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3154 Haematology > IC3+7 Drug-induced blood disorders > Flashcards

IC3+7 Drug-induced blood disorders Flashcards

1
Q

[Neutropenias]

Drugs for neutropenias:

A

Myeloid growth factors:

Granulocyte colony-stimulating factor (G-CSF)

  • Recombinant human G-CSF: Filgrastim
    • PEG: Pegfilgrastim
  • Combined with hematopoeitic stem cell mobilizer: Plerixafor

Granulocyte-macrophage colony-stimulating factor (GM-CSF)

  • Recombinant human GM-CSF: Sargramostim
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2
Q

[Neutropenias]

MOA of G-CSF: Filgrastim

A
  • Stimulate proliferation and differentiation of progenitors committed to neutrophil lineage
  • Activates phagocytic activity of mature neutrophils and prolongs their survival in circulation
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3
Q

[Neutropenias]

MOA of GM-CSF: Sargramostim

A
  • Stimulate proliferation and differentiation of early and late granulocytic, erythroid, and megakaryocyte progenitors

*GM-CSF has broader effects compared to G-CSF, but more adverse effects

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4
Q

[Neutropenias]

Adverse effects of myeloid growth factors

A
  • G-CSF: bone pain, reversible when discontinued
  • GM-CSF: fever, malaise, arthralgias, myalgias

Potentially fatal:

  • Severe sickle cell crisis, capillary leak syndrome, respiratory failure or acute respiratory distress syndrome (ARDs)
  • Rarely: splenic rupture

*Note that G-CSF more frequently used compared to GM-CSF as it is better tolerated

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5
Q

[Neutropenias]

Special precautions of myeloid growth factors

A
  • Pre-malignant or malignant myeloid condition, acute myeloid leukemia, sickle cell trait or disease, recent history of pneumonia or lung infiltrates, osteoporotic bone disease
  • Not indicated for use in chronic myeloid leukemia or myelodysplastic syndrome
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6
Q

[Thrombocytopenia]

Drugs for Thrombocytopenia:

A

Megakaryocyte growth factors / Platelet stimulating agents (PSA)

  • Recombinant interleukin 11 (stimulate megakaryocyte to produce more platelet): Oprelvekin
  • Fc-fusion protein thrombopoietin receptor agonist: Romiplostim
  • Oral non-peptide thrombopoietin receptor agonist: Eltrombopag
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7
Q

[Thrombocytopenia]

Adverse effects of drugs for thrombocytopenia:

A
  • Thromboembolic event (incr platelet)
  • Oprelvekin: fluid retention, peripheral edema, dyspnea on exertion
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8
Q

[Thrombocytopenia]

Special precautions for drugs for thrombocytopenia:

A
  • Hx of cerebrovascular disease
  • Risk factors for thromboembolism (e.g., immobilization, surgery, obesity, smoking, old age)
  • Eltrombopag: higher doses required for patients of non-East asian ancestry
  • Oprelvekin: chronic heart failure, susceptibility to fluid retention
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9
Q

5 leading causes of death among the drug-induced blood dyscrasias:

(from most to least common)

A
  • Thrombocytopenia
  • Megaloblastic anemia
  • Hemolytic anemia
  • Agranulocytosis
  • Aplastic anemia

TMHAA

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10
Q

[Megaloblastic anemia]

What drugs may induce megaloblastic anemia (mostly folate deficiency)?

A
  • Antimetabolites (e.g., methotrexate)
  • Cotrimoxazole
  • Phenytoin, phenobarbital - inhibits folate absorption or catalyse folate catabolism
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11
Q

[Megaloblastic anemia]

Management for each of the drugs:
- Methotrexate
- Cotrimoxazole
- Phenytoin/Phenobarbital

A

Methotrexate

  • Withdraw, give alternative

Cotrimoxazole

  • Folinic acid 5-10mg, up 4x a day

Phenytoin, phenobarbital

  • Switch antiseizure meds
  • Folic acid 1mg/day (controversial as it may reduce efficacy of phenytoin in some patients)
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12
Q

[Aplastic anemia]

What is aplastic anemia?

