PLATELET ACTIVATING FACTORS: MECHANISM OF ACTION AND CLINICAL USES, INTRODUCTION

1. ASSIGNMENT PRESENTED TO
Dr. TARIQUE MAHMOOD
ASSOCIATE PROFESSOR & HEAD
Mrs. ARSHIYA SHAMIM
ASST. PROFESSOR
PHARMACOLOGY - 1
PRY - 206
INTEGRAL UNIVERSITY , LUCKNOW
7/30/2021 1

2. Platelet activating factor:
Mechanism of action
&
Clinical uses
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3. Platelet-activating factor (PAF) is
a lipid mediator that is well-known
for its ability to cause platelet
aggregation, inflammation, and
allergic response at very low
concentrations (approaching
picomolar).
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4. 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 that are picked up
by platelets.
The platelets then rush
to the site of damage and
form a plug, or clot, to
repair the damage. 7/30/2021 4

5. 7/30/2021 5

6. In pharmacology, the
term mechanism of
action (MOA) refers to the
specific biochemical
interaction through which a
drug substance produces
its pharmacological effect. A
mechanism of
action usually includes
mention of the specific
molecular targets to which
the drug binds, such as an
enzyme or receptor.
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7. relating to or based on work done
with real patients : of or relating
to the medical treatment that is
given to patients in hospitals,
clinics, etc. : requiring treatment
as a medical problem. : of or
relating to a place where medical
treatment is given : of or relating
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8. What is platelet activating factor..??
Platelet-activating factor is a potent biological mediator
that exerts its effects in a variety of cells and tissues.
Platelet-activating factor, also known as
PAF, PAF- acether or AGEPC (acetyl-glyceryl-ether-
phosphorylcholine), is a potent phospholipid activator
and mediator of many leukocyte functions, including
platelet aggregation and degranulation, inflammation,
and anaphylaxis.
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9. It is also involved in changes to vascular
permeability, the oxidative burst, chemotaxis of
leukocytes, as well as augmentation of
arachidonic acid metabolism in phagocytes.
PAF is produced by a variety of cells, but
especially those involved in host defense,
such as , platelets, endothelial cells,
neutrophils,monocytes, and macrophages.
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10. Discovery of PAF.
In 1970, during a study of immunological
mechanisms involving histamine and serotonin
release from platelets in immunized rabbits, Henson
proposed that 'a soluble factor' was released from
leukocytes which stimulated platelets to release
vasoactive amines. This observation was confirmed
independently by Siraganian and Osler in 1971
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11. In 1972, Benveniste, Henson and Cochrane
demonstrated that the antibody involved in the
immunological reaction described was an IgE class
antibody and coined the term 'platelet-activating factor
(PAF)' for the soluble factor released from basophils
following IgE stimulation.
However, it was not until 1979 that Demopoulos,
Pinckard and Hanahan demonstrated that a
semisynthetic phosphoacylglycerol, l-O-alkyl-2-acetyl-
snglycero-3-phosphocholine (AGEPC), had
physiochemical as well as biological properties (i.e.
aggregation of platelets and secretion of serotonin)
indistinguishable from those of naturally-generated PAF
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12. Synthesis of PAF
The biosynthesis of PAF via remodeling of membrane
phospholipid
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13. The biosynthesis of PAF via de novo synthesis
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14. •This pathway may contribute to physiological levels of
PAF for normal cellular functions.
1-The synthesis of PAF may be stimulated during antigen–
antibody reactions or by a variety of agents, including
chemotactic peptides, thrombin, collagen, and other
autacoids.
2- PAF also can stimulate its own formation. Both the
phospholipase and acetyltransferase are Ca2+-dependent
enzymes; thus, PAF synthesis is regulated by the availability
of Ca2+.
3- The inactivation of PAF also occurs in two steps .
1)Initially, the acetyl group of PAF is removed by PAF acetyl
hydrolase to form lyso-PAF
2)Lyso-PAF is then converted to a 1-O-alkyl-2-acyl-
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15. 1- In addition to these enzymatic routes. PAF-like molecules can be
formed
from the oxidative fragmentation of membrane phospholipids
(oxidized
phospholipids).
2- These compounds are increased in settings of oxidant stress such
as
cigarette smoking.
3-They differ structurally from PAF in that they contain a fatty acid at the
sn-1
position of glycerol joined through an ester bond and various short-
chain
acyl groups at the sn-2 position.
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16. 5-Unlike the synthesis of PAF, which is highly controlled,
oxidized phospholipids production is unregulated;
degradation by PAF acetyl hydrolase, therefore, is
necessary to suppress the toxicity of oxidized
phospholipids.
6-Levels of PAF acetyl hydrolase (also known as
lipoprotein-associated phospholipase a2) are increased in
colon cancer, cardiovascular disease & stroke. 7-
Polymorphisms have been associated with altered risk of
cardiovascular events.
Remodelling of cell membrane phospholipid denevo 1-0-
alkyl-sn-glycero-3-phosphate
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17. Mechanism of action PAF
Extracellular PAF exerts its actions by stimulating a
specific GPCR that is expressed in numerous cell
types.
The PAF receptor's strict recognition requirements,
including a specific head group and specific atypical sn-
2 residue, also are met by oxPLs.
The PAF receptor couples with Gq to activate the
PLC–IP3–Ca2+ pathway and phospholipases A2 and D
such that AA is mobilized from diacylglycerol, resulting
in the synthesis of PGs, TxA2, or LTs, which may
function as extracellular mediators of the effects of PAF.
 PAF also may exert actions without leaving its cell of
origin.
For example, PAF is synthesized in a regulated
fashion by endothelial cells stimulated by inflammatory
mediators. 7/30/2021 17

