDEMIOLOGY
 Bone marrow involved: anemia +- neutropenia +-  Normal platelet counts vary widely by age, sex,
thrombocytopenia ethnicity
 Retroperitoneal and mesenteric involved:  Woman, young, non-Hispanic blacks have slightly
abdominal signs +- hepatosplenomegaly higher platelet counts
 Oropharyngeal involved: 5-10% sore throat and PATHOPHYSIOLOGY
obstructive apnea  Decreased platelet production:
 Extranodal involved: commonly GI tract, also tests, o Aplastic anemia, bone marrow suppression
bone, and kidney from drugs, chronic alcohol abuse,
INVESTIGATIONS inherited, viral infection, nutrient
 CBC: deficiencies, myelodysplastic syndrome,
o Normocytic normochromic anemia inherited
o Thrombocytopenia and neutropenia late  Increased platelet destruction:
 Biochemistries: o Anti-platelet abs bind to platelets and
o HIV, HepB, HepC serologies megakaryocytes (in immune), increased
o LFTs (liver involved?) platelet consumption within thrombi (in
o Increase in uric acid and LDH DIC and thrombotic microangiopathy)
 Flow cytometry:  Dilutional thrombocytopenia:
o Assessing peripheral blood lymphocytosis o Massive fluid resuscitation or transfusion
is valuable for low-grade NHL  Redistribution of platelets:
 Imaging and biopsies same as HL o Normally 1/3 platelet mass in spleen
TREATMENT o In splenomegaly and splenic congestion
 PET scan essential in identifying disease response (e.g. cirrhosis), increased platelet mass in
 Localized disease: spleen
CLINICAL PRESENTATION
o Radiotherapy to primary site and adjacent
nodal areas + adjuvant chemotherapy  >50,000 / µL rarely any symptoms
o Splenectomy in splenic marginal zone  Surgical bleeding when <50,000 / µL
lymphoma  Spontaneous bleeding when <10,000-20,000 / µL
 Indolent: symptom management INVESTIGATION
o Careful monitoring with PET  History:
o Radiation therapy for localized disease o Prior platelet count, infection, diet history,
medication list
o Bendamustine, rituximab, CHOP
 Physical exam:
 Aggressive: curative
o Petechiae, nonpalpable purpura, superficial
o CHOP + R if B-cell lymphoma ecchymosis, mucous membrane bleeding
o Radiation for localized/bulky disease (gingival bleeding, epistaxis)
o Relapse or resistant: high dose o Might have hepatomegaly and
chemotherapy, autologous SCT splenomegaly (e.g. lymphoma, CKD)
 Highly aggressive: curative o Might have enlarged lymph nodes (e.g.
o Burkitt: short bursts of intensive infections, autoimmune disorders)
chemotherapy “CODOX-M” also often  CBC:
used +- IVAC with rituximab o Anemia in infections, DIC, thrombotic
 Monitor response to all treatment with repeat microangiopathy, autoimmune
PET/CT and bloodwork
 o Leukocytosis in chronic inflammatory,  ET: JAK2 is non-receptor cytoplasmic tyrosine
infection, malignancy kinase
o Pancytopenia in myelodysplastic o Point mutation V617F
 Platelet function tests: o Leads to increased activation of
o Gold standard is platelet intracellular signaling pathways associated
aggregometry/lumiaggregometry with receptors of hematopoietic cytokines:
o Closure time, viscoelastometry, flow erythropoietin, thrombopoietin, and
cytometry, bleeding time controversial granulocyte colony-stimulating factor
 Peripheral blood smear:  CALR due to insertions or deletions causing
o WBC and RBC morphology reading frame shift which forms novel C terminus
o Schistocytes: thrombotic microangiopathy  MPL is point mutation
o Teardrop cells, nucleated RBCs,  Secondary: pathophysiology differs
leucoerythroblastic: marrow infiltration o Overproduction of thrombopoietin,
o Immature WBCs: leukemia interleukin-6, other cytokines or
o Hypersegmented neutrophils: nutritional catecholamines in inflammatory, infectious,
deficiencies neoplastic, or stress
 Bone marrow biopsy: o Megakaryocyte proliferation in iron-
o Indicated when cause unclear, or deficiency anemia
hematologic disorder suspected o Decreased platelet sequestration in asplenia
o Normal or increased megakaryocytes =  For bleeding complications:
platelet destruction; decrease = production o Especially in extreme (>1,000,000 / µL)
 In patients with thrombosis, consider heparin- o VWF bound to FVIII which protects from
induced thrombocytopenia (platelet factor 4 degradation
antibodies), APS (antiphospholipid abs), DIC and o High platelets  vWF binds to platelet
PNH (PT, aPTT, fibrinogen, LDH) receptor GPIb  vWF degradation via
TREATMENT ADAMTS13
 Asymptomatic: CLINICAL PRESENTATION
o Routine monitoring  ET: most commonly migraines, headache, dizziness
 Symptomatic  Various levels of thrombosis
o If bleeding/severe: platelet transfusion o Macrovascular: hepatic vein thrombosis
o Treat underlying cause hallmark, transient ischemic attack
 Primary immune: glucocorticoids o Microvascular: erythromelalgia (due to
and IV immune globulins to inhibit transient ischemia and vasodilation), easy
auto-ab production bruising
 Withhold causative drugs  Secondary: usually benign with symptoms due to
underlying disorder
THROMBOCYTHEMIA o Thrombotic events (e.g. MI, mesenteric
vein thrombosis, PE) in extreme
DEFINITION thrombocytosis
 WHO: platelets > 450,000 / µL with presence of INVESTIGATION
JAK2, CALR, or MPL mutation  History:
 Essential thrombocythemia (ET) is one of o Trauma or surgery, history of splenectomy
myeloproliferative neoplasms o Findings of infection/inflammation, meds,
o Polycythemia vera, primary myelofibrosis, systemic conditions suggesting malignancy
and essential polycythemia  Physical:
 Secondary (reactive) thrombocytosis o Splenomegaly, milder than other
ETIOLOGY myeloproliferative neoplasms
 Essential: overproduction of hematopoietic cells o Lymphadenopathy
due to somatic mutation of JAK2 (1/2), CALR, or  CBC:
MPL o Increased platelet count
o May be inherited or acquired (can be at any  Differentiate the cause:
