Pathoma Flashcards
1
Q
primary hemostasis
A
- transient vasoconstriction of damaged vessel by reflex neural stimulation and endothelin release
- platelet adhesion: vWF (derived from Weibel-Palade bodies of endothelial cells and a-grandules of platelets) binds exposed subendothelial collagen
- platelet degranulation→ ADP release promotes exposure of GPIIb/IIIa receptor on plaeteles; TXA2 synthesized by platelet COX
- platelet aggregation via GPIIb/IIIa using fibrinogen linker molecule
2
Q
disorders of primary hemostasis
A
- abnormalities in platelets → mucosal and skin bleeding (MC: epistaxis; petechiae, purpura, ecchymoses)
- immune thrombocytopenic purpura (ITP): IgG against platelet antigens (GPIIb/IIIa)
- microangiopathic hemolytic anemia: pathologic formation of platelet microthrombi in small vessels
- qualitative platelet disorders: bernard soulier; glanzmann thrombasthenia
3
Q
immune thrombocytopenic purpura (ITP)
A
- IgG against platelet antigens (GPIIb/IIIa)
- antibody bound platelets consumed by splenic macrophages→ MC cause of thrombocytopenia
- acute: children weeks after viral infection or immunization
- chronic: women of childbearing age, primary or secondary, antiplatelet IgG can cross the placenta
- labs: low platelet (<50), normal PT/PTT, high megakaryocytes on bone marrow biopsy
- treatment: corticosteroids, IVIG to raise platelet count, splenectomy (in refractory cases)
4
Q
microangiopathic hemolytic anemia
A
- platelet microthrombi in small vessels→ sheared→ hemolytic anemia with schistocytes
- TTP: decreased ADAMATS13 due to autoantibody (enzyme that normally cleaves vWF)→ abnormal platelet adhesion and microthrombi; CNS abnormalities
- HUS: endothelial damage by drugs or infection, classical e.coli O157:H7 dysentery (verotoxin damages endothelium); renal insufficiency
- Labs: thrombocytopenia with increased bleeding time, normal PT/PTT, anemia with schistocytes
- treatment: plasmapheresis, corticosteroids
5
Q
qualitative platelet disorders
A
- bernard-soulier: genetic GPIb deficiency→ imparied platelet adhesion; mild thrombocytopenia with enlarged platelets
- glanzmann thrombasthenia: genetic GPIIb/IIIa defieincy→ impaired platelet aggregation
- aspirin: irreversibly inactivates COX→ lack of TXA2 which impairs aggregation
- uremia: N builds up→ imparied aggregation and adhesion
6
Q
secondary hemostasis
A
- stabilizes weak platelet plug: coagulation cascade generates thrombin which converts fibrogen→ fibrin
- factors of coagulation cascade are made in liver in inactive state; activation requires
- exposire to activating substance
- intrinsic: damaged surface (subendothelial collagen)
- extrinsic: trauma (tissue thromboplastin)
- phospholipid surface of platelets
- Ca2+ (derived from platelet dense granules)
- exposire to activating substance
7
Q
disorders of secondary hemostasis
A
- usually due to factor abnormalities
- clinical features: deep tissue bleeding into muscle and joinrs and rebleeding after surgical procedure
- PT: measures extrinsic (VII) and common (II, V, X, fibrinogen) factors
- PTT: measures intrinsic (XII, XI, IX, VIII) and common (II, V, X, fibrinogen) factors
- hemophilia A: factor VIII deficiency
- hemophilia B: factor IX deficiency
- coagulation factor inhibitor: anti-VIII MC
- von willebrand disease: vWF deficiency
- vitamin K deficiency
8
Q
hemophilia A
A
- X-linked recessive FVIII deficiency; can arise de novo
- labs: high PTT, normal PT, low FVIII
- normal platelet count and bleeding time
- treat: recombinant FVIII
9
Q
hemophilia B
A
- FIX deficiency
- labs: high PTT, normal PT, low FIX
- normal platelet count and bleeding time
10
Q
von willebrand disease
A
- MC inherited coagulation disorder; multiple subtypes, MC is AD with decreased vWF
- presentation: milk mucosal and skin bleeding
- labs: increased bleeding time, high PTT, normal PT (vWF normally stabilized FVIII), abnormal ristocetin test (ristocetin induces platelet agglutination by causing vWF to ind platelet GPIb)
- treatment: desmopressin (ADH analog) which increased vWF release from weibel-palade bodies
11
Q
vitamin K deficiency
A
- disrupts function of multiple coagulation factors
- Vitamin K is activated by epoxide reductase in liver→ gamma carboxylates FII, VII, IX, X and proteins C and S
- newborns: lack of GI flora that normally synthesizes K (prophylaxis to all newborns to prevent HDFN)
- long-term antibiotic therapy: disrupts GI flora
