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PR3154 > drug induced haematological disorders > Flashcards

drug induced haematological disorders Flashcards

1
Q

functional classification of anemia

A
  • hypoproliferative (marrow damage/ Fe def/ decr stimulation - renal)
  • maturation disorders (cytoplasmic – Fe, thalassemia)
    (nuclear maturation – folata, vit B12)
  • hemorrhage (bloodloss, autoimmune disease, metabolic/ mem defects)
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2
Q

common causes of anemia

A

Fe deficiency
vit B12, folate deficiency
anemia of inflammation/ anemia of chronic disease
drug-induced

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3
Q

approach pt

A

hx, sx
physical examination
lab evalulation

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4
Q

drugs that can cause aplastic anemia

A

dose dependent direct drug toxicity (cancer chemo, chloramphenicol)

idiosyncratic, toxic metabolites (CBMZ, PT)

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5
Q

hx taking

A
  • Any blood loss?
  • Duration of anemia? Genetic or acquired?
  • Associated features? Due to infection or chronic diseases (CKD)
  • Malignancy?
  • Comorbidities known to cause anemia?
    ◊ RF, CKD, rheumatoid , arthritis, IBD
  • Ethnicity
  • New medication?
  • Diet?
  • Recurrent?
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6
Q

physical examination

A
  • Pallor – 70% sensitivity, 100% specificity
    ◊ Skin, tongue, nail bed
  • Jaundice
    ◊ Hemolytic anemia. Excess bilirubin
  • Others:
    Lymphadenopathy, hepatosplenomegaly, bone tenderness, petechiae, ecchymoses
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7
Q

lab evaluation

A
  • FBC
    F < 11 - 11.9 g/dL
    M < 11 -12.9 g/dL
    preg < 10-10.9 g/dL
  • reticulocyte count (0.5-2.5%)
  • peripheral smear (size, shape, number of blood cells)
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8
Q

reticulocyte count (0.5-2.5%)

A

decr: bone marrow failure, radiation, liver cirrhosis

incr: recent blood loss/ decr in RBC , preg (RECOVERY from deficiency)

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9
Q

peripheral smear

A

Microcytic: Smaller than the nucleus of a mature lymphocyte
- Fe deficient

Hypochromic: central pallor over 1/3 of cell

Macrocytic: large RBC
-Megaloblastic anemia (def of vit B12, folic acid)
- Non-megaloblastic

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10
Q

Fe deficient criteria

A

Microcytic

  • low MCV
  • low ferritin
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11
Q

Fe deficient prompts to find etiology

A
  • Scopes
    • Enteroscopy: upper GI
    • Colonoscopy
    • Endoscopy: SI
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12
Q

Fe deficient causes

A

Decr Fe absorption
* Celiac disease
* Gastric bypass
* H. pylori
* Ca rich food
* PPI (incr pH)

Blood/ Fe loss
* Pul hemosiderosis
* IV hemolysis
*Hematuria, hemoglobinuria

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13
Q

tx for Fe deficiency

A
  • Sufficient Fe = 1000 - 1500mg of elemental Fe for complete supplementation
    • Ferrous gluconate tab 30mg sangobion (12%)
    • Iron polymaltose 100mg Maltofer (100%)
    • (20-30 ~~ 200)
  • 3-6 mnths to replenish
  • Depends on :
    • Pt adherence
    • SE (GIT complaints, NV, C)
    • Pt severity
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14
Q

Anemia of chronic disease

features of RBC

A

Microcytic
- low MCV
- normal ferritin
- low TIBC/ TSAT/ transferrin

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15
Q

ferritin? TIBC?