time in life) o Rule out other causes, including reactive
o Driver mutations in development of (would show following):
myeloproliferative neoplasm  Acute phase reactants high CRP
 Secondary: more of a laboratory anomaly and ESR (inflammation)
o Transient (e.g. acute blood loss, infection,  Iron studies low iron (anemia)
exercise) or sustained (e.g. iron deficiency,  High ANA or RF (autoimmune)
asplenia, cancer, chronic inflammatory)  If cause is still unclear:
EPIDEMIOLOGY o Bone marrow biopsy
 ET is most common myeloproliferative neoplasm o ET: increased proliferation of
 Mostly in females and presenting between 50-60 megakaryocytic cell lines AND enlarged
 Secondary: 80-90% of thrombocytosis megakaryocytes w/ matured cytoplasm and
PATHOPHYSIOLOGY multilobulated nuclei
 o Genetic testing o2M: multimers present
TREATMENT o2N: significant decrease in VIII:C, can be
 ET: goal to prevent vascular complications such as confused with hemophilia A
thrombotic and hemorrhagic events  Acquired:
 Low-risk: o Non-specific antibodies bind to VWF
o Treat with aspirin unless abnormal vWF forming immune complex  increased
and/or bleeding clearance by reticular endothelial system
 High-risk: o Absorption of VWF on surface of
o Antiplatelet (aspirin) and cytoreductive tx malignant cells e.g. multiple myeloma/solid
o Hydroxyurea first line cytoreductive: tumors
reduce # of platelets and # of leukocytes o Proteolysis of VWF multimers e.g. MPN
o Anagrelide second line: inhibit o High shear stress  open conformation 
differentiation of megakaryocytes and more likely to be cleaved by ADAMTS13
platelet aggregation, but increases rate of CLINICAL COURSE
hemorrhage when combined with aspirin  Not all patients have clinically significant bleeding:
 Secondary: treat underlying condition o Recurrent and excessive bruising
o Anti-platelets usually not indicated unless o Prolonged bleeding from mucosal surfaces
>1,000,000 / µL and/or high risk of (epistaxis, dental extractions, menstruation)
developing complications and skin (petechiae, purpura, ecchymosis)
o Plateletpheresis if evidence of thrombosis o Prolonged bleeding from minor skin trauma
o Hematoma
POLYCYTHEMIA VERA  Qualitative defect:
o May present predominantly with bleeding
 To help differentiate primary and secondary causes, in soft tissues, joints, and hematuria rather
EPO will be appropriate suppressed in primary but than mucocutaneous bleeding
normal or high in secondary  Inherited:
o VWF gene highly polymorphic  large
VON WILLEBRAND DISEASE variation in baseline VWF and spectrum of
disease severity
DEFINITION INVESTIGATION
 VWF qualitative or quantitative <30% or <30  CBC:
IU/dL with personal or family history of bleeding o Platelets normal
tendency  Coagulation tests:
 30-50 is considered low VWF o PT should be normal
ETIOLOGY o aPTT may be prolonged as increased FVIII
 Inherited: degradation in VWD
o Type 1: autosomal dominant w/ partial  VWF assays:
quantitative deficiency o VWF Ag and VWF Act through ristocetin
o Type 2: autosomal dominant w/ qualitative cofactor and collagen binding activities
defects, 2A most common of 4 subtypes o Trial of desmopressin (DDAVP),
o Type 3: autosomal recessive w/ complete synthetic analog of vasopressin, if not
quantitative defect of both VWF and FVIII actively bleeding
 Acquired:  Successful = at least 30 IU/dL
o Lung cancer, Wilm’s tumor, gastric cancer, VWF activity, but ideally 50 IU/dL
MGUS, MM, chronic lymphocytic  Type 1 good, 2A variable, transient
leukemia, myeloproliferative neoplasms, but adequate, 2M and 2N poor or
lymphomas, SLE, autoimmune disorders, minimal response, 3 no response
drug side effects, states of high-vascular  FVIII assays:
flow e.g. AS, VSD, VAD, metallic cardiac o Decreased FVIII Ag and Act
valves, ECMO TREATMENT
EPIDEMIOLOGY  DDVAP leads to increased VWF and FVIII levels
 Affects ~1% of unselected population persisting up to 12 hours
 Equal distribution between males and females o Minor bleeding episodes (epistaxis,
PATHOPHYSIOLOGY menses) and minimally invasive surgery
 Inherited:  Antifibrinolytic agents
o Quantitative: decreased production,  VWF replacement in patients with type 3, severe
decreased secretion, increased clearance variants of type 1 and 2, and in serious bleeding
o 2A: significant decrease in VWF:C and scenarios such as trauma or major surgery
absence of large and intermediate
multimers HEMOPHILIA
o 2B: significant decrease in VWF activity
and absence of large multimers w/ DEFINITION
hypersensitivity to RIPA  Love (philia) of blood (hemo)
  Type A is FVIII deficiency or dysfunction  Life-threatening is intracranial bleeding (leading
 Type B is FIX deficiency or dysfunction cause of death), hypovolemic shock, airway
 Type C is FXI deficiency compromise
ETIOLOGY INVESTIGATION
 Inherited from defect or mutation in gene coding for  Prenatal genetic test:
specific clotting factor, ~30% spontaneous mutation o Chorionic villous sampling or
 Hemophilia A and B inherited via X-linked amniocentesis
recessive  Birth:
o FVIII and FIX on long arm of chromosome o Umbilical cord blood more accurate for
X FVIII, whereas FIX low at birth and takes
o Carriers may be affected if complete about six months to reach normal levels
inactivation of X through lionization, or  Post-partem:
partial or complete absence of X such as o CBC shows normal platelets
in Turner Syndrome o PT and BT normal
 Acquired: liver failure, vitamin K deficiency, auto- o PTT prolonged up to 2-3 times  then
antibodies mixing study  then FVIII and FIX assays
EPIDEMIOLOGY  Routine to measure FVIII
 Estimated frequency 1 in 10,000 live births inhibitors, esp. following
 A is most prevalent, 80-85% of hemophilia pop. therapeutic infusion, using
 Equally distributed across ethnic groups quantitative assays (e.g. Bethesda