- malabsorption: leads to deficiency of fat soluble vitamins
12
Q
other causes of abnormal secondary hemostasis
A
- liver failure→ decreased production of coagulation factors and decreased activation of K by epoxide reductase; follow with PT
- large volume transfusion: dilutes coagulation factors→ relative deficiency
13
Q
heparin induced thrombocytopenia
A
- platelet destruction secondary to heparin therapy
- 4 Ts
- Thrombocytopenia without bleeding
- Timing 5-14 days
- Thrombosis
- oTher causes ruled out
14
Q
disseminated intravascular coagulation (DIC)
A
- pathologic activation of coagulation cascade→ widespread microthrombi→ ischemia and infarction; consumption of platelets and factors→ bleeding
- usually secondary to another process
- OB complications: activated by tissue thromboplastin in amniotic fluid
- sepsis: activated by toxins (esp. e. coli or n. meningitidis)
- adenocarcinoma: activated by mucin
- APL: activated by primary granules
- rattlesnake bite: activated by venom
- low platelet, high PT/PTT, low fibrinogen, elevated fibrin split products esp. D-dimer (best screening test)
- treat underlying cause; transfusion with blood products and cryoprecipitate
15
Q
disorders of fibrinolysis
A
- normally
- tPA converts plasminogen→ plasmin which cleaves fibrin and serum fibrinogen, destroys coagulation factors and blocks platelet aggregation
- a2-antiplasmin inactivates plasmin
- disorders are due to plasmin overactivity→ excessive cleavage
- radical prostatectomy: urokinase activates plasmin
- cirrhosis: reduced a2-antiplasmin
- looks like DIC (high PT/PTT, high bleeding time) BUT normal platelet count and increased fibrogen split products without D-dimers
- treat: aminocaproic acid (blocks activation of plasminogen)
16
Q
thrombosis
A
- pathologic formation of intravascular blood clots (thrombus)
- MC in DVT of leg below knee
- caracteried by lines of zahn (alternating layers of platelets/fibrin and RBS) and attachment to vessel wall
- virchow’s triad of 3 risk factors: disruption in blood flow, endothelial cell damage (caused by atherosclerosis, vasculitis, and high levels of homocysteine), hypercoagulable state
17
Q
how does endothelial cell damage predispose thrombus formation?
A
normally endothelial cells prevent thrombosis by:
- blocking exposure to subendothelial collagen and underlying tissue factor
- producing PGI2 and NO→ vasodilation and inhibition of platelet aggregation
- secreting heparin-like molecules that august antithrombin III
- secreting tPA
- secreting thrombomodulin: redirects thrombin to activate protein C (instead of converting fibrinogen to fibrin)→ inactivation of FV and VIII
18
Q
hypercoagulable state
A
- classically presents as recurrent DCTs or DVT at young age
-
Protein C or S deficiency: AD, decreases negative feedback on coagulation cascade (normally inhibit FV, VIII)
- increased risk for warfarin skin necrosis (initially warfarin leads to temporary deficiency of proteins C and S due to shorter half life relative to FII, VII, IX, X); use heparin at same time until all coagulation factors become depleated
- FV Leiden mutated FV that lacks cleavage site for deactivation by proteins C and S
- Prothrombin 20210A: inherited point mutation in prothrombin→ increased gene expression
- ATIII deficiency: decreases protect effect of heparin-like molecules produced by endothelium (PTT does not rise with standard heparin dosing)
- OCPs: estrogen→ increased production of coagulation factors
19
Q
anemia
A
-
reduction in circulating RBC mass
- Hb, Hct, and RBC used as surrgoates for RBC mass (hard to measure)
- Hb<13.5 in men; Hb<12.5 in females
- presents with signs of hypoxia (weakness, fatigue, dyspnea, pale conjunctiva and skin)
20
Q
microcytic anemias
A
- MCV<80 due to decreased production of Hb (RBCs divide multiple times to maintain concentration of Hb/cell)
- types
- Fe deficiency anemia (decreased heme)
- ACD (Fe sequestered in macrophages)
- sideroblasic anemia (decrease in protoporphyrin)
- thalassemia (decrease in globin chain)
21
Q
iron deficiency anemia
A
- low Fe→ low heme→ low Hb→ microcytic anemia
- MCC of anemia; dietary lack or blood loss
- stages
- Fe depleated (low ferritin, high TIBC)
- Serum Fe depleated (low serum Fe, low % sat); high free erythrocyte protoporphyrin
- normocytic anemia: bone marrow makes fewer, normal sized RBCs
- microcytic hypochromic anemia: bone marrow smaller and fewer RBCs (high RDW)