A

ferritin: iron stores in body

TIBC: transferrin protein that transports Fe

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16
Q

anemia of chronic disease caused by (8)

A
  • Malignancy
  • HIV infection
  • Rheumatologic disorders
    • Incr hepcidin, decr Fe absorption
  • IBD
  • Castleman disease
  • HF
  • Renal insufficiency
  • COPD
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17
Q

other causes of microcytic anemia

  • low MCV
  • normal ferritin
  • high, norm TIBC/ TSAT/ transferrin
A

Thalassemia
* Disorder of Hb chain synthesis

Sideroblastic anemia
* Congenital defects in heme synthesis
* Alcohol abuse, Cu def, Pb poisoning
* Medications: isoniazid, linezolid

Myelodysplastic syndrome, acquired thalassemia
*Syndrome that lead to abnormal Hb chain synthesis

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18
Q

Vit 12 deficiency, pernicious anemia

A

Macrocytic
Megaloblastic anemia

  • high MCV
  • normal folate
  • low B12 (cobalamin)
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19
Q

diagnosis of pernicious anemia

A
  • reduced absorption
    • lack intrinsic factor/ gastric disruption
  • nutritional (B12 is found in meats, in developing countries)
  • Others (PPI, H2RA, H.pylori infection)
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20
Q

pernicious anemia causes

A
  • autoAb to intrinsic factor
    • Affect absorption of nutrients, vit B12
  • Diet
  • T1DM
  • Crohn’s disease
  • HIV
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21
Q

management of pernicious anemia/ vit 12 deficiency anemia

A
  • IM, SC vit B12 1000ug daily for 1 wk
  • Follow: 1000 ug weekly x 4wks
  • Follow: 1000ug mnthly for life

PO often insufficient

  • PO Vit B12, 1000ug ~ 2000ug daily
    • Absorbed by mass action, not rely on intrinsic factor action
      *or when IF not that low
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22
Q

folate deficiency

A

Macrocytic

Megaloblastic anemia

  • high MCV
  • low folate (B9)
  • normal B12
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23
Q

folate deficiency causes

A
  • Diet
  • Celiac disease

Megaloblastic = impair/ deficient of B12 or folate

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24
Q

folate deficiency tx

A

1mg/d folate for 1-4mnths

Or

Until hematologic recovery, normal Hb
Multivitamin (sangobion, ferrous gluconate)

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25
Q

drug induced haematologic disorders and what they affect

A

Agranulocytosis –> decr neut

haemolytic anemia –> RBC

thrombocytopenia –> PLT

aplastic anemia = all cell lines affected

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26
Q

aplastic anemia criteria

A

PRESENCE OF ANY 2

  • WBC count < 3,500 cells/mm3
  • Plt count < 55,000 cells/mm3
  • Hb value < 10g/dL
    + reticulocyte count < 30,000 cells/mm3

Mild, mod, severe: based on blood counts

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27
Q

causative drug of aplastic anemia
- bone marrow failure

A

cytotoxic, chemotherapy
radiation therapy that affects bone marrow

  • Chloramphenicol

observed in: CBMP, NSAID, PB, PT, SMX, thiazides

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28
Q

management of aplastic anemia

idiosyncratic, never know who will get and when

A

1) Withdraw causative drug

2) improve peripheral blood counts Transfusion of erythrocytes and PLT

  • Granulocyte-macrophage CSF: sargramostim,
    • G-CSF: filgrastim, pegfilgrastim
    • IL-14

3) minimise risk for infections
* Ab prophylaxis, antifungal
* Neutrophil count <500 cells/mm3

4) Haematopoietic stem cell transplant (HSCT)

5) Immunosuppressants while bone marrow recovers
* Glucocorticoids
* Ciclosporin
* Cyclophosphamide
* Azathioprine
* Antithymocyte Ig

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29
Q

do not heavily transfuse

A

iron overload

require Fe chelation
- Defoxamine
- Deferasirox

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30
Q

thrombocytopenia

A
  • PLT count < 100,000 cells/mm3
    • Or greater than 50% reduction from baseline values
  • Typically after 1-2wks after new drug initiated
  • May be immediate if: agent used intermittently in past (eg: UFH)
  • Rapid onset in GPIIb/ IIIa inhibitor drugs (eptifibatide)
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31
Q

what drugs causes immune thrombocytopenia

A

heparin
SMX
CBMZP
PT
glycoprotein IIb/ IIIa inhibitors (eptifibatide)

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32
Q

heparin-induced thrombocytopenia

A

LMWH does not directly cause, but due to cross-reactivity can also lead to HIT
○ Thrombosis: IV thrombin inhibitors

