Drugs induced blood disorder (Neutopenia and Anemia)

1. Drug induced hematology
Lecturer Nin Prapongsena
Huachiew Chalermprakiet University

2. Objective
• สามารถจาแนกความผิดปกติของเม็ดเลือด หรือเกล็ดเลือดได้อย่างถูกต้อง
• ทราบถึงยาที่เหนี่ยวนาให้เกิดความผิดปกติของเม็ดเลือด หรือเกล็ดเลือด
• ทราบถึงกลไกของยาที่เหนี่ยวนาให้เกิดความผิดปกติของเม็ดเลือด หรือเกล็ด
เลือด
• สามารถประเมินความผิดปกติที่เกิดโดยใช้ Naranjo’s algorithm
ได้อย่างถูกต้อง
• สามารถวางแผนการจัดการปัญหาที่เกิดขึ้นได้อย่างเหมาะสมกับผู้ป่วย
เฉพาะราย

3. Drugs induced hematology
Platelet
disorders
Blood
disorders
Anemia
Neutropenia
Thrombocytopenia
Thrombosis

4. Drugs induced platelet disorders
Thrombocytopenia Thrombosis

5. Thrombocytopenia
Severity Platelet count
Grade 1 75,001 – 150,000/ uL
Grade 2 50,001 – 75,000/ uL
Grade 3 25,001 – 50,000/ uL
Grade 4 < 25,000/ uL
Symptoms:
-เลือดกำเดำไหล - เลือดออกตำมไรฟัน - มีจ้ำเลือดใต้ชั้นผิวหนัง
- เกิดภำวะเลือดออกที่สมอง (stroke) ซึ่งจะพบว่ำผู้ป่วยเกิดอำกำรชัก

6. Mechanisms
1. Drug as hapten
ie. penicillins,
cephalosporins
2. Compound
epitope formation
ie. quinine, quinidine,
sulfonamides, NSAIDs
3. Drugs induced
Autoantibodies
ie. Gold,
procainamide
4. Heparin-induce
thrombocytopenia
(HIT) or Heparin-
associate
Thrombocytopenia
(HAT)
heparin
5. Fibrinogen
inhibitors
abciximab, tirofiban,
eptifibatide
6. Thrombotic
thrombocytopenic
purpura-hemolytic
uremic syndrome
(TTP-HUS)

7. 1. Drug as hapten

8. 2. Compound epitope formation
Platelets
Or
Glycoprotein
(hydrophobic domain)
Binding
Platelet
change
conformation
Antigens

9. 3. Drugs induced autoantibodies
IgG
(specific to glycoprotein V)
synthesis
Induce
Destroyed
platelets

10. 4. Heparin-induce thrombocytopenia
HAT HIT

11. 5. Fibrinogen inhibitors
Antigen

12. 6. Thrombotic thrombocytopenic
purpura-hemolytic uremic syndrome
(TTP-HUS)
Change pathophysiology (unknown mechanism)
Cause thrombocytopenia
ex. mitomycin C, cyclosporine, tacrolimus, sirolimus,
quinine, ticlodipine, clopidogrel, simvastatin

13. Condition
Prothrombin
time
Partial
thromboplastin
time
Bleeding time
Platelet
count
Vitamin K deficiency
or
warfarin
Prolonged
Normal or
mildly prolonged
-
-
Disseminated
intravascular
coagulation
Prolonged Prolonged Prolonged Decreased
Von Willebrand
disease
- Prolonged Prolonged
-
Hemophilia - Prolonged - -
Aspirin - - Prolonged -
Laboratory findings in various platelet
and coagulation disorders
Thrombocytopenia - - Prolonged Decreased
Factor V deficiency Prolonged Prolonged - -
Factor X deficiency Prolonged Prolonged - -
Factor XII deficiency - Prolonged - -

16. Management

17. Thrombosis
Deep Vein
Thromboembolism
(DVT)
Pulmonary Embolism
(PE)
Stroke

18. Drugs induced thrombosis
- Hemostatic agents - Anticoagulants
- Hematopoietic agents - Estrogen-containing agents
- Antiandrogenic agents - Selective estrogen receptor
modulators
- Aromatase inhibitors - Androgenic agents
- Follicle-stimulating hormone - Antineoplastic agents
- Immunologic agents - Antipsychotic agents
- COX2-inhibitor
- Miscellaneous (ex. procainamide, botox, ergotamine, sidenafil)