PATHOPHYSIOLOGY and Nijmegen)
 Intrinsic pathway of coagulation cascade not  Molecular genotyping:
appropriate activated  reduced formation and o Confirm diagnosis and predict disease
stabilization of platelet clot by fibrin severity
CLINICAL COURSE  Other:
 General signs of bleeding: tachycardia, tachypnea, o CT/MRI for head, CT/MRI for chest and
hypotension, unexplained bruising, abdomen, US for joints
musculocutaneous hemorrhage after intramuscular TREATMENT
injection  Prophylaxis:
 Mild hemophilia: o Goal of factor levels > 1-2% which
o >5-40% FVIII activity increases to 30-90% when acute bleeding
o Bleeding after significant trauma or surgery o Continuous or intermittent (<45 w/year)
 Moderate hemophilia: o Continuous can be primary, secondary,
o 1-5% FVIII activity and tertiary depending on before/after 2
o Bleeding after trauma, injury, dental work, major bleeds in large joint AND onset of
or surgery osteochondral joint disease
 Severe hemophilia:  Primary: prophylaxis 1-2/week and
o <1% FVIII activity increase until full prophylactic dose
o Spontaneous and/or internal bleeding reached at 12-18 months
 Recurrent frequent as early as in o Also vaccinate against Hep. B and C
utero because no transplacental because rare risk of infection with
passage of VIII and IX transfusion
o Joints bleeds  painful, swollen, warm,  Management of acute bleeding:
with restricted range of motion o Goal of hemostasis within 2 hours of onset
 Repetitive joint bleeds lead to o Immediate replacement with high-dose
hemophilic arthropathies clotting factor concentrate (CFC) of
o Intra- and extracranial brain bleeds  FVIII (50 IU/kg) or IX (100-120 IU/kg)
falls, confusion, lethargy, meningismus,  Surgery depending on bleed
coma location
o Ocular bleeds  vision changes and o Then frequent factor assays and CFC as
restriction of eyeball movement due to required to allow healing
ocular muscle entrapment o Avoid aspirin and NSAIDs due to effects
o Thoracic bleeds  chest pain, SOB, on platelets
hemoptysis, airway compromise  Recombinant is more safe than plasma-derived
o Occult abdominal bleeds  abdominal FVIII:
pain, distention with guarding or rigidity, o Third-generation recombinant FVIII most
hematemesis, CVA tenderness, hematuria common because no animal/human
 Timeline: severe manifests in first few months of products
life VS. later in childhood/adolescence for others  Pharmacological options:
 Typical presentation: o DDAVP: mainly used in prevention or
o Severe hemophilia w/ hallmark of joint treatment of carriers of hemophilia A 
(hemarthroses) and muscle bleeding cheaper, no risk of viral infection BUT
careful of water retention in children <2
 years (cerebral edema) and adults with activation of leukocytes and endothelium
CVD  formation of adhesion molecules 
o Tranexamic acid and Epsilon promote plt activation
aminocaproic acid: antifibrinolytic agents o Also increases available TF
promote clot stability  Arterial mechanism:
 Novel therapies: o Lipid plaques in arterial wall  provoke
o Gene therapy, monoclonal antibodies chronic inflammatory cells and plt
(mimics function of FVIIIa but does not activation
resemble structurally or immunologically) o Evolution of lipid into fibrous plaques 
rupture of fibrous plaque  erosion of
VWD VS. HEMOPHILIA plaque surface releases pro-coagulating
factors
 Hemophilia more seen in males, whereas VWD o In heart, microthrombi from blood stasis
seen in males and females equally due to CVD
 Hemophilia bleeding musculoskeletal vs.
mucocutaneous in VWD (nosebleeds, gum bleeds, DEEP VEIN THROMBOSIS
easy bruising, heavy menstruation)
o VWD is more primary and hemophilia DEFINITION
more secondary because 1) VWD may not  Thrombosis within deep veins
be severe enough to reduce FVIII and 2) o Usually of leg but can occur in arms,
VWF involved in primary but FVIII not mesenteric, cerebral veins
 Differentiated by factor-specific assays EPIDEMIOLOGY
 VTE is third most common cause of death of CVD
SEPSIS after heart attacks and stroke
 DVT annual incidence ~80/100,000, more prevalent
 Sepsis (fever, bacteremia)  disseminated in African Americans and white
intravascular coagulation  platelets consumed and o Most common below knee starting at low-
also use up intrinsic pathway coagulation proteins flow sites such as soleal sinuses
 low fibrinogen  both INR and PTT increased ETIOLOGY
 Primary hypercoagulability:
MECHANISMS OF THROMBOSIS o Genetic deficiencies in anticoagulation
proteins C and S, antithrombin, FV
 Multifactorial pathogenesis based on Virchow’s:  Acquired hypercoagulability:
o A) Damage to endothelial lining o Cancer, sepsis, MI, HF, IBD, nephrotic
 Includes direct disruption by syn., vasculitis, HTN, DM, smoking, oral
catheter, trauma, surgery estrogens
o B) Hypercoagulable state o Constitutional: obesity, pregnancy,
 Increased prothrombotic factors or advanced age (most >40), surgery
deficiencies of anticoagulant  Risk factors:
factors o Reduced blood flow (immobility),
 Acquired (oral contraceptives, mechanical compression or functional
estrogen, inflammatory conditions) impairment leading to venous
more common than inherited (AT, hypertension (neoplasm, stenosis,
C and S, FV Leiden, prothrombin congenital anomaly), mechanical injury to
mutation) vein (trauma, surgery, catheter, drug
o C) Blood stasis abuse), increased blood viscosity
 Immobility, pregnancy, impaired (polycythemia vera, thrombocytosis,
blood flow (residual clot, vascular dehydration), anatomical in venous
fibrosis, atherosclerosis)  Staging: provoked (acquired), unprovoked
 Arterial vs. venous: (idiopathic, more likely to suffer from recurrence if
o Venous typically initiated by endothelial anticoagulation discontinued), proximal (above
