Platelet activation disorders

The assay, introduced by Bom (1962a,b), has become a standard method in clinical diagnosis of platelet function disorders and of aspirin intake. Furthermore, the method is used in the discovery of antiplatelet drugs with the advantage of rapid measurement of a functional parameter in intact human platelets. However, processing of platelets during the preparion of PRP, washed or filtered platelets from whole blood results in platelet activation and separation of large-size platelets. 

Polycythemia is usually defined as a hematocrit above 0.50 in males and 0.47 in females. Polycythemia rubra vera or primary polycythemia, a myeloproliferative disorder, may be complicated by TIAs, ischemic stroke or intracranial venous thrombosis (Silverstein et at 1962 Pearson and Wetherley-Mein 1978 Markus and Hambley 1998). Ischemic complications may occur because the platelet count is raised and platelet activity enhanced, or... 

StcmnoricenH, GogstadG,Sbleeding disorder lade of platdet aggregatory response to adrenalin and lack of secondary aggr ation to ADP and platelet activating factor (PAF). Ihromb Res. 1982 29 391 402... 

When compared to humans, none of the animal species arc predisposed to thrombotic disorders or arterial vascular pathology. Recent studies of in vivo platelet activation and platelet-dependent thrombosis provide evidence that the relationships between intrinsically highly active platelets and thrombotic diseases is not coincidental. 

Previous work with A6-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-l -ol, hereinafter referred to as A6-THC], has indicated that derivatives of this compound may prove clinically useful. The 7-carboxy derivative of A6-THC [A6-THC-7-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued Nov. 27, 1990 to Sumner Burstein). Another derivative, (3S,4S)-7-hydroxy-A6-THC-l,l-dimethylheptyl, has been reported to possess analgesic and antiemetic activities. (U.S. Pat. No. 4,876,276). 

Understanding of the role of platelets, platelet activation and consumption in diseases characterized by thromboembolic phenomena or thrombocytopenia (Baldini and Myers 1980 Letter et al. 1986 International Committee for Standardization in Hematology 1988 Vallabhajosula et al. 1986) as well as in vascular disorders or endothelial (surface) abnormalities (Baldini and Myers 1980 Vallabhajosula et al. 1986 Harker et al. 1977)... 

The inhibition of platelet activation is a critical component in the treatment and prevention of cardiovascular diseases and cerebral ischemia/thrombotic disorders. Nitric oxide and prostacyclins inhibit platelet activation by elevating intracellular levels of both cGMP and cAMP, respectively. In platelets, the most abundant PDE is PDE3A, which lowers the intracellular concentration of cAMP. Inhibitors of PDE3A serve as potential antiplatelet agents by elevating cAMP levels. One PDE3-type selective inhibitor cilostazol, which has both antiplatelet, antithrombotic, and vasodilatory effects, is used for the treatment of intermittent claudication and for the prevention of short- and medium-term vessel closure (22). 

Levels of platelet-activating factor are elevated in several neurological and visceral disorders, including brain trauma, seizures, stroke, multiple sclerosis, and viral and bacterial infections, as well as in a variety of other conditions such as asthma, thrombosis, toxic shock, and dermatitis. Administration of PAF antagonists slows down the progression of these disorders. Thus, the development of new non-toxic PAF antagonists would result in better treatment of visceral and neurological disorders. 

Ginkgolide B is a selective antagonist of platelet aggregation induced by platelet-activating factor (PAF). PAF, an inflammatory autacoid, is involved in various inflammatory, cardiovascular, and respiratory disorders. " Ginkgo extract has also displayed anti-inflam-matroy activity in a number of conditions and disease models such as colitis, arthritis, skin inflammation, and rat paw edema. " Antiinflammatory mediators have been suppressed by the extract. ... 

---