(Circulation. 1997;95:614-617.)
© 1997 American Heart Association, Inc.
Articles |
In Vitro Effects of the Platelet Glycoprotein IIb/IIIa Receptor Antagonist c7E3 Fab on the Activated Clotting Time
the Departments of Anesthesiology (T.A.) and Medicine (L.E.S., B.S.C.), Mount Sinai Medical Center, New York, NY.
Correspondence to Tameshwar Ammar, MD, Mount Sinai Medical Center, Department of Anesthesiology, Box 1010, One Gustave L. Levy Place, New York, NY 10029.
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Abstract |
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Background In the Evaluation of 7E3 for the Prevention of Ischemic Complications study (EPIC), the activated coagulation (clotting) times (ACTs) were longer in heparinized patients treated with c7E3 Fab than in those treated with placebo. The present study was designed to further investigate this observation by assessing whether the in vitro addition of c7E3 Fab to blood would affect the ACT.
Methods and Results Native or heparinized blood obtained from normal volunteers was preincubated with antibodies c7E3 Fab (anti-GPIIb/IIIa and anti-
vß3), 10E5 (anti-GPIIb/IIIa), or LM609 (anti-vß3). The ACTs of the heparinized, but not native samples were significantly prolonged by the addition of c7E3 Fab and 10E5 but not LM609, indicating that the prolongation was due to GPIIb/IIIa blockade. The addition of c7E3 Fab also significantly prolonged the ACTs of blood anticoagulated with the direct thrombin inhibitors hirudin and D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone, indicating that the effect of c7E3 Fab was not exclusively related to decreased release of PF4, a heparin-neutralizing factor, from platelets.
Conclusions These data support the conclusion that the prolongation of the ACT in patients in EPIC was due to c7E3 Fab blockade of GPIIb/IIIa receptors. This raises the possibility that in vivo c7E3 Fab functions not only as an antiplatelet agent but also as an anticoagulant; direct in vivo data will, however, be required for assessment of this possibility.
Key Words: platelets • c7E3 Fab • activated clotting time
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Introduction |
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Blockade of platelet GPIIb/IIIa receptors by monoclonal antibodies or by small molecules patterned on the arginine-glycine-aspartic acid cell recognition motif inhibits platelet aggregation and protects against thrombosis and ischemic damage in animal models.1 2 In a population of patients at a high risk of developing ischemic complications, the conjunctive use of a bolus plus a 12-hour infusion of c7E3 Fab administered with the combination of aspirin and heparin was shown in the EPIC study to significantly reduce the risk of ischemic complications during the first 30 days and of clinical restenosis during the first 6 months after coronary artery angioplasty or atherectomy.3 4 These patients, however, also had an increased risk of bleeding. Phase I and phase II studies with other GPIIb/IIIa-blocking agents have shown similar trends.1 2
The ACT,5 which is a modification of the Lee-White clotting time6 with the addition of a contact activator (eg, diatomaceous earth) to shorten the coagulation time and provide a reproducible activation stimulus, was performed as part of EPIC. The ACTs were longer in patients treated with c7E3 Fab than in patients treated with placebo, despite uniform recommendations regarding heparin dosing (10 000 U bolus of porcine intestinal heparin and repeat boluses to maintain the ACT at >300 seconds) suggesting that c7E3 Fab decreases in vitro thrombin generation in this assay.7 The present study was designed to further investigate this observation by assessing whether the in vitro addition of c7E3 Fab to blood would affect the ACT.
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Methods |
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Materials
The c7E3 Fab (abciximab [ReoPro]) was supplied by Centocor, Inc, as a 1 mg/mL solution in PBS (0.15 mol/L NaCl, 0.01 mol/L sodium phosphate buffer, pH 7.2). Murine monoclonal antibody 10E5 (anti-GPIIb/IIIa) was prepared as previously described,8 and murine monoclonal antibody LM609 (anti-
vß3 vitronectin receptor)9 was a gift of Dr David Cheresh (Scripps Clinic, La Jolla, Calif). Both antibodies were available as 1 mg/mL in 0.15 mol/L NaCl, 0.01 mol/L Tris/HCl, and 0.05% azide buffer, pH 7.4. Equivalent amounts of the appropriate buffer without antibody were added to control samples in each experiment so that there were no differences in sample dilution. Bovine lung heparin (heparin sodium, 100 U/mL) was obtained from Upjohn, and porcine intestine heparin (100 U/mL) was obtained from Elkins-Sinn Inc. Hirudin (1000 U/mL) was obtained from Sigma Chemical Co, and PPACK was obtained from Chemica Alta Ltd.