18. This PAF is presented on the surface of the
endothelium, where it activates the PAF receptor on
juxtaposed cells, including platelets,
polymorphonuclear leukocytes, and monocytes,
and acts co-operatively with P-selectin to promote
adhesion.
Endothelial cells under oxidant stress release
oxPLs, which activate leukocytes and platelets and
can spread tissue damage.
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19. Physiological and pathophysiological effects of
PAF
1-Platelet aggregation and secretion, thrombosis.
2-Stimulation of neutrophils and macrophages.
3-Acute inflammation.
4-Asthma and systemic anaphylaxis.
5-Endotoxin and immune factor-induced shocks.
6-Gastrointestinal ulceration.
7-Glycogenolysis and increased portal pressure.
8-Pancreatitis.
9-Cardiac anaphylaxis (negative inotropic effect and increased heart
beating rate).
10-Pregnancy and ovo implantation.
11-Ovulation.
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20. Platelet aggregation
1.Platelet aggregate or clump together using fibrinogen of vWF
as a
connecting agent.
2.The most abundant platelet aggregation receptor is
glycoprotein
Iib /3A. Activated platelets will adhere, via glycoprotein Ia to
the
collagen that is exposed by endothelial damage.
3.Aggregation and adhesion act together to form platelet plug.
Platelet
aggregation is stimulated by ADP , Thromboxane and a2
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21. 7/30/2021 21

