Hem Onc Flashcards
work-up of anemia
CBC
retic count - young blood cell, in 24hrs it matures to a RBC
- problem in bone marrow or outside the bone marrow
- takes 5-7 days before you can get a reticulocyte response
- have to correct reticulocyte count for degree of anemia - (HCT/45)*reticulocyte count given
- why correct? - because in anemia, the pts blood cells are depleted so retics will be falsely elevated - 3% or greater retics = good response for anemia
- you can see RNA filaments in reticulocytes - reticulocyte is still making Hb = blue RBC
- IMPORTANT in working up normocytic anemias
polychromasia present - basophilic immature RBCs, 2-3d before they become a mature RBC (so even younger than reticulocytes)
- another correction needed - (corrected retic count)/2
rule of 3: 3Hb = HCT
every unit of packed RBCs transfused = increase Hb by 1, HCT by 3%
Fe deficiency anemia
most common cause of anemia WW
- most common cause of Fe-def anemia = GI bleed
- pt is losing blood - usually from GI tract
- note - vegetarians have decreased Fe consumption
increased in RDW - why?
- you dont develop microcytic anemia overnight - Fe-deficiency starts with normocytic anemia and progresses to microcytic anemia
Tests:
serum Fe - nl 100
ferretin - ferritin is found in organs, very small amount circulating in the blood. Also represents the amount of Fe stored in bone marrow.
transferrin - carries Fe to macrophages in bone marrow
- transferrin = TIBC
- when Fe stores in the bone marrow are deficient –> liver is signaled to make more transferrin –> TIBC is increased
percent saturation - serum Fe/TIBC
what you would see: low serum Fe, high TIBC, low percent saturation, serum ferretin is low
causes - prematurity (not gaining Fe from mom), bleeding Meckel’s diverticulum (most common cause of Fe deficiency in a newborn, child), menorrhagia (woman under 50), PUD (duodenal ulcer, in men under 50), colon cancer (folks over 50)
Plummer-Vinson syndrome - Fe-def anemia, esophageal webs, dysphagia
target cells
markers for alcoholics (alters cholesterol content of membrane) and hemoglobinopathies
microcytic anemia
increased central pallor - because all microcytic anemias have low Hb
when RBC is developing in the marrow - Hb concentration determines the number of cell divisions
- if Hb synthesis is decreased –> signal to marrow to INCREASE division
Hb synthesis: heme + globin
- heme = Fe + protoporphyrin
Fe-deficiency, thalassemias, sideroblastic anemias
anemia of chronic disease
normocytic anemia –> can become microcytic
inflammation - body responds like there is an infection
- most common anemia
- can also occur during cancers - RCC (variable change in RBCs), HCC
Fe remains trapped in bone marrow macrophages - transferrin cant pick up this Fe and take it to the RBCs
- also decreased Fe absorption from gut
Fe studies - low serum Fe, low TIBC, low percent sat, high serum ferritin
sideroblastic anemias (rare)
heme synthesis:
- porphyrin synthesis begins in mitochondria
1) succinyl coA + glycine, ALA-synthase, B6 –> d-ALA
2) …… bilinogens
3) ferrochelatase combines Fe + protoporphyrin = heme - increased heme inhibits ALA-synthase
causes
- alcoholics (mitochondrial poison, uncouples oxidative phosphorylation) - Fe enters damaged mitochondria and cant get out, mitochondria is located around nucleus of RBC ==> ringed sideroblast
- B6 deficiency - isoniazid treatment, ….again ringed sideroblast
- genetic, Cu deficiency, myelodysplastic syndromes
- Pb poisoning - Pb denatures enzymes esp ferrochelatase
- will also cause basophilic stippling - Pb denatures ribonuclease (which normally break down ribosomes)
- Pb will also deposit in epiphyses –> failure to grow
- lead lines (Burton lines) in gingiva
- other symptoms - severe abdominal colic and diarrhea, cerebral edema (due to increased vessel permeability and accumulation of d-ALA, which is neurotoxic), hand nerve palsies
- loss of developmental milestones (infants) and learning problems (kids)
- headaches, memory loss and demyelination in adults
- wrist and foot drop - use dimercaprol and EDTA to treat
- can use succimer to chelate in kids
- flint water crisis, automobile batteries (contain Pb), moonshine (alcohol brewed in lead-lined tub), paint (houses, pottery)
Fe stains with Prussian blue stain = Pappenheimer bodies
Fe studies:
increased Fe, increased ferritin, normal/decreased TIBC
a-thalassemia
Asian populations and Black population
microcytic anemia
2 gene deletions - minor
3 gene deletions - HbH (4 beta chains)
- also a hemolytic component to this
4 gene deletions - hydrops fetalis (edema in 2+ fetal compartments), HbBarts (4 gammas)
- increased spontaneous abortions in far East –> increased incidence of choriocarcinoma here
note HbH and HbBarts ~ myoglobin - extremely high affinity for O2
b-thalassemia
Black, Greek, Italian
AR
mutations - splicing defects, promoters, stop codons
- -> microcytic RBCs that are prone to hemolysis (because of precipitated a chains)
- mutations in promoters = AUG+ kozak sequence (if kozak sequence is altered, 40S ribosome will not be able to find the correct AUG)