ACT Determinations
With institutional review board approval, written informed consent was obtained from healthy volunteers who had no known bleeding disorder and had not ingested aspirin or other antiplatelet medications for 
7 days. For each experiment, blood from different volunteers was used. There were a total of 36 volunteers, and blood samples from 26 of these volunteers were studied twice. Blood was obtained with a 21-gauge needle and syringe and anticoagulated as described below. Hematocrit values and platelet counts were determined for all subjects. Mixing and incubation of samples were conducted in disposable polypropylene tubes. All ACTs were performed on 2-mL aliquots of whole blood using glass tubes containing 12 mg of celite (Tube 509, International Technidyne) in a Hemochron ACT instrument (International Technidyne). After incubation (as described below), 2 mL of blood was added to a celite-containing tube, and the tube was immediately added to a well that had been preheated to 37°C. The tubes were continually rotated at 1 rpm, and the clotting time was defined as the interval from the insertion of the tube into the well until the clot formed, trapping the magnetic bar and moving it away from a magnetic detector. The instrument provided a digital display of the clotting time, which was then recorded. To control for possible temporal drift during the time needed to perform all of the ACTs, control ACT assays were performed on the same heparinized control sample before and after test sample ACT values were determined.
Assay variability studies were performed using bovine lung heparin. Intra-assay variability was determined by performing 10 ACT procedures on a single sample of heparinized blood (1.75 U/mL). Interassay variability was determined by testing both the native and heparinized blood (1.75 U/mL) from a single individual on 10 separate occasions. Interindividual variability was determined by analyzing the ACTs of the 36 subjects the first time that they were studied.
Effect of c7E3 Fab on ACT of Native and Heparinized Blood
Studies were conducted with both bovine lung and porcine intestine heparins.
Bovine Lung Heparin
Fifteen subjects were studied: 4 women and 11 men, with a mean age of 29 years (age range, 27 to 32 years). We obtained 12 mL of blood from each subject. One half of the blood was not anticoagulated (native blood), and the other half anticoagulated with bovine lung heparin to a final concentration of 1.75 U/mL. ACT values were then determined for 2-mL aliquots of native and heparinized blood without or with preincubation for 3 minutes at 22°C with 20 µg/mL c7E3 Fab, a concentration that produces near-saturation binding to surface GPIIb/IIIa receptors.10
Comparison of Bovine Lung and Porcine Intestine Heparins
Fifteen healthy volunteers were studied: 3 women and 12 men with a mean age of 29 years (age range, 25 to 36 years). We obtained 8 mL of blood from each as described above. Half of the blood was anticoagulated with 1.75 U/mL porcine intestine heparin, and the other half was anticoagulated with 1.75 U/mL bovine lung heparin. The anticoagulated samples were divided into two equal aliquots. c7E3 Fab (20 µg/mL) was added to one of the aliquots, and ACT values were determined.
Comparison of Effects of Antibodies c7E3 Fab, 10E5, and LM609
Because the 7E3 monoclonal antibody binds to both the platelet GPIIb/IIIa receptor and the vß3 vitronectin receptor,11 we used two additional monoclonal antibodies to assess the contributions of each of these receptors to the prolongation of the ACT produced by c7E3 Fab. 10E5 is specifically directed against the GPIIb/IIIa receptor,8 and LM609 is directed against the vß3 receptor.9
Twelve subjects were studied: 2 women and 10 men with a mean age of 30 years (age range, 26 to 36 years). We obtained 18 mL of blood from each subject. As described above, ACT values were determined for native blood or blood anticoagulated with 1.75 U/mL bovine lung heparin either with or without preincubation with 20 µg/mL c7E3 Fab, 10E5, or LM609.
Determination of Heparin Equivalence of c7E3 Fab Prolongation of ACT
To express the ACT prolongation effect of c7E3 Fab as a heparin concentration equivalent, a standard curve of ACT versus bovine lung heparin concentration was determined. Blood was anticoagulated with increasing concentrations of heparin to obtain ACT values similar to those produced with heparinized blood treated with c7E3 Fab.
