Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia

Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/microL (9 x 10(10)/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P =.0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.     

Drug-Induced Thrombocytopenia: Is it a Serious Concern for Glycoprotein IIb/IIIa Receptor Inhibitors?

Over the past decade, several glycoprotein IIb/IIIa receptor antagonists have been developed and tested clinically as adjuncts to coronary intervention and/or treatment of acute coronary syndromes. Thrombocytopenia associated with this class of compounds has been described in most large studies to date and when it occurs in combination with bleeding represents a major safety concern. Cases of thrombocytopenia caused by GP IIb/IIIa antagonists vary in their clinical presentation according to time of onset (following the first dose or delayed), severity (profound, i.e., <20,000 cells/mm³, or mild), and may or may not be associated with clinically important bleeding. More than one etiology appears responsible for thrombocytopenia associated with GP IIb/IIIa antagonists, including acute, idiosyncratic, as well as delayed immune-mediated mechanisms. Comparison of the incidence of thrombocytopenia across the different agents currently being studied and the one agent commercially available is complicated by varying definitions of thrombocytopenia used to date; different clinical settings in which GP IIb/IIIa antagonists have been studied; use of concomitant medications such as heparin, which itself may cause thrombocytopenia; relatively infrequent occurrence of thrombocytopenia; and the limited number of patients exposed to these agents. Review of the large studies presented and published to date suggests that thrombocytopenia due specifically to GP IIb/IIIa receptor antagonists occurs in less than 5% of treated patients and may vary depending on the type of agent, concomitant therapy, and clinical scenario. Current standard management includes immediate cessation of the GP IIb/IIIa antagonist and, in severe cases, platelet transfusions. In cases with associated hemorrhage, other anticoagulants and antiplatelet agents should be discontinued and possibly reversed. There may be a role for IV IgG and steroids, especially for cases of thrombocytopenia that are immune-mediated; however, further investigations are necessary.     

Platelet activation as a potential mechanism of GP IIb/IIIa inhibitor-induced thrombocytopenia.

The blockade of the platelet integrin glycoprotein (GP) IIb/IIIa has proved to be an effective antiplatelet therapy. Profound thrombocytopenia has repeatedly been described as an adverse effect in patients treated with GP IIb/IIIa inhibitors, but its mechanism has not been elucidated yet. With use of flow cytometry, the activation status of platelets was monitored in 26 patients presenting with acute myocardial infarction who were treated with the GP IIb/IIIa inhibitor abciximab alone or in combination with the fibrinolytic agent reteplase. Fibrinogen and PAC-1 (a GP IIb/IIIa activation-specific monoclonal antibody) binding, as well as P-selectin expression on unstimulated platelets were constant in 25 patients throughout a follow-up of 7 days. In 1 patient (D.F.), the percentage of platelet-binding fibrinogen increased from 2.2% to 17.8%, for PAC-1 from 2.8% to 13.2%, and for P-selectin expression from 10.2% to 58.3% 10 minutes after the start of treatment. Furthermore, D.F. had a decrease in single platelet count in ethylenediaminetetraacetic acid-, citrate-, and heparin-anticoagulated and native blood. Blood films revealed platelet aggregates. In vitro testing of D.F.'s blood 2 and 4 weeks after initial admission demonstrated a reinduction of fibrinogen and PAC-1 binding to platelets, an increase of P-selectin expression, and formation of platelet aggregates following exposition of platelets to abciximab in vitro. In summary, this report describes the induction of platelet activation by a GP IIb/IIIa inhibitor in vivo and reinduction in vitro in direct association with thrombocytopenia. Platelet activation by GP IIb/IIIa inhibitors may be one potential mechanism for GP IIb/IIIa inhibitor-induced thrombocytopenia.     

Successful use of eptifibatide as an adjunct to coronary stenting in a patient with abciximab-associated acute profound thrombocytopenia

A 72-year-old male who was given abciximab for unstable angina developed acute profound thrombocytopenia with a platelet count nadir of 6,000/mm3. He was treated with steroids and platelet transfusion. Four days later, he underwent coronary angioplasty after pretreatment with eptifibatide without development of thrombocytopenia. This suggests that the development of thrombocytopenia with abciximab is not necessarily a contraindication to subsequent use of glycoprotein (GP) IIb/IIIa receptor antagonists. Eptifibatide may be an appropriate consideration in high-risk patients who would benefit from a GP IIb/IIIa receptor antagonist, in spite of acute profound thrombocytopenia due to abciximab therapy.     