- clinical features: anemia, koilonychia (spoon nails), pica
- treat with supplemental ferrous sulfate
22
Q
Fe transport/storage and measurements
A
- absorption in duodenum (heme is more readily absorbed by enterocyte)→ Fe transport into blood via ferroportin→ transferrin transports Fe in blood to liver and bone marrow macrophages→ stored intracellularly bound to ferritin (prevents free radical formation)
- serum Fe: Fe in blood
- TIBC: mesausre of transferrin in blood
- % sat: percentage of transferrin bound by Fe (33% is normal)
- serum ferritin: iron stores in macrophages and liver
23
Q
plummer-vinson syndrome
A
iron deficiency anemia with esophageal wed and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue
24
Q
anemia of chronic disease
A
- chronic disease→ acute phase reactants including hepcidin
- hepcidin: prevent bacteria from accessing Fe (necessary for survival); sequesters Fe in storage sites by limiting Fe transfer from macrophages to erythroid precursons and suppressing EPO production
- low available Fe→ low heme→ low Hb→ microcytic anemia
- high ferritin, low TIBC, low serum Fe, low % sat
- high free erythrocyte protoporphyrin
- treat underlying cause
25
sideroblastic anemia
* defective protoporphyrin synthesis
* succinyl CoA→ ALA via ALAS and B6 cofactor (rate limiting)
* ALA→ porpho B→ proto+Fe→ heme (ferrochelatase attaches proto to Fe in mitochondria)
* if no proto, Fe trapped in mitochondria→ Fe ring around nucleus **(ringed sideroblasts)**
* congential: ALAS defects
* acquired: alcoholism (mitochondrial poison), Pb poisoning (inhibits ALAD and ferrochelatase); B6 deficiency (ALAS cofactor; side effect of isoniazid)
* **iron overload: high ferritin, low TIBC, high serum Fe, high % sat**
26
a-thalassemia
gene *deletion* on chromosome 16
* 1 deletion: asymptomatic
* 2 deletions: mild anemia with high RBC (cis deletion in Asians, trans in African/African Americans)
* 3 deletions: severe anemia, ß tetramers (HbH) damage RBCs
* 4 deletions: lethal in utero y tetramers (Hb Barts) damage RBCs
27
ß thalassemia
gene *mutation* on on chromosome 11
* **minor (ß/ß+):** mildest form, asymptomatic with increased RBCs→ *microcytic hypochromic RBCs and target cells*
* decreased HbA, increased HbA2 and HbF
* **major (ß0/ß0):** severe anemia after birth (high HbF is protective); unpaired a chains precipitate and damage RBCs→ ineffective erythropoeisis and *extravascular hemolysis*→ *massive erythroid hyperpasmia*→ *microcytic hypochromic RBCs with target cells and nucleated RBCs*
* chronic transfusions necessary, risk for secondary hemochromatosis
28
macrocytic anemia
* anemia with MCV\>100
* **MC due to folate or B12 deficiency (megaloblastic anemia)**
* impaired synthesis of DNA precursors→ pancytopenia, imparied division/enlargement of RBC precursors, imparied divison of granulocytic precursors leading to hypersegmented neurophils
29
folate deficiency anemia
* folate from green veggies absorbed in jejunum
* deficiency develops in months; caused by poor diet, increased demand, and folate antagonists
* **macrocytic RBCs, hypersegmented neutrophils**
* gossitis (cells of tongue aren't turning over)
* low serum and RBC folate
* **high serum homocysteine** (increases risk for thrombosis)
* **normal methylmalonic acid** (rules out B12 deficiency)
30
vitamin B12 deficiency
* B12 is complexed to animal protein, amylase liberates, binds to R-binder, cleaved by pancreatic proteases, B12 binds IF (from gastric parietal cells) and is absorbed in ileum
* takes years to develop (large hepatic stores)
* **MCC is pernicious anemia:** autoimmune destruction of parietal cells leads to IF deficiency and risk of gastric cancer
* macrocytic RBCs, hypersegmented neutrophils
* glossitis
* **subacute combined degeneration of spinal cord** (B12 is cofactor for methylmalonic acid→ succinyl CoA, causes demyelination)
* **low serum B12, high serum homocysteine, high methylmalon acid**
31
normocytic anemia
* MCV 80-100
* due to increased peripheral destruction or underproduction
* reticulocyte count helps distinguish (young RBCs, blue due to residual RNA)
* **properly functioning marrow responds to anemia by increased corrected retic count \>3%**
* **(corrected= count x Hct/45)**
* peripheral destruction is either **extravascular (macrophages)** or **intravascular (destruction within vessels)**
32
extravascular hemolysis
* RBC destruction by macrophages of spleen, liver, and lymph nodes
