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Blood disorders
1-Thrombosis,
2-Bleeding,
3- Anemia.
Thrombosis: the formation of an unwanted clot within a blood vessel, is the most common abnormality of
hemostasis. Thrombotic disorders include mainly:
-Acute myocardial infarction,
-Deep vein thrombosis
-Pulmonary embolism,
- Acute ischemic stroke. These are prevented &/or treated with drugs such
as antiplatelets, anticoagulants and fibrinolytics.
Antiplatelets (Platelet inhibitors)
physiology
The following figures illustrating that creation of an unwanted thrombus involves many of the same steps as
normal clot formation, except that the triggering stimulus is a pathologic condition in the vascular system
rather than an external physical trauma:
( Normal) Platelets act as
vascular sentries,
monitoring the integrity of
the endothelium. In the
absence of injury, resting
platelets circulate freely,
because the balance of
chemical signals indicates
that the vascular system is
not damaged.
FIG1
platelet
( Normal)
-Healthy,intact
endothelium,releases
prostacyclin into plasma.
This Prostacyclin binds to
platelet
membrane
receptors, causing
synthesis of cAMP.
-cAMP
1-stabilizes inactive GP
IIb/IIIa receptors and
2-inhibits release of Ca2+
-This prevents platelet
activation
and
the
subsequent
release
of
platelet aggregation
agents.
FIG2
(Abnormal)
endothelial
when
cells
are
damaged in some area,
platelets cover and adhere
to exposed collagen of the
subendothelial surface and
become activated.
FIG3
Activated platelets release
The
following
chemical
mediators:
1-Thromboxane
A2
(synthesized
from
arachidonic acid).
2-
ADP
=
adenosine
diphosphate
3-Serotonin
4-
PAF
=
platelet-
activation factor
FIG4
Thromboxane
A2,
ADP,Serotonin, PAF do
the followings:
1- bind to receptors in the
outer membrane of
the
nearby resting circulating
platelets and bring them to
the exposed collagen to be
activated in turn leading to
further release of the same
chemical mediators from
these
platelets.
FIG5
newly
activated
2-Activation
of
glycoprotein (GP) IIb/IIIa
receptors;
Activated GP IIb/IIIa in
turn bind to fibrinogen ( a
soluble and weak) that
binds to GP IIb/IIIa
receptors on two separate
platelets,
resulting
in
platelet cross-linking and
platelet aggregation
FIG6 A & B
Local stimulation of the
coagulation
cascade
(coagulation factors) by
tissue mediators released
from the injured tissue,
convert prothrombin (
factor II) which is inactive
into thrombin (factor IIa)
which is active. ; thrombin
is coagulation factor that
convert fibrinogen ( {weak,
soluble} into fibrin (strong,
insoluble)
which is
incorporated into the plug.
Subsequent cross-linking of
the fibrin strands stabilizes
the clot and forms a
hemostatic platelet-fibrin
plug .
FIG7
FIG8
PLATELET AGGREGATION INHIBITORS
Because these agents have different mechanisms of actions, synergistic or additive effects may be achieved
when agents from different classes are combined. These agents are beneficial in the prevention and treatment
of occlusive cardiovascular diseases, in the maintenance of vascular grafts and arterial patency, and as
adjuncts to thrombin inhibitors or thrombolytic therapy in myocardial infarction (to be discussed in the next
lecture).
A- Aspirin: Mechanism of action
Activation of platelets results in Stimulation of platelet membrane phospholipases that liberate arachidonic
acid from membrane phospholipids. Arachidonic acid is first converted to prostaglandin H2 by COX-1
(Figure). Prostaglandin H2 is further metabolized to thromboxane A2, which is released into plasma.
Thromboxane A2 produced by the aggregating platelets further promotes the clumping process that is
essential for the rapid formation of a hemostatic plug. Aspirin inhibits thromboxane A2 synthesis from
arachidonic acid in platelets by irreversible acetylation and inhibition of COX-1 . The aspirin-induced
suppression of thromboxane A2 synthesis and the resulting suppression of platelet aggregation last for the life
of the platelet, which is approximately 7 to 10 days.