Bleeding complications of platelet glycoprotein IIb/IIIa inhibitor abciximab (ReoPro )

Studies of patients scheduled for percutaneous coronary intervention with acute coronary syndrome have shown that the addition of intravenous glycoprotein (GP) IIb/IIIa inhibitors to aspirin and heparin is associated with a reduction in death or myocardial infarction compared to therapy with aspirin and heparin alone. The principle safety issue with GP IIb/IIIa inhibitors is the risk of bleeding, as the potent antiplatelet effect of these drugs may adversely affect hemostasis. In addition, antagonists of GP IIb/IIIa may increase the risk of thrombocytopenia. We report a case of abciximab-induced severe thrombocytopenia which led to fatal intra-cranial hemorrhage.     

Chemical structures and mode of action of intravenous glycoprotein IIb/IIIa receptor blockers: A review

Glycoprotein (GP) IIb/IIIa receptor antagonists compose a subcategory of antiplatelet medications that reduce thrombus formation through the blockade of key binding sites needed to stabilize the forming platelet aggregate. The GP IIb/IIIa receptors have been identified as a therapeutic target in reducing the occurrence of platelet-dependent thrombus formation. One advantage of GP IIb/IIIa receptor antagonists is that because GP IIb/IIIa is platelet-specific, inhibition of this receptor does not affect platelet adhesion. This may contribute to hemostasis without leading to ischemic damage. The platelet-specific pharmacological activity of GP IIb/IIIa receptor antagonists has allowed for its broad use in clinical settings. Based on clinical trials, GP IIb/IIIa receptor antagonists have been extensively studied and used in patients with acute coronary syndrome or during percutaneous coronary interventions. The goal of the present article is to provide a detailed review of the chemical structures and mode of action of currently used Food and Drug Administration-approved GP IIb/IIIa receptor antagonists in the United States.     

Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression,fibrinogen binding,and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.     

Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression,fibrinogen binding,and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed. P-selectin expression and fibrinogen binding of single platelets were unchanged at any of the dosing intervals compared to the pre-dose values, whereas microaggregate formation was reduced. Blood was also collected in hirudin to maintain physiological calcium concentrations and stimulated with platelet agonists to test whether GP IIb/IIIa antagonists lower the threshold for platelet activation. After stimulation with a concentration range of ADP and TRAP, P-selectin expression was not altered by Roxifiban administration compared to pre-dose levels. Fibrinogen binding and microaggregate formation were reduced by Roxifiban dosing in a dose-dependent manner. Inhibition of both parameters was retained at trough and no increase above pre-dose values was observed at any time. This study provides evidence for a dose-dependent inhibition of platelet functions by an orally active GP IIb/IIIa antagonist and does not detect paradoxical activation of platelets by a GP IIb/IIIa antagonist in humans.     

Comparative Pharmacology of GP IIb/IIIa Antagonists

GP IIb/IIIa antagonists are qualitatively different from classical antiplatelet agents, such as aspirin or clopidogrel. They do not inhibit platelet activation, i.e. intraplatelet signal generation or conduction but primarily act outside the platelet by competing with ligand (e.g. fibrinogen) binding that is essential for platelet bridging and aggregate formation. Three compounds are in clinical use: abciximab, an antibody fragment and two low-molecular weight compounds, tirofiban and eptifibatide. In comparison to the low-molecular weight compounds, abciximab has a substantially longer platelet half-life (4 h), i.e. slow off-rate and a short plasma half-life (20-30 min) without significant distribution into the extravascular space. The plasma half-life of tirofiban and eptifibatide is about 2 h and parallels the antiplatelet effect. The off-rate from the platelet GP IIb/IIIa receptor is much faster and there is a significant distribution into the extravascular space. These pharmacokinetic variables might influence the competition between the antagonists and fibrinogen for GP IIb/IIIa binding. Other pharmacological variables are a partial agonistic activity, facilitation of thrombolysis, modification of other integrin-related actions, including inflammatory responses, effects on vascular cells and apoptosis. Importantly, GP IIb/IIIa antagonists might also interfere with prothrombin binding to the platelet surface and, thus, might influence the coagulation pathway. There is no clear evidence that the biological activity of the agents is modified by gene polymorphism (HPA-1). All three compounds may cause thrombocytopenia, possibly related to drug-induced antibodies. There is no clear data suggesting that these pharmacological differences transfer into significant differences in clinical outcome, for example in patients with acute coronary syndromes (ACS) subjected to acute percutaneous coronary interventions (PCI). The only head-to-head comparison of all three clinically used parenteral compounds did not demonstrate differences in major adverse cardiac effects (MACE) at 30 days although those have been described in particular with long-term use of oral antagonists. The inherent problems with all GP IIb/IIIa antagonists are the narrow therapeutic range because the same mechanisms are involved in hemostasis and thrombosis and their inability to inhibit platelet activation.     