* globin→ amino acids
* heme→ Fe (recycled) and proto→ unconjugated BR
* findings: splenomegaly, jaundice, increased risk for BR gallstones
* marrow hyperplasia with corrected reticulocyte count \>3%
33
intravascular hemolysis
* destruction of RBCs within vessels
* **inititally low serum haptoglobin (binds up Hb that leaks out into blood)**
* hemoglobinemia
* hemoglobinuria
* hemosiderinuria (renal tubular cells pick up Hb that is filtered in urine and break it into Fe which accumulates as hemosiderin, tubular cells are eventually shed)
34
normocytic anemias with predominant extravascular hemolysis
* hereditary spherocytosis
* sickle cell anemia
* HbC
35
hereditary spherocytosis
* inherited defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectrin, or band 3.1)
* membrane blebs are formed→ round cells (with loss of central pallor) less able to maneuver through spleen→ consumed by macrophages
* high RDW and **high MCHC**
* splenomegaly, jaudice, increased risk for BR gallstones
* **diagnosis: osmotic fragility test in hypotonic solution**
* treatment: splenectomy→ spherocytes and howell-jolly bodies
36
sickle cell anemia
* AR mutation in ß chain of Hb (single AA change replaces glutamate with valine)
* HbS polymerizes when deoxygenated, aggregates into needles→ **sickle cells and target cells on smear**
* HbF protects against sickling **(hydroxyurea increases HbF)**
* cyclic sickling→ RBC membrane damage→
* **extravascular hemolysis**
* intravasclar hemolysis (RBCs with damaged membranes dehydrate→ hemolysis with low haptoglobin and target cells)
* massive erythroid hyperplasia *(risk of aplastic crisis with parvovirus B19)*
* irreversible sickling→ vasoocclusion
* **dactylitis** (vasoocclusive infact in bone)
* autosplenectomy (risk of infection with encapsulated organisms, **MCC death in kids)**
* acute chest syndrome (preciptated by pneumonia, **MCC death in adults**)
37
sickle cell trait
* 1 mutated and 1 normal ß chain→ 50% HbS
* generally asymptomatic with no anemia
* RBCs with \<50% HbS do not sickle **except in renal medulla (extreme hypoxic and hypertonic environment)**→ microinfarcts→ microscopy hematuria and eventually decreasedability to concentrate urine
38
how do you test for sickle cell anemia and trait?
* metabisulfate screen: causes all cells with HbS to sickle (positive in both disease and trait)
* Hb electrophoresis confirms presence and amound of HbS
39
hemoglobin C
* AR mutation in ß chain (normal glutamate replaced by lysis)
* characteristic **crystals in RBCs** on blood smear
* presents with mild anemia due to extravascular hemolysis
40
normocytic anemias with predominant intravascular hemolysis
* paroxysmal nocturnal hemoglobinuria (PNH)
* G6PD deficiency
41
paroxysmal nocturnal hemoglobinuria
* acquired defect in myeloid stem cells→ **absent GPI (secures DAF and MIRL to RBC, inhibiting C3 convertase, protects against complement-mediated damage)**
* episodic intravascular hemolysis esp in PM due to **mild respiratory acidosis**→ activates complement→ hemoglobinemia and hemoglobinuria esp. in AM
* screen with sucrose test, confirm with acidified serum test or flow cytometry to detect lack of CD55 (DAF)
* **MCC of death is thrombosis** of hepatic, portal, or cerebral veins (destroyed platelets release cytoplasmic contents inducing thrombosis)
* **complications: Fe deficiency anemia (chronic loss of Hb in urine), AML (develops in 10% of patients**
42
G6PD deficiency
* X-linked recessive disorder→ reduced ½ life of G6PD→ cells are susceptible to oxidative stress (infections, drugs, fava beans)
* low G6PD→ low NADPH → low GSH
* african variant: mildly reduced ½ life→ mild intravascular hemolysis
* mediterranean varient: markedly reduced ½ life→ marked intravascular hemolysis
* oxidative stress **precipitates Hb as heinz bodies**→ hemoglobinuria and back pain (Hb is nephrotoxic) hours after exposure to oxidative stress
* use heinz stain, enzyme studies can only confirm weeks at hemolytic episode because the cells without NADPH have already disease
43
immune hemolytic anemia
* antibody mediated (IgG or IgM) destruction of RBC
* diagnose with coombs test: directly (RBCs coated with antibody) or indirectly (does serum have antibody)
* **IgG: extravascular** hemolysis; binds RBCs in **warm temp of central body**, membrane of antibody-coated RBC is consumed by splenic macrophages→ spherocytes
