The document provides an overview of drug-induced hematological disorders, defining conditions such as aplastic anemia, agranulocytosis, hemolytic anemia, megaloblastic anemia, and thrombocytopenia, along with their pathophysiology, symptoms, causative drugs, and management strategies. It details the mechanisms by which these disorders occur and emphasizes the importance of recognizing and removing offending drugs, as well as supportive treatments and specific therapies like stem cell transplantation and immunosuppressive agents. The document serves as a comprehensive guide for understanding the implications of drug therapy on blood cell production and health.

1. DRUG-INDUCED
HEMATOLOGICAL
DISORDERS: A PRECISE
INSIGHT
PRESENTED BY:
VISHNU.R.NAIR,
FIFTH YEAR PHARM.D,
NATIONAL COLLEGE OF PHARMACY, KERALA
EMAIL ID: rxvichu623@gmail.com

2. A. DEFINITION:
• “Rare, adverse hematological events, associated with drug therapy”.

3. B. TYPES :
Include:
1. APLASTIC ANEMIA
2. AGRANULOCYTOSIS
3. HEMOLYTIC ANEMIA
4. MEGALOBLASTIC ANEMIA
5. THROMBOCYTOPENIA.

4. DRUG-INDUCED APLASTIC
ANEMIA

5. 1. DEFINITION:
- “Condition, in which body is UNABLE to produce ENOUGH NEW BLOOD CELLS”
2. PATHOPHYSIOLOGY:
Drug-inducedAplastic Anemia can be caused by 3 mechanisms:
i. Direct, dose-related drug toxicity
ii. Idiosyncratic mechanisms
iii. Drug-induced autoimmune aplastic anemia.

6. i. DIRECT, DOSE-RELATED DRUGTOXICITY :
- Drug  causes transient bone-marrow failure , depending on dose escalation
- Caused by chemotherapy/ radiation therapy.
ii. IDIOSYNCRATIC MECHANISMS:
- Potentiality for toxicity increases with:
a. Toxic metabolite of parent drug
b. Pharmacokinetic variations among individuals, with respect to the affecting drug
c. Genetic polymorphisms  causes hypersensitivity of stem cells towards drug/ its
metabolites.
iii. DRUG-INDUCED IMMUNE APLASTIC ANEMIA:
- Drug  activates cells & cytokines of immune system  causes stem cell destruction.

7. 3. CLINICAL MANIFESTATIONS:
- WBC count < 3,500 cells/cumm
- Low Hb count(<10 g/dL)
- Fatigue
- Fever
- Weakness
- Bleeding
- High propensity for infections.

8. 4. CAUSATIVE DRUGS:
Include:
- Aspirin
- Chloroquine
- Hydrochlorothiazide
- Chloramphenicol
- Chlorpromazine.

9. 5. MANAGEMENT:
- Early withdrawal of offending drug
- Supportive care
- Antibiotics(For infections, use BROAD-SPECTRUM ANTIBIOTICS)
- Transfusion(to supplement RBCs & PLATELETS)
- HSCT(Hematopoietic Stem CellTransplantation)
- IMMUNOSUPPRESSIVE THERAPY:
a. Usually combination of ATG(Antithymocyte Globulin) & CYCLOSPORINE is used
b. ATG is derived from horses/rabbits
c. ATG  consists of polyclonal IgG  directed againstT-CELLS
d. Dose of ATG : 40 mg/kg/day, for 4 days.

10. e. CYCLOSPORINE  blocks IL-2 production  reducesT-CELL activity
f. Dose of cyclosporine  5 mg/kg/day, in 2 divided doses.
- CORTICOSTEROIDS:
a. Mainly used to reduce the ADRs ofATG therapy
b. Drug/s used: METHYLPREDNISOLONE/ PREDNISOLONE  1 mg/kg/day, for 2-4 weeks.

11. DRUG-INDUCED
AGRANULOCYTOSIS

12. A. DEFINITION:
“Condition, in which there is a reduction in the number of MATURE MYELOID
CELLS(Granulocytes & immature ones) in the body, to a total count of 500 cells/mm3, or
less.”
B. PATHOPHYSIOLOGY:
OCCURS BY 4 MECHANISMS:
1. HAPTEN MECHANISM:
- Drug / metabolite  binds to surfaces of neutrophils  forms a complex  complex acts
as “HAPTEN”  Stimulates ANTIBODY PRODUCTION  Antibodies bind to complex 
destruction of neutrophils, via complement & phagocytic systems.
- Caused by high, repeated doses of PENICILLIN.