Association of glycoprotein IIb/IIIa inhibitors and long-term survival following administration during percutaneous coronary intervention for acute myocardial infarction

Objectives: We sought to evaluate the impact of GP IIb/IIIa receptor blockers on long-term mortality in patients undergoing PCI for AMI. Background: Glycoprotein (GP) IIb/IIIa inhibitors are potent suppressors of platelet aggregation and when used during percutaneous coronary intervention (PCI) for the treatment of acute myocardial infarction (AMI) may improve short-term clinical outcomes, including survival. However, the impact of GP IIb/IIIa treatment during PCI for AMI on long-term survival is unknown. Methods: Patients undergoing primary or rescue PCI for AMI within 24 hours of symptom onset with or without GP IIb/IIIa inhibitor treatment were identified from a multicenter PCI database. All cause mortality at a mean follow-up of 3 years was the primary end point. Results: Of the 269 patients treated with primary or rescue PCI for AMI, 107 (40%) received a GP IIb/IIIa antagonist. Patients treated with GP inhibitors were more likely to present with or develop heart failure (13% vs. 6.2%, P = 0.052). Left ventricular ejection fraction was reduced in those treated with GP IIb/IIIa antagonists (44% vs. 48%, P = 0.051). The extent of coronary artery disease did not differ between groups. Stent use was 80% in both groups. Procedural success was high and did not differ between groups. In-hospital mortality was low and did not differ between groups. The mortality at a mean follow-up of 3 years was 1.9% among patients treated with a GP IIb/IIIa antagonist and 15% for those who were not treated (log-rank P = 0.0005). Treatment with a GP IIb/IIIa antagonist was independently associated with a significant reduction in the hazard of long-term mortality (Hazard Ratio, 0.159; 95% Confidence Interval, 0.034–0.729; P = 0.018). Conclusions: Treatment of patients undergoing PCI for AMI with GP IIb/IIIa antagonists appears to be associated with a profound reduction in late mortality.     

Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis

BACKGROUND: Despite the increasingly prevalent role of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors in acute coronary syndromes and percutaneous coronary interventions, the incidence and clinical relevance of thrombocytopenia occurring with their use remain unclear. METHODS: We identified 8 placebo-controlled, randomized, large trials of GP IIb/IIIa receptor inhibitors reporting the incidence of thrombocytopenia, grouped by severity. The clinical courses of 42 patients with GP IIb/IIIa-related thrombocytopenia in these studies and other case reports were reviewed for bleeding complications. RESULTS: Abciximab increased mild thrombocytopenia compared with placebo (4.2% vs 2.0%; P <.001; odds ratio 2.14) and increased severe thrombocytopenia compared with placebo (1.0% vs 0.4%; P =.01; odds ratio 2.48). Small-molecule IIb/IIIa inhibitors did not significantly increase mild or severe thrombocytopenia compared with placebo. Mild thrombocytopenia occurred more frequently in acute coronary syndrome trials than in coronary intervention trials, even in patients not receiving any IIb/IIIa inhibitors. No major bleeding sequelae were reported in 23 patients with severe thrombocytopenia or in 19 patients with profound thrombocytopenia. CONCLUSIONS: Abciximab, but not eptifibatide or tirofiban, increases the incidence of thrombocytopenia compared with placebo in patients also treated with heparin. Thrombocytopenia associated with GP IIb/IIIa inhibition does not routinely lead to severe bleeding complications.     

Uneventful use of tirofiban as an adjunct to coronary stenting in a patient with a history of abciximab-associated thrombocytopenia 10 months earlier

A 52-year-old male undergoing a percutaneous coronary intervention after an inferior infarction treated with thrombolytic therapy was given abciximab with development of early severe reversible thrombocytopenia (platelet count nadir of 50,000 per mm3). The same patient underwent another percutaneous coronary intervention 10 months later and was given tirofiban without development of thrombocytopenia. This observation suggests that the development of thrombocytopenia with abciximab is not necessarily generalizable to other unique IIb/IIIa receptor antagonists. Tirofiban may be an appropriate consideration for patients who would benefit from a IIb/IIIa receptor antagonist and who are not candidates for abciximab therapy due to an episode of abciximab-associated thrombocytopenia. Further investigation of thrombocytopenia associated with IIb/IIIa receptor antagonists is warranted to determine appropriate approaches to the management of patients with a history of abciximab-associated thrombocytopenia.     