* associated ith SLE, CLL, penicillin/ cephalosporin (drug may attach to RBC or induce production of autoantibodies)
* **IgM: intravascular hemolysis, complement mediate lysis of RBCs in cold temp of extremities**
44
microangiopathic hemolytic anemia
* intravascular hemolysis from vascular pathology (RBCs are destroyed as they pass through circulation)→ **microthrombi produce histocytes**
* Fe deficiency anemia occurs with chronic hemolysis
* occurs with microthrombi (TTP-HUS, DIC, HELLP), prosthetic heart valves, and aortic stenosis
45
malaria
* infection of RBCs and liver with *plasmodium*
* RBCs rupture as part of plasmodium lifecycle→ intravascular hemolysis and cyclical fever
* p. falciparum: daily fever
* p. vivax/ovale: fever every other day
* spleen also consumes some infected RBCs→ mild extravascular hemolysis with spenomegaly
46
anemia due to underproduction
* decreased production of RBCs→low reticulocyte count
* etiologies include:
* causes of microcytic and macrocytic anemia
* renal failure (decreased EPO by petibular interstitial cells)
* damage to bone marrow precursor cells
* **parvovirs B19**
* **aplastic anemia**
* **myelophthisic process**
47
parvovirus B19
* infects **progenitor RBCs**→temporary halt on erythropoiesis
* significant anemia in setting of preexisting marrow stress (e.g. sickle cell)
* infection is self-limited
48
aplastic anemia
* damage to hematopoietic stem cells→**pancytopenia with low reticulocyte count**
* etiology: drugs, chemicals, virus, autoimmune
* biopsy reveals **empty, fatty marrow**
* treatment: cessation of causative agent, supportive care with transfusions and marrow-stimulating factors
49
myelophthisic process
* pathologic process (e.g., metastatic cancer) that replaces bone marrow
* hematopoesis is impaired→ pancytopenia
50
arbovirus
* groups of RNA viruses transmitted by arthropod vectors
* lifecycle of vectors→ predictable transmission patterns (seasonality)
* clinical syndromes include:
* **systemic febrile illness:** chikungunya, dengue
* **fever with arthritis:** chikungunya
* **encephalitis:** JE, West Nile, VEE, EEE, WEE
* **hemorrhagic fever:** yellow fever, dengue, chikungunya
51
EEE, WEE, VEE
* togaviridae, alphavirus, +ssRNA, enveloped
* bird reservoir, horses and humans as dead-end hosts; mosquito vector
* **MC in summer**
* symptoms range from unapparent to flu-like to encephalitis
* **probability for developing encephalities varies (highest for EEE, lowest for VEE)**
* **mortality rates vary: 5% WEE, 35% VEE, 50% EEE**
* treatment is supportive; neurologic sequelae possible
52
japanese encephalitis
* flaviviridae, +ssRNA
* pigs are natural host
* mosquito vector; sexual transmission between mosquitos is possible
* JEV circulates as a single serotype→ **2 vaccines available**
53
yellow fever
* flavivirus
* hemorrhagic fever virus
* jungle cycle (monkeys as natural host) that can result in urban epidemic; mosquito vector
* **faget's sign:** bradycardia present despite rising temperature
* **YF vaccine can cause adverse reactions**
* viscerotropic (high mortality)
* neurotropic (encephalitis)
54
dengue fever
* flavivirus
* **MC arbovirus causing human infection in subtropical and tropical regions;** endemic in FL
* **maculopapular rash (petechiae):** sign of coagulopathy because blood is leakng into vascular space
* **shock syndrome:** severe form of hemorrhagic fever due to intravascular volume depletion from plasma leaking into 3rd space and/or blood loss→ cardiovascular collapse
55
strep pyogenes
* group A, ß hemolytic, bacitracin sensitive; spherical, grows in chains
* pilli: cause surface infections
* toxins: streptokinase, streptodornase, pyrogenic toxic, erythrogenic toxin
* **strep pharyngitis:** direct contact via carrier or infected person→ swelling and inflammation fof throat
* **rheumatic fever:** group A strep sequalae (M3, M5, M13 strains)→ high fever, arthritis, endocaditis, that tends to reoccur (damage is cumulative)
56
strep pharyngitis
* swelling and inflammation of the throat
* transmission: direct contact via carrier or infected person
* diagnosis: rapid office test with antibody assays (not 100% sensitive, takes a lot of swabbing); confirm with lab
* treatment: penicillin, arythromycin, cephalosporins once diagnosed
* complications
* spread to tonsils: peritonsillar abcess
* spread to floor of mouth/tongue: ludwig's angina
* spread to middle ear→ mastoiditis
* **scarlet fever:** skin rash due to circulating erythrogenic toxin, strawberry tongue (diagnostic sign)