damage while arterial by atherosclerosis knee, likely to lead to complications), distal
o High vs. low shear forces in arterial vs. PATHOPHYSIOLOGY
venous  white (plts & less small  Same as venous mechanism
molecules e.g. fibrin) vs. red (RBCs and  Can either fully or partially resolve
fibrin) o Partially resolved can travel along with
 Antiplatelet agents in prevention blood flow (extend and embolize)
and treatment of arterial thrombosis o OR merge with vessel wall and fibrose
o Arterial in heart, coronary arteries, carotid CLINICAL COURSE
 Venous mechanism:  History:
o Damage to vessel wall  production of o Pain, redness, swelling
pro-inflammatory and pro-thrombotic  Physical exam:
cytokines  promote adhesion and
 o Limb edema may be unilateral or bilateral  tPA
(if extends to pelvic veins), red and hot  Streptokinase (binds with free circulating
skin, dilated veins, tenderness plasminogen, converts additional plasminogen to
INVESTIGATION plasmin)
 NICE guidelines:  Urokinase (directly cleaves plasminogen into
o D-dimers (sensitive but not specific) plasmin)
o Coagulation profile  Indications: symptomatic iliofemoral DVT,
o Proximal leg vein US, when + indicates symptoms less than 14 days duration, good
should be treated as having DVT functional status, life expectancy >=1 year, low risk
 Depends on probability of DVT by Wells score: of bleeding
o 0-1, 1-2: probability low and moderate
 If D-dimer test + (>=500ng/mL) PULMONARY EMBOLISM
then whole leg US or proximal
compression US within 4 hours DEFINITION
o >=2: probability high  Embolus blocking pulmonary artery or its branches
 Whole leg US or CUS within 4  Usually thrombotic origin from DVT but rarely
hours  if negative, D-dimer test from air, fat, tumor cells
 if D-dimer + but US – then ETIOLOGY
repeat scan 6-8 days later  Same as DVT
TREATMENT  Hemodynamically unstable: PE which results in
 Aims to prevent PE, recurrent thrombosis, ‘post- hypotension as defined by SBP < 90 mmHg or drop
thrombotic’ syndrome, major causes of morbidity in SBP >= 40 mmHg from baseline
 DOAC in acute management: o More likely to die from obstructive shock,
o Rivaroxaban, apixaban i.e. severe RV failure
o 3 months if transient coagulopathy, 6  Hemodynamically stable: spectrum from small,
months if unprovoked DVT, life-long if mildly symptomatic or asymptomatic or those with
ongoing coagulopathy right ventricle dysfunction
 LMWH unless patient also renal failure: PATHOPHYSIOLOGY
o Dalteparin or enoxaparin  Pulmonary emboli typically multiple
o Discontinued when INR 2-3 for 2  Lower lobes more frequent, bilateral common
consecutive days  V/Q mismatch, physiologic dead space 
o In renal failure, unfractionated heparin hypoxemia
 Warfarin started same time as LMWH  Local inflammatory mediators stimulate respiratory
 Consider thrombolytics if threatening limb drive  hypocapnia and respiratory alkalosis
compromise  Thrombus mechanical obstruction AND hypoxic
ANTICOAGULANTS vasoconstriction  pulmonary vascular
 Unfractionated heparin: resistance  increased RV afterload  RV
o Potentiates AT for FXa and thrombin dilation and decreased RV outflow  reduced LV
o Binds non-specifically to plasma proteins, filling  compromised CO
unpredictable dose response CLINICAL COURSE
 LMWH: enoxaparin, dalteparin, tinzaparin,  Dyspnea, pleuritic chest pain, hemoptysis, cyanosis,
nadroparin hypoxia, tachypnea, fever
o Potentiates AT more selectively on FXa  Unreliable for diagnosis, investigation often needed
than thrombin INVESTIGATION
o Less binding to plasma proteins, more  Determine need to investigate via PERC score
predictable dose response o If 0/8, PE excluded
 Fondaparinux: o If >=1/8, calculate PE Well’s criteria
o Potentiates AT for FXa  If Well’s PE score <2, do D-dimer assay
o No binding to other plasma proteins, good o If <500ng/mL, PE excluded
predictability  If Well’s PE score >2, or if D-dimer from previous
 Vitamin K-dependent antagonists: warfarin >500ng/mL, CT pulmonary angiogram
o Inhibits vitamin K epoxide reductase, o If negative, PE excluded
needed for gamma-carboxylation of  V/Q scan useful in pregnancy, when CT
vitamin-K dependent proteins angiography N/A, or IV contrast contraindicated
 DOACs/NOACs: oral anticoagulants which inhibit  Other:
FIIa and FXa o ECG/CXR to rule out other causes
o Direct thrombin inhibitors: bivalirudin, o ECG in PE: sinus tach, right ventricular
argatroban, dabigatran strain, T wave inversions ant/inferior leads
o Direct FXa inhibitors: rivaroxaban, o CXR in PE: Hampton’s hump (triangular
apixaban, edoxaban, betrixaban density from pleura) or Westermark’s sign
 Increased treatment duration in cancer, recurrent (dilation of vessels proximal to obstruction,
DVT, unprovoked DVT, etc. with collapse of vessels after, sharp cutoff)
THROMBOLYTICS TREATMENT
  Anticoagulation and duration of tx same as DVT
 Consider thrombolysis if extensive PE causing
hemodynamic compromise or cardiogenic shock
 Catheter-directed thrombolysis or surgical
thrombectomy if massive PE or anticoagulation
contraindicated
 Admit if hemodynamically unstable, require
supplemental O2, major comorbidities

CASE TAKEUP

 Low volume, low HB  bleeding  eliminate GI

bleeding (common cause is colorectal cancer)
 Heparin can be reversed with protamine
 Anti-IIa and anti-Xa cannot be reversed
 For the majority of febrile neutropenia patients, the
offending pathogen usually originates from
endogenous flora inhabiting body; for example, the
gram-negative bacteria of gastrointestinal tract
 Any new fever in a patient with severely low
neutrophils (called febrile neutropenia) is
emergency
 Neutrophils, part of our innate immune response,
are at the front lines in fighting bacteria
 Granulocyte colony stimulating factor (GCSF) may
be used to stimulate the growth of neutrophils.
