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:

FIG1

( 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.

FIG2

( Normal) -Healthy,intact endothelium,releases prostacyclin into plasma. This Prostacyclin binds to platelet membrane receptors, causingsynthesis of cAMP.-cAMP 1-stabilizes inactive GP IIb/IIIa receptors and 2-inhibits release of Ca2+ -This prevents plateletactivation and the subsequent release of platelet aggregationagents.

FIG3

(Abnormal) when

endothelial cells are

damaged in some area,

platelets cover and adhere

to exposed collagen of the

subendothelial surface and

become activated.

platelet

FIG4

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

FIG5

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 newly activated

platelets.

FIG6 A & B

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

FIG7

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 .

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.