ic7 - anemia and drug induced hematological disorders

Question 1

how do you classify the different types of anemia

Answer 1

1. hypoproliferative (marrow damage, Fe deficiency, decr stimulation due to diseases or inflamm)
2. maturation disorders (cytoplasmic defects and nuclear maturation defect)
   [cytoplasmic defects incl thalaseemia, Fe deficiency, sideroblastic] [nuclear maturation Fe defect incl folate and vB12 deficiency, refractory anemia]
3. hemorrhage/ hemolysis (blood loss, intravascular hemolysis, autoimmune disease, hemoglobinopathy, metabolic/ membrane defect)

Question 2

why would CKD patients have anemia

Answer 2

CKD pts have decr production of EPO thus decr production or RBC

Question 3

what is thalassemia

Answer 3

inherited disorder of Hb chain synthesis

Question 4

what is sideroblastic anemia and what are its common causes

Answer 4

result from acquired congenital defects in heme synthesis

common causes include lead poisoning, alcohol abuse, copper deficiency, medications like isoniazid and linezolid

Question 5

what are the most common causes of anemia

Answer 5

Fe deficiency
vitB12 deficiency or folic acid deficiency
anemia of chronic disease/ anemia of inflamm
drug induced anemia

Question 6

what are the types of mechanisms of Fe deficiency and list conditions that causes these mechanisms

Answer 6

decr Fe absorption (atrophic gastritis, PPI, other medications that decr gastric acidity, H pylori infection, gastric bypass, Ca rich food)

blood or Fe loss (pulmonary hemosiderosis, intravascular hemolysis, hematuria or hemoglobinuria)

Question 7

where is Fe absorbed in in the body

Answer 7

stomach

Question 8

what tx should be given for Fe deficiency (what agents for Fe supplementation) and how long would tx last

Answer 8

1000-1500mg of elemental Fe for complete supplementation for 3-6m for Fe stores to replete

ferrous gluconate (sangiobion) if not that deficient -> contains 30mg of elemental iron per tablet

iron polymaltose drops or tablets (maltofer) if CKD or early CKD -> contains 50mg/ml or 100mg of elemental iron

Question 9

why might CKD patients be given Fe supplementation

Answer 9

CKD patients likely given EPO which requires Fe as a substrate to produce more EPO to produce more RBC

Question 10

what are the conditions that can cause anemia of chronic disease/ anemia of inflamm and why would a chronic disease cause anemia

Answer 10

chronic inflamm states incr chemical hepcidin which is a hormone that regulates how our body uses Fe and when there is incr hepcidin, it inhibits intestinal Fe absorption

malignancy, HIV, rheumatologic disorders, IBS, castleman disease, HF, renal insufficiency, COPD

Question 11

what is the steps to take when approaching a pt to diagnose anemia

Answer 11

hx taking: any blood loss, duration of anemia, genetic or aquired, assoc features due to infection or malignancy, any comorbs known to cause anemia

physical examination: pallor, jaundice, others which are RED FLAGS (lymphadenopathy, hepatosplenomegaly, bone tenderness, petechiae, ecchymoses)

lab evaluation (draw out flow chart): FBC (Hb count), reticulocyte count, peripheral smear

path 1 -> MCV, serum ferritin, TIBC
path 2 -> MCV, vitB12 and folate levels
path 3 -> MCV, reticulocyte count, WBC and PLT count

Question 12

what is the Hb cut off to diagnose anemia

Answer 12

<11 for males, <13 for females

Question 13

what does peripheral smear show

Answer 13

it can show:

microcytic (smaller nucleus than mature RBC)

hypochromic (more than 1/3 cell central pallor)

poikilocytosis (RBCs of different shapes)

Question 14

what is petechiae and ecchymoses

Answer 14

petechiae is purple spots on skin

ecchymoses is small bruise resulting from blood leaking from broken blood vessels into skin tissues or mucus membranes

Question 15

what is serum ferritin indicative of

Answer 15

Fe stores in body

Question 16

what is TIBC

Answer 16

total Fe binding capacity which refers to the capacity of the body to carry Fe stores to sites for RBC production

Question 17

what is TSAT

Answer 17

transferrin saturation which is ratio of serum Fe to TIBC

Question 18

compare levels of ferritin, Fe and TIBC between Fe deficient anemia and anemia of chronic diseases

Answer 18

Fe deficient anemia: low Fe, low ferritin, high TIBC

anemia of inflamm: normal or decr ferritin, decr Fe, decr TIBC

Question 19

what are megaloblasts and macrocytes

Answer 19

megaloblasts are large nucleated RBC precursors with non condensed chromatin due to impaired DNA synthesis

macrocytes are enlarged RBCs with increased MCV

Question 20

what are the possible causes of vitB12 deficiency

Answer 20

causes of pernicious anemia incl decreased absorption (lack of intrinsic factor or gastric disruption), nutritional deficiencies (vitB12 found exclusively in meats), other causes (PPI and H2RA which increases gastric pH but acidic pH req for B12 and Fe absorption, and H pylori infection)