Guidelines for the use of this drug have been
established. In brief, for solid tumours, GCSF is
initiated in a prophylactic mode for subsequent
chemotherapy treatments following an episode of
febrile neutropenia or a dose delay due to
neutropenia. It may be initiated during an episode
of neutropenia when the patient is unstable or has
significant co-morbidities. In some hematologic
(bone marrow) malignancies, there is a reluctance
to give anything that might ‘stimulate’ the marrow
CANCER GENETICS o Gene amplification  excessive amount
TUMOR SUPPRESSOR GENES
 Risk of cancer: variations in oncogene or tumour  Growth-suppressing | loss-of-function mutations
suppressor genes  Functions: control cell division, repair DNA
o Sporadic or inherited mutations damage, control apoptosis
o Rare and common constitutional variants  Gatekeeper genes: regulate cell cycle involving
 Features of cancer: evading apoptosis, self- cell proliferation and apoptosis
sufficiency in growth signals, insensitivity to anti- o Gatekeepers interact directly or indirectly
growth signals, limitless replicative potential, with cyclin-Cdk complexes
sustained angiogenesis, tissue invasion & o Bypassing cell cycle checkpoints 
metastasis proliferation, differentiation, immortality
 Oncogenesis: multiple cell divisions  mitotic o Examples: RB1 (inhibition of cell cycle);
replication errors  accumulate sporadic mutations p53 (cell cycle and apoptosis regulator)
o Most mutations corrected or have no  Caretaker genes: identify and repair DNA thus
phenotypic effect maintaining integrity of genome
o Emphasize multi-step nature of o Examples: MLH1/MSH2 (mismatch
oncogenesis repair), p53 (DNA repair), BRCA1 (DNA
 Oncogenic mutations: repair)
o Occur in genes that regulate cell growth  Landscaper genes: products that create micro-
and programmed cell death environment that control cell growth
o Disable control mechanisms and confer o Mechanisms: ECM proteins, cellular
growth/survival advantage surface markers, adhesion molecules,
 Tumor progression: initiation  accumulate growth factors
additional genetic damage via mutations or FAILURE OF DNA REPAIR BY CARETAKERS
epigenetic  Damaging agent:
o In proto-oncogenes, tumor suppressor o Base-excision repair: x-rays, oxygen
genes radicals, alkylating agents, spontaneous
o In genes that promote vascularization reactions
o In genes that promote tumor spread, both o Nucleotide-excision repair: UV light,
local invasion and distant metastasis polycyclic aromatic hydrocarbons
 Idea: gene mutations happen all the time (usually o Recombinational repair: X-rays, anti-
detects and repairs, or if can’t be repaired then tumor agents (e.g. cis-Pt, MMC)
apoptosis) o Mismatch repair: replication errors
o More likely if mutation affects gene  Consequences:
involved with cell division or apoptosis o Transient cell cycle arrest
o Normally takes multiple mutations; but if o Apoptosis via inhibition of transcription
inherited mutation, then easier and quicker and/or replication
for enough mutations to accumulate  thus o Cancer, aging, inborn disease via
occur earlier in life mutations or chromosome aberrations
PROTO-ONCOGENES KNUDSON’S TWO-HIT HYPOTHESIS
 Growth-promoting | gain-of-function mutations  Proto-oncogenes require 1 gain-of-function
 Oncogene: DNA sequence in retrovirus that makes mutation
infected cell malignant  Tumor suppressor genes require 2 loss-of-function
o Encodes oncoproteins: stimulate cell mutations (one in each copy) to be deactivated
division and proliferation but inhibits cell  Loss of heterozygosity:
death o Chromosome loss, allele deletion, loss and
 Proto-oncogene: human gene homologous to reduplication, point mutation, unbalanced
oncogene but stimulate normal cell growth/division translocation, mitotic recombination
o Becomes oncogene with activating EPIGENETICS
mutation  Features:
 Examples of proto-oncogenes: o Mitotically or meiotically heritable
o Transcription factors: jun, fos, myc, ets o Affect gene expression but not the sequence
o Intracellular signaling molecules: GTPase o Acquired through environmental chemicals,
(RAS), cytoplasmic kinases drugs, aging, lifestyle
o Growth hormone receptors: EGFR, TKR  DNA methylation: methyl group activates or
o Growth factors: c-sis, erbB2 (Her2), kit suppresses genes
 Activating mutations:  Histone modification: factors bind to histone tails
o Coding mutation  abnormal protein and alters extent that DNA is wrapped by histone
(hyperactive) o More wrapped = inhibits transcription
o Translocation  novel fusion protein
(overproduction or hyperactive) HEREDITARY CANCER
o Regulatory mutation  excessive amount
  90-95% of cancer is not hereditary o Composed of retinoblasts, basophilic cells
 Somatic mutation: with hyperchromatic nuclei and scanty
o Nongermline tissues, nonheritable cytoplasm, mostly undifferentiated
o Common for all cancers o Invasion into optic nerve, subarachnoid
 Germline mutation: space
o Egg or sperm, heritable, all cells affected in  Etiology:
offspring o Mutation in RB1 tumor suppressor gene at
o Homozygous  100% of passing on long arm of chromosome 13 at locus 14
o Heterozygous  50% of gametes mutated, o In bilateral, 98% germline mutation
50% normal following autosomal recessive
o Cause cancer family syndromes  Due to mutation in all cells
 Cancer syndromes:  Significant risk of nonocular
o Very few examples of oncogene, but many cancers