Medical uses:
Aspirin is currently used in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence
of recurrent myocardial infarction, and to decrease mortality in pre- and post-myocardial infarct patients. The
recommended dose of aspirin ranges from 50 to 325 mg, with side effects determining the dose chosen.
Formerly known as “baby aspirin,” 81-mg aspirin is most commonly used .
** Aspirin is frequently used in combination with other drugs having anticlotting properties, such as heparin
or clopidogrel.
* Aspirin is the only NSAID that irreversibly exhibits antithrombotic efficacy.
*Adverse effects:
Bleeding time is prolonged by aspirin treatment, causing complications that include an increased incidence of
hemorrhagic stroke as well as gastrointestinal (GI) bleeding, especially at higher doses of the drug.
*Drug-drug interactions;
Non selective non steroidal anti-infl ammatory drugs (NSAIDs), such as ibuprofen, inhibit COX-1 by
transiently competing at the catalytic site. Ibuprofen, if taken concomitantly with, or 2 hours prior to aspirin
can obstruct the access of aspirin to the serine residue and, thereby, antagonize the platelet inhibition by
aspirin.
B. Ticlopidine, clopidogrel, and prasugrel: are closely related thienopyridines that also block platelet
aggregation.
Mechanism of action:
These drugs irreversibly inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit calcium
ion release and the consequent activation of the GP IIb/IIIa receptors required for platelets to bind to
fibrinogen and to each other (Figure).
Therapeutic use:
Prevention of transient ischemic attacks and strokes for patients with a prior cerebral thrombotic
event.Although ticlopidine and clopidogrel are similar in both structure and mechanism of action, ticlopidine
is generally reserved for patients who are intolerant to other therapies, due to its life-threatening hematologic
adverse reactions, including neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and
aplastic anemia, Clopidogrel has a better overall side-effect profile, although TTP may also occur with this
agent, but and the incidence of neutropenia is lower . Prasugrel is the newest ADP receptor antagonist.
Pharmacokinetics:
The maximum effect is achieved in 3-5 days.
Elimination of the drugs and metabolites occurs by both the renal and fecal routes.
C. Abciximab, Eptifibatide and tirofiban
Mechanism of action:
abciximab is a human immunoglobulin directed against the GP IIb/ IIIa receptor. By binding to GP IIb/IIIa,
the antibody blocks the binding of fibrinogen, and, consequently, aggregation does not occur (Figure).
Eptifibatide is a cyclic peptide that also binds to GP IIb/IIIa at the site that interacts with fibrinogen.
Tirofiban is is not a peptide, but it blocks the same site as eptifibatide.
Medical uses:
Abciximab is given intravenously along with either heparin or aspirin as an adjunct to percutaneous coronary
intervention for the prevention of cardiac ischemic complications. It is also approved for unresponsive
unstable angina and for prophylactic use in myocardial infarction.
Eptifibatide and tirofiban, like abciximab, can decrease the incidence of thrombotic complications associated
with acute coronary syndromes. When intravenous (IV) infusion is stopped, these agents are rapidly cleared
from the plasma, but their effect can persist for as long as 4 hours where as with abciximab, the effect can
persist for up to 48 hours .
Adverse effect
The major adverse effect of these three drugs is the potential for bleeding, especially if the drug is used with
anticoagulants or if the patient has a clinical hemorrhagic condition. Abciximab is expensive, limiting its use
in some settings.
D. Dipyridamole and Cilostazol
Mechanism
Dipyridamole and Cilostazol increase
intracellular levels of cAMP by inhibiting cyclic nucleotide
phosphodiesterase. cAMP stabilizes inactive GP IIb/IIIa receptors and inhibits release of Ca2+ and platelet
aggregation agents. Thus dipyrimadole potentiate the effect of prostacyclin to antagonize platelet stickiness
and, therefore, decrease platelet adhesion to thrombogenic surfaces.
Adverse effects
Dipyridamole has been described as “inappropriate” for use in the elderly as a sole agent due to adverse GI
and orthostasis problems.
Headache and GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal pain) are the most
common adverse effects observed with cilostazol.