Question 21

what is the tx for pernicious anemia

Answer 21

parenteral (IM or SQ) vitB12 given 1000mcg daily for 1w f/b 1000mcg q1w for 4w f/b 1000mcg q1m for life

Question 22

how is PO vitB12 absorbed

Answer 22

by mass action and not reliant on action of intrinsic factor but PO often insufficient

Question 23

what is vitB9

Answer 23

folate

Question 24

what are the possible causes of folate deficiency

Answer 24

nutritional

Question 25

what is the tx for folate deficiency

Answer 25

1mg/d of folate for 1-4m until hematologic recovery as seen from normalising Hb

Question 26

what are the drug induced hematologic disorders

Answer 26

aplastic anemia drug induced neutropenia/ agranulocytosis hemolytic anemia megaloblastic anemia thrombocytopenia

Question 27

how to determine what kind of drug induced hematological disorder

Answer 27

link based on which cell line the hematopoietic stem cell differentiates into agranulocytosis: from myeloblasts -> metamyelocyte -> neutrophil hemolytic anemia: from proerythroblasts -> normoblast -> RBC thrombocytopenia: from megakaryoblast -> megakaryocyte -> PLTs

Question 28

what are the drugs assoc with aplastic anemia

Answer 28

drugs that cause bone marrow failure (chemotx, radiation tx) CBZ, PHT, sulfonamides, NSAIDs, PB, aspirin, chloramphenicol, dapsone, ticlopidine

Question 29

what is the diagnostic criteria for aplastic anemia

Answer 29

any two of the following WBC 3500 cells/mm3 and below (3.5x10^9) PLT 55000 cells/mm3 and below (55 x10^9) Hb 10 g/dL and below AND reticulocyte count 30000 cells/mm3 and below (30x10^9)

Question 30

what are the types of aplastic anemia

Answer 30

inherited: fanconi's, blackfan diamond acquired: drugs, viruses (may present with pancytopenia), chemical exposure (may present with pancytopenia)

Question 31

what is pancytopenia

Answer 31

lower than normal RBC, WBC and PLT count

Question 32

what is the tx for aplastic anemia

Answer 32

step 1: withhold offending drug step 2: manage risk for infections -> prophylactic abs and antifungal agents when neutrophil count <500cells/mm3 (0.5x10^9), if febrile neutropenia aka presenting with fever then give broad spectrum abx step 3: manage risk for bleeding (due to low PLT) -> transfusion support with erythrocytes and PLT step 4: consider HSCT and immunosuppressive tx using ciclosporin

Question 33

what happens if heavily transfused with erythrocytes and PLT and what should the next step be

Answer 33

overtransfusion can lead to Fe toxicity iron chelation therapy by using IV deferoxamine or PO defasirox

Question 34

what are the goals of tx for aplastic anemia

Answer 34

to improve peripheral blood counts, limit the requirement for transfusions and minimise risk of infection

Question 35

how do you define neutropenia and agranulocytosis based on absolute neutrophil count (ANC)

Answer 35

neutropenia is when ANC is <1500/mcL (1.5x10^9) agranulocytosis is when ANC = 0 aka absence of granulocytes but also loosely defines severe neutropenia when ANC <100, 200, 500/ mcL

Question 36

what is ANC

Answer 36

ANC is absolute neutrophil count which is numerically equal to the product of WBC and fraction of polymorphonuclear cells and band forms noted on the differential analysis

Question 37

what are the drugs assoc with neutropenia/ agranulocytosis and how and how fast do these drugs result in neutropenia/ agranulocytosis

Answer 37

antipsychotics, abx, antithyroid antipsychotics like clozapine and other phenothiazines show effect 2-15w after initiation (peak onset 3-4w) which is slightly faster than antithyroid antithyroid causes it via unknown mechanism but genomics may be involved (HLAB*38:02 and HLADRB1*08:03 in chinese, HLAB*27:05 in white), more freq in >40yo and within 2m after initiation abx has rapid onset of sx and is dose related likely due to accumulation of drug to toxic conc

Question 38

what should pts look for for indications of neutropenia

Answer 38

fever, cough, sob, sore throat, chills and sweat (think infection sx)

Question 39

what is the tx for neutropenia/ agranulocytosis

Answer 39

step 1: withhold drug step 2: note that blood cell counts typically normalise within 2-4w depending on which cell line affected bc each have their own half life and own production path step 3: give SQ filgrastim 300mcg/d if neutrophil nadir <100cells/mm3 (0.1x10^9) step 4: unlikely to restart offending drug unless penicillin then maybe restart at lower dose if necessary

Question 40

what is nadir

Answer 40

lowest point

Question 41

how do you diagnose hemolytic anemia

Answer 41

through direct and indirect coomb's test

Question 42

what are the types of hemolytic anemia

Answer 42

immune (IgG and IgM mediated RBC destruction, drug or non drug dependent) metabolic (G6PD deficiency, Hb oxidation causing hemolysis)

