TOXIC RESPONSES OF THE BLOOD

Blood as a Target Organ

HEMATOTOXICITY
The study of adverse effects of exogenous chemicals on blood and blood-forming tissues.
PRIMARY TOXICITY
One or more blood components are directly affected.
The serious effects of xenobiotics, particularly drugs.
SECONDARY TOXICITY
The toxic effect is a consequence of other tissue injury or systemic disturbances.
Exceedingly common, due to the propensity of blood cells to reflect various local and
systemic effects of toxicants on their tissues.
HEMATOPOIESIS
The production of blood
A highly regulated sequence of events by which blood cell precursors proliferate and
differentiate.
Site of hematopoiesis: the bone marrow in the axial skeleton and proximal limbs

TOXICOLOGY OF THE ERYTHRON

ERYTHROCYTE
Red blood cells or RBC
Serve as the principal vehicle for transportation of oxygen from the lungs to peripheral
tissues and of carbon dioxide from tissues to the lung
Involved as a carrier &/or reservoir for drugs & toxins
ALTERATIONS IN RED CELL PRODUCTION
ERYTHROCYTE PRODUCTION
Continuous process that is dependent on frequent cell division and a high rate of
haemoglobin synthesis
Abnormalities that lead to decreased hemoglobin synthesis:
Iron deficiency anemia result of dietary deficiency or increased blood loss
Sideroblastic anemia defects in the synthesis of porphyrin ring of heme
accumulation of iron in bone marrow erythroblasts
XENOBIOTICS ASSOCIATED WITH SIDEROBLASTIC ANEMIA
Chloramphenicol

Isoniazid

Copper chelation/deficiency

Lead intoxication

Cycloserine

Pyrazinamide

Ethanol

Zinc intoxication

Megaloblastic anemia deficiency of folate &/or vitamin B12

XENOBIOTICS ASSOCIATED W/ MEGALOBLASTIC ANEMIA
B12 Deficiency

Folate Deficiency

Antimetabolites

Neomycin

p-Aminosalicyclic acid

Omeprazole

Carbamazepine

Phenobarbital

Cholestyramine

Phenytoin

Colchicine

Primidone

Ethanol

Sulfasalazine

Fish tapeworm

Triamterine

Hemodialysis

Zidovudine

Malabsorption syndromes
Aplastic anemia characterized by peripheral blood pancytopenia, reticulocytopenia and bone
marrow hypoplasia
Pure red cell aplasia is a syndrome that may be due to genetic defects, infection, immune
mediated injury, myelodysplasia, drugs, or other toxicants
DRUGS AND CHEMICALS ASSOCIATED WITH THE DEVELOPMENT OF APLASTIC ANEMIA
Allopurinol
Chlortetracycline
Amphotericin B
Cimetidine
Azidothymidine
Diclofenac
Benzene
Dinitrophenol
Bismuth
Ethosuximide
Carbamazepine
Felbamate
Carbimazole
Gold
Carbon tetrachloride
Indomethacin
Carbutamide
Isoniazid
Chloramphenicol
Mefloquine
Chlordane
Mepazine
Chlordiazepoxide
Meprobamate
Chlorphenothane
Mercury
Chlorpropamide
Chlorpromazine

DRUGS AND CHEMICALS ASSOCIATED WITH THE DEVELOPMENT OF APLASTIC ANEMIA

Methazolamide
Propylthiouracil
Methicillin
Potassium perchlorate
Methylphenylethylhydantoin
Pyrimethamine
Methylmercaptoimidazole
Streptomycin
Metolazone
Sulfamethoxypyridazine
Organic arsenicals
Sulfisoxazole
Phenylbutazone
Sulfonamides
Quinacrine
Thiocyanate
Tetracycline
Ticlopidine
Parathion
Tolbutamide
Penicillin
Trimethadione
D-Penicillamine
Trifluoroperazine Tripelennamine

Alterations in Erythrocyte Survival

Erythrocytes normally circulate blood for about 120 days.
Erythrocytes or red blood cells are the most common type of blood cell and the vertebrate
organism's principal means of delivering O 2 to the body tissues via the blood flow through
the circulatory system.
The cytoplasm of erythrocytes is rich in hemoglobin, an iron-containing biomolecule that
can bind oxygen and is responsible for the red color of the cells.
The cell membrane is composed of proteins and lipids.
ANEMIA AND HEMOLYTIC ANEMIA
Anemia is a condition in which the body does not have enough healthy red blood cells.
Hemolytic anemia occurs when antibodies form against the body's own red blood cells and
destroy them, because the immune system mistakenly recognizes these blood cells as foreign.

