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IIIa inhibitors
266
In this Issue
J Lab Clin Med May 2004
for sensitive isolates, and are still effective agents (at higher doses) for isolates that show intermediate resistence on susceptibility testing. If an isolate shows high-level penicillin resistance, it is prudent to use a third-generation cephalosporin of one of the newer fluoroquinoline drugs.
“COAT” platelets: A clue to the lack of clinical efficacy of glycoprotein IIb/IIIa inhibitors The glycoprotein IIb/IIIa complex on platelets can bind fibrinogen and von Willebrand factor; the complex is partially cryptic, becoming more fully exposed and more fully functional when the platelet has been activated. The complex is quite important to platelet aggregation and to platelet interaction with subendothelial matrix, so it seemed quite an attractive idea that drugs binding to the complex might be useful in the prevention of coronary or other small-artery thrombotic events. Indeed, administering intravenous IIb/IIIa inhibitors (such as monoclonal antibodies) could prevent early reocclusion following angioplasty. Unfortunately, the chronic administration of oral IIb/IIIa inhibitors has not been much of a success story, and in some studies has even increased the incidence of acute coronary events. A possible explanation for this disappointing development is offered in an article in this month’s issue of the Journal. Dr Stephen Hamilton and his co-authors from the University of Oklahoma examined the ability of IIb/IIIa inhibitors to influence the generation of activated platelets in vitro. There exists an interesting subset of platelets, termed “COAT” platelets—activated by both thrombin and collagen. These platelets have especially large amounts of factor V and fibrinogen on their surface, and the fibrinogen is not readily displaced (nor is its initial binding much inhibited) by monoclonal antibodies against IIb/IIIa. One might expect that these platelets would not be as sensitive as ordinary platelets to the effects of IIb/IIIa inhibitors—indeed, the drugs may have trouble reaching their target site of action. What if the patients receiving IIb/IIIa inhibitors had a higher proportion of COAT platelets than did normal people? What if the inhibitors actually led to an increased number of such platelets? As a first test of this idea, the investigators examined COAT platelets and IIb/IIIa inhibitors in vitro. As one would guess from the monoclonal antibody data already known, the IIb/IIIa inhibitors (eptifibatide, tirofiban and an experimental agent) failed to inhibit the retention of fibrinogen on COAT platelets. Perhaps more importantly, those agents increased (by anywhere from 5%-35%) the proportion of COAT platelets produced when fresh platelets were exposed to collagen and thrombin. Interestingly, this increase in generation of activated platelets was not seen when abciximab was used as the IIb/IIIa inhibitor. So at least in this in-vitro model, the non-antibody IIb/IIIa inhibitors may do more harm than good in the presence of platelet activation stimuli. The authors then asked whether this were limited to collagen and thrombin as platelet stimuli; the answer was “no.” If they used an Fc receptor agonist rather than collagen as the co-activator with thrombin, they produced a subset of activated platelets that were phenotypically very like COAT platelets. The production of these platelets (termed FcRT platelets) was also greater in the presence of each of the IIb/IIIa inhibitors. The authors speculate that in many patients, the influence of these drugs on the generation of activated platelet subsets may be great enough to offset any benefit that might result from their functional inhibition of non-pre-activated platelets. The paper may be found on page 320.
Cytokine receptors, HIV infection, and cytokine levels Several interesting lines of observation have converged to show that (a) there are co-receptors and/or co-factors for HIV binding to target cells, and (b) some of these “co-receptors” are also binding sites for important cytokines. Abnormalities in some of these sites may explain the inherently high resistance to HIV infection shown by some oft-ree¨ xposed people, and a specific
In this Issue
J Lab Clin Med May 2004
for sensitive isolates, and are still effective agents (at higher doses) for isolates that show intermediate resistence on susceptibility testing. If an isolate shows high-level penicillin resistance, it is prudent to use a third-generation cephalosporin of one of the newer fluoroquinoline drugs.
“COAT” platelets: A clue to the lack of clinical efficacy of glycoprotein IIb/IIIa inhibitors The glycoprotein IIb/IIIa complex on platelets can bind fibrinogen and von Willebrand factor; the complex is partially cryptic, becoming more fully exposed and more fully functional when the platelet has been activated. The complex is quite important to platelet aggregation and to platelet interaction with subendothelial matrix, so it seemed quite an attractive idea that drugs binding to the complex might be useful in the prevention of coronary or other small-artery thrombotic events. Indeed, administering intravenous IIb/IIIa inhibitors (such as monoclonal antibodies) could prevent early reocclusion following angioplasty. Unfortunately, the chronic administration of oral IIb/IIIa inhibitors has not been much of a success story, and in some studies has even increased the incidence of acute coronary events. A possible explanation for this disappointing development is offered in an article in this month’s issue of the Journal. Dr Stephen Hamilton and his co-authors from the University of Oklahoma examined the ability of IIb/IIIa inhibitors to influence the generation of activated platelets in vitro. There exists an interesting subset of platelets, termed “COAT” platelets—activated by both thrombin and collagen. These platelets have especially large amounts of factor V and fibrinogen on their surface, and the fibrinogen is not readily displaced (nor is its initial binding much inhibited) by monoclonal antibodies against IIb/IIIa. One might expect that these platelets would not be as sensitive as ordinary platelets to the effects of IIb/IIIa inhibitors—indeed, the drugs may have trouble reaching their target site of action. What if the patients receiving IIb/IIIa inhibitors had a higher proportion of COAT platelets than did normal people? What if the inhibitors actually led to an increased number of such platelets? As a first test of this idea, the investigators examined COAT platelets and IIb/IIIa inhibitors in vitro. As one would guess from the monoclonal antibody data already known, the IIb/IIIa inhibitors (eptifibatide, tirofiban and an experimental agent) failed to inhibit the retention of fibrinogen on COAT platelets. Perhaps more importantly, those agents increased (by anywhere from 5%-35%) the proportion of COAT platelets produced when fresh platelets were exposed to collagen and thrombin. Interestingly, this increase in generation of activated platelets was not seen when abciximab was used as the IIb/IIIa inhibitor. So at least in this in-vitro model, the non-antibody IIb/IIIa inhibitors may do more harm than good in the presence of platelet activation stimuli. The authors then asked whether this were limited to collagen and thrombin as platelet stimuli; the answer was “no.” If they used an Fc receptor agonist rather than collagen as the co-activator with thrombin, they produced a subset of activated platelets that were phenotypically very like COAT platelets. The production of these platelets (termed FcRT platelets) was also greater in the presence of each of the IIb/IIIa inhibitors. The authors speculate that in many patients, the influence of these drugs on the generation of activated platelet subsets may be great enough to offset any benefit that might result from their functional inhibition of non-pre-activated platelets. The paper may be found on page 320.
Cytokine receptors, HIV infection, and cytokine levels Several interesting lines of observation have converged to show that (a) there are co-receptors and/or co-factors for HIV binding to target cells, and (b) some of these “co-receptors” are also binding sites for important cytokines. Abnormalities in some of these sites may explain the inherently high resistance to HIV infection shown by some oft-ree¨ xposed people, and a specific