Ten subjects were studied: 2 women and 8 men with a mean age of 27 years (age range, 25 to 30 years). We obtained 24 mL of blood from each subject. The 8-mL aliquots were anticoagulated with 1.00, 1.75, or 2.50 U/mL bovine lung heparin. Each 8-mL anticoagulated aliquot was then divided into four equal samples: the first sample was incubated with 20 µg/mL c7E3 Fab, the second sample was incubated with 0.4 U/mL bovine lung heparin, and the third sample was incubated with 0.5 U/mL bovine lung heparin. Buffer was added to the fourth aliquot. ACTs were determined on all four samples from each aliquot.
Comparison of Effect of c7E3 Fab on ACT of Blood Anticoagulated With Heparin, Hirudin, and PPACK
Because PF4 neutralizes heparin, the release of PF4 from platelet -granules during clot formation may neutralize heparin during the ACT. Antiplatelet agents that inhibit the release reaction may therefore prolong the ACT via this mechanism rather than via a direct effect on thrombin generation. To assess this possibility, we also tested the effect of c7E3 Fab on blood anticoagulated with the direct thrombin inhibitors hirudin and PPACK because PF4 does not neutralize these anticoagulants.
Ten subjects were studied: 1 woman and 9 men with a mean age of 27 years (age range, 25 to 31 years). We obtained 18 mL of blood from each subject. The 4-mL aliquots of blood were mixed with 1.75 U/mL bovine lung heparin, 20 U/mL hirudin, or 5 µmol/L PPACK (0.25 mol/L stock solution in 0.15 mol/L sodium chloride, pH 7.4). One half of each aliquot was incubated with 20 µg/mL c7E3 Fab for 3 minutes at 22°C, and ACTs were determined for both the untreated and the c7E3 Fab–treated samples.
Statistical Analysis
Data were analyzed using Student's t test for paired data with a value of P<.05 considered statistically significant.
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Results |
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Assay Variability
There was a 3.1% coefficient of variation in the ACTs performed on a single sample of heparinized blood (intra-assay variability, Table 1
). Interassay coefficients of variation of the ACTs obtained from the same individual on 10 occasions were 2.2% (native blood) and 1.9% (heparinized blood). The interindividual variability among the 36 separate normal donors was considerably greater, with coefficients of variation of 9.6% (native blood) and 13.4% (heparinized blood).
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Effect of c7E3 Fab on ACT
Bovine Lung Heparin
In the absence of bovine lung heparin, the addition of c7E3 Fab did not prolong the ACT (120±13 seconds [mean±SD] without c7E3 Fab versus 121±11 seconds with c7E3 Fab). The ACTs of the heparinized samples, however, were significantly prolonged by the addition of 20 µg/mL c7E3 Fab (317±46 versus 351±55 seconds, P=.0004; Figure).
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Comparison of Bovine Lung and Porcine Intestine Heparins
Porcine intestine heparin (1.75 U/mL) prolonged the ACT to a greater extent than did bovine lung heparin when blood samples were anticoagulated with a 1.75 U/mL concentration of each preparation (389±66 versus 322±24 seconds, respectively, P<.05). The presence of c7E3 Fab prolonged the ACTs of blood anticoagulated with either porcine or bovine heparin (424±57 versus 367±29 seconds, respectively, P<.01 for both values when compared with samples without c7E3 Fab).
Comparison of Effects of Antibodies c7E3 Fab, 10E5, and LM609
Antibodies 10E5 and LM609 also failed to increase the ACT of unheparinized blood (122±12 seconds without antibody versus 122±15 seconds with 10E5, 120±10 seconds with LM609, and 120±13 seconds with c7E3 Fab). As shown in Table 2, however, the ACTs of heparinized samples were prolonged by 10E5 to levels comparable to those produced by c7E3 Fab. The vß3 vitronectin receptor–blocking antibody LM609 did not, however, prolong the ACT of the heparinized samples.
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Heparin Equivalence of c7E3 Fab Prolongation of ACT
The data from the experiment designed to determine the heparin equivalence of the addition of 20 µg/mL c7E3 Fab to blood anticoagulated with 1.00, 1.75, or 2.50 U/mL bovine lung heparin are presented in Table 3. The addition of 20 µg/mL 7E3 to blood anticoagulated with 1.00, 1.75, or 2.50 U/mL heparin prolonged the ACT to an extent comparable to that achieved with the addition of 0.4 to 0.5 U/mL heparin.