A

Aplastic anemia is caused by damage to stem cells inside the bone marrow, therefore body stops producing enough new blood cells

(Normal MCV and low reticulocyte count)

All cell lines are affected: Hb, Reticulocyte, Neutrophil, WBC, platelets

DEFINED BY: any two of the three following

  • Low WBC count
  • Low platelet count
  • Low Hb value =<10g/dL + Low reticulocyte count

VS Pancytopenia - caused by disease state

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13
Q

[Aplastic anemia]

Examples of drugs associated

A

Dose-dependent direct drug toxicity:

  • Chloramphenicol
  • Cancer chemotherapies (cytotoxic chemotherapy, radiation therapy) - cause bone marrow failure

Idiosyncratic (toxic metabolites) - unpredictable severity and time to recovery:

  • Carbamazepine
  • Phenytoin
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14
Q

[Aplastic anemia]

Goal of therapy

A

Improve peripheral blood counts, limit requirement for transfusions, minimize risk for infections

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15
Q

[Aplastic anemia]

Management

A
  • Withdraw causative drug
  • Infection prevention: prophylactic antibiotics and antifungal agents when neutrophil counts <500 cells/mm3 (0.5 x 10^9/L); start broad spectrum in febrile neutropenia
  • Symptomatic treatment for infections
  • Transfusion of erythrocytes and platelets (in bleeding)
  • Allogenic hematopoietic stem cell transplantation (HSCT)
  • Immunosuppressants: cyclosporin, glucocorticoids, cyclophosphamide, azathioprine, antithymocyte immunoglobulin

Others (IC3):

  • Granulocyte-macrophage colony-stimulating factor (GM-CSF: Sargramostim)
  • Granulocyte colony-stimulating factor (G-CSF: FIlgrastim)
  • Interleukin-14 (B cell proliferation)
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16
Q

If heavily transfused (erythrocytes and platelets), what might be administered to prevent iron overload/iatrogenic iron toxicity?

A

Iron chelators:

Deferoxamine or Deferasirox

17
Q

[Agranulocytosis]

What is agranulocytosis?

A

Low absolute neutrophil count

Neutropenia (disease state) and Agranulocytosis (drug-induced) can be used interchangeably

18
Q

[Agranulocytosis]

Drugs associated

A

3As:

  • Antipsychotics: Clozapine, Chlorpromazine
  • Antibioics: B-lactams, Sulfonamides
  • Antithyroid agents: Thioamides (Carbimazole, Methimazole), Propylthiouracil

Direct drug toxicity:

  • Chlorpromazine
  • Thiamazole
  • Ticlopidine
  • Busulfan
  • Zidovudine

Toxic metabolite:

  • Clozapine
  • Carbimazole (for hyperthyroidism)

Immune (hapten or complement-mediated):

  • B-lactam
  • Propylthiouracil
19
Q

[Agranulocytosis]

Onset of agranulocytosis:

  • Antipsychotics: Clozapine, Phenothiazines - Chlorpromazine
A

Clozapine:

  • 2 to 15 weeks after initiation of therapy, with peak onset between 3-4 weeks (TCU)
  • Strict WBC monitoring protocols required if Clozapine used
20
Q

[Agranulocytosis]

Mechanism of agranulocytosis:

  • Antibioics: B-lactams, Sulfonamides
A

Penicillins:

  • Rapid onset of symptoms, dose-related
  • Accumulation of drug to toxic concentrations could be the cause of Agranulocytosis

*Impt to adjust Penicillin according to renal function to prevent accumulation

21
Q

[Agranulocytosis]

Mechanism of agranulocytosis:

  • Antithyroid agents: Thioamides (Carbimazole, Methimazole), Propylthiouracil
A

Mechanism unknown

  • More frequent in pt over 40y, and within 2m after initiation of therapy
  • Some reports after longer term use
  • Possible HLA allele association
22
Q

[Agranulocytosis]

Goal of therapy

A

Improve mortality rate

  • Pt at higher risk of mortality include: elderly, renal failure, bacteremia, shock
23
Q

[Agranulocytosis]

Management

A
  • Withdraw causative drug

=> Blood counts return to normal within 2-4 weeks; frequently within 4-24 days

  • G-CSF: Filgrastim SQ 300mcg/d recommended if neutrphils count less than 100cells/mm3 (0.1 x 10^9/L)
  • Prophylactic administration of hematopoietic growth factors (GM-CSF: Sargramostim, G-CSF: Filgrastim)
  • Routine (weekly) monitoring of WBC count, particularly for pt treated with Clozapine (low WBC count - vv high risk of infection)
24
Q

[Agranulocytosis]

Should offending agent be restarted after agranulocytosis is resolved?

A

No, unless Penicillin

  • may restart at lower dose after neutropenia has resolved without any recurrence of drug-induced agranulocytosis
25
Q

[Hemolytic Anemia]

What is hemolytic anemia?