Prospective evaluation of the clinical usefulness of an antigen- specific assay (MAIPA) in idiopathic thrombocytopenic purpura and other immune thrombocytopenias

The diagnosis of idiopathic immune thrombocytopenia remains a clinical diagnosis based on the exclusion of other causes of immune and nonimmune thrombocytopenia. Measurement of platelet-associated Ig (PAIg), while sensitive, is nonspecific for the diagnosis of immune thrombocytopenia. Published experience of antigen capture assays (including monoclonal antibody immobilization of platelet antigens or MAIPA) suggest a high sensitivity and specificity (70% to 80%) in selected groups of patients. In a prospective evaluation of 158 patients with thrombocytopenia from all causes, we report a sensitivity of 51% and specificity of 80% for direct MAIPA assays. MAIPA was considerably better in discriminating immune from nonimmune thrombocytopenia than two assays of PAIgG. Antiplatelet antibodies detected by MAIPA were more frequently directed against the glycoprotein (GP) IIb/IIIa than the GP Ib/IX complex. Our experience suggests that MAIPA assays are useful in the laboratory assessment of thrombocytopenia, should be performed before therapy, and that some patients with 'nonimmune' thrombocytopenia may have genuine antiplatelet antibodies.     

Optimizing glycoprotein IIb/IIIa receptor antagonist use for the non-ST-segment elevation acute coronary syndromes: risk stratification and therapeutic intervention

Despite extensive data supporting their use for non-ST-segment elevation acute coronary syndromes, glycoprotein (GP) IIb/IIIa antagonists are underutilized. This is likely the consequence of confusion as to which patients should receive these agents, as well as to the most appropriate timing and venue for their initiation. We will review the advances in the understanding of GP IIb/IIIa antagonist therapy, emphasizing methods of identifying those most likely to benefit from the use of GP IIb/IIIa receptor blockade. In addition, we will consider appropriate methods/venues for use of GP IIb/IIIa receptor antagonism, including its role in an “early invasive” catheterization strategy.     

Glycoprotein IIb/IIIa complex is the target in mirtazapine-induced immune thrombocytopenia

Mirtazapine (MW 265.36), a tetracyclic antidepressant of the piperazine-azapine group which augments central noradrenergic and serotonergic activity, is currently used as an oral antidepressant. We report a case of severe thrombocytopenia in a 66-year-old patient occurring after mirtazapine administration, suggesting an immune mechanism. This report documents the first case of mirtazapine-induced immune thrombocytopenia. The patient's serum was screened for drug-induced anti-platelet antibody with the chromium(51) (Cr(51)) platelet lysis technique. The drug-dependent antibody was characterized using flow cytometry, the monoclonal antibody immobilization of platelet antigens assay (MAIPA assay), and immunoprecipitation. By the Cr(51) platelet lysis technique, we obtained an equivocal result for the detection of mirtazapine-induced antibody. However, the patient's serum tested positive for mirtazapine-induced antibody by flow cytometry. The results showed that the binding ratio of 5.7 (mean fluorescence intensity) in the presence of the patient's serum and mirtazapine in a final concentration of 1.0 mmol/L was strongly positive. The antibody was found to bind the glycoprotein (GP) IIb/IIIa complex by MAIPA assay by using five different monoclonal antibodies against GP complexes Ib/IX, GPIIb/IIIa, or GPIa/IIa. Immunoprecipitation studies showed that the GPIIb/IIIa complex was precipitated by antibody in the presence, but not in the absence, of mirtazapine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to the antidepressant mirtazapine. This is the first well-documented case of mirtazapine-induced immune thrombocytopenia.     

Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa

Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 x 10(9)/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are "naturally occurring" or are induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced in the GPIIb/IIIa heterodimer when it reacts with a ligand-mimetic drug.     

Combining enoxaparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: final results of the National Investigators Collaborating on Enoxaparin-3 (NICE-3) study

Background

In high-risk patients with acute coronary syndromes (ACS), there have been concerns relating to the safety of using low molecular weight heparins (LMWH) in combination with a glycoprotein (GP) IIb/IIIa antagonist, and the continued use of LMWH in patients brought to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI).

Methods

The National Investigators Collaborating on Enoxaparin-3 (NICE-3) study was an open-label observational study of enoxaparin in combination with any 1 of 3 available GP IIb/IIIa antagonists in patients presenting with non-ST-elevation ACS. The primary end point was the incidence of major bleeding not related to coronary artery bypass graft (CABG) surgery. Data were also recorded on the incidence of death, myocardial infarction (MI), and urgent revascularization for repeat ischemia.