19. Mechanism of action
Hypercoagulability
(Direct/Indirect)
Blood coagualation
impairment
Anticoagulant
inhibition
Tissue factor pathway inhibitors
Antithrombin III
Protein C and protein S pathway
Inhibit fibrinolysis

20. Anticoagulant inhibition

21. Anticoagulant inhibition (continue)

22. Mechanism of action
Blood coagualation
impairment
Inhibit fibrinolysis
Activated plasminogen
activator inhibitor (PAI)
antiplasmin:plasmin complex activation
Inhibit plasminogen synthesis

23. 1
2
3
4

24. Symptoms of thrombosis

25. Wells score for DVT/PE evaluation

26. Wells score for DVT/PE evaluation (continue)

28. DVT management
American College of Chest Physicians (ACCP)’s Guidelines for Diagnosis &
Management of DVT / PE, 9th Ed.

29. PE management
American College of Chest Physicians (ACCP)’s Guidelines for Diagnosis &
Management of DVT / PE, 9th Ed.

30. Drugs induced blood disorders
Anemia Neutropenia
Aplastic anemia
Hemolytic anemia
Macrocytic anemia

31. Anemia evalulation
Mild to Moderate:
- Hb < 12.3 (F) or 14 (M) g/dL
- Fatigue
- Shortness of breath
- Dizziness
- Pallor

32. Severe:
- Respiratory rate (> 20/min)
- O2 saturation (< 95%)
- Hb (< 7 g/dL)
- Hct (< 21%)
- Tachycardia
- Hypoxia or cyanosis (yes)
Anemia evalulation
Blood Transfusion

34. Aplastic anemia
Direct
toxic
Hematopoietic stem cell
Immune mediated
Antigen
Non-immune mediated
(ex. chemotherapy)

35. Drug Incidence
*Acetazolamide 1:18,000 each year
Captopril Not known
*Carbamazepine 4:100,000
*Felbamate 127:1,000,000
Furosemide Not known
*Gold salt Death1.5:10,000
pescriptions
Imatinib Not known
Nonsteroidal anti-inflammatory
drugs
Diclofenac
Ibuprofen
Indomethacin
Salicylates
Sulindac
Not known
Phenytoin Not known
Sulfonamides
Sulfisoxazole
Sulfasalazine
Mesalamine
Not known
Temozolomide Not known
Ticlodipine Not known
Aplastic anemia

36. Disorders of pluripotent stem cell
Neutropenia
(Low WBC)
Thrombocytopenia
(Low platelets)
Pancytopenia
(Low RBC)
Cytotoxic drugs,radiations,
antimicrobials, pesticides, viral infection
Genetic disorder
(Fanconi anemia)
Aplastic anemia: symptoms

37. NCCN guideline

38. NCCN
guideline

39. Hemolytic anemia

40. Hemolytic anemia (life span < 120 d)
• Generate autoantibody
Autoantibody
specific to RBC
Generate
RBC Destruction
Methyldopa,
levodopa,
procainamide
• Neoantigen
Antigen
Activated
complement
RBC destructed by spleen
• Induce RBC destructive
quinine,
quinidine
penicillins,
cephalosporins,
tetracyclines

41. Drug Incidence
*Carbamazepine 4:100,000 pescriptions
Cephalosporins
Cefazolin
Cefotaxime
Cefotetan
Cefoxitin
Ceftizoxime
Ceftriazone
Cefuroxime
Cephalothin
Ceftazidime
Not known
Fluroquinolones
Ciprofloxacin
Levofloxacin
Not known
H2-antagonist
Cimetidine
Famotidine
Ranitidine
Nizatidine
Not known
Isoniazid Not known
Methyldopa/Levodopa Not known
Nonsteroidal anti-inflammatory drugs
Diclofenac
Ibuprofen
Indomethacin
Salicylates
Sulindac
Not known
Piperacillin/tazobactam Not known
Probenecid Not known
Quinidine/Quinine Not known
Hemolytic anemia

42. S & O in hemolytic anemia
• Found after receive drugs 2 wk -3 mth
• Severe stomachache
• Jaundice: (increased bilirubin)
• Splenomegaly
• Hepatomegaly: (Increased free iron)
- ferritin (ค่าปกติ 15-200 ng/mL)
- transferring saturation (TSAT; ค่าปกติ ≥ 20%)