b minor (mild): due to splicing defects --> decreased HbA, increased HbA2 (greater than 3.5%) and HbF - heterozygote
b0 (homozygote) = Cooley’s anemia - require constant transfusions, will die from Fe overload
- anisopoikilocytosis - varying sizes
- marrow expansion - crew cut on skull xray, chipmunk facies, HSM
- increased risk of parvovirus induced aplastic crisis
HbS/B heterozygote - mild sickle cell disease, because of reduced b-globin production
bd thalassemia - electrophoresis will show HbF (hereditary persistence of HbF), asymptomatic
- low b, low d, normal a, normal y
Fe overload
Fe high, ferritin high, low transferrin, low TIBC, high percent saturation
B12 and folate
macrocytic anemia, hypersegmented neutrophils
deficiency –> problem making deoxythymidine phosphate
- nucleus is unable to mature –> nucleus stays large in all cells and all body cells are large
- mature nucleus are (somewhat) condensed
folate deficiency is more common - alcoholics and preggos
- dihydrofolate reductase - bactrim, methotrexate block this, THF cant be reformed
- phenytoin and sulfonamides can also cause deficiency
- folate - you eat it as a polyglutamate form –> converted to monoglutamate form before you can absorb it (intestinal conjugase), phenytoin (anti-epileptic) blocks intestinal conjugase
- monoglutamate form cant be absorbed if pt is taking OCP or alcohol
- folate has a 3-4 month reserve
B12 takes the methyl group off methyl-THF
- B12 donates this methyl group to homocysteine –> methionine
- THF starts DNA synthesis
- serum homocysteine level is HIGH in B12 and folate deficiency
- methylmalonic acid level is high in B12 deficiency
- helps metabolize odd chained fatty acids - converts methylmalonyl coA to succinyl coA
- myelin synthesis is affected –> dementia, demyelination of DCML and LCST (UMN problems)
- test for propioception is Romberg test - pt closes their eyes, you push them - B12-R complex cleaved by pancreatic enzymes –> B12-IF associates (pancreatitis…)
- pernicious anemia - achlorhydria –> risk factor for gastric carcinoma
- diphylbothrium fish tapeworm - B12 deficiency
- bacterial overgrowth - peristalsis problem, B12 and bile salt deficiency
- remember - 6-9 year reserve in liver
- deficiency results in subacute COMBINED degen (DCML, CSTs, spinocerebellar tracts) due to abnormal myelin
hematopoietic cells are made outside the sinusoids - need to squeeze through and enter the sinusoids to get into the blood, BUT they are too big
- macrophages are consuming/biting these cells
- pancytopenia in peripheral blood
Schilling’s test - localizes B12 deficiency
- given radioactive B12 by mouth and a subQ injection an hour later - normal B12 will saturate tissue receptors, SO if radioactive B12 is absorbed by GI tract –> it will be excreted in urine
- radioactive B12 + IF - tons of radioactive B12 in urine, means that pt has pernicious anemia
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orotic aciduria (AR) - cant convert orotic acid –> UMP (pyrimidine synthesis pathway)
- NO hyperammonemia
- presentation: kids with failure to thrive, developmental delay, and megaloblastic anemia
- treat with UMP to bypass the mutated enzyme
normocytic anemia
1) Corrected retic count < 2%
early Fe deficiency
- Fe deficiency but NO anemia - low serum ferritin, next Fe decreases, TIBC increases, percent decreases –> normocytic anemia –> microcytic anemia
- first low storage, then compensatory mechanisms kick in
other causes - anemia of chronic disease, blood loss for less than 1 week, aplastic anemia (chloramphenicol, indomethacin, phenylbutasone, thyroid-related drugs, hepatitis C, radiation)
2) Corrected retic count > 3%
hemolysis
- autoimmune hemolytic anemias (IgG mediated, warm autoimmune anemia) - EXTRAvascular hemolysis
- spherocytes and sickle cell RBCs will be removed extravascularly (they cant get out of the sinusoids of the spleen)
- Howell-Jolly bodies - piece of nucleus, macrophage will try to ingest this body –> also extravascular hemolysis
phagocytosis of RBCs –> UCB –> jaundice
- normally RBCs are recycled and protoporphyrin is degraded into UCB in the spleen –> binds to albumin –> conjugated in the liver
- UCB does not get into urine - because it is lipid soluble and bound to albumin
- will see spherocytes in peripheral smear
intravascular hemolysis - if RBC gets sheared (valve defects
- IgM mediated will be intravascular hemolysis - cold autoimmune anemia)
- Hb released into the bloodstream, Hb-uria, low haptoglobin levels
hemolytic anemia
INTRINSIC defect of RBC, nothing wrong with bone marrow (corrected retic count is greater than 3%)
MAD:
Membrane defect (spherocytosis, paroxysmal nocturnal Hb-uria)
- spherocytosis (spectrin, ankyrin, band 3 mutations, AD) - defective binding of RBC cytoskeleton to membrane –> spherocytes –> RBCs cant get out of spleen –> splenomegaly, gallstones. Spherocytes are smaller! - so they have increased MCHC. Osmotic fragility test in hypertonic saline. Treat with splenectomy.