of tumor suppressor mutations o In unilateral, 90% sporadic mutation
o Oncogene: multiple endocrine neoplasia o Most cases are sporadic
type 2 (RET), hereditary papillary renal cell  Spectrum of RB1 mutations
carcinoma (MET) o Cytogenetic deletions
o Tumor suppressor: hereditary breast and o Large, submicroscopic deletions
ovarian cancer (BRCA1/2), Lynch o Point mutations: single base, small
syndrome (MLH1, MSH2, MSH6, PMS2, deletions and insertions
EPCAM), Li-Fraumeni syndrome (p53), o Promoter hypermethylation (somatic)
familial adenomatous polyposis (APC), o Mitotic recombination (second mutation)
neurofibromatosis (NF1), Cowden  Inheritance pattern
syndrome (PTEN), retinoblastoma (RB1) o Majority of hereditary retinoblastoma is
highly penetrant (most with germline
CLINICAL APPLICATION OF GENETICS mutation will develop retinoblastoma)
o Penetrance and expressivity strongly related
 Diagnosis: confirm, molecular classification to the type of germline mutation
 Prognostic markers: risk of disease recurrence,  Presentation:
compare outcomes between marker+ and marker- o Leukocoria most common, strabismus
both with and without treatment second most common
 Predictive markers: response to particular o Symptoms: painful red eye, decreased
treatment, tailored therapy? vision, restriction of extraocular
 Risk assessment: identify families at high risk, movements
implement screening and prevention o Signs: intraretinal (homogenous, dome-
HEREDITARY VS. SPORADIC shaped whitish lesion with calcification),
 Provides explanation to individuals/family, cancer endophytic (vitreous as whitish lesion and
risk, recurrence risk, screening and early detection, seeds), exophytic tumor (white subretinal
prophylactic surgeries mass causing retinal detachment)
 Features of hereditary: cancer in two or more close  Treatment:
relatives on same side of family, bilateral o Chemotherapy is mainstay
presentation, multiple generations affected, early o IV carboplatin, etoposide, and vincristine
age onset, multiple primary tumors, some cancers depending on grade
related to each other (e.g. osteosarcoma and
retinoblastoma, breast and ovarian cancer) CANCER IN ADULTS VS. CHILDREN
TREATMENT
 Simple cancers: single dominant mutation, small  Childhood cancers not strongly linked to lifestyle or
mutational load, monotherapy effective, resistance environmental risk factors
is rare, late, involves same pathway o Still only small number are heritable
 Smart cancers: multiple mutations large mutational  Different locations: primary in pediatric are
load, multi-targeted therapy, resistance is common, leukemias, lymphomas, brain tumors, bone cancer
early, involves multiple pathways  Children respond better to certain treatments
 Targeted therapies: o Respond well to chemotherapy because
o Hormone therapies, signal transduction involve fast-growing cells
inhibitors, gene expression modulators,  Exposure in children more pregnancy, in adults
apoptosis inducers, angiogenesis inhibitors, more environmental
immunotherapies  Longer follow up (usually 5 years in adults)
RETINOBLASTOMA
 Long-term side effects more common, esp. with
 Definition: chemotherapy and radiotherapy
o Most common primary intraocular o Brain: learning disabilities, seizures,
malignancy of childhood frequent headaches
o Eyes: vision problems, glaucoma
 o Ears: ringing, dizziness o Alopecia, sterility, infertility, infusion
o Thyroid, muscles and bones, heart, lungs, reactions, increased risk of infection from
teeth, growth, sexual development, immunosuppression
fertility  Organ-specific: toxicity to cardio, nephro, neuro,
oto, pulmonary, GI
APPROACH TO CANCER CARE o Nephrotoxicity: hypertonic saline
(chloruresis)
 Common clinical signs: fatigue (astenia), weight o Cardiotoxicity: dexrazoxane (ICRF-187)
loss  Secondary malignancies: from alkylating and
 Diagnosis: biopsy  pathology  type of cancer topoisomerase inhibitors
o Genetic tests MYELOSUPPRESSION
 Work up: TNM (tumor, nodes, metastasis) or stages  Cytotoxicity to hematopoietic stem and progenitor
 Treatments: chemotherapy, radiation, surgery, cells in the bone marrow  bone marrow
innovative treatments suppression manifesting as anemia, leukopenia
 Follow up (neutropenia), thrombocytopenia, and/or
 Complications = cancer itself, treatment lymphopenia
ONCOLOGIC EMERGENCIES o Leukopenia/thrombocytopenia earlier
 Spinal cord compression, superior vena cava o Anemia in 10-15 days
syndrome, tumour lysis syndrome, pain crisis o Suppressed most at 7-10 days, ~4 weeks
recovery
CHEMOTHERAPY  Life-threatening infections, SOB, fatigue, bleeding
 Managed with dose reductions and delays in
 Goal: inhibit cell proliferation and tumor addition to rescue interventions (e.g. growth factors
multiplication  prevent invasion and metastasis (G-CSF), transfusions, EPO-stimulating agents)
 General function: o Administer based on guidelines and clinical
o Cell death by direct effect OR trigger manifestations
apoptosis
o Combination tx to prevent development of ACUTE MYELOID LEUKEMIA
resistant clones by promoting cytotoxicity
in resting and dividing cells DEFINITION
 Mechanisms of action:  Clonal expansion of undifferentiated myeloid
 1. Alkylating agents (cyclophosphamide): yield precursors (blasts) in peripheral blood and bone
unstable alkyl group which reacts with nucleophilic marrow of myeloblasts
centers on proteins and nucleic acids  80% of acute adult leukemias, 10-15% of childhood
