explain the factor that effect platelet directly and indirectly

1. BY DINA ADDAI
UNIVERSITY OF BAGHDAD / COLLEGE OF
PHARMACY
DIPLOMA OF PHARMACOLOGY AND
TOXICOLOGY
UNDER SUPERVISED OF DR. AMMAR A .
HUSSEIN
Xenobiotic effect on
hematopoietic system(platelet )

3. Platelets or thrombocytes
 Platelets are tiny blood cells that help your body form
clots to stop bleeding. If one of your blood vessels
gets damaged, it sends out signals to the platelets.
The platelets then rush to the site of damage. they
form a plug (clot) to fix the damage. Platelets, also
known as thrombocytes

4. Platelet aggregation
 Platelet aggregation: The clumping together
of platelets in the blood. Platelet aggregation
is part of the sequence of events leading to
the formation of a thrombus (clot).

5. What is platelet adhesion
 Platelet adhesion is an essential function in
response to vascular injury and is generally viewed
as the first step during which single platelets bind
through specific membrane receptors to cellular and
extracellular matrix constituents of the vessel wall
and tissues

6. Platelet adhesion
 Platelet adhesion, activation and aggregation play a
pivotal role in the cascade of events leading
to arterial thrombosis making antiplatelet therapy
essential for the treatment of patients with coronary
artery disease (CAD) manifestations Platelet
adhesion to biomaterial surfaces or an injured vessel
wall is the primary and most important step leading
to the spreading and activation of platelets to form a
thrombus

7.  The process of spreading across the surface of a
damaged blood vessel to stop bleeding is called
adhesion. This is because when platelets get to the
site of the injury, they grow sticky tentacles that help
them stick (adhere) to one another. They also send
out chemical signals to attract more platelets. The
additional platelets pile onto the clot in a process
called aggregation.

9. Blood (indirect effect on the platelet)
 The blood system can be damaged by agents that
affect blood cell production (bone marrow), the
components of blood (platelets, red blood cells, and
white blood cells), or the oxygen-carrying capacity of
red blood cells. Bone Marrow. Bone marrow is the
source of most components in blood. Agents that
suppress the function of bone marrow include:

10.  Arsenic, used in pesticides and paints.
 Bromine, used to manufacture gasoline antiknock
compounds, ethylene dibromide, and organic dyes.
 Methyl chloride, used as a solvent, refrigerant, and
aerosol propellant.
 Ionizing radiation, produced by radioactive materials and
x-rays is associated with leukemia.
 Benzene, a chemical intermediate associated with
leukemia.

11. Direct effect on the platelet
 Blood Components. Among platelets (thrombocytes)
are blood components that help prevent blood loss
by forming blood clots. Among chemicals that affect
this action are

12.  Aspirin, which inhibits cloning.
 Benzene, which decreases the number of platelets.
 Tetrachloroethane, which increases the number of
platelets.

13. Aspirin and clopidogrel mechanism of action
 The antithrombotic action of aspirin is mainly due to
inhibition of platelet COX-1, which prevents the
synthesis of thromboxane A2.
 Clopidogrel is a platelet inhibitor. It is a
thienopyridine and inhibits adenosine diphosphate
(ADP) receptor–mediated platelet activity. A related
drug is ticlopidine. Because this mechanism is
different from the aspirin-inhibiting effect on platelets,
clopidogrel is more effective than aspirin alone and
has been used concurrently with aspirin

14.  Dual antiplatelet therapy with aspirin and clopidogrel
is routinely indicated in patients with acute coronary
syndromes and following percutaneous coronary
intervention to reduce the risk of cardiovascular
mortality and ischaemic events. Although clinical
guidelines recommend aspirin lifelong and
clopidogrel for between one and 12 month

15. • Xenobiotic-induced thrombocytopenia may result
from increased platelet destruction or decreased
platelet production, which lead to decreased platelet
aggregation and bleeding disorders.
• Blood coagulation is a complex process involving a
number of proteins whose synthesis and function
can be altered by many xenobiotic.

16. The Thrombocytopenia
 Platelets are essential for the formation of a stable
hemostatic plug in response to vascular injury.
Platelets initially adhere to the damaged wall.
Activation of a pathway of several factors permits
fibrinogen and other multivalent adhesive molecules
to form cross-links between nearby platelets,
resulting in platelet aggregation. Xenobiotic may
interfere with the platelet response by causing
thrombocytopenia or interfering with platelet
function

17.  Like anemia, thrombocytopenia may be due to
decreased production or increased destruction.
 Thrombocytopenia is a common side effect of
intensive chemotherapy because of the
predictable effect of ant proliferative agents on
hematopoietic precursors.
 Chemotherapy or radiation therapy: These
treatments suppress or kill off the blood-producing
cells (megakaryocytes) in your bone marrow, leading
to low platelet production.

