Thrombocytopenia

Agents that react with the platelet glycoprotein (GP) IIb/IIIa complex ([alpha]IIb/[beta]3 integrin) to block fibrinogen binding and platelet-platelet aggregation have been proved to be effective in reducing the incidence of complications following coronary angioplasty and are now widely used for this purpose. Acute thrombocytopenia, which is sometimes severe and life-threatening, is a recognized side effect of this class of drugs. In contrast to other types of drug-induced thrombocytopenia, this complication can occur within a few hours of a patient's first exposure to the medication. Accumulating evidence has indicated that drug-dependent antibodies, which can be naturally occurring, are the cause of platelet destruction in such individuals. In this review, we will consider the clinical aspects of thrombocytopenia resulting from sensitivity to GPIIb/IIIa inhibitors and will review evidence that the platelet destruction is antibody-mediated.

Key words: abciximab; eptifibatide; glycoprotein IIb/IIIa inhibitors; thrombocytopenia; tirofiban

Abbreviations: DITP = drug-induced immune thrombocytopenia; EDTA = ethylendiaminetetraacetic acid; GP = glyeoprotein; RGD = Arg-Gly-Asp

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The glycoprotein (GP) IIb/IIIa inhibitors are a new class of antithrombotic agents that are effective because they block the binding of fibrinogen to activated GPIIb/IIIa, thereby inhibiting platelet-platelet interaction and thrombus formation. (l-3) GPIIb/IIIa inhibitors have been shown to reduce secondary complications following coronary angioplasty and are now being evaluated for their ability to prevent thromhosis in patients with other conditions. Three GPIIb/IIIa inhibitors, abciximab, tirofiban, and eptifibatide, have been approved for clinical use in the United States and other countries. All are given by IV administration, usually for 12 to 18 h after the patient undergoes angioplasty. Agents designed for oral administration are in various stages of development. (4)

Drug-induced immune thrombocytopenia (DITP) is an unpredictable and sometimes serious side effect of many medications, including heparin, quinine, sulfonamides, and other antibiotics, especially vancomycin, rifampicin, cephalosporins, other sulfon amide compounds, and nonsteroidal antiinflammatory drugs. (5,6) It has been recognized (7,8) that DITP is a relatively common side effect of GPIIb/IIIa inhibitors. The mechanisms by which GPIIb/IIIa inhibitors induce thrombocytopenia differ from those thought to be responsible for thrombocytopenia induced by drugs such as quinine and certain antibiotics. This review will consider the clinical features and pathogenetic mechanisms of thrombocytopenia induced by the GPIIb/IIIa inhibitors.

IMMUNE THROMBOCYTOPENIA IN PATIENTS TREATED WITH ABCIXIMAB

Clinical Presentation

Acute Thrombocytopenia After First or Second Exposure to Abciximab: Abciximab (ReoPro; Eli Lilly; Indianapolis, IN) is a chimeric (human/mouse) Fab fragment that is derived from a murine monoclonal antibody, 7E3, that binds to an epitope on the GPIIb/IIIa complex close to a critical binding site for fibrinogen, thereby inhibiting its reaction with the activated integrin. (1) To create abciximab, N-terminal sequences in 7E3 that control its specificity were incorporated into a human IgG1 framework. The intact chimeric IgG molecule then was cleaved by papain to produce the Fab fragment abciximab. (1) In clinical trials (8,9) of abciximab and in subsequent experience, it was found that about 1% of patients given this drug experienced acute, often severe thromboeytopenia. After a second exposure to the drug, the rate for this complication rises to about 4%. (10) In some instances, the onset of thrombocytopenia was accompanied by fever, dyspnea, hypotension, and even frank anaphylaxis, occurring soon after starting the drug. (11-13) Although most patients with abciximab-associated thromboeytopenia recover uneventfully, life-threatening bleeding has been described, (13) and several patients have experienced intracranial hemorrhage. (14.15)

Delayed Thrombocytopenia After Abciximab: Although abciximab-induced thrombocytopenia usually occurs within a few hours of starting therapy with the drug, a subgroup of patients has been described in whom the drop in platelet levels occurred 5 to 8 days after the drug was administered. (16,17) Recent studies have provide an explanation for this type of presentation (see below).

Abciximab-Associated Pseudothrombocytopenia: A subset of patients with abciximab-induced "thrombocytopenia" actually will have a circulating platelet count in the normal range. In such cases, low platelet counts obtained with automated counting instruments were found to be a consequence of the in vitro clumping of platelets in blood samples anticoagulated with ethylenediaminetetraacetic acid (EDTA) (18,19) Pseudothrombocytopenia in patients who have received abciximab can usually be distinguished from true thrombocytopenia by repeating a platelet count in blood that has been anticoagulated with citrate and/or by estimating the platelet levels in a peripheral blood smear prepared from a fingerstick. The mechanism by which abciximab promotes the in vitro clumping of platelets in blood anticoagulated with EDTA is not known.