57
rheumatic fever
* **group A strep sequela (M3, M5, M13 strains) cause immune reaction→ sterile lesions and blood**
* symptoms: high fever, arthritis/arthralgias, erythema marginatum
* **mitral valve inflammatory vegetation** (not bacterial)→ permanent incompetance of valve→ HF/murmur
* vegetations pick up bacteria→endocarditis
* high sed. rate
* no treatment, prevent with penicillin for initial strep infection
58
strep viridans
* a hemolytic, optochin resistant; spherical, grows in chains
* virulence factors: sugar metablizing enzymes (LMW sugars→ dental plaques and acids that decalcify→ caries)
* dental procedures can produce viridans bacteremia (MCC extraction of 4 first premolars)
* bacterial endocarditis due to chronic infection→ shower emboli→ metastatic abscesses and hemorrages
* treatment: prolongued penicillin/erythromycin; poor prognosis
* diagnosis: xrays, blood cultures
59
corynebacterium diptheriae
* aerobic gram + rod; non-spore forming; metachromatic granules, strains may be toxigenic or not (diphtheroids)
* inhabits skin and mucus membranes, may be asymptomatic
* spread by respiratory droplets, direct contact
* **toxin causes local and cardiac necrosis** (strep just causes inflammation not destruction of epithelium)
* necrotic coagulum of bacteria, epithelial cells, fibrin, leukocytes, erythrocytes form gray-brown **"pesudomembrane" covering oropharynx**
* diagnosis: swab (tellurite media), PCR confirmation of tox gene
* treatment: antitoxin (equine), peniccilin/erythromycin, mechanical ventilation
* vaccine: diptheria toxoid, boosters at 1 and 5
60
leukopenia
* \<5K WBCs
* **neutropenia**
* drug toxicity (e.g. chemo) damages stem cells; treat with GM-CSF or G-CSF
* severe infection (increased movement of neutrophils into tissues results in decreased circulating neutrophils
* **lymphopenia**
* immunodeficiency (e.g, DiGeorge, HIV)
* high cortisol state induces apoptosis of lymphocytes (e.g., exogenous corticosteroids or cushing's)
* autoimmune destriction
* whole body radiation (lymphocytes are highly sensitive)
61
leukocytosis
* \>10K WBCs
* **neutrophilic**
* bacterial infection or tissue necrosis→ release of marginated pool of BM neutrophils (including immature wih decreased Fc (CD16), L shift)
* high cortisol state impairs leukocyte adhesion→ release of marginated pool of neutrophils
* **monocytosis**: chronic inflammatory states and malignancy
* **eosinophilia:** allergic rxns (type 1 HSR), parasitic infections, and Hodgkin's lymphoma (high IL-5)
* **basophilia:** classically seen in CML
* **lymphocytic**
* viral infections (T lymphocytes undergo hyperplasia)
* bordatella infection→ lyphocytosis promoting factor (blocks lymphocytes from leaving blood→ lymph node)
62
infectious mononeucleosis
* **EBV→ lymphocytic leukocytosis of reactive CD8+ T cells**
* transmitted by saliva; infects oropharynx, liver, B cells
* CD8+ T cell response→
* generalized LAD due to T cell hyperplasia in paracortex
* splenomegaly due to hyerplasia in PALS (white pulp)
* high WBC with atypical lymphocytes
* mono spot test detects IgM antibodies that cross-react with horse/sheep RBCs (heterophile antibodies), confirm with serologic testing for EBV viral capsid
* complications: increased risk for splenic rupture, dormancy of virus in B cells→ risk of recurrence and B cel lymphoma (esp if immunocompromised)
63
acute leukemias
* **neoplastic proliferation of blasts (\>20% in BM) that crowd out normal hematopoeisis**→ acute presentation with anemia, thrombocytopenia, or neutropenia
* blasts→ blood→ high WBC count
* divided into ALL and AML
64
ALL
* **lyphoblasts (\>20% in BM) characterized by TdT+ nuclear staining (type of DNA polymerase)**
* MC in children, associated with Down syndrome (usually arises **after** 5 yo)
* **B-ALL (MC type)**
* **TdT+ lymphoblasts that are CD10/19/20+**
* excellent response to chemo; t(12;21) has good prognosis; t(9;22) has poor pronosis and is more commonly seen in adults (Ph ALL)
* **_T_-ALL**
* **TdT+ lymphoblasts that are CD2-CD8+, no CD10**
* presents in teenagers as a mediastinal (**_t_**hymic) mass (called acute lymphoblastic lymphoma)
65
AML
* **accumulation of immature myeloid cells (\>20% in BM)**
* **MPO+ cytoplasmic stain**; crystal aggregates can be seen as **Auer rods** (risk for DIC)
* arises in older adults (50-65); may also arise from pre-existing dysplasia (myelodysplastic syndrome) esp with prior exposure to alkylating agents or radiotherapy