43. Hemolytic anemia management
• Hgb < 7g/dL:
recommend blood transfusion
• Iron overload (ferritin ≥ 1,000 ng/mL):
recommend deferoxamine, deferiprone หรือ
deferasirox
• Immune mediated hemolytic anemia:
recommend corticosteroids or IVIg

44. Macrocytic anemia
(MCV > 100 fL)

45. Folic acid
and
Vit B12
Depletion

46. Macrocytic anemia (How induced ???)
• Inhibited folate synthesis
Trimetoprim
MTX
• Interfered folate absorption
or increased folate excretion
Phenytoin
• Interfered heme synthesis
Zidovudine

47. Macrocytic anemia
Drug Incidence
Azathioprine Not known
Leflunomide Not known
Metformin Not known
Phenytoin Not known
Sulfonamides
Sulfisoxazole
Sulfasalazine
Mesalamine
Not known
Trimetroprim-
sulfamethoxazole
Not known
Zidovudine Not known

48. • Recommend prevent macrocytic anemia
(folate/ Vit B12 deficiency)
Add Folic acid oral 5 mg/d
or Vit B12 oral 1-2 mg/d
• Recommend stop drug that inhibited
heme synthesis + supportive care
Macrocytic anemia (Management)

49. Drugs induced blood disorders
Anemia Neutropenia
Aplastic anemia
Hemolytic anemia
Macrocytic anemia

50. Neutropenia
• Classified neutropenia by National Cancer Institute
(NCI) risk category:
Mild: ANC (1000-1500/µL)
Moderate: ANC (500-1000/µL)
Severe: ANC (<500/µL)

51. How drugs induced Neutropenia???
• Immune mediated
Generated autoantibody
specific to
- granulocytic precursor
- neutrophils
Ex. chlorpropramide,
methimazole,
propylthiouracil
• Direct toxic
- Damaged to myeloid precursors:
(cimetidine, quinidine)
- Intefered development process:
(ticlodipine)
- Damaged to neutrophils:
(sulfonamides)
• Multiple mechanisms
Flecainide, clozapine

52. - Alkylating agents - Antimetabolites,
- Anthracyclines - Topoisomerase inhibitors
- Taxanes - Vinca alkaloids
- Antithyroids - Antirheumatic
- Antiarrythmic - Antipsychotic
- Tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib)
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
Drugs induced Neutropenia

53. Risk factors of neutropenia
-อายุมากกว่า 50 ปี
-โรคประจาตัวที่เกี่ยวกับ autoimmune disease
-การได้รับการรักษาด้วยการฉายรังสี (radiation)
-เพศหญิงมีความเสี่ยงมากกว่าเพศชาย 2 เท่า
-ความผิดปกติทางพันธุกรรม
-การติดเชื้อจุลชีพหรือไวรัสบางชนิด
-ได้รับยาต้านมะเร็งหลายชนิด
-ใช้ยาหลายตัว
-ขาดสารอาหาร
-ไตหรืออวัยวะอื่นๆ มีการทางานผิดปกติ

54. Clinical presentation
-ไข้ (fever)
-หนาวสั่น (chills)
-ง่วงซึม (lethargy)
-ปวดกล้ามเนื้อ (myaglia)
-อ่อนเพลีย (weakness)
-หลอดลมอักเสบ (bronchitis)
-เหงือกอักเสบ (gingivitis)
-คออักเสบ (pharyngitis)
-ติดเชื้อในกระแสเลือด (sepsis)
-ไซนัสอักเสบ (sinusitis)
-เยื่อบุทางเดินอาหารอักเสบ (stomatitis)
-Etc.

55. Drugs induced neutropenia management
Reduced dose or stopped drug use
+
Antibiotic
±
CSF/ GCSF/ GMCSF

56. Evalulated prophylactic by CSFs

57. Addition to initial empiric regimen

58. Addition to initial empiric regimen

59. Addition to initial empiric regimen

60. Addition to initial empiric regimen

61. Reference
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patients with cancer: 2007 American society of hematology American society of clinical
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5. National Comprehensive Cancer Network®. NCCN guidelines® Cancer – and
Chemotherapy-Induced Anemia. Version 2. National Comprehensive Cancer Network, Inc.,
2012.
6. Crawford J. Neutropenia in cancer patients: risk factor and management. Cancer World.
2012
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Version 1. National Comprehensive Cancer Network, Inc., 2012.
8. National Comprehensive Cancer Network®. NCCN guidelines® Prevention and Treatment
of Cancer-Related Infections. Version 2. National Comprehensive Cancer Network, Inc.,
2012.