Carbenicillin and Penicillin G Inhibit Platelet Function In Vitro by Impairing the Interaction of Agonists with the Platelet Surface

Shattil, Sanford J.; Bennett, Joel S.; McDonough, Margaret; Turnbull, Judy

doi:10.1172/jci109676

Cited by 108 publications

(31 citation statements)

References 38 publications

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“…Among these, thromboxane synthesis, changes in intracellular cAMP, and translocations of calcium ions across the membranes are thought to be major events (48,51,52). Our data make it unlikely that ticlopidine acts by affecting one or more of these basic events of platelet activation since, as in thrombasthenia, these processes are normal in platelets from ticlopidine-treated subjects.…”

Section: Discussionmentioning

confidence: 75%

“…Current evidence (48,52,60) suggests that plasma membrane receptors are glycoproteins presumably embedded within the membrane's lipid bilayer. Since ticlopidine is a lipophilic substance and can alter the fluidity of platelet membranes in the rat, it might interfere with the binding of several agonists to the platelet surface, either by interacting directly with specific receptors or by affecting the surrounding lipid milieu.…”

Section: Discussionmentioning

confidence: 99%

“…Drugs like carbenecillin and penicillin G inhibit platelet function by impairing the interaction of several agonists with their specific receptors on the platelet surface membrane (48). We wondered, therefore, whether the inhibition of fibrinogen was a selective event or that ticlopidine might inhibit platelet function by interfering with the binding of other agonists to the platelet surface.…”

Section: Introductionmentioning

confidence: 99%

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Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Minno¹,

Cerbone²,

Mattioli³

et al. 1985

J. Clin. Invest.

201

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To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets obtained from eight healthy volunteers before and 1 wk after daily administration of 500 mg of ticlopidine. We found the following: ticlopidine significantly (P < 0.001) prolonged the skin bleeding time and impaired the binding of radiolabeled fibrinogen and von Willebrand Factor, the clot retraction and the aggregation of platelets in response to ADP, epinephrine, thrombin, ionophore A23187, collagen, or arachidonic acid. In contrast, the administration of this drug did not affect intraplatelet levels of cAMP, agglutination and binding of von Willebrand Factor in response to ristocetin, shape change in response to ADP, collagen, thrombin, or arachidonic acid, or binding of prostaglandin El to resting platelets. Secretion of ATP in response to ADP or epinephrine was completely inhibited, whereas secretion as well as thromboxane synthesis in response to high concentrations of collagen, arachidonic acid, calcium ionophore A23187, or thrombin was unaffected. Studies with monoclonal antibodies showed that the glycoprotein IIb-IIIa complex (the putative receptor for fibrinogen and von Willebrand Factor on the surface of platelets exposed to naturally occurring aggregating agents) was quantitatively unaffected by ticlopidine. This observation was further confirmed by densitometric scannings of Periodic Acid-Schiff-stained gels of platelet suspensions. The onset, as well as the cessation of the inhibitory effect of ticlopidine on platelets was very slow, and reached a maximum after a 3-5-d administration. In addition, ticlopidine appeared to be a much more potent inhibitor when administered to subjects than when added in vitro to platelets. Finally, abnormalities comparable to those found in volunteers taking ticlopidine were observed when platelets from untreated subjects were incubated in the plasma of ticlopidine-treated subjects.We conclude that ticlopidine induces a thrombasthenic state in normal platelets without affecting the glycoprotein IlbIIIa complex quantitatively. Furthermore, our data suggest that one or more active metabolites rather than the native drug Portions of this work were presented at a symposium ("Ticlopidine: Quo vadis?") in Montpellier, France, 1983, and were published in abstract form in the proceedings of that symposium.Address reprint requests to Dr. Di Minno.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Minno¹,

Cerbone²,

Mattioli³

et al. 1985

J. Clin. Invest.

201

View full text Add to dashboard Cite

show abstract

“…The mechanism is thought to be through the inhibition of epinephrine and ADP-induced platelet aggregation and granule release and interference with platelet-VWF interactions. 14 Cephalosporins and other ␤-lactams given at lower doses can also inhibit platelet function in vitro. However, the clinical significance of this has not been clearly established.…”

Section: Medications That Inadvertently Inhibit Platelet Functionmentioning

confidence: 99%

Acquired Disorders of Platelet Function

Konkle

2011

Hematology

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Platelet dysfunction is commonly acquired due to medications, procedures, medical conditions, and underlying hematologic disease. These issues are presented, the data reviewed, and recommendations given herein. Many medications and dietary supplements have platelet-inhibitory effects in vitro, although the clinical effects on bleeding risks are unclear for many. Platelet-inhibitory drugs are key in the treatment of vascular disease. Data are available to aid in the management of these medications to prevent hemorrhagic complications. Bleeding in patients with renal failure has decreased with improved dialysis and the use of erythropoietin, but remains a challenge. Platelet dysfunction accompanies cardiac valvular disease and use of cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation. Hematologic disorders including myeloproliferative disorders (MPDs), myelodysplasia, paraproteinemias, and immune thrombocytopenia (ITP) can also be associated with hemorrhagic complications due to platelet dysfunction. Knowledge of which factors affect bleeding risk and how to treat individuals with acquired platelet dysfunction are important in optimizing patient care.

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“…18 Clinical bleeding and abnormal platelet function occur in patients given large doses of various β-lactam antibiotics (penicillins > cephalosporins), attributable in large part to impairment of the interaction between agonist-receptor pairs. 19 The clinical effect is most severe in hypoalbuminemic patients because higher levels of unbound drug interact with the platelet surface, and impaired hemostasis may be long-lasting due to a residual impairment of receptor function even after the antibiotic is discontinued. β-lactam compounds only contribute to clinical bleeding when there is a co-existing hemostatic defect, such as uremia, thrombocytopenia or vitamin K deficiency.…”

Section: Medicationsmentioning

confidence: 99%

Acquired Disorders of Platelet Function

Hassan

Kroll

2005

Hematology

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A qualitative abnormality of platelet function should be considered in patients with mucocutaneous bleeding in the absence of thrombocytopenia or von Willebrand disease. Antiplatelet drugs are the most common cause of acquired platelet disorders leading to bleeding. Uremia, hepatic cirrhosis, myeloma and related disorders, polycythemia vera, essential thrombocythemia, and cardiopulmonary bypass have long been recognized as clinical situations in which platelet dysfunction may contribute to bleeding. When an acquired platelet disorder is suspected, it is useful to examine platelet function by measuring the bleeding time, examining platelet-dependent closure time in a platelet function analyzer and performing platelet aggregometry. When a specific acquired platelet disorder is diagnosed, many treatment options are available including controlling the underlying disease, giving platelet transfusions and administering a hemostatic drug.

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Carbenicillin and Penicillin G Inhibit Platelet Function In Vitro by Impairing the Interaction of Agonists with the Platelet Surface

Abstract: A B S T R A C

Cited by 108 publications

References 38 publications

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Acquired Disorders of Platelet Function

Acquired Disorders of Platelet Function

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