TOXICOLOGY OF THE LEUKON

Components of blood leukocytes
Leukocytes/white blood cells
Monocytes
Lymphocytes
Granulocytes
o Neutrophils
o Eosinophils
o Basophils
GRANULOCYTES AND MONOCYTES
- are nucleated ameboid cells that are phagocytic. They play a central role in the
inflammatory response and host defense.
- unlike the RBCs which resides exclusively within blood, granulocytes and monocytes are
merely pass through the blood on their way to extravascular tissues where they reside in
large numbers.
NEUTROPHILS
- is the largest component of blood leukocytes
- highly specialized in the mediation of inflammation and the ingestion and destruction of
pathogenic microorganism
EOSINOPHILS AND BASOPHILS
- modulate inflammation through the release of various mediators.
EVALUATION OF GRANULOCYTES
- In the blood, neutrophils are distributed between circulating and marginated pools, which
are of equal size and in constant equilibrium.
- Blood neutrophils count assess only the circulating pool, which remains remarkably
constant (1800 to 7500 uL-1) in a healthy adult men.

TOXIC EFFECTS ON GRANULOCYTES

Effects on Proliferation
- High rate of proliferation of neutrophils make their progenirator and precursor granulocyte
pool particularly susceptible to inhibitors of mitosis.
Myelototoxicity is commonly seen with cytoreductive cancer chemotherapy agents, which
often act to inhibit DNA synthesis or directly attack its integrity through the formation of DNA
adducts or enzyme-mediated breaks.
EFFECTS ON FUNCTION
Ethanol and glucocorticoids impair phagocytosis and microbe ingestion.
Iohexol and ioxaglate, components of radiographic contrast media, have also been
reported to inhibit phagocytosis.
Superoxide production, required for microbial killing and chemotaxis, is reportedly reduced
in patients using parenteral heroin as well as in former opiate abusers on long-term
methadone maintenance.
Chemotaxis is also impaired following treatment with zinc salts in anti-acne preparations.
MECHANISM OF TOXIC NEUTROPENIA
Immune-mediated neutropenia
Non-immune-mediated toxic neutropenia
Immune-mediated neutropenia is an antigen-antibody reactions lead to destruction of
peripheral neutrophils, granulocyte precursors or both.
Non-immune-mediated toxic neutropenia often shows a genetic predisposition. Direct
damage may cause inhibition of granulopoiesis or neutrophil function.

EXAMPLES OF TOXICANT THAT CAUSE IMMUNE AND NON IMMUNE IDIOPATHIC

NEUTROPENIA
Drug associated with WBC antibodies
Aminopyrine
Levamisole
Ampicillin
Lidocaine
Aprindine
Methimazole
Azulfidine
Metiamide
Chlorpropamide
Phenytoin
Clozapine
Procainamide
CPZ/phenothiazines
Propylthiourasil
Dicloxacillin
Quinidine
Gold
Tolbutamide
Drugs not associated with WBC antibodies
Allopurinol
Flurazepam
Ethambutol
Hydrochlorothiazide

Isoniazide
Phenothiazines

Rifampicin

LEUKOMOGENESIS AS A TOXIC RESPONSE

HUMAN LEUKEMIAS
Leukemias are proliferative disorders of hematopoietic tissue that originate from individual
bone marrow cells.
It has been classified as myeloid or lymphoid, referring to the major lineages for
erythrocytes/granulocytes/thrombocytes or lymphocytes.
ACUTE LEUKEMIAS
Acute lymphoblastic leukemia (ALL)
Avute myelogenous leukemia (AML)

CHRONIC LEUKEMIAS
Chronic lymphocytic leukemias (CLL)
Chronic myelogenous leukemias (CML)
Myelodysplastic syndromes (MDS)
MECHANISMS OF TOXIC LEUKOMOGENESIS
Acute myelogenesis leukemia (AML) is the dominant leukemia associated with drug or
chemical exposure, followed by myelodysplastic syndromes (MDS).
This represents a continuum of one toxic response that has been linked to cytogenetic
abnormalities, particularly the loss of all or part of chromosomes 5 and 7.
AML patients occupationally exposed to benzene, who also show aneuploidy with a high
frequency of involvement of chromosome 7.
LEUKEMOGENIC AGENTS
Most alkylating agents used in cancer chemotherapy can cause MDS and/or AML.
Benzene leukemogenic
Treatment with the topoisomerase II inhibitors, etoposide and teniposide can induce AML.
Exposure to high-dose y- or x-ray radiations has long been associated with ALL, AML and
CML.
Controversial agents: 1,3-butadiene, nonionizing radiation (electromagnetic, microwave,
infrared and the high end of the ultraviolet spectrum), cigarette smoking and form
aldehyde.
TOXICOLOGY OF PLATELETS AND HEMOSTASIS
Hemostasis is a multicomponent system responsible for preventing the loss of blood from
sites of vascular injury and maintaining circulating blood in a fluid state.
Loss of blood is prevented by formation of stable hemostatic plugs.
The major constituents of the hemostatic system include circulating platelets, a variety of
plasma proteins and vascular endothelial cells.
Alterations in these components or systemic activation of this system can lead to the
clinical manifestations or deranged hemostasis, including excessive bleeding and
thrombosis.
The hemostatic system is a frequent target of therapeutic intervention as well as
inadvertent expression of the toxic effect of a variety of xenobiotics.

