Disorders associated with platelet dysfunction
Others have specific actions on platelet function - some rendering them less active, others increasing their capacity to respond to stimuli.
Classes of Drugs and agents
Aspirin and other non-steroidal anti-inflammatory analgesics have been shown to interfere with platelet prostaglandin synthesis by inhibiting platelet fatty acid cyclo-oxygenase. This in turn reduces synthesis of labile endoperoxides PGG2 and PGH2 from platelet membrane arachidonic acid, in turn reducing the production of TXA2 (Thromboxane A2), the extremely potent mediator of platelet aggregation.
It is now known that the interference with endoperoxide production inhibits stimulus-induced ADP release, so it is probably the inhibition of cyclo-oxygenase that is the root cause of aspirin-induced platelet dysfunction.
Aspirin acts on cyclo-oxygenase by causing irreversible acetylation of the enzyme, and therefore the effect is irreversible for the life of that platelet (7-10 days). Other non-steroidal anti-inflammatory analgesics have a reversible action on that enzyme, and hence only act until the drug is cleared from the circulation.
Aspirin also inhibits cyclo-oxygenase in the endothelial cells of blood vessels. This action results in inhibition of PGI2 production. PGI2 is the most potent inhibitor of platelet aggregation know. However, endothelial cells can actively synthesise cyclo-oxygenase, so recovery of PGI2 synthesis is possible with intermittent aspirin ingestion.
How can normal platelet function will be restored?
DDAVP has been shown to reduce significantly the mean operative and postoperative blood loss in patients undergoing cardiopulmonary bypass surgery, a situation in which there is almost certainly an acute acquired defect in the formation of the platelet plug. This transient impairment of platelet function is mediated bby platelet activation during passage through the oxygenator apparatus, and involves secondary release and partial depletion of alpha granules, but not dense granules.
Desmopressin Acetate (DDAVP) is a synthetic vasopressin analogue that lacks vasoconstrictor activity. It has been used to improve haemostasis in patients with mild haemophilia or von Willebrand's disease, in whom it shortens bleeding time, apparently by inducing the release of factor VIII:von Willebrand factor, particularly the larger multimers. It has also been shown to reduce the bleeding time and reduce surgical blood loss in other conditions involving abnormal platelet function, but wit hno known defect in the structure or function of von Willebrand factor. Such conditions include urenia, certain thrombotic states, and aspirin ingestion.
Various studies have shown that DDAVP shortens bleeding time in all patients within 1 hour of intravenous infusion of 0.2-0.4 micrograms/Kg of DDAVP. (Infused 50 ml over 15 minutes)
Mechanism of hemostatic effect of desmopressin acetate is uncertain.
It is known that the drug shortens the bleeding time of patients with mild hemophilia or von Willebrand's disease (and may precipitate platelet aggregation in type IIb von Willebrand's disease), as well as patients with uremia. These effects are accompanied by an increase in the plasma concentration of von Willebrand factor, especially the higher molecular weight multimers, and also of tissue plasminogen activator.
It may be the increased levels of von Willebrand factor, including binding of this factor to endothelial surfaces, that is the mechanism of action of DDAVP in reducing bleeding time. It has been shown that platelet adhesion to artery subendothelium is mediated by factor VII:von Willebrand factor bound to the subendothelium.
These substances act by inhibiting most platelet reactions, such as shape change; adhesion to collagen- coated or subendothelial surfaces; platelet aggregation induced by ADP, adrenaline, collagen, thrombin; platelet release of stored substances; generation of platelet factor 3; and clot retraction.
These antibiotics may also intercalate into the bilipid layer of the platelet plasma membrane and interfere with binding of various agonists to receptor sites. Such a mechanism would be consistent with the global effects of these drugs on platelet functions, and the observed relationship between the lipid solubility of various drugs and their antiplatelet effects.
1) Sakariassen KS, Bolhuis PA, Sixma JJ. Human blood platelet adhesion to artery subendothelium is mediated by factor VII:von Willebrand factor bound to the subendothelium. Nature 279:636,1979
2) Connor AM, Laposta M. A rapid assay for platelet thromboxane production and its use in assessing prior aspirin ingestion. Am J Clin Pathol 1988;89:216-221