22. Initially, PAF was found to effect aggregation of platelets at
concentrations as low as 10^-11 M, and it induced a hypertensive
response at very low levels also. More generally, it is now
recognised that its primary role is to mediate intercellular
interactions.
For example, by binding to its specific receptor, PAF activates the
cytoplasmic phospholipase A2 and phospholipase C. The result
of the latter is an increase in intracellular Ca2+ downstream of
the cell and activation of protein kinase C.
It is now known to exert effects on many different types of non-
inflammatory biological events and functions, including glycogen
degradation, reproduction, brain function and blood circulation
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23. Thrombus formation
The function of platelets is the maintainence of haemostasis,this is achievd by the
formation of thrombi when damage to endothelium of blood vessels occurs.
Conversely ,thrombus formation must be inhibited at times when there is no
damage to the endothelium, Activation-the inner surface of blood vessel is lined
with a thin layer of endothelial cells,that in normal haemostasis acts to inhibit
platelet activation by producing endothelial ADPase, nor-adrenaline and PGI2.
Endothelial ADPase clears away ADP,a platelet activator,from platelet surface
receptors. Endothelial cells produce a protein called von Willebrand factor,a cell
adhesion ligand,which helps endothelial cells adhere to collagen in the basement
membrane. Under physiological condition collgen does not pass into the
bloodstream;however vWF is secreted constitutively into the plasma by the
Endothelial cells that
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24. Produce it or otherwise is stored within the endothelial cells or in
platelets. When endothelial damage occurs platelets comes into
contact with exposed collagen and vWF,
causing a reduction in secretion of endothelium platelet
inhibitors the inner surface of blood vessels is lined with a thin
layer of endothelial cells. Under this is a layer of collagen.
When the endothelial layer is injured the collagen is exposed.
When platelets contact collagen they are activated
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25. Pharmacological actions
CVS
1-PAF is a potent dilator in most vascular beds; when
administered intravenously, it causes hypotension in all species
studied.
2- PAF-induced vasodilation is independent of effects on sympathetic
innervation, the renin–angiotensin system, or arachidonate metabolism and
likely results from a combination of direct and indirect actions.
3- PAF induces vasoconstriction or vasodilation depending on the
concentration, vascular bed, and involvement of platelets or leukocytes.
For example, the intracoronary administration of very low concentrations of PAF
increases coronary blood flow by a mechanism that involves the release of a
plateletderived vasodilator.
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26. 4-Coronary blood flow is decreased at higher doses
by the formation of intravascular aggregates of
platelets and/or the formation of TXA2. 5-The
pulmonary vasculature is also constricted by PAF
and a similar mechanism is thought to be involved.
6-Intradermal injection of PAF causes an initial
vasoconstriction followed by a typical wheal and
flare. 7-PAF increases vascular permeability and
edema in the same manner as histamine and
bradykinin. but PAF is more potent than histamine
or bradykinin by three orders of magnitude.
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27. Platelets
1-PAF potently stimulates platelet aggregation in vitro.
2-While this is accompanied by the release of TxA2 and the
granular contents of the platelet, PAF does not require the
presence of TxA2 or other aggregating agents to produce this
effect.
3-The intravenous injection of PAF causes formation of
intravascular platelet aggregates and thrombocytopenia
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28. Smooth Muscle
1-PAF generally contracts gastrointestinal, uterine, and pulmonary smooth muscle.
2- PAF enhances the amplitude of spontaneous uterine contractions; quiescent
muscle contracts rapidly in a phasic fashion.
3- These contractions are inhibited by inhibitors of PG synthesis.
4-PAF does not affect tracheal smooth muscle but contracts airway smooth muscle.
Most evidence suggests that another autacoid (e.g., LTC4 or TxA2) mediates this
effect of PAF.
5-When given by aerosol, PAF increases airway resistance as well as the
responsiveness to other bronchoconstrictors.
6-PAF also increases mucus secretion and the permeability of pulmonary
microvessels; this results in fluid accumulation in the mucosal and submucosal
regions of the bronchi and trachea
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29. Stomach
1-In addition to contracting the fundus of the
stomach, PAF is the most potent known
ulcerogen. 2-When given intravenously, it causes
hemorrhagic erosions of the gastric mucosa that
extend into the submucosa
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30. Kidney
 When infused intrarenally in animals, PAF
decreases renal blood flow, glomerular filtration
rate, urine volume, and excretion of Na+ without
changes in systemic hemodynamics
 These effects are the result of a direct action on
the renal circulation.
 PAF exerts a receptor-mediated biphasic effect
on afferent arterioles, dilating them at low
concentrations and constricting them at higher
concentrations.
 The vasoconstrictor effect appears to be
mediated, at least in part, by COX products,
whereas vasodilation is a consequence of the
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31. Pathophysiological function of PAF
PAF generally is viewed as a mediator of pathological
events. Dysregulation of PAF signaling or degradation
has been associated with some human diseases, aided
by data from genetically modified animals.
platelet
1-Since PAF is synthesized by platelets and promotes
aggregation, it was proposed as the mediator of
cyclooxygenase inhibitor–resistant, thrombin-induced
aggregation.
2-However, PAF antagonists fail to block thrombin-induced
aggregation, even though they prolong bleeding time and
prevent thrombus formation in some experimental models.
3-Thus, PAF does not function as an independent mediator of
platelet aggregation but contributes to thrombus formation in a
manner analogous to TxA2 and ADP
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32. Inflammatory & allergic
response
1-The proinflammatory actions of PAF and its elaboration by
endothelial cells, leukocytes, and mast cells under
inflammatory conditions are well characterized.
2-PAF and PAF-like molecules are thought to contribute to
the pathophysiology of inflammatory disorders, including
anaphylaxis, bronchial asthma, endotoxic shock, and skin
diseases.
3-The plasma concentration of PAF is increased in
experimental anaphylactic shock, and the administration of
PAF reproduces many of its signs and symptoms, suggesting
a role for the autacoid in anaphylactic shock.
4- In addition, mice overexpressing the PAF receptor exhibit
bronchial hyperreactivity and increased lethality when treated
with endotoxin.
5-PAF receptor knockout mice display milder anaphylactic
responses to exogenous antigen challenge, including less
cardiac instability, airway constriction, and alveolar edema;
they are, however, still susceptible to endotoxic shock.
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33. 6-Despite the broad implications of these
observations, the effects of PAF antagonists in the
treatment of inflammatory and allergic disorders
have been disappointing.
7- Although PAF antagonists reverse the
bronchoconstriction of anaphylactic shock and
improve survival in animal models, the impact of
these agents on animal models of asthma and
inflammation is marginal.
8-Similarly, in patients with asthma, PAF
antagonists partially inhibit the bronchoconstriction
induced by antigen challenge but not by challenges
of exercise, or inhalation of cold air.
9-These results may reflect the complexity of
these pathological conditions and the likelyhood
that other mediators contribute to the inflammation
associated with these disorders.
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