Pathogenesis

The development of severe thrombocytopenia within hours of a patient's first exposure to abciximab is in distinct contrast to most types of DITP, which occurs in patients who have previously been exposed to the sensitizing drug or have received it for a number of days. Accordingly, nonimmune mechanisms were initially considered as a possible explanation for the acute platelet destruction that is typical of this condition. Some reports were consistent with this possibility, but others (24,25) argued against it, leaving this question unresolved.

Thrombocytopenia After Second Exposure to Abciximab: Direct evidence for the immune destruction of platelets in patients who have received abciximab was provided by studies (13) showing that a group of patients who developed severe thromboeytopenia after a second exposure to the drag all had strong IgG and/or IgM antibodies that reacted with abeiximab-coated platelets in a flow cytometric assay (Fig 1). The specificity of this finding was called into question by the observation that some healthy individuals (both those who were exposed to the drug and those unexposed) have similar types of antibodies, although they are generally weaker than those found in patients with abciximab-induced thromboeytopenia. (13) However, it was found that most antibodies from patients with abciximab-induced thrombocytopenia can be distinguished from the antibodies commonly found in healthy individuals in two ways. First, the antibodies found in healthy subjects recognize the papain cleavage site at the C-terminus of the abciximab molecule (13,26) and can thus be inhibited by Fab fragments, whereas patient antibodies are resistant to this treatment. Second, the antibodies from patients react preferentially with platelets coated with the intact monoclonal antibody 7E3, from which the specificity-determining sequences incorporated into abciximab were derived, whereas antibodies from nonthrombocytopenic individuals do not (13) (Fig 2). It has been known for many years that healthy individuals can have naturally occurring antibodies that recognize enzymatic cleavage sites in human Igs. (27,28) It appears that antibodies found in healthy individuals that react with abciximab-coated platelets recognize the papain cleavage site at the C terminus of the abciximab molecule and are probably not capable of causing thrombocytopenia in patients who have received the drug. (13) In contrast, antibodies from patients with abciximab-induced thrombocytopenia recognize either murine sequences incorporated into abciximab or conformational changes induced by abciximab in GPIIb/IIIa when abciximab binds (Fig 3). Why such antibodies cause platelet destruction, whereas antibodies found in many healthy individuals that recognize a different target on abciximab-coated platelets apparently do not is unresolved.

[FIGURES 1-3 OMITTED]

Thrombocytopenia After First Exposure to Abciximab: There are no published reports characterizing antibodies in patients who developed thrombo-cytopenia after a first exposure to abciximab, although our unpublished observations suggest that antibodies similar to those found in patients given abciximab a second time are responsible for platelet destruction in most cases. These antibodies can be found in pretreatment blood samples, indicating that they are naturally occurring.

Delayed Thrombocytopenia After Abciximab Treatment: Abciximab remains bound to circulating platelets for several weeks after its infusion. (29,30) As noted, some patients who have received abciximab have a normal or near-normal platelet count for the first few days after treatment starts but develop thrombocytopenia 5 to 7 clays later. Recent studies (31) have indicated that "delayed thrombocytopenia" occurring in such individuals is caused by newly formed antibodies or weak preexisting antibodies stimulated to a high titer by abciximab exposure.

THROMBOCYTOPENIA FOLLOWING TREATMENT WITH LIGAND-MIMETIC GPIIB/IIIA INHIBITORS

Clinical Presentation

A second class of GPIIb/IIIa inhibitors, the ligand-mimetic agents, act by binding specifically to the Arg-Gly-Asp (RGD) recognition site on GPIIb/IIIa, thereby rendering the integrin incapable of binding fibrinogen. (2-4) Two drugs of this class, tirofiban (Aggrastat; Merck; Whitehouse Station, NJ) and eptifibatide (Integrelin; COR Therapeutics Inc; South San Francisco, CA) are currently approved for clinical use by IV infusion (Fig 4). Other IV and oral agents of this class are in development. Like abciximab, tirofiban and eptifibatide have been shown (32,33) to reduce the incidence of secondary complications following coronary angioplasty.

[FIGURE 4 OMITTED]

As with abciximab, a subset of patients treated with ligand-mimetic GPIIb/IIIa inhibitors will develop acute, severe thromboeytopenia. (32-35) In some reported eases, (36-39) the onset of thrombocytopenia was accompanied by systemic symptoms such as chills, fever, and hypotension. The various ligand-mimetic GPIIb/IIIa inhibitors appear to differ in their tendency to cause thrombocytopenia. In trials of the oral inhibitors xemilofiban and orbofiban, about 0.6% of 12,000 patients who received one of these drugs, but only 0.03% of patients who received placebo, experienced thrombocytopenia that was judged by a blinded review committee to be "possibly drug-induced." (40) A second oral drug, roxifiban, caused drug-induced thrombocytopenia in about 2% of treated individuals. (41) The incidence of drug-induced thrombocytopenia in patients who received tirofiban or eptifibatide has not been rigorously defined but is probably less than either of these estimates. The fact that oral inhibitors are administered daily for an extended period of time, whereas IV drugs are usually infused for less than a day, probably explains the greater tendency of the former to cause thrombocytopenia.

