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)
2
Q
common causes of anemia
A
Fe deficiency
vit B12, folate deficiency
anemia of inflammation/ anemia of chronic disease
drug-induced
3
Q
approach pt
A
hx, sx
physical examination
lab evalulation
4
Q
drugs that can cause aplastic anemia
A
dose dependent direct drug toxicity (cancer chemo, chloramphenicol)
idiosyncratic, toxic metabolites (CBMZ, PT)
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?
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
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)
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)
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
10
Q
Fe deficient criteria
A
Microcytic
- low MCV
- low ferritin
11
Q
Fe deficient prompts to find etiology
A
- Scopes
- Enteroscopy: upper GI
- Colonoscopy
- Endoscopy: SI
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
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
14
Q
Anemia of chronic disease
features of RBC
A
Microcytic
- low MCV
- normal ferritin
- low TIBC/ TSAT/ transferrin
15
Q
ferritin? TIBC?
A
ferritin: iron stores in body
TIBC: transferrin protein that transports Fe
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
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
18
Q
Vit 12 deficiency, pernicious anemia
A
Macrocytic
Megaloblastic anemia
- high MCV
- normal folate
- low B12 (cobalamin)
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)
20
Q
pernicious anemia causes
A
- autoAb to intrinsic factor
- Affect absorption of nutrients, vit B12
- Diet
- T1DM
- Crohn’s disease
- HIV
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
- Absorbed by mass action, not rely on intrinsic factor action
22
Q
folate deficiency
A
Macrocytic
Megaloblastic anemia
- high MCV
- low folate (B9)
- normal B12
23
Q
folate deficiency causes
A
- Diet
- Celiac disease
Megaloblastic = impair/ deficient of B12 or folate
24
Q
folate deficiency tx
A
1mg/d folate for 1-4mnths
Or
Until hematologic recovery, normal Hb
Multivitamin (sangobion, ferrous gluconate)
25
drug induced haematologic disorders and what they affect
Agranulocytosis --> decr neut
haemolytic anemia --> RBC
thrombocytopenia --> PLT
aplastic anemia = all cell lines affected
26
aplastic anemia criteria
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
27
causative drug of aplastic anemia
- bone marrow failure
cytotoxic, chemotherapy
radiation therapy that affects bone marrow
- Chloramphenicol
observed in: CBMP, NSAID, PB, PT, SMX, thiazides
28
management of aplastic anemia
idiosyncratic, never know who will get and when
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
29
do not heavily transfuse
iron overload
require Fe chelation
- Defoxamine
- Deferasirox
30
thrombocytopenia
* 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)
31
what drugs causes immune thrombocytopenia
heparin
SMX
CBMZP
PT
glycoprotein IIb/ IIIa inhibitors (eptifibatide)
32
heparin-induced thrombocytopenia
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
4T score for thrombocytopenia
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
4T score points
0-3 = low prob
4-5 = intermediate
6-8 = high probability
35
tx for HIT
* 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
tx for immune thrombocytopenia
* Withdraw causative drug
* Immunosuppressants (KIV)
* Glucocorticoids
* Ciclosporin
* Cyclophosphamide
* Azathioprine
* Antithymocyte Ig
* Transfusion of PLT
* Clinically sig bleeding
* oprelvekin, (romiplostim), (eltrombopag)
37
Neutropenia, agranulocytosis
* Neutropenia (absolute neut count) < 1500/ uL
* Agranulocytosis (absence of granulocytes)
* Degree of neutropenia (<100, <200, <500/ uL)
ANC: WBC x fraction of PMNs
38
3 grps of drugs likely to cause agranulocytosis
1) anti thyroid = direct toxic
(thiamazole, chlorpromazine, carbimazole, propylthiouracil)
2) clozapine and other phenothiazines = toxic metabolite (antipsychotics)
3) penicillins, CMX = haptens
39
Anti-thyroid agents -- propylthiouracil and methimazole
○ More freq in pt > 40yo. Within 2mnths after initiate
○ Unpredictable: occur after longer term use
○ HLA allele may be associated (genotype)
40
clozapine, other phenothiazides
○ 2-15 wks after initiate therapy
○ Peak onset between 3-4 wks
○ Strict monitoring, FU period (TCU)
41
penicillins
○ Rapid onset of sx and dose-related
○ Accumulation of drug to toxic conc
○ Adj based on renal function
42
agranulocytosis tx
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
restart offending drug?