A

Hemolytic anemia is a disorder in which red blood cells are destroyed faster than they can be mad, defined by low RBC, high reticulocyte count

Normal MCV, high reticulocyte counts as bone marrow is working hard to replace the destroyed red blood cells.

26
Q

[Hemolytic Anemia]

How is it diagnosed?

A

Direct and Indirect Coombs’ test

  • The Coombs test checks your blood for antibodies that attack red blood cells
27
Q

[Hemolytic Anemia]

Types of Hemolytic Anemia

A
  1. Immune hemolytic anemia
  • IgG and IgM mediated RBC destruction
  • Drug-dependent (methyldopa) vs non-drug dependent
  1. Metabolic hemolytic anemia
  • G6PD deficiency
  • Hemoglobin oxidation causing hemolysis
28
Q

[Hemolytic Anemia]

Drugs associated

A

Immune hemolytic anemia:

  • Drug-induced true autoantibody pdn: Methyldopa
  • Innocent bystander (immune complex) autoantibody pdn: Quinine, Quinidine
  • Hapten-induced hemolysis: Penicillins, Cephalosporins, Streptomycin

Non-immune hemolytic anemia

  • Protein adsorption: Cisplastin, Oxaliplatin, Beta-lactamase inhibitors

Metabolic

  • G6PD: fluoroquinolone (ciprofloxacin), sulfonylureas (glipizide), primaquine, tafenoquine, kidney beans, naphthalene, henna coumpounds [prob safe: chloroquine, hydroxychloroquine, sulfa drugs - Bactrim]

Hemoglobin oxidation causing hemolysis

  • Sulfamethoxazole, nitrofurantoin
29
Q

[Hemolytic Anemia]

Management

A
  • Withdraw causative drug
  • RBC transfusion (pt with low Hb)
  • Hemodialysis (pt with acute renal failure)
  • Steroids and immunoglobulins
  • Rituximab (human anti-CD20 monoclonal antibodies) - for autoimmune hemolytic anemia
30
Q

[Immune thrombocytopenia]

What is immune thrombocytopenia?

A

Low platelet count defined as:

  • =< 100,000 cells/mm3 (100 x 10^9/L)

OR

  • greater than 50% reduction from baseline values
31
Q

[Immune thrombocytopenia]

Drugs associated

A
  • Heparin
  • Glycoprotein IIb/IIIa inhibitors (e.g., Eptifibatide)
  • ASMs: Carbamazepine, Phenytoin, Phenobarbital, Valproic acid
  • Abx: Sulphonamides
32
Q

[Immune thrombocytopenia]

Onset of thrombocytopenia

A

Typically presents 1-2 weeks after new drug is initiated, but may present immediately after a dose when an agent has been used intermittently in the past (e.g., UFH)

Typically start monitoring for HIT after 5 days of daily heparin (given not taken before previously)

GP IIb/IIIa inhibitor class has rapid onset

33
Q

[Heparin-induced thrombocytopenia]

How does Heparin lead to Heparin-Induced thrombocytopenia?

A

Heparin binds to PF4 on activated platelet surface

Heparin-PF4 complex trigger formation of IgG antibodies against them

34
Q

[Heparin-induced thrombocytopenia]
*Type II is significant

  • Explain any cross-reactivity, implications and management
A

Cross-reactivity with LMWH

Implications:

  • Unlike thrombocytopenia, HIT is paradoxically a/w thrombosis

Management:

  • IV thrombin inhibitors are the DOC (NA in SG)
  • Oral thrombin inhibitor (DOACs) - Dabigatran, Rivaroxaban can be used (off-label)
35
Q

[Immune thrombocytopenia]

Management of immune thrombocytoepnia

A
  • Withdraw causative drug

=> Recovery begins within 1-2 days of discontinuation of the offending agent, and is complete at one week (platelet lifespan)

  • Immunosuppressants (corticosteroids if severe)
  • Platelet transfusions

Avoid agent indefinitely as antibodies may persist for years

36
Q

[Heparin-induced thrombocytopenia]

4T score to determine HIT probability

What score determines low, intermediate, and high probability?

A
  1. Thrombocytopenia (platelet count fall >50%)
  2. Timing of platelet count fall (clear onset b/w days 5-10 or platelet fall =<1day provided prior heparin exposure within 30days)
  3. Thrombosis or other sequelae (new thrombosis e.g., stroke; skin necrosis; acute systemic reaction)
  4. Thrombocytopenia (other causes)

Low: 1-3
Intermediate: 4-5
High: 6-8

3154 Haematology (14 decks)

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