- paroxysmal nocturnal Hb-uria - complement-decay accelerating factor absence - protein on RBC cell surfaces that inhibits C3 convertases. Nocturnal because complement sits on RBCs during respiratory acidosis, which occurs when we sleep.
- increased incidence of acute leukemias - defect is in PIGA gene of multipotent hematopoietic stem cells. Gene defect means GPI anchor (necessary to anchor CD55 and CD95) is not made).
- triad: coombs negative hemolytic anemia, pancytopenia, venous thrombosis
- CD55/59 negative RBCs non flow cytometry
- treat with eculizumab - terminal complement inhibitor
Abnormal Hb
HbS: valine is nonpolar –> sickling
- note if you have sickle cell trait, you will not have sickle cells in your peripheral blood - RBC will sickle if it has 60% or more HbS
- microscopic hematuria - get a sickle cell screen, esp in black population
- splenomegaly –> autoinfarct at age 18 or 19 (brown!, fibrosed, atrophied spleen), spleen has stopped working at 2 yo
- Howell-Jolly body is a sign that the spleen is not working - a piece of nucleus in the RBC, if the spleen was working, the macrophage would have plucked out this nucleus
- S. pneumo sepsis - cant get pneumovax until 2 years of age
- H. flu is the next most common cause - penicillin prophylaxis
- N. menin, Salmonella, GBS are other encapsulated bac
- first vaso-occlusive crisis occurs around 6-9 months of age - HbS as accumulated at this point (ex of vaso-occlusive crisis is if pt comes in with scleral icterus and tenderness over bones)
- splenic sequestration crisis - marked Hb decrease, rapidly enlarging spleen
- renal papillary necrosis - decreased PO2 in papilla and microhematuria (medullary infarcts)
- decreased life-expectancy, normocytic anemia with increased retics
- treat with hydroxyurea (increases HbF) and hydration
- Gardos channel blockers - this channel allows K and water to leave, if you block it –> prevent sickle cell dehydration
HbC: glutamic acid to lysine
- crystals inside RBCs and target cells
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Deficient enzyme:
G6PD deficiency - XR, primaquine, dapsone (leprosy), Heinz bodies (denatured Hb), bite cells
- seen in blacks, greeks, italians
- can cause prolonged neonatal jaundice, but mild anemia, in newborn
Pyruvate kinase deficiency (AR, last step of glycolysis) –> decreased ATP –> rigid RBCs –> extravascular hemolysis
- increased 2,3-BPG... - hemolytic anemia in a newborn
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EXTRINSIC
- IgG = warm reacting antibodies - most common cause is lupus, also seen in lupus and CLL
- IgG and C3b on the surface of RBCs
- direct Coombs - directly detect antibodies on RBCs (v.s. indirect Coombs - screens for IgG in serum)
- IgM = cold reacting antibodies - seen in CLL, M. pneumo, mono
- second most common cause is penicillin - piece of penicillin attaches to RBCs
- can get IgG antibodies against this chunk of penicillin = type 2 HSR
- methyldopa - can be given to pregnant women with HTN (hydralyzine can also be given –> drug induced-lupus, second to procainamide)
- methyldopa screws up your Rh antigens - you make IgG against your Rh antigens –> autoimmune hemolytic anemia
- immune complex - quinidine-IgM complex circulates in blood stream
- IC sits on an RBC - attracts complement –> intravascular hemolysis
- microangiopathic hemolytic anemia - schistocytes
- most common cause is aortic stenosis –> chronic intravascular hemolysis –> losing a lot of Hb in urine –> can get secondary Fe-deficiency anemia
- other causes - DIC, TTP/HUS, SLE, HELLP, malignant HTN
- infections - malaria, Babesia
malaria
plasmodium falciparum - ring forms of trophozoites and banana-shaped gametocytes
fever spikes when RBCs rupture
leukemoid reaction
site of immune response activation, note 2 follicles are the active ones
looks like leukemia - but benign
- can distinguish from ALL because there is no anemia and no thrombocytopenia
Tb, sepsis >30,000-50,000 neutrophils in periphery
- commonly kids get this - ex kid with otitis media
- will see leukocytes with Dohle bodies (basophilic ribosome-RER granules), toxic granulation, and cytoplasmic vacuoles
lymphocytic leukocytosis
- pertussis - bacteria produces lymphocytosis promoting factor (prevents lymphocytes from leaving blood and entering LNs)
lupus
thrombocytopenia and hemolytic anemia = type 2 HSR
other symptoms are related to IC
pt on creatine supplements
pt will have extremely high creatinine levels, but BUN is normal
polycythemia
RBC mass (mass of RBCs in circulation, unchanged with plasma volume) v.s. RBC count (concentration in blood, will increase if you are dehydrated)
relative polcythemia - decrease in plasma volume, RBC mass is unchanged
absolute polycythemia
- appropriate increases - tissue hypoxia
inappropriate absolute polycythemia
- polycythemia rubivera = myeloproliferative disease - bone marrow stem cell disease
- propensity to go into leukemia - EPO-producing tumor - renal adenocarcinoma
myeloproliferative disorders - stem cell has lost regulation (nothing can inhibit it)
- according to pathoma - proliferation of mature cells, all cells are increased, but named for cell that is predominantly increased
- disease of late adulthood
- initially high WBC count and hypercellular marrow –> progresses to marrow fibrosis (spent phase)
1) polycythemia vera
- H - hyperviscosity –> increased peripheral resistance, increased risk of thrombosis (Budd-chiari - hepatic vein thrombosis), phlebotomy to reduce viscosity and to create Fe deficient
- Budd-Chiari syndrome - liver infarction
- H - hypervolemia - plasma volume increases to match increased RBC mass (unique to this polycythemia)
- H - hyperhistaminemia - RBCs, white cells, mast cells, basophils are increased
- scenario: I itch all over when I take a hot shower - temperature changes cause mast cell degranulation –> generalized itching. Pt will also have ruddy/red face, headaches (all due to vasodilation due to histamine).