Toxic Effects on Platelets

The Thrombocyte
- Platelets are essential for formation of a stable hemostatic plug in response to vascular
injury.
- It adheres to the damaged wall.
- Xenobiotics may interfere with the platelet response by causing thrombocytopenia or
interfering with platelet function.
Thrombocytopenia
- May be due to decreased production or increase destruction.
- It is a common side effect of intensive chemotherapy, due to the predictable effect of
antiproliferative agents of hematopoietic precursors.
- Exposure to xenobiotics may caused increased destruction through any one of the several
mechanisms.
- A second mechanism of immune thrombocytopenia is initiated by change in a platelet
membrane glycoprotein caused by the xenobiotic.
- Thrombocytopenia is an uncommon but serious complication of inhibitors of factors
involved in the clot-formation cascade.
- These inhibitors can change the conformation of these factors, causing exposure of certain
peptides (called neoepitopes because they are newly exposed to the immune system) on
the factors that react with endogenous antibodies.
- Exposure of epitopes that react with naturally occurring antibodies represents a third
mechanism of immune mediated platelet destruction.
- Heparin-induced thrombocytopenia (HIT) represents a fourth mechanism of immunemediated platelet destruction.
- Thrombotic thrombocytopenia purpura (TTP) is a syndrome characterized by the sudden
onset of thrombocytopenia, a microangiopathic haemolytic anemia and multisystem organ
failure.

Toxic Effects on Platelet Function

- Platelet function is dependent on the coordinated interaction of a number of biochemical
response pathways.
- Major drug groups that affect platelet function include NSAIDS, lactam-containing
antibiotics, CVS drugs, particularly beta blockers, psychotrophic drugs, anesthetics,
antihistamines and some chemotherapeutic agents.
Toxic Effects on Fibrin Clot Formation
COAGULATION
Coagulation is a complex process by which blood forms clots. Blood must be remain fluid
within the vasculature and yet clot quickly when expose to non endothelial surface at a
site of vascular injury.
It is an important part of haemostasis (the cessation of blood loss from a damaged vessel),
where in a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to
stop bleeding and begin repair of the damaged vessel.
Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting
(thrombosis).

Toxicology of Agents Used to Modulate Hemostasis

Oral Anticoagulants are medicines used for people who are at risk of developing abnormal
blood clotting.
The oral anticoagulants are a class of pharmaceuticals that act by antagonizing the effects
of vitamin K.
Clots can dislodge and go to the lungs, known as pulmonary embolism.
Oral Anticoagulant: Warfarin
Warfarin is a synthetic derivative of coumarin, a chemical found naturally in many plants,
like, woodruff (Galium odoratum, Rubiaceae), and at lower levels in licorice, lavender,
species.
Warfarin is prescribed to people with an increased tendency for thrombosis or in those
individuals that have already formed a blood clot (thrombus).
Warfarin is contraindicated in pregnancy, as it passes through the placental barrier and
may cause bleeding in the fetus.
Warfarin antagonist: Vitamin K
Mechanism of Action
Warfarin is an analogue of Vitamin K. Warfarin inhibits the vitamin K-dependent synthesis
of biologically active forms of the calcium-dependent clotting factors II, VII, IX and X, as
well as the regulatory factors protein C.
Invivo and invitro: Heparin
Heparin is a non-uniform mixture of straight chain mucopolysaccharides with MW 10,000
to 20,000.
It carries strong electronegative charges and is the strongest organic acid present in the
body.
It is metabolized in liver by enzyme heparinase.
Heparin antagonist: Protamine sulfate
Pharmacological Actions
Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and
in vitro.
Heparin produces its anticoagulant effect by activating plasma antithrombin iii(AT III a
serine proteinase inhibitor) and may be other similar cofactors.

I can do all things through Christ who gives me strength.

Phil.4:13 [