13. 2. INNOCENT BYSTANDER PHENOMENON:
- Drug  binds to drug-specific antibody  forms complex This complex binds/ adsorbs
non-specifically to neutrophil membrane  induces antibody production  destruction of
neutrophils, via complement & phagocytic systems.
- Caused by QUINIDINE.
3. PROTEIN-CARRIER MECHANISM:
- Drug  binds to protein carrier forms complex  this complex adsorbs to neutrophil
surface  induces antibody production  destruction of neutrophils.
4. PRODUCTION OF AUTOANTIBODIES TO SPOILT MEMBRANE:
- Drug  alters structure of neutrophil membrane  induces formation of autoantibodies 
auto-antibodies bind to neutrophils  destruction of neutrophils, via phagocytosis.

14. 3. SIGNS & SYMPTOMS:
- Chills
- Malaise
- Increased propensity towards infections
- Sore throat
- Fever
4. CAUSATIVE DRUGS:
Drugs, that causeAGRANULOCYTOSIS include:
a. Ampicillin
b. Chloramphenicol
c. HCQ

15. d. Gentamicin
e. Captopril
f. Quinine .
5. MANAGEMENT:
- Remove offending drug
- Treat infections with antibiotics
- Vigilant hygiene practices
- FILGRASTIM(300 mcg/day; s.c) , SARGRAMOSTIM {Only if NEUTROPHIL COUNT<100
cells/mm3}.

16. DRUG-INDUCED HEMOLYTIC
ANEMIA

17. A. DEFINITION:
“Process of premature RBC destruction, in which RBCs are destroyed at a rate, faster than
bone marrow can replace them.”
B. PATHOPHYSIOLOGY:
Caused by 4 mechanisms, under 2 broad headings:
DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA:
1. HAPTEN MECHANISM:
- Caused by :
• Penicillin
• Cephalosporins
• Streptomycin.

18. 2. INNOCENT BYSTANDER PHENOMENON:
- Caused by:
• Sulfonamides
• Quinine
• Quinidine
3. DRUG-INDUCED AUTOIMMUNE HEMOLYTIC ANEMIA:
- Drug  induces true auto-antibodies to RBCs

19. DRUG INDUCED OXIDATIVE HEMOLYTIC ANEMIA:
- Found in patients with G6PD, glutathione peroxidase deficiencies
- G6PD deficiency is a disorder of HMP SHUNT
- G6PD deficiency  causes lack of NADPH concentration in RBCs  reduces
GLUTATHIONE levels (in reduced form)  no substrate available for
glutathione peroxidase to bind on  reduces protective effect of glutathione
peroxidase on RBCs  PEROXIDES attack RBCs  oxidative stress  leads to
hemolysis
- With reduced glutathione levels  oxidizing drugs oxidize –SH group of
Hemoglobin  leads to PREMATURE RBC DESTRUCTION  leads to
HEMOLYSIS.

20. C. SIGNS & SYMPTOMS:
1. Pallor
2. Fatigue
3. SOB
4. Malaise.
D. CAUSATIVE DRUGS:
Drugs, that cause hemolytic anemia, include:
1. Metformin
2. NTU
3. Sulfacetamide
4. Sulfanilamide
5. Sulfamethoxazole.

21. E. MANAGEMENT:
1. TREATMENT OF DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA:
- Remove offending drug
- Supportive care
2.TREATMENT OF DRUG-INDUCED OXIDATIVE HEMOLYTIC ANEMIA:
- Remove offending drug.

22. DRUG-INDUCED
MEGALOBLASTIC ANEMIA

23. 1. DEFINITION:
“Condition, in which there is abnormal development of RBC PRECURSORS(Megaloblasts), in
bone marrow”.
2. PATHOPHYSIOLOGY:
- VITAMIN B12, FOLATE DEFICIENCY  causes impaired proliferation & maturation of
hematopoietic cells  causes cell-cycle death, with subsequent sequestration.
- Drugs(Methotrexate, co-trimoxazole)  block DHFRase  Deoxy-thymidine triphosphate
is not formed  DNA synthesis doesn’t occur.
- Since CO-TRIMOXAZOLE is LESS-SPECIFIC to human DHFRase  disease occurs ONLY IN
THOSE,WITH VITAMIN B12/ FOLATE DEFICIENCIES.
- ANTI-EPILEPTIC DRUGS(Phenobarbital, primidone, phenytoin)  cause disease in 2 ways:
a. Blockage of folate metabolism
b. Increased folate catabolism.