- side note - only bile salt deposition in skin can produce generalized itching
- classic symptom is erythromelalgia - blood clots in extremities –> severe, burning pain and red-blue discoloration
- Hyperuricemia - nucleated hematopoietic cells are elevated… (urate nephropathy - have to put chemo pts on allopurinol)
- treat with phlebotomy, hydroxyurea
2) CML - 9;22 Bcr-Abl
- tyrosine kinase (and PDGF mutations play a role)
- leukocytosis
- treat with imatinib
- splenomegaly! - enlarging spleen suggests accelerated phase of disease –> transformation to AML* or ALL thereafter
3) myelofibrosis (agnogenic myeloid dysplasia) - spleen will be huge (can cause early satiety)
- megakaryocytes –> stimulate fibroblast proliferation –> fibroses bone marrow
- 10% of cells stay in marrow (rest have moved to the spleen) - when these cells move through fibrosed marrow = tear-drop cells
- early stages = marrow is hypercellular, late stages = pancytopenia
- blood cells in spleen (there is no reticulin gate to prevent immature blood cells from leaving) –> blasts and nucleated RBCs on smear
4) essential thrombocythemia (least common)
- hemorrhagic and thrombotic symptoms (easy bruising, microangiopathic occlusion)
except for CML, others have JAK2/STAT gain-of-function mutations
- treat with ruxolitinib = JAK2 inhibitor (approved for primary myelofibrosis)
……..
5) myelodysplastic syndrome (pre-leukemia)
leukemia
malignancy of stem cells in marrow, can met anywhere - generalized LAD, HSM
- abnormal cells in peripheral blood - blasts
- normocytic anemia, thrombocytopenia, neutropenia - normal cells in marrow have been crowed out
- increase in white cell count - because of increased abnormal white cells
- blasts = large immature cells, with a punched out nucleolus
- chronic v.s. acute - count blasts
- blasts GREATER 30% of marrow = acute
- chronic leukemia is proliferation of MATURE lymphocytes (so nothing pro-)
myelodysplastic syndrome - cytopenias with hypercellular bone marrow (cells cant get out of bone marrow)
- can progress to acute leukemia - if blasts increases 20% (according to Pathoma)
- will see ringed sideroblasts
lymphoblasts are TdT+, PAS pos
myeloblasts = Auer rods
- Auer rods stain for peroxidase
age will tell you leukemia
0-14 years = ALL
- B-ALL is most common - C10, CD19, CALA antigen positive (in general B cell markers are more reliable)
- T-ALL - CD1, CD2, CD5, present with large mediastinal mass
15-39: AML
- risk factors for AML - chemo/benzene/radiation, myeloproliferative disorders, DS
- Pseudo-Pelger-Huet anomaly - neutrophils with bilobed nuclei, seen after chemo - myeloblast with Auer rod (abnormal lysosomes, crystallized MPO)
- acute monocytic leukemia - lack MPO, will infiltrate gums
- APML - 15;17 translocation, treat will all-trans retinoic acid (causes blasts to mature), almost always associated with DIC (Auer rods activate coagulation cascade, medical emergency!)