Don’t need monitor PLT everyday, need time for Antibodies to form before PLT drops (within 30days of heparin use)

33
Q

4T score for thrombocytopenia

A

2) thrombocytopenia (PLT count fall > 50%)

2) timing of PLT count fall (clear onset d5-10 / PLT fall <1day after Heparin)

2) thrombosis or other sequelae (new thrombosis, skin necrosis)

2) other causes for thrombocytopenia (none)

34
Q

4T score points

A

0-3 = low prob

4-5 = intermediate

6-8 = high probability

35
Q

tx for HIT

A
  • Hold offending drug
    • Recover in 1-2 days. Complete in 1wk
    • Ab may persist for years, do not restart. avoid indefinitely
  • KIV corticosteroid if severe
  • Heparin-induced thrombocytopenia
    *DOAC: dabigatran (off-label)
36
Q

tx for immune thrombocytopenia

A
  • Withdraw causative drug
  • Immunosuppressants (KIV)
    • Glucocorticoids
    • Ciclosporin
    • Cyclophosphamide
    • Azathioprine
    • Antithymocyte Ig
  • Transfusion of PLT
    • Clinically sig bleeding
      • oprelvekin, (romiplostim), (eltrombopag)
37
Q

Neutropenia, agranulocytosis

A
  • Neutropenia (absolute neut count) < 1500/ uL
  • Agranulocytosis (absence of granulocytes)
    • Degree of neutropenia (<100, <200, <500/ uL)

ANC: WBC x fraction of PMNs

38
Q

3 grps of drugs likely to cause agranulocytosis

A

1) anti thyroid = direct toxic
(thiamazole, chlorpromazine, carbimazole, propylthiouracil)

2) clozapine and other phenothiazines = toxic metabolite (antipsychotics)

3) penicillins, CMX = haptens

39
Q

Anti-thyroid agents – propylthiouracil and methimazole

A

○ More freq in pt > 40yo. Within 2mnths after initiate
○ Unpredictable: occur after longer term use
○ HLA allele may be associated (genotype)

40
Q

clozapine, other phenothiazides

A

○ 2-15 wks after initiate therapy
○ Peak onset between 3-4 wks

○ Strict monitoring, FU period (TCU)

41
Q

penicillins

A

○ Rapid onset of sx and dose-related
○ Accumulation of drug to toxic conc
○ Adj based on renal function

42
Q

agranulocytosis tx

A

1) Withdraw causative drug
- blood count usually returns to norm in 2-4wks (~4-24days)

2) Prophylactic administration of hematopoietic GF
* GM -CSF: sargramostim
○ More potent, more ADR as it stimulates diff type of blood cells
* G-CSF: filgrastim (sc 300mcg/day), pegfilgrastim

  • Weekly monitor WBC count
    • Esp for pt with clozapine
43
Q

restart offending drug?

A

not recomm

but for penicillin can restart at lower doses (esp if some infections require penicillin)

restart after neutropenia resolved, without recurrance of drug-induced agranulocytosis

benefit > risk

44
Q

Haemolytic anaemia causes

Normal MCV

A

1) Immune
* IgG and IgM mediated RBC destruction
* Drug-dependent (methyldopa) vs non-drug dependent

2) Metabolic
* G6PD deficiency (class I > II > III)
* Hb oxidation cause haemolysis

45
Q

what immune causes hemolytic anemia

A

immune

1) drug induced autoAb (methyldopa)

2) immune complex auto Ab (quinine, quinidine)

3) hapten-induced (penicillin, cephalosporins, streptomycin)

non-immune, protein adsorption
(cisplatin, beta-lactamase inhibitors, oxalipatin)