Results

A total of 671 patients with validated data were treated with enoxaparin; 628 of these patients also received a GP IIb/IIIa antagonist (tirofiban, n = 229; eptifibatide, n = 272; abciximab, n = 127); 283 of 628 underwent percutaneous coronary intervention (PCI). The 30-day incidence of non-CABG major bleeding was 1.9%, and was not significantly higher than a prespecified historical control rate of 2.0%. Outcome events included death (1.0% at hospital discharge and 1.6% at 30 days), MI (3.5% and 5.1%, respectively), and urgent revascularization (2.7% and 6.8%, respectively).

Conclusions

The safety of enoxaparin plus a GP IIb/IIIa antagonist was comparable to that of unfractionated heparin plus a GP IIb/IIIa antagonist, as reported in other recent major trials. Patients undergoing PCI can be safely managed with enoxaparin and a GP IIb/IIIa antagonist, without supplemental use of unfractionated heparin.     

Oral platelet glycoprotein IIb/IIIa inhibition

Platelet aggregation plays a central role in the pathogenesis of thrombosis and the acute coronary syndromes. When given intravenously, potent selective antagonists of fibrinogen binding to the glycoprotein (GP) IIb/IIIa receptor, the final common pathway for platelet aggregation, have been effective in the treatment of acute coronary syndromes. Their benefit ceases, however, with the end of the infusion. Aspirin reduces the incidence of secondary vascular events by 25% to 30% after an acute coronary syndrome, and clopidogrel provides modest improvement over aspirin. However, both are relatively weak antiplatelet agents that each block only one of many pathways to platelet activation and surface membrane expression of the competent GP IIb/IIIa receptor. With the success of the intravenous GP IIb/IIIa antagonists in the acute setting, recent interest has focused on the potential benefit of oral GP IIb/IIIa antagonists used long-term for secondary prevention. The oral agents tested in phase III studies thus far have not performed up to expectations, however. The following paper reviews these studies and the implications of their results.     

Presence of cross-reactive antibody between human immunodeficiency virus (HIV) and platelet glycoproteins in HIV-related immune thrombocytopenic purpura.

We previously reported the presence in platelet eluates of autoantibodies directed against epitopes of the platelet glycoprotein (GP)IIb/IIIa complex in acquired immunodeficiency syndrome (AIDS)-free human immunodeficiency virus (HIV)-infected patients with immunologic thrombocytopenic purpura (ITP). We investigated whether HIV antibodies recognized platelet membrane antigens to determine whether the virus might be directly or indirectly responsible for the thrombocytopenia in this context. Direct eluates of platelets from 25 patients with HIV-related ITP contained IgG reacting with HIV-GP160/120 and also, in 45% of patients, detectable antiplatelet antibodies, immunochemically characterized as anti-GPIIb and/or anti-GPIIIa in 5 patients. Furthermore, serum HIV-GP160/120 antibodies could be absorbed on and eluted from platelets from normal non-HIV-infected healthy blood donors (indirect eluates). In contrast, GP160/120 antibodies present in the serum of nonthrombocytopenic HIV-infected patients were not absorbable on normal platelets in most patients, suggesting a pathogenic role in HIV-related ITP. We performed detailed studies of a patient with the highest titer of both HIV-GP160/120 and GPIIb/IIIa antibodies in direct and indirect platelet eluates. No antibody binding to GPIIb/IIIa-deficient Glanzmann thrombasthenic platelets was detected. Furthermore, binding/elution experiments conducted with insoluble recombinant GP160 (expressed in baculovirus) and purified platelet GPIIb/IIIa demonstrated that the patient's IgG bound specifically, through the F(ab')2 portion, to a common epitope of HIV-GP160/120 and platelet GPIIb/IIIa. This common epitope was present on a recombinant GP160 expressed in baculovirus but absent from another recombinant GP160 expressed in vaccinia virus, suggesting that the cross-reactivity is dependent on the glycosylation or conformational structure of the GP. We conclude that molecular mimicry between HIV-GP160/120 and platelet GPIIb/IIIa may explain at least some cases of ITP in AIDS-free HIV-infected patients.     

Pharmacokinetics and Pharmacodynamics of Low-Molecular-Weight Heparins and Glycoprotein IIb/IIIa Receptor Antagonists in Renal Failure

Data regarding the use of low-molecular-weight heparins (LMWHs) and glycoprotein (GP) IIb/IIIa receptor antagonists in patients with renal failure are limited. Renal failure has the potential to increase the risk of adverse drug events associated with LMWHs and GP IIb/IIIa receptor antagonists. This is due to changes in the pharmacokinetic and pharmacodynamic profiles of these agents in patients with renal failure. Until more data are available, clinicians should consider alternative therapies in this patient population.