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
Haemolytic anaemia causes
Normal MCV
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
what immune causes hemolytic anemia
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
tx for hemolytic anemia
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
drug induced megaloblastic anemia
- high MCV
- normal/ low folate
- normal/ low B12
48
drugs that cause megaloblastic anemia + tx
- drugs that inhibit foltae deficiency
* 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
tx for leukemia, myelodysplastic syndromes & lymphoma
○ Corticosterois, immunosuppressants, cytotoxic (chemo), targeted synthetic drugs, biologics
○ Supportive therapies for cytopenia
- anemia, neutropenia, thrombocytopenia
50
drugs to tx anemia (nutrient, erythropoeisis)
* Nutrients
○ Vit B12, folate deficiency
○ Fe deficiency
* Erythropoiesis-stimulating agents
○ darbepoetin alfa, epoetin alfa
51
neutropenia drugs
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
thrombocytopenia tx drugs
Megakaryocyte GF/ plt-stimulating agents
* Recombinant IL-11: oprelvekin
* Fc-fusion protein thrombopoietin receptor agonist (romiplostim)
* PO nonpeptide thrombopoietin receptor agonist (eltrombopag)
53
vit B12, folate vs Fe deficient anemia
* 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
PO Fe preparation
Ferrous gluconate tab 30mg sangobion
12% elemental Fe
Iron polymaltose 100mg Maltofer
100% elemental Fe
55
Fe: ferrous sulphate (PO), iron sucrose (IV)
PK and ADR
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
Fe reversal for overdose
deferoxamine (IV), deferasirox Fe chelators (PO)
57
Vit B12/ cyanocobalamin drug
hydroxocobalamin (IV)
- more protein bind, retained in circ, preferred
- not affected by GI malabsorption
58
PK of hydroxocobalamin
no PO as GI malabsorption
Excretion: bile, urine
Excess stored in liver (3yr supply)
T1/2: 26-31hr
59
ADR of hydroxocobalamin
- Photosensitive, inj site,
- Hypertension, hot flush, arrhy, 2* hypoK, GI disturbances, dizzy, tremor, headache, paraesthesia, chromaturia, acneiform, bullous eruption, rash, itch
60
DDI of vit B12
PPI reduce PO absorption
61
Folic acid PK
A: bioavail 100%, peak plasma conc: 1hr
M: in liver and plasma
□ Active metabolite 5methyltetrahydrofolate
□ Enterohepatic circ
E: urine
62
Folic acid CI
* Untx cobalamin deficiency
* Untx pernicious anemia, or other causes (lifelong vege)
* malignant disease
63
special precautions of folic acid
* 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
folic acid ADR
* GIT, bitter taste, ND, flatulence
* Immune: allergic rxn (rash, pruritus, erythema, urticaria, dyspnoea, shock, sensitisation
* Metabolic, nutrition: anorexia
65
DDI with folic acid
* 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
ESA Darbepoetin alfa, epoetin alfa MOA
*Acts like erythropoietin, stimulate division & differentiation of erythroid (RBC lineage)
*Regulate reticulocytes (immature RBC) --> erythrocyte after release from bone marrow
67
PK of ESA
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
CI of ESA
Uncontrolled hypertension
hypersensitive
69
precaution of ESA
§ Hypertension, hist of seizure
§ Ischemic vascular disease
§ Hepatic, renal impari, sickle cell anemia
§ Preg, lact, child
70
ADR of ESA
§ Hypertension, oedema, thrombosis
§ Incr plt count, stroke, hyperK, seizure, myalgia, arthralgia, limb pain, GIT (NV)
§ E (pruritus)
§ Darbe: dyspnoea, cough, bronchitis
71
neutropenia - myeloid GF MOA
G-CSF, GM-CSF
stimulate myeloid progenitor cells
G-CSF: neut lineage, activate mature neutrophils
GM-CSF: broader spectrum. early, late granulocytic, erythroid, megakaryocyte progenitors
72
ADR of myeloid GF
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
G-CSF ADR
▪ Better tolerated
Bone pain, reversible with discontinue
74
GM-CSF ADR
More ADR.
Fever, malaise, arthralgias, myalgias
75
precautions of myeloid GF
(neutropenia)
○ 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
thrombocytopenia -- megakaryocyte GF MOA
Recombinant IL-11: oprelvekin
Fc-fusion protein thrombopoietin receptor agonist: romiplostim
Oral nonpeptide thrombopoietin receptor agonist: eltrombopag
77
megakaryocyte GF ADR
Thromboembolic events
oprelvekin: fluid retention, peripheral oedema, dyspnea on exertion
78
special precaution of megakaryocyte GF
○ 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