* subclassification based on cytogenetics
* **APL: t(15:17) translocation of retinoic acid receptor**, blocks maturation and promyelocytes accumulate; ATRA is treatment
* **acute monocytic leukemia:** proliferation of monoblasts; usually lack MPO and chracteristically **infiltrate the gums**
* **acute megakaryoblastic leukemia:** lack MPO, associated with Down syndrome (arises **before** 5 yo)
66
chronic leukemias
* neoplastic proliferation of mature circulating lymphocytes characterized by a high WBC
* usually insideious in onset and seen in older adults
* **CLL**
* **hairy cell leukemia**
* **adult T-cell leukemia/lymphoma ATLL**
* **mycosis fungiodes**
67
CLL
* **neoplastic proliferation of naive B cells that coexpress CD5 (normally on T cell) and CD20**
* increased lymphocytes and smudge cells
* involvement of lymphndoes and generalized lymphadenopathy
* complications: **hypogammaglobulinemia (infection is MCC of death), transformation to diffuse large B-cell lymphoma (Richter transformation**) marked clinically by an enlarging lymph node or spleen
68
hairy cell leukemia
* **neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes**
* **TRAP+**
* **splenomegaly** (accumulation of hair cells in **red pulp**) and **"dry tap"** on BM aspiration (due to fibrosis)
* excellent response to 2-CDA (adenosine deaminase inhibitor)
* "trapped in red pulp, trapped in bone marrow, so can't go to lymph node"
69
adult t cell leukemia/lymphoma (ATLL)
* **neoplastic proliferation of mature CD4+ T cells**
* **associated with HTLV-1, MC seen in japan and caribean**
* **rash, lytic bone lesions with hypercalcemia (similar to myeloma except for rash)**
70
mycosis fungiodes
* **neoplastic proliferation of mature CD4+ T cells that infiltrate skin**
* rash, plaques, nodules, **pautrier microabcesses (aggregates of neoplastic cells in epidermis)**
* **Sezary syndrome:** cells spread to involved blood→lymphocytes with cerebriform nuclei (sezary cells)
71
myeloproliferative disorders
* proliferation of mature cells of myeloid lineage (classified on dominant cell produced but all myeloid lineages are increased)
* complications: **risk of hyperuricemia/gout** (high turnover of cells) and **progress to marrow fibrosis or transformation to acute leukemia**
* **CML**
* **polycythemia vera**
* **essential thrombocythemia**
* **myelofibrosis**
72
chronic myeloid leukemia (CML)
* neoplastic proliferation of mature myeloid cells esp. granulocytes **(basophils)**
* **t(9:22) Philadelphia chromosome→ BCR-ABL fusion with increase tyr kinase activity**
* imantinib blocks tyr kinase
* spenomegaly **(enlarging spleen suggests progression to accelerated phase**)
* transforms to AML (2/3 cases) or ALL (1/3 cases) since mutation is in a pluripotent stem cell
* distinguish from leukemoid reaction:
* negative leukocyte alk phos stain
* increased basophils
* t(9:22)
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polycythemia vera
* neoplastic proliferation of mature myeloid cells esp. **RBCs**
* associated with **JAK2 kinase mutation**
* symptoms due to hyperviscosity of blood
* blurry vision/headache
* increased risk of venous thrombosis
* flushed face
* itching (esp. after bathing)
* fatal without phlebotomy (or hydroxyurea)
* distinguish from reactive polycythemia
* **PV: EPO decreased and normal O2 sat**
* RP due to high alt. or lung disease: O2 sat low and EPO increased
* RP due to ectpic EPO from renal cell carcinoma: high EPO, normal O2 sat
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essential thrombocythemia
* neoplastic proliferation of mature myeloid cells, esp. **platelets**
* associated with **JAK2 kinase mutation**
* symptoms related to increased risk of bleeding/thrombosis
* rarely progresses to marrow fibrosis or acute leukemia
* no significant risk of hyperuricemia/gout
75
myelofibrosis
* neoplastic proliferation of mature myeloid cells esp. **megakaryocytes**
* **JAK2 kinase mutation** (50% of cases)
* **megakaryocytes produce excess PDGF**→ marrow fibrosis
* splenomegaly due to extramedullary hematopoiesis
* leukoerythroblastic smeal (tear drop RBCs, nucleated RBCs, immutre granulocutes)
* increased risk of infection, thrombosis, bleeding
76
lymphadenopathy
* painful: lymph nodes that are draining a region of acute infection
* painless: chronic inflammation, metastatic carcinoma, or lymphoma