- acute megakaryoblastic anemia - lack MPO, associated with DS before the age of 5
- eosinophilic subtype of AML - chromosome 16 inversion
40-49: AML and CML
- separate by %blasts
- CML = Philadelphia chromosome, 9;22, BCR-ABL - increased non-receptor tyrosine kinase activity
- splenomegaly - enlarging spleen suggests accelerated phase of disease –> transforms to AML* or ALL (mutation is in hematopoietic stem cell)
- leukocyte alkaline phosphatase - mature neutrophils have alk phos, neoplastic neutrophils dont (way to distinguish between CML and leukemoid reaction)
- treat with imatinib - blocks tyrosine kinase activity
60+: CLL
- hypogammaglobulinemia - neoplastic B cells cant transform into plasma cells
CML is the most cause of leukemia regardless of age
most common cause of generalized, non-tender LAD in pt over 60 - METs to LN
hairy cell leukemia
rare, adult males - chronic leukemia
B cell neoplasm that infiltrates bone marrow and red pulp of spleen –> pancytopenia
TRAP (tartrate-resistant acid phosphatase) stain positive, cells have spikes
massive splenomegaly (red pulp), drug tap with bone marrow aspiration --> bone marrow is fibrosed, LAD absent (-note this can look like myelofibrosis)
cladribine - adenosine deaminase inhibitor
- adenosine accumulates to toxic levels –> cell death
- pentostatin can also be used
LNs
- painful LAD is NEVER malignant* - being cause by inflammatory condition (infection, lupus)
- pain because you are stretching capsule
- generalized painful LAD - HIV, EBV, lupus
non-tender LAD
1) mets - most common
2) primary lymphoma
germinal follicles - form when macrophages deliver antigen to B cells –> B cells are dividing –> plasma cells that make antibodies
= reactive LAD, benign
tumors:
- follicular lymphoma - most common non-Hodgkins B-cell lymphoma
-14;18 - apoptosis gene was knocked off
- small cleaved cells (centrocytes) and large noncleaved cells (centroblasts)
Bruttons agammaglobulinemia
- germinal follicle would be absent
DiGeorge
- no paratrabecular region or germinal follicle - T cell country
histiocytosis - sinusoids
SCID - due to adenine deaminase deficiency
- would only have sinusoids/histiocytes
Langerhans cell histiocytosis
scenario: kid with rash, non-tender LAD, monomorphic cells, CD1 positive
- CD1 = histiocytes, also S100 positive (mesodermal)
- Birbeck granule in histiocyte - tennis racket
(remember C. tetani spore also looks like a tennis racket)
- may have eos granulomas that affect the skull and bones
- kid comes in with fracture - red herring is osteosarcoma
- Letterer-Siwe disease - malignant - skin rash and cystic skeletal defects (recurrent otitis media) in an infant
- Hand-Schuller-Christian disease - malignant - scalp rash, lytic skull defects, DI, and exopthalmos
tissues that cancer cant invade
cartilage and elastic tissue - cancer cells cant invade these tissues
Burkitt’s lymphoma
EBV, 8;14, c-myc oncogene translocation
- c-myc = transcription activator, controls cell proliferation, differentiation, and apop
- 3rd most common cancer in kids - great prognosis
- Africa - jaw
- US - abdomen (peyers patches, periaortic nodes, testicle)
starry-sky appearance - stars are normal, benign macrophages
mycosis fungoides
chronic leukemia - neoplastic cell = CD4 T cell, adults
skin and lymph nodes (?) involved
–> aggregates of neoplastic T cells in epidermis = Pautrier microabscesses
Sezary syndrome - malignant cells are now in peripheral blood
- lymphocytes with cerebriform nuclei
Hodgkins
non-tender generalized LAD
bimodal age distribution
overall prognosis is better than that of non-Hodgkins
owl-eyes = RS cells, CD15 adn CD30 positive
- RS is the malignant cell - more RS cells, worse prognosis
- RS secrete cytokines
- but reactive inflammatory cells make up the bulk of the tumor
1) nodular sclerosing Hodgkins - more common in young adult women
- 2 hard, non-painful nodes - in anterior mediastinum and in a node above the diaphragm
2) lymphocyte-rich = best prognosis
3) mixed cellularity - eos!
4) lymphocyte depleted- worst prognosis, elderly, HIV
antithrombin
inhibits factor Xa AND thrombin (F2a)
note - anticoagulation therapy for 3 months to prevent recurrent thromboses in a pt who has had a DVT
heparin (IV, SC) - negatively charged, naturally present in mast cells
unfractionated heparin - seals antithrombin-Xa complex and antithrombin-thrombin complex
- use in ACS, PE, MI, DVT for immediate anticoagulation
- short half-life
- reverse with protamine sulfate - positively charged molecule that binds to heparin
- ADRs - many, osteoporosis
LMWH (enoxaparin, dalteparin) - seals antithrombin-Xa complex (not long enough to act with thrombin..)
- better bioavailability, long t1/2 does not need lab monitoring
- not easily reversible
pentasaccharide (fondaparinux) - sequence in both that binds to antithrombin
- fondaparinux has much lower AT activity
antithrombin deficiency - diminishes the increase in PTT following heparin administration
- woman on OCPs
alteplase
binds fibrin and converts plasminogen to plasmin –> plasmin hydrolyzes bonds in the fibrin matrix
direct thrombin inhibitors
direct thrombin inhibitor (bivalirudin, dabigatran, argatroban) - inhibit thrombin-mediated fibrin formation
- used for DVT prevention/treatment and in afib
lepirudin and argatroban used for H-I-T
doesnt require lab monitoring
can reverse dabigatran with idarucizumab
- other options - prothrombin complex concentrate or tranexamic acid
clopidogrel and ticlopdidine
others - ticagrelor, prasugrel
inhibit ADP-mediated platelet aggregation - by binding P2Y12 (component of ADP receptors on platelets) –> prevent expression of Gp2b/3a
use in ACS, stenting, and stable angina (if ASA cant be tolerated)
ADRs: neutropenia (ticlopidine), TTP
Factor 5 Leiden
thrombosis, recurrent pregnancy loss
- heterozygote carriers have increased thrombosis risk
normal hemostasis: activated protein C RESTRICTS clot formation –> cleaves and inactivates factors 5a and 8a
- point mutation - 5a Leiden cant be cleaved
- 5a is a cofactor in the conversion of prothrombin to thrombin –> increased thrombi (D-VENOUS-T!)