Question 43

what are the drugs assoc w hemolytic anemia

Answer 43

methyldopa, quinidine, quinine, penicillin, cephalosporin, streptomycin

Question 44

what are the drugs assoc w oxidative hemolytic anemia

Answer 44

dapsone, metformin

Question 45

how to classify degree of G6PD deficiency and which are of clinical significance and differentiate between each

Answer 45

class I, II or III are of clinical significance class I variants have severe enzyme deficiency (<10% of normal) and assoc w chronic hemolytic anemia class II variants also have severe enzyme deficiency but usually only intermittent hemolysis typically on exposure to oxidant stress class III variants have moderate enzyme deficiency (10-60% of normal) with intermittent hemolysis typically assoc w significant oxidant stress

Question 46

what is the role of G6PD

Answer 46

G6PD protects RBC from oxidative damage

Question 47

what are the drugs and substances unsafe in moderate to severe G6PD deficiency

Answer 47

fluoroquinolones (ciprofloxacin), quinine and primaquine and tafenoquine for malaria tx, sulfonylureas (glipizide), fava beans, henna compounds, naphthalene in moth balls and lavatory deodorant)

Question 48

what is megaloblastic anemia

Answer 48

characterised by very large RBC and very few RBC

Question 49

what are the drugs assoc w megaloblastic anemia and what should be done for each drug

Answer 49

antimetabolite (MTX for chemotx) -> hold off and give alternative co-trimoxazole -> (esp when vitB12 or folate deficiency) give folinic acid 5-10mg up to QDS ASM (PHT, PB) -> inhibits folate absorption or catalyse folate catabolism, give folic acid 1mg/d (but controversial bc may decr efficacy of PHT for some thus can just switch to another ASM)

Question 50

how to diagnose thrombocytopenia

Answer 50

any of the following: PLT count 100,000 cells/mm3 or less (100x10^9) or greater than 50% reduction from baseline

Question 51

how fast are onset of sx indicating thrombocytopenia

Answer 51

1-2w after new drug initiated or immediately if agent used intermittently in past (eg. UFH) or rapid onset for GPIIb/IIIai (eg. eptifibatide)

Question 52

what are the drugs assoc w thrombocytopenia

Answer 52

ASM (PHT, CBZ, VPA, PB) and abx heparin, GPIIb/IIIai

Question 53

what are the types of heparin induced thrombocytopenia

Answer 53

HIT I and HIT II HIT I is not significant

Question 54

what to note if there is HIT

Answer 54

cross reactivity with LMWH

Question 55

for what types of pts is heparin commonly used for

Answer 55

for dialysis, heparin used to flush catheter for PCI, bolus UFH given

Question 56

what class of drugs can be used for managing HIT

Answer 56

DOACs (eg. dabigatran)

Question 57

what is the tx for thrombocytopenia

Answer 57

step 1: withhold offending drug step 2: recovery begins 1-2d after discontinuation of drug and is likely to be done after 1w (bc of PLT half life) but Ab likely to persist indefinitely thus unlikely to reinitiate offending drug (eg. pts who experienced HIT may have PF4 Ab)

Question 58

how to predict probability of HIT

Answer 58

using 4T score, if score = 6 then high probability thrombocytopenia timing of PLT count fall thrombosis or other sequelae other causes for thrombocytopenia thrombocytopenia: PLT fall >50% and PLT count nadir 20 and above [2] PLT fall 30-50% or PLT nadir 10-19 [1] PLT fall <30% or PLT nadir <10 [0] timing of PLT fall: clear onset between days 5-10 or PLT fall in 1 or less days with prior heparin exposure within 30d [2] consistent with days 5-10 fall but not clear/ onset after day 10 or fall in 1 or less days with prior heparin exposure 30-100days [1] PLT count fall <4 days without recent exposure [0] thrombosis or other sequalae: new thrombosis/ skin necrosis, acute systemic rxn postIV UFH bolus) [2] progressive or recurrent thrombosis/ non necrotising skin lesions/ suspected thrombosis [1] none [0] other causes for thrombocytopeia: none [2] possible [1] definite [0]

Question 58

how to predict probability of HIT

Answer 58

using 4T score, if score = 6 then high probability thrombocytopenia timing of PLT count fall thrombosis or other sequelae other causes for thrombocytopenia thrombocytopenia: PLT fall >50% and PLT count nadir 20 and above [2] PLT fall 30-50% or PLT nadir 10-19 [1] PLT fall <30% or PLT nadir <10 [0] timing of PLT fall: clear onset between days 5-10 or PLT fall in 1 or less days with prior heparin exposure within 30d [2] consistent with days 5-10 fall but not clear/ onset after day 10 or fall in 1 or less days with prior heparin exposure 30-100days [1] PLT count fall <4 days without recent exposure [0] thrombosis or other sequalae: new thrombosis/ skin necrosis, acute systemic rxn postIV UFH bolus) [2] progressive or recurrent thrombosis/ non necrotising skin lesions/ suspected thrombosis [1] none [0] other causes for thrombocytopeia: none [2] possible [1] definite [0]