* **follicular hyperplasia (B cell region):** RA and early stages of HIV infection
* **paracortex hyperplasia (T cell region):** viral infections
* **hyperplasia of sinus histiocytes (in medulla):** lymph nodes that are draining a tissue with cancer
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non-Hodgkin vs. Hodgkin lymphomas
* **non-hodgkin (60%)**
* malignant cell: lymphoid cells
* composition: **lymphoid cells**
* **painless LAD; late adulthood**
* diffuse spread
* staging is of limited importance; leukemic phase occurs
* **hodgkin (40%)**
* malignant cell: **reed-sternberg cell**
* composition: **reactive cells**
* **painless LAD; young adults**
* contigous
* staging guides therapy; no leukemic phase
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follicular lymphoma
* neoplastic proliferation of **small B cells (CD20+) that form follicule-like nodules (HL)**
* **t(14:18)→ overexpression of Bcl2 (inhibits apoptosis)**
* treatment: rituximab (anti-CD20 antibody)
* progression to diffuse large B cell lymphoma is important complication (enlarging lymph node)
* distinguish from reactive follicular hyperplasia
* disruption of normal lymph architechture
* **lack of tingible body macrophages** in germinal centers
* BCl2 expression
* monoclonality
79
mantle cell lymphoma
* neoplastic proliferation of **small B cells (CD20+) that expand marginal zone (HL)**
* associated with chronical inflammatory states (hasimoto, sjogren, h. pylori)
* **MALToma:** marginal zone lymphoma in mucosal sites
80
burkitt lymphoma
* neoplastic proliferation of **intermedate sized B cells (CD20+); HL** **associated with EBV**
* **extranodal mass in child/y.a.**
* **african form involves jaw**
* **sporadic form involves abdomen**
* **t(8:14): c-myc overexpression promotes cell growth**
81
diffuse large B cell lymphoma
* neoplastic proliferation of **large B cells (CD20+) that row diffusely in sheets (HL)**
* **MC form of NHL; clinically aggressive**
* sporadically or from transformation of a low-grade lymphoma (e.g., follicular)
* presents in late adulthood as enlarging lymph node/extranodal mass
82
hodgkin lymphoma
* neoplastic proliferation of **reed sternberg cells (large B cells with multilobed nuclei and prominent nucleoli--owl eyed); CD15/CD30+**
* RS→ cytokines
* reactive inflammatory cells make up bulk of tumor (form basis of classification)
83
subtypes of hodgkin lymphoma
* **nodular sclerosis MC (70%):** enlarging cervical or mediastinal lymph node in y.a., female; **node is divided by bands of sclerosis, RS cells in lake-like spaces**
* **lymphocyte rich:** best pronosis
* **mixed cellulary:** associated with abundant eosinophilas (RS produces IL5)
* **lyphocyte depleted:** most aggressive; seen in elderly and HIV+
84
dyscrasias
plasma cell disorders
* mutiple myeloma
* monoclonal gammopathy of undetermined significants
* waldenstrom macroglobulemia
85
mutiple myeloma
* malignant proliferation of plasma cells in BM
* **MC primary malignancy of bone**
* high serum IL6 may be present (stimulates plasma cel growth and Ig production)
* **bone pain with hypercalcemia:** plasma cells activate RANK receptor on osteoclasts→ **lytic punched out lesions**
* **elevated serum protein:** M spike of IgG or IgA
* **increased risk of infection:** monoclonal antibodies lack antigenic diversity
* **rouleux formation**
* **primary AL amyloidosis**
* **Bence Jones proteinuria**
86
monoclonal gammopathy of undetermined significance
increased serum protein with M spike but no lytic lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria; common in elderly (5% of 70 y.o.)
87
waldenstrom macroglobulinemia
* **B cell lymphoma with monoclonal IgM production**
* generalized LAD, no lytic bone lesions
* **M spike of IgM**
* **visual and neurologic deficits: IgM is large and causes serum hyperviscosity**
* **bleeding: high viscosity→ defective platelet aggregation**
88
langerhans cell histiocytosis
* langerhans cells: specialized dendritic cells in skin; derived from BM monocytes, present antigen to naive T cells
* neoplastic proliferation→ Birbeck (tennis racket) granules; CD1a+ and S100+
* **letterer-siwe:** malignant; skin rash and cystic skeletal defect in \<2 y.o.; rapidly fatal
* **eosinophilic granuloma:** benign proliferation→ pathologic fracture in adolescent; no skin involvement
* **hand-schuller-christian:** malignant; scalp rash, lytic skull defects, diabetes, exopthalmos in \< 3 y.o.