LAD
reactive hyperplasia = benign
- polyclonal
- follicular hyperplasia
- sinus hyperplasia - sinuses fill and enlarge with histiocytes
- diffuse hyperplasia - lymphocytes, immunoblasts, macrophages
malignant transformation (lymphoma)
- MONOclonal - examine TCR genes (the answer is “monoclonal TCR gene rearrangement), especially characteristic of non-Hodgkins lymphoma
- normal node architecture is effaced
microtubule dysfunction
vinca alkaloids - vincristine and vinblastine bind b- tubulin monomers, prevent polymerization
- M phase arrest
- neurotox (arreflexia, etc.), constipation (paralytic ileus)
taxanes - paclitaxel, cause microtubular dysfunction
- stabilize polymerized microtubules –> anaphase cant occur
5-FU
enzymatic converted to floxuridine monophosphate
- -> binds THF and thymidylate synthetase in a stable-reaction intermediate
- effectively decreasing the amount of thymidylate synthetase available for thymidine synthesis
- 5-FU has a REDUCED cytotoxic effect in cells that are folate deficient - giving 5-FU and leucovorin will potentiate toxicity
5-deoxyuridine also inhibits thymidylate synthetase
methotrexate
irr inhibits DHF reductase - so THF cant be made, prevents folic acid metabolism
- folic acid is a 1C donor involved in making thymidine, aas, purines
- effective for rapidly dividing cells
methotrexate undergoes polyglutamation (and gets trapped in the cell)
leucovorin - does not require reduction, rescues normal cells
ADRs of methothrexate
- GI ulcerations, alopecia, pancytopenia = rapidly dividing cells
- hepatotox and pulmonary fibrosis
RB gene
retinoblastoma and osteosarcoma
Rb - encodes a nuclear phosphoprotein that regulates the G1–> S checkpoint
- active when HYPOphosphorylated - will halt cell at G1
EGFR mutations
lung cancers - ERBB1
breast - ERBB2 aka Her2
ovarian
gastric
multiple myeloma
high serum IL6
neoplastic plasma cells produce IL1
polyclonal gammopathy = benign, chronic inflammation (G-A-M)
- monoclonal gammopathy - malignancy of plasma cells (other plasma cell clones are suppressed, usually IgG malignancy)
- side note: SPEP shows a1,a2, y1, y2, albumin peaks (can ddx a1-antitrypsin deficiency)
multiple myeloma - cookie cutter lytic area
- Padget’s disease of bone - diffuse borders of lysis
plasma cells - sheets of rER (see on EM)
Rouleaux formation on blood smear - increased protein decreases charge between RBCs
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v.s. Waldenstrom macroglobulinemia - IgM
hyperviscosity (retinal hemorrhage, blurred vision, Raynauds)
- but also increased risk of bleeding - defective platelet aggregation in hyperviscous blood
treat acute complications with plasmapheresis
amyloid
calcitonin –> amyloid (medullary carcinoma of the thyroid)
pre-albumin –> amyloid
light chains (multiple myeloma) –> amyloid
DS –> b-amyloid (death by Alzheimer’s, earlier death by cardiac defects)
Lysosomal storage disorders
Gaucher disease - AR
deficient glucocerebrosidase, (lipid-laden) macrophages with wrinkled cytoplasm
- glucocerebrosidase is a component of leukocyte and erythrocyte cell membrane
- Gaucher cells invade the bone marrow –> pancytopenia
- HSM
Niemann-Pick
- missing sphingomyelinase - bubbly cytoplasm
- mental retardation
Pompe - only glycogen storage disease that is LYSOsomal
- missing lysosomal enzyme that breaks down glycogen
- death by cardiac causes -glycogen deposition in heart
hemostasis overview
Virchows triad
- stasis of blood flow
- endothelial injury
- hypercoagulable
why dont we form clots in small blood vessels?