24. 3. SIGNS & SYMPTOMS:
a. SOB
b. Malaise
c. Muscle weakness
d. Irregular heartbeats
e. Dizziness.
4. MANAGEMENT:
- For CO-TRIMOXAZOLE induced anemia  FOLINIC ACID (5-10 mg), QID
- ForAED-induced anemia  FOLICACID, 1 mg/day (Check for effectiveness ofAED in
patients, after starting FOLICACIDTHERAPY).

25. DRUG-INDUCED
THROMBOCYTOPENIA

26. A. DEFINITION:
“Condition, in which platelet count goes below 1,00,000 cells/mm3.”
B. PATHOPHYSIOLOGY:
Caused by 3 mechanisms:
1. DIRECT TOXICITY REACTIONS:
- CHEMOTHERAPEUTIC AGENTS  suppress thrombopoiesis  causes reduction in no. of
megakaryocytes in bone marrow.
2. HAPTEN-TYPE IMMUNE REACTIONS:
- Drug  binds to platelet glycoproteins  forms complex  induces ANTIBODY
FORMATION  antibodies bind to platelet surface  destruction of platelets, by
COMPLEMENT & PHAGOCYTIC SYSTEMS.

27. - Caused by:
a. Quinidine
b. Quinine
c. Rifampin
d. Heparin
e. Gold salts
f. Sulfonamides
3. DRUG-INDUCED AUTOIMMUNE THROMBOCYTOPENIA:
- Drug  induces production of auto-antibodies  auto-antibodies bind to platelet
membrane  cause platelet destruction
- Caused by:
a. Gold salts b. Procainamide .

28. C. SIGNS & SYMPTOMS:
1. Petechiae
2. Ecchymoses
3. Increased bruising
4. Bleeding from mucous membranes
5. Severe purpura
6. Epistaxis.

29. D. MANAGEMENT:
- Remove offending drug
- Supportive treatment
- FOR HEPARIN-INDUCEDTHROMBOCYTOPENIA:
i. Remove/discontinue all sources of HEPARIN
ii. Focus on ALTERNATIVE ANTICOAGULATION
iii. Go for DIRECT THROMBIN INHIBITORS, like LEPIRUDIN, BIVALIRUDIN,
ARGATROBAN
iv. ARGATROBAN:
- Requires dosage adjustments in liver dysfunction
- Can be used in ESRD patients.

30. v. BIVALIRUDIN:
- Requires dosage adjustment in severe renal failure.
vi. LEPIRUDIN:
- Obtained from leeches
- Requires dosage adjustments in kidney dysfunction
- 30% of patients  when treated with LEPIRUDIN for 1st time  formed
ANTIBODIES  Thus, focus on ONLY ONE TREATMENT COURSE FOR
LEPIRUDIN.

31. C. REFERENCE/BIBLIOGRAPHY:
1. Johnston FD. Granulocytopenia following the administration of sulfanilamide
compounds. Lancet 1938;2:1004–1047.
2. van der Klauw MM, Goudsmit R, Halie MR, et al. A population-based case-cohort study of
drug-associated agranulocytosis. Arch Intern Med 1999;159:369–374.
3. Maluf EM, Pasquini R, Eluf JN, et al. Aplastic anemia in Brazil: incidence and risk factors.
Am J Hematol 2002;71:268–274.
4. ASHP guidelines on adverse drug reaction monitoring and reporting. American Society of
Hospital Pharmacy. Am J Health Syst Pharm 1995;52:417–419.
5. Brodsky RA, Jones RJ. Aplastic anaemia. Lancet 2005;365:1647–1656.
6. Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al.Treatment of aplastic anemia with
antilymphocyte globulin and methylprednisolone with or without cyclosporine.The
GermanAplastic Anemia Study Group. N Engl J Med 1991;324:1297–1304.

32. 7. Tabbara IA. Hemolytic anemias. Diagnosis and management. Med Clin North Am
1992;76:649–668.
8. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002;69:258–
271.
9. Scott JM, Weir DG. Drug-induced megaloblastic change. Clin Haematol 1980;9:587–606.
10. George JN, Raskob GE, Shah SR, et al. Drug-induced thrombocytopenia: a systematic
review of published case reports. Ann Intern Med 1998;129:886–890.

33. THANK YOU!!!!!!