 2. Antimetabolites (methotrexate, cytarabine): EPIDEMIOLOGY
affect cellular pathways in DNA, RNA synthesis  New cases around 4.2/100,000
 3. Mitotic inhibitors (vinblastine/cristine): e.g.  Incidence increases with age
interfering with spindle assembly  Median age of onset 65 years old
 4. Antibiotics (bleomycin): inhibit RNA and DNA ETIOLOGY
synthesis  Primary: de novo
 5. Anthracyclines (doxorubicin): inhibit RNA and  Secondary: hematologic malignancies (e.g.
DNA synthesis myeloproliferative disorders and MDS), or previous
 6. Agents inhibit DNA synthesis (hydroxyurea chemotherapeutic agents (e.g. alkylating)
damages DNA)  Risk factors:
 7. Agents that inhibit DNA repair (PARP o Male, old, smoking, obesity, MDS
inhibitors) common, myelofibrosis, aplastic anemia,
 8. DNA topoisomerase I or II inhibitors benzene, radiation, Down or Bloom
 9. Inhibitors of DNA methylation syndrome, alkylating agents, radiation
 10. Nitrosoureas therapy
 11. Antibodies (rituximab) against specific proteins PATHOPHYSIOLOGY
 12. Signal transduction inhibitors  Mutations in genes of hematopoietic stem cells
 13. Differentiation agents: ATRA, HDAC inhibitors o Nucleophosmin 1 mutations most common
(25-30%) and has female predominance
 14. Hormones and hormone antagonists
(prednisone) o Tp53 mutations associated with very poor
prognosis and resistant to chemotherapy
 15. Proteasome inhibitors
 Uncontrolled growth of blasts in marrow lead to:
 16. Chimeric toxic protein
o Suppression of normal hematopoietic cells
 Consequences:
o Accumulation of blasts in other sites (e.g.
 Affect rapidly multiplying cells (e.g. bone marrow) skin, gums)
o Myelosuppression (see below) o Appearance of blasts in peripheral blood 
o Nausea, vomiting (anti-emetics) risk of leukostasis
o Hemorrhagic cystitis (mesna) o Metabolic consequences, tumor lysis
o Mucositis: leucovorin, carboxypeptidase syndrome
CLINICAL COURSE o Complications: pancytopenias, bleeding, GI
 Develop over period of weeks system issues, kidney failure due to tumor
 Bone marrow failure: lysis syndrome, electrolyte disturbances
o Anemia, thrombocytopenia (associated with  2. Consolidation: chemo to prevent recurrence
DIC in promyelocytic leukemia), o 1) High dose cytarabine, called HiDAC,
neutropenia (even with normal WBCs) and 2) allogeneic stem cell transplantation
 Bruising, excessive bleeding for patients younger than 60
 Weakness, fatigue, SOB, chest  Treatment for APL:
tightness, pallor from anemia o Emergency because DIC often present
 Leads to infections, fever o All-trans-retinoic-acid (ATRA) added to
 Accumulation of blast cells in marrow: induce differentiation
o Skeletal pain, bony tenderness (esp.  Supportive care:
sternum) o Fever  culture and sensitivity all orifices;
 Organ infiltration: CXR; start antibiotics
o Gingival hypertrophy, extramedullary o Platelet and RBC transfusions +-EPO
involvement (hepatosplenomegaly), skin: o Prevention and treatment of metabolic
leukemia cutis or myeloid sarcoma, eyes: abnormalities
hemorrhages or whitish plaques, Roth  Allopurinol, rasburicase for
spots, cotton wool spots, and vision prevention of hyperuricemia
changes o Leukostasis
o In acute lymphocytic leukemia (ALL):  Needs immediate cytoreductive
hepatosplenomegaly, lymphadenopathy, therapy (i.e. hydroxyurea)
gonads
 Metabolic effects: HYPOVOLEMIC SHOCK
o Increased uric acid  nephropathy, gout
o Release of phosphate  decreased Ca, Mg DEFINITION
o Release of procoagulants  DIC  Hemorrhage or fluid loss  severe hypovolemia 
 Tumor lysis syndrome: decreased peripheral perfusion  ischemic injury
o PUKE calcium (phosphorus, uricemia, of vital organs  multi-system organ failure
potassium excreted, calcium decreased) ETIOLOGY
after tx from lysed cells  Hemorrhagic shock: trauma most common,
o Some forms can present with hypokalemia bleeding from GI, ectopic pregnancy, surgery, or
due to secreted muramidase that causes K+ vaginal
wasting from renal tubules  Fluid loss:
 Thrush: oropharyngeal candidiasis caused by o GI: vomiting, diarrhea, external drainage
yeast-like fungus called Candida albicans via stoma or fistulas
INVESTIGATION o Renal: diuretic therapy, hyperglycemic
 Blood work: diuresis, tubular and interstitial diseases
o CBC: anemia, thrombocytopenia, variable causing salt-wasting
WBC o Skin loss: burns, skin lesions, hot and dry
o INR, aPTT, fibrin degradation products, o Third-space sequestration: intestinal
fibrinogen (in case of DIC) obstruction, pancreatitis
o Biochemistry: increased LDH, uric acid, PATHOPHYSIOLOGY
and phosphate (released by leukemic blasts)  Compensation:
o Baseline renal and liver function tests o Increased sympathetic tone  increase in
 Peripheral blood film: HR, cardiac contractility, peripheral
o Circulating blasts with Auer rods vasoconstriction
(azurophilic granules) are pathognomonic o Tachypnea when lactic acidosis
 Confirmatory bone marrow aspirate:  Decompensation:
o Blast count: AML >20% (normal <5%) o First change in vitals is increase in DBP
o Morphologic, cytochemical, with narrowed pulse pressure  then SBP
immunophenotypic features to establish drops  O2 delivery to vital organs unable
lineage and maturation to meet oxygen demand  cells switch to
 Other: anaerobic metabolism  lactic acidosis
o CXR to rule out pneumonia o Blood flow diverted from other organs to
o ECG, MUGA prior to chemo (cardiotoxic) preserve blood flow to heart and brain 
TREATMENT propagates ischemia and lactic acidosis
 All subtypes treated similar except acute TREATMENT
promyelocytic (APL) with t(15:17) translocation  If hemorrhage, balanced transfusion using 1:1:1 or