- heparin (GAG) - enhances AT3 (AT3 is made in the liver)
- AT3 neutralizes most of the coagulation factors (the ones that are serine proteases) - PGI2 aka prostacyclin - made by endothelial cells, vasodilator, inhibits platelet aggregation and adhesion, increased vascular permeability, stimulates leukocyte chemotaxis
- damaged endothelial cells lose the ability to synthesize prostacyclin –> development of thrombi and hemostasis - proteins C and S - INactivate factors 5 and 8
- tPA
- birth control is thrombogenic - estrogen increases synthesis of F5&8 and fibrinogen, and inhibits AT3
- aka heparin antagonist - smoking is thrombogenic - due to damaged endothelial cells
STEP 1 small cut - what stops you from bleeding from SMALL vessels
- bleeding time - used to evaluate platelet function/platelet plug (cut on volar aka palm/sole aspect)
1) cut the vessel
2) tissue thromboplastin released - extrinsic coagulation system activated (has nothing to do with bleeding time)
3) subendothelial collagen exposed - factor 12 (Hageman factor) activated, intrinsic system activated (nothing to do with bleeding time)
4) endothelial cells (Weibel-Palade bodies) AND megakaryocytes/platelets (a granules) make vWF - damage to small blood vessels exposes vWF - platelets have receptors for vWF - release reaction - binding of vWF to GP1B on platelets causes platelets to release preformed ADP
- ADP causes platelets to aggregate
- upon release reaction - platelets begin synthesizing TXA2 –> potent vasoconstrictor (infact TXA2 causes Prinzmetals), bronchoconstrictor, platelet aggregator –> bleeding time has ended
- platelet plug = platelets and fibrinogen
platelets are similar to mast cells
- mast cells release preformed histamine, heparin, tryptase, and eosinophilic chemotactic factors
- following release reaction - makes PGs and LTs
prolonged bleeding time
- thrombocytopenia
- vWF disease (most common genetic hereditary disease) - AD
- ASA - irr blocks platelet COX1 and 2 by acetylation–> prevents platelet aggregation
- note NSAIDs (rev COX2* and COX1, 48hrs/ASA inhibit platelet COX (not COX in other cells) - side note - COX2 is preferentially expressed at sites of inflammation, COX1 has a role in platelets, GI tract
- signs - petechiae, ecchymoses/purpura, epistaxis
tests for platelets
- platelet count (NSAIDS render platelets non-functional, platelet transfusion)
- bleeding time - platelet function
- ristocetin cofactor assay - tests vWF presence
- ristocetin activates vWF to bind to Gp1b
STEP 2 end-product of coagulation system = thrombin
- thrombin converts fibrinogen to fibrin
STEP 3 plasminogen will be activated –> plasmin –> vessels will recanalize
hemophilia A
in general coagulation cascade problems have - LATE rebleeding problems, menorrhagia, hemarthroses
hemophila A = XR, deficient F8 (bleeding time is normal!)
ex appendectomy - start to massive amounts of blood
- only things that were holding vessels together were sutures and (weak) platelet plugs
- fibrinogen will not be converted to fibrin
question - bleeding with molar tooth removal?
- platelet plugs will dislodge when you rinse your mouth out –> people choke to death on their own blood
treat with recombinant F8
VS coagulation factor inhibitor:
acquired antibody - anti-F8 is the most common
- similar to hemophilia A
distinguish by mixing study - mix normal plasma and pts plasma
- PTT does not correct upon mixing (v.s. in hemophilia, it will correct)
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Hemophilia B, XR - deficiency in F9
- all else is the same
Hemo B, AR - deficiency in F11
coagulation systems
extrinsic system - factor 7
instrinsic - 12, 11, 9, 8
common pathway - 10
(~complement - C3 is common)
PT - evaluates extrinsic system
- 7, 10, 5, 2, 1
- INR = PT/PTref
- check when pt is on warfarin - 3/4 warfarin affected factors are tested by PT (PTT will also be prolonged)
PTT - evaluates intrinsic system
- 12, 11, 9, 8, 10, 5, 2, 1
- of all these - factor 8 (hemophilia A) deficiency is most common (next most common is vWF)
- test in heparin therapy - AT3 knocks off 12, 11, 10, 7, 2, thrombin (again PTT does a better job, PT is also prolonged)
thrombin time - serum (that contains anticoagulants) + excess of thrombin –> time required to form a clot
- measures the rate of conversion of fibrinogen to fibrin - prolonged in pts with low fibrinogen (liver disease)
fibrinolytic system
plasminogen to plasmin by tPA
- tPA, reteplase, and tenecteplase are fibrin specific
plasmin breaks down fibrinogen, fibrin, coagulation factors, blocks platelet aggregation
a2-antiplasmin inactivates plasmin - so clots can be formed in the first place
- produced by liver
fibrin degradation products
- D-dimer = proves that fibrin clot was there
- D-dimer is the best test for DIC
- factor 13 = fibrin stabilizing factor - puts strands in between fibrin
Disorders of plasmin overactivity
- can look like DIC
- increase PT/PTT, increased bleeding time
- normal platelet count
- increased fibrinogen split products but NO increase in D-dimer - there is no clot to cleave
- treat with aminocaproic acid - blocks plasmin activation
-radical prostatectomy - release of urokinase activates plasmin
vessel abnormalities
old person - back of hands have purpura = senile purpura
- subQ tissue thins with age - blood vessels rupture
Osler-Weber-Rendu disease aka hereditary telangiectasia
- telangiectasias - on GI tract, mucosa, etc. –> bleed –> Fe deficiency anemia
platelet disorders
cant make platelet plug - bleeding from superficial scratches, petechiae, purpura, epistaxis
ITP - IgG against platelet Gp2b/3a
- IgG produced by plasma cells in the SPLEEN
- kid with URI –> next week he gets epistaxis… self-limited
- woman with pos ANA - comes in with epistaxis, petechiae, splenomegaly, generalized LAD
- lady has IgG antibody against platelet
- may cause short-lived thrombocytopenia in offspring - increased megas in bone marrow - compensatory response
- treat with corticosteroids, IVIG acutely (splenic macrophages will consume IVIG instead), splenectomy
thrombotic thrombocytopenic pupura and HUS
- PT and PTT normal, bleeding time will be prolonged
- something in plasma damages small vessels throughout body - platelets stick and aggregate –> firm platelet plugs, RBCs will get sheared on these plugs
- coagulation cascade is not activated so you dont get DIC - microangiopathic hemolytic anemia (shistocytes), etc.