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Comparison of Effect of c7E3 Fab on ACT of Blood Anticoagulated With Heparin, Hirudin, and PPACK
The effects of c7E3 Fab on the ACTs of samples anticoagulated with heparin, hirudin, and PPACK are presented in Table 4. In this group of subjects, the ACT was more prolonged by 1.75 U/mL bovine lung heparin alone than in the previous three sets of experiments (360±30 versus 317±46, 321±51, and 314±33 seconds), presumably reflecting interindividual variation; hirudin (20 U/mL) prolonged the ACT to 275±20 seconds, and PPACK (5 µmol/L) prolonged the ACT to 411±83 seconds. The addition of c7E3 Fab significantly prolonged the ACTs of blood anticoagulated with each of the anticoagulants. The percentage increase in ACT was greatest with the heparinized samples (23%) and similar with samples anticoagulated with hirudin or PPACK (8% for each). In the previous experiments with heparin, however, c7E3 Fab increased the ACT by 11%, 10%, and 14%, respectively—values only slightly greater than those obtained with the direct thrombin inhibitors.
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Discussion |
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Previous studies have documented the ability of antiplatelet agents to prolong the ACT of heparinized blood. Moorehead et al12 showed that prostacyclin prolonged the ACT of blood anticoagulated in vitro and that carbacyclin markedly prolonged the ACTs of blood obtained from patients heparinized during heart-lung bypass surgery. Neither prostacyclin nor carbacyclin affected the ACT of unheparinized blood.
Our study demonstrates that the addition of c7E3 Fab to heparinized blood of normal volunteers in vitro prolongs the ACT. These data support the conclusions of Moliterno et al7 that the prolongation of the ACT in patients in the EPIC study treated with c7E3 Fab in addition to aspirin and heparin compared with patients treated with aspirin and heparin alone was, in fact, due to the c7E3 Fab, although other possibilities exist. The addition of c7E3 Fab to blood lacking anticoagulant did not prolong the ACT, presumably because the rate of thrombin generation and the amount of thrombin generated are much greater in the absence of thrombin inhibitors. One limitation of our study is that we did not study patients with vascular disease, whose platelet GPIIb/IIIa receptor number or function may differ from that of normal subjects. Neumann et al13 reported that platelet GPIIb/IIIa immunoreactivity correlated with the risk of subacute stent thrombosis. Bray et al14 suggested that women may have more active GPIIb/IIIa receptors. Trip et al15 found a correlation between platelet hyperreactivity and prognosis after myocardial infarction. Weiss et al16 found an association between a GPIIIa polymorphism and premature coronary artery disease. Thus, the results of our studies may not be directly extrapolatable to patients with vascular disease. Another limitation of the present study is that the experiments were conducted in vitro, so the results may not be extrapolatable to the intravenous use of c7E3 Fab.
It is unlikely that the c7E3 Fab effect we observed is caused only by the inhibition of PF4 release from platelets (and thus the inhibition of PF4-mediated neutralization of heparin) because c7E3 Fab also prolonged the ACT of blood anticoagulated with hirudin and PPACK, anticoagulants that are not affected by PF4. Inhibition of PF4 may play some role, however, because c7E3 Fab prolonged the ACT of heparinized blood somewhat more (on a percentage basis) than blood anticoagulated with hirudin or PPACK.
The mechanism or mechanisms by which c7E3 Fab prolongs the ACT remain to be elucidated. It is possible that c7E3 Fab affects more than one step in the coagulation cascade, including factor Xa generation. Because 10E5 also prolonged the ACT, blockade of GPIIb/IIIa receptors by c7E3 Fab probably plays a dominant role. The inability of LM609 to prolong the ACT makes it unlikely that the blockade of vß3 vitronectin receptors by c7E3 Fab makes a major contribution, but a minor role may still exist. In other studies, we have shown that c7E3 Fab decreases thrombin generation produced by the addition of tissue factor to defibrinated plasma containing gel-filtered platelets by nearly 50%.17 Thus, c7E3 Fab appears to be able to decrease the release of platelet factor Va and/or the ability of platelets to undergo activation to a state that enhances their catalytic efficiency in thrombin generation. It remains possible, however, that c7E3 Fab affects other aspects of the ACT, including blocking the interaction of platelets with celite.
