Hematotoxicity refers to adverse effects of toxicants on blood cells. Drugs can cause decreased red blood cell production by damaging bone marrow, inhibiting DNA synthesis, or incorporating into DNA to trigger cell death. They may also cause megaloblastic anemia by interfering with vitamin B12 or folate, which are needed for DNA synthesis. Additionally, drugs can induce immune-mediated hemolysis through three mechanisms: by acting as haptens to modify red blood cells and stimulate antibody production; forming ternary complexes with red blood cell receptors; or by altering red blood cell membranes to induce autoantibodies.

1. Drug-Induced Hematotoxicity
Dr. NITIN KUMAR SEN
Assistant professor
Department of pharmacology
SJIPR, Palghar

2. Hematotoxicity
Hematotoxicity refers to adverse effects of toxicants on blood-forming
organs such as bone marrow or the constituents of blood, including
platelets, leukocytes and erythrocytes. Due to time and space constraints, I
will confine my discussion to erythrocytes. Red blood cells are highly
vulnerable to toxicity because of the marked proliferation rate, lack of
organelles and limited ability to make energy. Adverse drug reactions
involving erythrocytes can result in decreased production, increased
destruction or altered function.

3. Decreased Erythrocyte Production
Many chemotherapeutic drugs cause myeloid suppression including anemia because
chemotherapeutics tend to affect rapidly dividing cells. Some chemotherapeutics
decrease DNA synthesis while others produce chemical lesions in DNA. These are
dose related, reversible, pharmacological reactions and most chemotherapy regimes
are designed to minimize myeloid suppression.
The number of cell lines involved depends on the degree of differentiation of affected
cells. Pancytopenia occurs if the initial target is a pluripotent cell rather than a
committed cell while pure red cell aplasia occurs if affected cells are committed
erythrocyte precursors. Anemias are less commonly seen than leukopenias as
erythrocytes have a longer half life than granulocytes and thus anemias develop more
gradually than leukopenias.

4. Alkylating agents such as chlorambucil, busulfan and lomustine cause
myelosuppression by binding DNA base pairs and cross-linking the DNA double
strands.
This leads to misreading of the genetic codes, excision of bases and eventually
prevents DNA transcription and RNA synthesis. The marrow toxicity is cumulative
and a function of the total dose. Prolonged use can cause a severe prolonged aplastic
anemia.
DNA synthesis is blocked by cytarabine which inhibits DNA polymerase. The purine
analogues 6-mercaptopurine and 6-thioguanine are converted to nucleotides and
incorporated into the DNA strand.
These are recognized as mismatched pairs and trigger apoptosis. Doxorubicin inactivates
DNA by both intercalating DNA base pairs and by inhibition of topoisomerase II. This
blocks the synthesis of RNA and proteins and also generates free oxygen radicals by redox
cycling of quinone groups.

5. Megaloblastic anemia occurs due to asynchronous maturation of the nucleus and
hemoglobin (Hgb). Hemoglobin synthesis is dependent on coordinated synthesis of α
and β globin chains. Hydroxyurea causes a megaloblastic anemia by increasing the
production of γ globin chains (fetal hemoglobin chains with a greater affinity for O2
).
This alters the synchronized maturation of the erythrocyte nucleus and hemoglobin.
Vitamin B12 and folate are needed for the synthesis of thymidine which is
required for DNA synthesis. Deficiency of either Vit B12 or folate is associated
with a megaloblastic anemia. Neomycin, omeprazole and colchicines can all cause
Vit B12 deficiency while folate deficiency can occur with methotrexate or
sulfasalazine.(6)
Isoniazid and chloramphenicol can cause defective synthesis of the porphyrin
ring. This results in a sideroblastic anemia with accumulation of Fe in bone
marrow erythroblasts. The Fe precipitates in mitochondria causing intracellular
injury and creating Prussian blue positive, ringed sideroblasts.

6. Immune Mediated Hemolysis
1. Hapten Mediated
Drug molecules are usually too small to be immunogenic but some drugs serve as
haptens, modifying proteins and creating autoantigens with the protein-drug
complex becoming the target of the immune system. This type of reaction usually
occurs with high doses. A common example is penicillin but it can also occur with
cephalosporins and tetracyclines.At high dosages of penicillin, erythrocytes are
coated with tightly bound penicillin and penicillin metabolites. Most individuals
treated with penicillin develop IgM antibodies to the benzylpenicilloyl determinants
of penicillin but these Ig's do not cause hemolysisLow numbers of individuals
treated with penicillin develop IgG antibodies to benzylpenicilloyl or other penicillin
determinants. The IgG bound to the hapten and erythrocytes leads to phagocytosis of
erythrocytes by splenic macrophages

7. Immune Mediated Hemolysis
1. Hapten Mediated
Drug molecules are usually too small to be immunogenic but some drugs serve as
haptens, modifying proteins and creating autoantigens with the protein-drug
complex becoming the target of the immune system. This type of reaction usually
occurs with high doses. A common example is penicillin but it can also occur with
cephalosporins and tetracyclines.At high dosages of penicillin, erythrocytes are
coated with tightly bound penicillin and penicillin metabolites. Most individuals
treated with penicillin develop IgM antibodies to the benzylpenicilloyl determinants
of penicillin but these Ig's do not cause hemolysisLow numbers of individuals
treated with penicillin develop IgG antibodies to benzylpenicilloyl or other penicillin
determinants. The IgG bound to the hapten and erythrocytes leads to phagocytosis of
erythrocytes by splenic macrophages

8. 2. Ternary Complex Mechanism
This differs from hapten mediated hemolysis in that it requires a
small concentration of drug with weak binding to specific erythroid
receptors (for example Rh) to form a neoantigen.
The neoantigen is stabilized by binding to an Fab domain of an
Ig.Destruction is usually via complement but phagocytosis by
splenic macrophages can also occur. Examples include
temafloxacin, rifampicin, thiopental and quinidine

9. 3. Autoantibody Reaction
In the third mechanism, antibodies are produced against erythrocytes after a
drug is no longer present. Examples include α-methyldopa, cephalosporins
and mefenamic acid.
Binding of some drugs to erythrocyte cell membranes is inhibited by the
presence of hemoglobin. Therefore drugs such as α-methyl dopa bind to and
alter cell membranes of early erythrocyte precursors before the cells contain
hemoglobin. This can induce the formation of an autoantibody (IgG) against
the mature red blood cell and eventually leads to hemolysis by splenic
sequestration of IgG coated cells