46
Q

tx for hemolytic anemia

A

1) Withdraw causative drug

  • RBC transfusion for pt with low Hb
  • Haemodialysis in acute RF
  • Steroids, Ig in serious cases
  • Autoimmune hemolytic anaemia
    Rituximab (human anti-C20 Mab) used
47
Q

drug induced megaloblastic anemia

A
  • high MCV
  • normal/ low folate
  • normal/ low B12
48
Q

drugs that cause megaloblastic anemia + tx

  • drugs that inhibit foltae deficiency
A
  • Antimetabolite = Hold off drug
    ○ MTX, chemotherapy
  • Co-trimoxazole = Folinic acid 5-10mg QDS
    ○ Esp in folate/ vit B12 deficient
  • Phenytoin, phenobarbital = Switch drug/ folic acid
    ○ Inhibit folate absorption or catalyse folate catabolism
    § Folic acid 1mg/day but may decr phenytoin efficacy
49
Q

tx for leukemia, myelodysplastic syndromes & lymphoma

A

○ Corticosterois, immunosuppressants, cytotoxic (chemo), targeted synthetic drugs, biologics

○ Supportive therapies for cytopenia
- anemia, neutropenia, thrombocytopenia

50
Q

drugs to tx anemia (nutrient, erythropoeisis)

A
  • Nutrients
    ○ Vit B12, folate deficiency
    ○ Fe deficiency
  • Erythropoiesis-stimulating agents
    ○ darbepoetin alfa, epoetin alfa
51
Q

neutropenia drugs

A

Myeloid GF

  • granulocyte colony sitmulating factor (G-CSF)
    ○ recombinant human GCSF – filgrastim
    ○ Filgrastin covalently conjugated with PEG – pegfilgrastin
  • GM-CSG (macrophage)
    ○ recombinant human GCSF – sargramostim
52
Q

thrombocytopenia tx drugs

A

Megakaryocyte GF/ plt-stimulating agents
* Recombinant IL-11: oprelvekin
* Fc-fusion protein thrombopoietin receptor agonist (romiplostim)

  • PO nonpeptide thrombopoietin receptor agonist (eltrombopag)
53
Q

vit B12, folate vs Fe deficient anemia

A
  • Inhibit DNA synthesis (cell multiplication)
    ○ Vit B12, folate deficiency
    ○ Few large Hb rich erythrocytes
  • Inhibit Hb synthesis
    ○ Fe deficiency
    ○ Few small Hb-poor erythrocytes
54
Q

PO Fe preparation

A

Ferrous gluconate tab 30mg sangobion
12% elemental Fe

Iron polymaltose 100mg Maltofer
100% elemental Fe

55
Q

Fe: ferrous sulphate (PO), iron sucrose (IV)
PK and ADR

A

PK: minimal E in faeces, bile , urine, sweat. Careful dosing to avoid toxicity

Acute
□ Necrotising gastroenteritis with V, ab pain, bloody diarrhea –> shock, lethargy, dyspnea, metabolic acidosis, coma, death

Chronic
□ Haemochromatosis, Fe deposit in heart, liver, pancreas, other organs –> fail –> death

56
Q

Fe reversal for overdose

A

deferoxamine (IV), deferasirox Fe chelators (PO)

57
Q

Vit B12/ cyanocobalamin drug

A

hydroxocobalamin (IV)
- more protein bind, retained in circ, preferred
- not affected by GI malabsorption

58
Q

PK of hydroxocobalamin

A

no PO as GI malabsorption
Excretion: bile, urine
Excess stored in liver (3yr supply)
T1/2: 26-31hr

59
Q

ADR of hydroxocobalamin

A
  • Photosensitive, inj site,
  • Hypertension, hot flush, arrhy, 2* hypoK, GI disturbances, dizzy, tremor, headache, paraesthesia, chromaturia, acneiform, bullous eruption, rash, itch
60
Q

DDI of vit B12

A

PPI reduce PO absorption

61
Q

Folic acid PK

A

A: bioavail 100%, peak plasma conc: 1hr
M: in liver and plasma
□ Active metabolite 5methyltetrahydrofolate
□ Enterohepatic circ
E: urine