Pathogenesis

The onset of acute thromboeytopenia within hours of the first exposure of a ligand-mimetic GPIIb/IIIa inhibitor suggested that nonimmune factors might be responsible. Several reports (42,43) were consistent with this possibility, but observations to the contrary have also been described, (44,45) and no convincing nonimnmne mechanisms have yet been advanced to explain acute platelet destruction following drug administration. Recent reports (36,38,46) have indicated that patients with thrombocytopenia induced by tirofiban, eptifibatide, and several other oral inhibitors (40,41,47) often have antibodies that recognize GPIIb/IIIa in the presence of the agent being administered. As in some patients with abciximabinduced thrombocytopenia, (13) such antibodies can be identified in blood samples obtained prior to treatment with the drug, indicating that they can be naturally occurring (36) (Fig 5). Antibodies of this type were not found in patients who received the same drugs and did not experience thrombocytopenia, although weaker tirofiban-dependent and eptifibatide-dependent antibodies were found in about 3% of healthy persons. (36)

[FIGURE 5 OMITTED]

Although accumulating evidence indicates that thrombocytopenia associated with the administration of ligand mimetic GPIIb/IIIa inhibitors is caused by antibodies that recognize ligand-occupied GPIIb/ IIIa, the sites on the integrin for which these antibodies are specific have not yet been defined. By several criteria, the antibodies appear to recognize more than one and perhaps many target epitopes. First, the binding of some antibodies is totally blocked by precoating drug-treated platelets with abciximab, whereas the binding of others is unaffected. Second, the antibodies differ from one another in respect to the levels of ionized calcium required for drug-dependent binding to their targets (Fig 6). (36) It is known that ligand-mimetic compounds such as tirofiban and eptifibatide induce conformational changes in the GPIIb/IIIa complex that are recognized by certain murine monoclonal antibodies. (48,49) Possibly, tirofiban-dependent and eptifibatide-dependent antibodies recognize similar epitopes (ie, ligand-induced binding sites) on GPIIb/ IIIa. If so, it would appear that certain healthy individuals have strong, naturally occurring antibodies that recognize the GPIIb/IIIa complex that are "activated" by ligand-mimetic drugs, and are capable of causing severe and sometimes life-threatening thrombocytopenia following drug administration.

TREATMENT OF THROMBOCYTOPENIA INDUCED BY GPIIB/IIIA INHIBITORS

A platelet count should be performed routinely before and within 2 to 6 h after starting treatment in any patient given a GPIIb/IIIIa inhibitor to enable the early diagnosis of drug-induced thrombocytopenia. Some patients who develop thrombocytopenia are asymptomatic or exhibit only scattered petechial hemorrhages. Others experience bleeding from sites of catheterization, GI hemorrhage, or hematoma formation. Because the function of platelets remaining in the circulation is impaired by the inhibitor, all patients with this complication should be considered to be at risk for bleeding, and those with significant hemorrhage should be given platelet transfusions. Because tirofiban and eptifibatide are cleared from the circulation within hours of discontinuing their infusion, (50,51) the duration of thrombocytopenia and hemorrhagic risk in patients who have received these drugs is of short duration. Patients who have received abciximab are at risk for a longer period of time because platelet function is impaired for up to 1 week, (30) and thrombocytopenia sometimes persists for 3 to 5 days. On the basis of limited experience, it appears that patients who are sensitive to abciximab can safely receive tirofiban or eptifibatide at a later time. (52,53) It is likely that the converse is true, but this has not yet been documented.

CAN THROMBOCYTOPENIA AFTER TREATMENT WITH GPIIB/IIIA INHIBITORS BE PREVENTED BY PRETREATMENT SCREENING?

Since thrombocytopenia in patients who have received GPIIb/IIIa inhibitors is usually caused by preexisting antibodies, it seems possible that pretreatment screening to detect such antibodies might prevent this complication. In studies of patients who have been treated with the oral, ligand-mimetic GPIIb/IIIa inhibitor roxifiban, Seiffert et al (41) reported that the incidence of thrombocytopenia can be reduced by about ten fold by screening for antibodies before the drug is administered, and for newly formed antibodies about 1 week later. Whether it is practical and feasible to perform such screening remains to be determined.

* From the Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI.

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Supported in part by grants HL-44612 and HL-13629 from the National Heart, Lung, and Blood Institute.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Richard H. Aster, MD, Blood Research Institute, The Blood Center of Southeastern Wisconsin, PO Box 2178, Milwaukee, WI 53201-2178; e-mail: rhaster@bcsew.edu

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