18.  Exposure to xenobiotics may cause increased
immune-mediated platelet destruction through any
of several mechanisms.
 1) Some drugs, such as penicillin, function as
haptens, binding to platelet membrane components
and eliciting an immune response that is specific for
the hapten. The responding antibody then binds to
the hapten on the platelet surface, leading to removal
of the antibody-coated platelet from the circulation.

20.  2) A second mechanism of immune
thrombocytopenia is initiated by xenobiotic induced
exposure of a neoepitope on a platelet membrane
glycoprotein. This elicits an antibody response, with
the responding antibody binding to this altered
platelet antigen in the presence of drug, resulting in
removal of the platelet from the circulation by the
mononuclear phagocytic system e.g quinidin.

21.  3) Thrombocytopenia is an uncommon but serious
complication of inhibitors of GPIIb/IIIa such as
abciximab .The mechanism appears to be related to
exposure of epitopes on GP IIb/IIIa that react with
naturally occurring antibodies Ligand binding is
known to alter the conformation of GP IIb/IIIa The
GP IIb/IIIa inhibitors bind at the ligand binding site
and also cause a conformational change in GP
IIb/IIIa, permitting naturally occurring antibodies to
bind to and initiate clearance of platelets by the
mononuclear phagocytic system

22.  4) Heparin-induced thrombocytopenia (HIT)
represents another mechanism of immune-mediated
platelet destruction. This disorder is due to the
development of antibodies that react with a
multimolecular complex formed by the interaction
between heparin and a protein, usually platelet
factor 4 (PF 4), also streptokinase same mechanism.

23. 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 nonsteroidal anti-inflammatory
agents; B-lactam-containing antibiotics;
cardiovascular drugs, particularly beta blockers;
psychotropic drugs; anesthetics; antihistamines; and
some chemotherapeutic agents.

24.  Xenobiotic may interfere with platelet function through a
variety of mechanisms. Some drugs inhibit the
phospholipase A2/cyclooxygenase pathway and the
synthesis of thromboxane A2 (e.g., nonsteroidal anti-
inflammatory agents). Other agents appear to interfere
with the interaction between platelet agonists and their
receptors (e.g., antibiotics, ticlopidine, clopidogrel). As
the platelet response is dependent on a rapid increase in
cytoplasmic calcium, any agent that interferes with the
translocation of calcium may inhibit platelet function
(e.g., calcium channel blockers). Occasionally, drug-
induced antibodies bind to a critical platelet receptor and
inhibit its function.

25. Toxic Effects on Fibrin Clot Formation
Coagulation
 Fibrin clot formation results from the sequential activation of
a series of serine proteases that culminates in the formation of
thrombin. Thrombin is a multifunctional enzyme that
converts fibrinogen to fibrin; activates factors V, VIII, XI, and
XIII, protein C, and platelets; and interacts with a variety of
cells (e.g., leukocytes and endothelial cells), activating cellular
signaling pathways ,Most proteins involved in the coagulation
cascade are synthesized in the liver. Therefore, any agent that
impairs liver function may cause a decrease in the production
of coagulation factors. The common tests of the coagulation
cascade—prothrombin time (PT) and activated partial
thromboplastin time (aPTT)—may be used to screen for liver
dysfunction and a decrease in clotting factors.

26. References
1. University of Nebraska Lincoln
Toxicology &exposure guidelines. 12/2002.
2. Toxic response of the blood /Casarett &Doulls ch. 11.
JUNE 2018
3. Toxic response of the blood as a target organ
Hematotoxicology . pharmacy.uobasrah.edu.iq.
4-what are platelets ?Health Encydopedia ,University of
Rochoter,2020.
5-Antiplatelet drug in the management of coronary Artery
Disease ,Jae Youn Moon ,Dominick J.Angiolilo,In Platelets
( fourth Edition )2019

27. REFRENCES
 6- Blood –device interaction ,Michael J. Simmonds,…
Jarod Horobin ,in mechanical circulatory and
Respiratory Support , 2018 .
 7-The function of blood platelets or thrombocytes by
Suzanne Dixon , MPH,RH, Medically reviewed by
Richared N. Fogoros ,MD, November 30,2019 .
 8- Definition of platelet aggregation –Medicin Net ,by :
William C. Shiel Jr.MD. FACP, FACR. 12/21/2018
 9-Glopidogrel Mark G. Papich , DVM,MS,DACVCP, in
Saunders Handbook of Veterinary drugs (FOURTH
EDITION), 2016 .

28. Thank you