We were able to equate the ACT-prolonging effect of c7E3 Fab on blood anticoagulated with 1.00, 1.75, or 2.50 U/mL bovine lung heparin with the addition of 0.4 to 0.5 U/mL heparin. Without knowing the mechanism or mechanisms by which c7E3 Fab prolongs the ACT, however, it is not clear that c7E3 Fab produces the equivalent anticoagulant effect of 0.4 to 0.5 U/mL heparin in vivo. Although it is highly likely that the ability of c7E3 Fab to decrease the frequency of acute ischemic events after angioplasty or atherectomy is due primarily to its inhibition of GPIIb/IIIa receptor–dependent platelet aggregation, if c7E3 Fab actually decreases thrombin generation in vivo, this anticoagulant effect may contribute to its antithrombotic effects. Furthermore, because thrombin has been implicated in enhancement of smooth muscle cell migration and intimal hyperplasia after vascular injury,18 it is also possible that a decrease in thrombin generation (and thus clot-bound thrombin) by c7E3 Fab may contribute to its possible long-term effect on clinical restenosis.4
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants 19278 and 54469 from the National Heart, Lung, and Blood Institute.
Received July 26, 1996; revision received September 9, 1996; accepted September 12, 1996.
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References |
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The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med.. 1994;330:956-961.
4. Topol EJ, Califf RM, Weisman HF, Ellis EG, James TE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee K, Willerson JT. Randomized trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet.. 1994;1:881-886.
5. Hattersley PG. Activated coagulation time of whole blood. JAMA.. 1966;196:150-154.
6. Lee R, White P. A clinical study of the coagulation time of blood. Am J Med Sci.. 1913;145:495-503.
7. Moliterno DJ, Califf RM, Aguirre FV, Anderson K, Sigmon KN, Weisman HF, Topol EJ. Effects of platelet glycoprotein IIb/IIIa integrin blockade on the activated clotting time during percutaneous transluminal coronary angioplasty or directional atherectomy. Am J Cardiol.. 1995;75:559-562.[Medline] [Order article via Infotrieve]
8. Coller BS, Peerschke EI, Scudder LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal patients and binds to glycoprotein IIb and/or IIIa. J Clin Invest.. 1983;72:325-338.
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Charo IF, Nannizzi L, Smith JW, Cheresh DA. The vitronectin receptor Vß3 binds fibronectin and acts in concert with 5ß1 in promoting cellular attachment and spreading on fibronectin. J Cell Biol.. 1990;111:2795-2800.
10. Coller BS, Scudder LE, Gold HK, Folts JD, Cavagnaro J, Jordan R, Wagner C, Iuliucci J, Knight D, Ghrayeb J, Smith C, Weisman HF, Berger H. Monoclonal antibodies to platelet glycoprotein IIb/IIIa as antithrombotic agents. Ann N Y Acad Sci.. 1991;614:193-213.[Medline] [Order article via Infotrieve]
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Coller BS, Cheresh DA, Asch E, Seligsohn U. Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thromasthenia in Israel. Blood.. 1991;77:75-83.
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Moorehead MT, Westengard JC, Bull BS. Platelet involvement in the activated clotting time of heparinized blood. Anesth Analg.. 1984;63:394-398.
13. Neumann FJ, Gawaz M, Ott I, May A, Mossmer G, Schomig A. Prospective evaluation of hemostatic predictors of subacute stent thrombosis after coronary Palmaz-Schatz stenting. J Am Coll Cardiol.. 1996;27:15-21.[Abstract]
14. Bray PF, Becker LC, Goldschmidt-Clermont PJ. Differences in platelet fibrinogen binding relate to recurrent myocardial ischemic events and are dependent upon gender, age, and hormonal status. Blood. 1995;86(suppl 1):1188a. Abstract.
15. Trip MD, Cats VM, van Capelle FJL, Vrecken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med.. 1990;322:1549-1554.[Abstract]
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Weiss EJ, Bray PF, Taybach M, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med.. 1996;334:1090-1094.
17. Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated tissue factor–induced thrombin generation by the mouse/human chimeric 7E3 antibody: potential implications for the effect of c7E3 Fab treatment on acute thrombosis and `clinical restenosis.' J Clin Invest.. 1996;98:863-874.[Medline] [Order article via Infotrieve]
18.
Okazaki H, Majesky MW, Harker LA, Schwartz SM. Regulation of platelet-derived growth factor ligand and receptor gene expression by -thrombin in vascular smooth muscle cells. Circ Res.. 1992;71:1285-1293.
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