 1. Induction: chemo to induce complete remission 1:1:2 of plasma to platelets to packed RBCs
o Several possible regimens o Anti-fibrinolytic administration
o Must ensure reversal of DIC, platelet  If hypovolemic, start with 2L of isotonic crystalloid
transfusions if <10 solution infused rapidly; colloid solution alternative
  Vasopressors generally not used because can o Adrenal crisis: volume depletion and
worsen tissue perfusion in absence of adequate history of glucocorticoid deficiency 
resuscitation fluid resuscitation and dexamethasone 4mg
 Reverse etiology  Diagnostic non-imaging:
o ECG
APPROACH TO SHOCK o ABGs
o Serum lactate
WHEN TO SUSPECT SHOCK o Cardiac enzymes and natriuretic peptides
 Clinical findings of undifferentiated shock vary o Renal and liver function tests
according to etiology and stage (pre-shock, shock, o CBC and differential
end-organ dysfunction) o Coagulation studies and D-dimer level
 Highly suspicious:  Diagnostic imaging:
o Hypotension, tachycardia, oliguria, o CXR, POC US, CT of head, chest,
tachypnea, cool, clammy, cyanotic skin, abdomen and pelvis, transesophageal
metabolic acidosis, hyperlactatemia, echocardiogram
abnormal mental status  Monitor using vitals and tests above, especially
INITIAL APPROACH blood biochemistry and kidney tests
 Airways, breathing, circulation:
o Stabilize airway and breathing with oxygen INNATE IMMUNE SYSTEM
and/or mechanical ventilation
o Secure IV access to immediately infuse  Non-specific first line of defense
fluids (bolus) to restore tissue perfusion  Minutes to hours but impermanent
 Conditions needing lifesaving interventions:  Physical and chemical mechanisms
o Anaphylactic shock: stridor, oral and  Cellular (granulocytes, NK) and humoral
facial edema, hives  intramuscular EN (complement) defense mechanisms
o Tension pneumothorax: unilateral chest PHYSICAL AND CHEMICAL
pain, distended neck veins, tracheal  Outer skin and mucous membranes (barriers)
deviation  emergent tube thoracostomy o Tight junctions btw epithelial cells
o Pericardial tamponade: distant heart o Ciliated epithelium of trachea and bronchi
sounds, pulsus paradoxus, POC US 
pericardiocentesis o Gastric acid and vaginal flora with acidic
pH
 Except in aortic dissection or
myocardial rupture because bleed o Normal flora that protect against pathogens
 In these patients surgery  Mucus:
o Hemorrhagic shock: o Lysozyme: enzyme from neutrophils,
 Large volumes of blood products granulocytes, and macrophages that can
and vasopressors avoided lyse linkages in peptidoglycans
 Traumatic hemorrhagic shock: o Lactoferrin: exhibits enzyme-like
surgery to identify and control properties and binds iron
bleed o Igs: bridge innate and adaptive
 Non-traumatic hemorrhagic: CT,  Processes: endocytosis, coughing and sneezing
transesophageal echo, abdominal  Antimicrobial: defensins, acid hydrolases, RNases
US CELLULAR
o Life-threatening arrhythmias:  Granulocytes and neutrophils against extracellular
cardioversion, atropine or infusions of  NK cells for intracellular
vasoactiveagents, or permanent pacemaker RESPIRATORY/OXIDATIVE BURST
o Septic shock: fever, suspected septic  IV  Generation of ROS in phagocytes (neutrophils,
antibiotics and fluid resuscitation monocytes) to destroy pathogens in phagosomes
o Cardiogenic shock: o O2 radicals from O2 via NADPH oxidase
 Myocardial infarct: administration o H2O2 via superoxide dismutase
of pharmacologic agents, coronary o HClO radicals from H2O2 and Cl- via
revascularization, or balloon pump myeloperoxidase
 Acute aortic or MV insufficiency: o Oxidative burst also leads to K+ influx,
POC US or echo  surgery releasing lysosomal enzymes in
o Dissection of ascending aorta: phagosome
hypotension, aortic insufficiency, HLA SYSTEM
pericardial tamponade, MI  contrast-CT  MHC class I
or transesophageal echo  cardiac surgery o Surface of all nucleated cells and platelets
o Pulmonary embolism: dyspnea and o Encoded in HLA-A, HLA-B, HLA-C
hypoxemia  systemic thrombolytic o Continuously presents endogenous
therapy fragments of proteins in cell  rapid
detection of cells infected by intracellular
pathogens (e.g. viruses) and cells that
 produce atypical proteins (e.g. neoplastic)
 cytotoxic T-cell reaction
o Absence of MHC class I receptors on
infected or malignant is recognized by NK
 MHC class II
o Surface of APCs (dendritic cells,
monocytes, B lymphocytes)
o Encoded in HLA-DR, HLA-DP, HLA-DQ
o Ingest exogenous material into fragments
 activate CD4+ T lymphocytes  activate
B lymphocytes
 TLRs
o PRRs that bind to pathogen-associated
molecular patterns (PAMPs)
o Activate the NF-kB pathway
HUMORAL MECHANISMS
 Proteins secreted into bodily fluids or blood initiate:
o Vasodilation and increased permeability 
blood flow
o Activation, proliferation, and attraction
(chemotaxis) of immune cells
o Killing pathogen
 Complement system is group of proteins that
circulate as inactive precursors  various stimuli
 enhances functions of antibodies and phagocytes
 Activation:
o Classical: IgM or IgG binding to pathogen,
C1
o Alternative: directly by pathogen, C3
o Lectin: C1-like complex
 Effect:
o Opsonization:
 Altering bacteria to increase
susceptibility to phagocytosis
 Mainly C3b and IgG
o Lysis of bacteria:
 C5-C9 form membrane attack
complex  perforation of cell wall
 cell lysis
o Activation of mast cells and granulocytes
(C3/C4/C5)  anaphylaxis
o Chemotaxis of neutrophils (C5a)
o Clearance of immune complexes (C3b)
 Inhibition:
o DAF decay accelerating factor (CD55)
o C1 esterase inhibitor