62
Q

Folic acid CI

A
  • Untx cobalamin deficiency
  • Untx pernicious anemia, or other causes (lifelong vege)
  • malignant disease
63
Q

special precautions of folic acid

A
  • Folate-dependent tumor, haemolytic anemia, alcoholism
  • Women pre-exist DM, obesity, fam hist / previous preg affected by neural tube defect
  • Not mono therapy for
    □ Pernicious, aplastic, normocytic anemias
    □ Anemia w/ vit B12 def
  • Children, Preg, lactation
64
Q

folic acid ADR

A
  • GIT, bitter taste, ND, flatulence
  • Immune: allergic rxn (rash, pruritus, erythema, urticaria, dyspnoea, shock, sensitisation
  • Metabolic, nutrition: anorexia
65
Q

DDI with folic acid

A
  • Reduce conc of anticonvulsants
    □ Phenytoin, phenobarbital, carbamazepine, valproic acid
  • Enhance efficacy of Lithium
  • Decr therapeutic effect of Methotrexate chemo
  • Reduce absorption of folic: Sulfasalazine, triamterene
  • Elimination incr of folic: Aspirin
  • Folate metabolism
    □ Chloramphenicol and SMX+ TMP
66
Q

ESA Darbepoetin alfa, epoetin alfa MOA

A

*Acts like erythropoietin, stimulate division & differentiation of erythroid (RBC lineage)

*Regulate reticulocytes (immature RBC) –> erythrocyte after release from bone marrow

67
Q

PK of ESA

A

A: IM =slow, SC=slow, incomplete, IV=rapid
D: conc liver, kidney, bone marrow
M: limited
E: feces, small amt urine
□ T1/2: E (4-13hr), D(20-25hr)
□ Methoxy PEG prolongs t1/2 (2wk-1mn dosing interval)

68
Q

CI of ESA

A

Uncontrolled hypertension
hypersensitive

69
Q

precaution of ESA

A

§ Hypertension, hist of seizure
§ Ischemic vascular disease
§ Hepatic, renal impari, sickle cell anemia
§ Preg, lact, child

70
Q

ADR of ESA

A

§ Hypertension, oedema, thrombosis
§ Incr plt count, stroke, hyperK, seizure, myalgia, arthralgia, limb pain, GIT (NV)

§ E (pruritus)
§ Darbe: dyspnoea, cough, bronchitis

71
Q

neutropenia - myeloid GF MOA

G-CSF, GM-CSF

A

stimulate myeloid progenitor cells

G-CSF: neut lineage, activate mature neutrophils

GM-CSF: broader spectrum. early, late granulocytic, erythroid, megakaryocyte progenitors

72
Q

ADR of myeloid GF

A

GM-CSF > G-CSF(this is better tolerated)

Severe ADR:
○ Severe sickle cell crisis, cap leak syndrome
○ resp failure or acute resp distress (ARDS)
○ rare splenic rupture

73
Q

G-CSF ADR

A

▪ Better tolerated
Bone pain, reversible with discontinue

74
Q

GM-CSF ADR

A

More ADR.
Fever, malaise, arthralgias, myalgias

75
Q

precautions of myeloid GF

(neutropenia)

A

○ Pt with pre-malignant or malignant myeloid condition
○ Acute myeloid leukemia
○ Sickle cell trait, disease
○ Recent hist of pneumonia, lung infiltrate
○ Osteoporotic bone disease

CI in
▪ Chronic myeloid leukemia
▪ Myelodysplastic syndrome

76
Q

thrombocytopenia – megakaryocyte GF MOA

A

Recombinant IL-11: oprelvekin

Fc-fusion protein thrombopoietin receptor agonist: romiplostim

Oral nonpeptide thrombopoietin receptor agonist: eltrombopag

77
Q

megakaryocyte GF ADR

A

Thromboembolic events

oprelvekin: fluid retention, peripheral oedema, dyspnea on exertion

78
Q

special precaution of megakaryocyte GF

A

○ Pt with or with hist of cerebrovascular disease

○ Risk factor for thromboembolism
- Advanced age, prolonged period of immobilisation, malignancy, surgery/trauma, bleed, obesity, smoke, contraceptives, HRT

○ Eltrom: higher dose for non east Asian
○ oprel: CHRONIC HF/ risk of developing HF, susceptible to fluid retention

PR3154 (11 decks)

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