- fever, neuro, and renal symptoms (AKI because of damage to glomerular endothelium)
- treat with plasmapheresis, steroids
- TTP - decreased AdamsTS13 enzyme (autoimmune) - enzyme that cleaves vWF into monomers for eventual degradation
- vWF multimers –> abnormal platelet aggregation –> microthrombi and thrombocytopenia
- can also have renal failure, neuro manifestations, and fever - HUS - O157:H7 E coli (beef, toxin damages vessels…) and Shigella toxin
- occurs most commonly in kids <10 and in association with EHEC treatment with antibiotics
- two organs affected in both - kidneys (HUS), CNS (TTP)
- increased megas in bone marrow
- treat with plasmapheresis (to remove autoantibody) and corticosteroids
coagulation factor deficiencies
hemophilia A - XR
- only 8 coagulant is missing
v. s. VW disease - AD
- most common inherited coagulation disorder
- platelet adhesion defect
- but also have mild factor 8 deficiency (vWF stabilizes 8 coagulant, increased PTT)
- so will have mixed bleeding symptoms
- 3 parts of factor 8 molecule: vWF, 8 coagulant, 8 antigen (chauffeur for the other 2 parts) - and all 3 of these are decreased
- abnormal ristocetin test - normal is platelet aggregation
- ddAVP - will increase the production of all factor 8 molecules - also treats MILD hemophilia A
scenario: woman who with menorrhagia - stops when she goes on OCP, restarts when she discontinues OCP
- she has VW disease - estrogen also increases the synthesis of all factor 8 molecules
- OCP is treatment of choice for women
- test ristocetin cofactor assay
Anti-phospholipid syndrome - spont abortion
- lupus anticoagulant (also seen in HIV)
- anti-cardiolipin antibodies (common feature of lupus) - produces false positive in syphillis (VRDL tests use beef cardiolipin)
- both antibodies cause vessel THROMBOSIS
DIC
causes: septic shock (endotoxin and macrophages produce IL1 and TNF - indirect activators), rattle snake bite, ARDs, placental injury or abruption (trophoblasts contain tissue factor aka thromboplastin), adenocarcinoma (esp mets, mucin can activate coag cascade), acute pancreatitis, nephrotic syndrome, transfusion, fatty liver in pregnancy
- note on amniotic fluid embolism - can cause DIC, but you would see hypotension and cardiogenic shock
clots in small vessels
- fibrinogen, 5, 8, 2, platelets are consumed in a clot –> increased PT and PTT
- test with d-dimer - product of lysed cross-linked fibrin
pt will bleed out of any orifice (penis, etc.), scratch, mucosa
treat by addressing underlying cause, transfuse blood products and cryoprecipitate arises (?)
blood types
O blood type
- anti-A IgM, anti-B IgM, anti-AB IgG
A group, B group
- A associated with gastric cancer
- O with duodenal ulcer
AB rarest - no antibodies
Rh negative - anti-D IgG
newborn - no antibodies in blood
- newborns dont synthesize IgM until they are born
- 2-3mo of age, they synthesize IgG
elderly - dont have any antibodies (or very low levels)
- old person can get a transfusion of the wrong blood and will not have a reaction
Rh antigens (5 antigens) - Rh positive = means positive for D antigen
Duffy antigen missing in black population
- not as likely to P. vivax malaria
- thalassemias protect from P. falciparum (RBC has a shorter life span)
major cross match - are there any antibodies in pts serum will attack donor cells
- antibody screen by indirect Coombs (pts serum is added to RBCs)
(direct Coombs - take pts RBCs and add anti-human Ig, cells will agglutinate if they have anti-RBC antibodies bound to them)
- side note- more blood transfusions means you will make antibodies against those foreign cells.. harder to find blood matches
Weibel-Palade bodies
vWF factor, P-selectin
platelet receptor changes
platelet plug:
injury - endothelin and neural vasoconstriction
platelets release vWF
vWF lines subendothelial collagen
platelets binds vWF via GP1B = platelet adhesion
platelets get activated and release ADP and TXA2
fibrinogen links to Gp2b/3a = platelet aggregation
move on to coagulation cascade
quantitative bleeding
platelet count <50K is an issue
bleeding time - nl = 2-7 min
mucosal and skin bleeding (this includes menorrhagia),
intracranial bleeds
petechiae, purpura, ecchymoses
