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(Circulation. 1998;97:251-256.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparisons With a Low-Molecular-Weight Heparin and With a Direct Thrombin Inhibitor

Zihui Xiao, MSc; ; Pierre Théroux, MD

From the Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Canada.

Correspondence to Dr Pierre Théroux, Montreal Heart Institute, 5000 Bélanger St E, Montreal, Quebec H1T 1C8, Canada.

	Abstract

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Background—The growing use of heparin in acute thrombotic disorders, coupled with the availability of many new antithrombotic agents, emphasizes the need for adequate characterization of the platelet effects of the various anticoagulants. Controversial platelet effects have been reported with heparin (eg, enhanced platelet activation in vitro with high doses and no such effect in vivo at therapeutic doses). This study examined platelet receptor activation and platelet aggregation at therapeutic concentrations of unfractionated heparin (UFH), of enoxaparin, a low-molecular-weight heparin, and of argatroban, a direct thrombin inhibitor.

Methods and Results—Platelet P-selectin (CD62) and activated GP IIb/IIIa (PAC-1) expression on platelet membrane was quantified in whole blood as well as platelet aggregation in platelet-rich plasma in 43 patients with unstable angina before and during treatment with UFH or enoxaparin. Studies were also carried out in blood of seven normal volunteers after addition ex vivo of UFH (0.25 U/mL), enoxaparin (0.25 U/mL), argatroban (1 ng/mL), and normal saline. UFH in patients with unstable angina increased the percentage of circulating platelets positive to PAC-1 from 2.7±1.7% to 4.4±3.4% (P<.05) and to CD62 from 1.6±0.9% to 2.7±1.5% (P<.01). Platelets were also hyperresponsive to stimulation with ADP and with the thrombin-receptor agonist peptide. Aggregation to ADP increased from 6.8±4.6% to 11.2±7.0% and to TRAP from 5.2±3.5% to 11.1±6.0% (P<.001). The addition of UFH to blood of normal volunteers resulted also in activation of GP IIb/IIIa receptors, expression of P-selectin, and enhanced platelet aggregation. Enoxaparin had only minor effects on platelet activation in vivo and ex vivo, and argatroban, evaluated ex vivo, had no detectable effects.

Conclusions—Therapeutic concentrations of UFH are associated with platelet activation.

Key Words: platelets • cell adhesion molecules • glycoproteins • heparin

	Introduction

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The indications for anticoagulant therapy have expanded to include the acute phase of coronary syndromes, resulting in a soaring use of heparin in clinical practice. Simultaneously, new anticoagulants have been developed, including LMWHs and direct thrombin inhibitors,^{1 2} defining a need for a thorough understanding of the effects of these drugs on the mechanisms of blood clot formation. Thus, although many studies documented that in vitro heparin could enhance platelet aggregation,^{3 4 5 6 7 8 9} the drug prolongs bleeding time in vivo,¹⁰ inhibits many platelet functions^{11 12 13 14} to create a platelet defect,^{13 14} and promotes bleeding risk.¹⁵

The present study characterized the platelet effects of therapeutic concentrations of UFH and of enoxaparin, a LMWH, and argatroban, a direct thrombin inhibitor. Platelet aggregation was quantified in PRP by light transmission, and the expression of activation-dependent platelet membrane markers was quantified in whole blood by use of flow cytometry.

	Methods

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Study Drugs
The drugs studied were unfractionated porcine heparin of molecular weight 5000 to 30 000 D (mean, 15 000; purchased from Leo Laboratories); enoxaparin, a LMWH of 3500 to 5500 D (mean, 4500; provided by Rhône-Poulenc Rorer Canada Inc); and argatroban, a direct inhibitor of the catalytic site of thrombin (provided by Texas Biotechnology Corp).

Study Design
In vivo studies were performed in 43 patients admitted for unstable angina. Twenty-seven patients, six women and 21 men 61±11.0 years of age (range, 41 to 84 years), received UFH, and 16 patients, 6 women and 10 men 64±12.7 years of age (range, 32 to 79 years) received enoxaparin. The UFH was administered as an intravenous bolus of 5000 U followed by an infusion at a rate of 1000 U/h titrated after 6, 12, and 18 hours to an activated partial thromboplastin time 2 to 2.5 times control values. Enoxaparin was administered subcutaneously at a dose of 1 mg/kg at 12-hour intervals. These doses of UFH and LMWH resulted in plasma antifactor Xa activity ranging between 0.3 and 0.6 U/mL. All patients received aspirin, but none had had a previous exposition to heparin or to enoxaparin.

Flow cytometric studies were performed in 16 patients administered heparin and in 16 administered enoxaparin, and platelet aggregation studies were done in all patients before the start of the drug and 24 hours later.

For the ex vivo studies, fresh blood was obtained in a fasting state from seven normal healthy volunteers, three women and four men 35±7.5 years of age (range, 24 to 46 years). These volunteers had not been taking any medication in the preceding 2 weeks and had not previously been exposed to heparin therapy. Blood (30 mL) was withdrawn in citrate and immediately divided into four different tubes. Standard heparin was added in one of the aliquots to a concentration of 0.25 U/mL, enoxaparin in another to a concentration of 0.25 U/mL, argatroban in a third to 1 µg/mL, and an equal volume of normal saline as control to the last aliquot.

All blood samples were obtained with a 21-gauge butterfly needle from an antecubital vein. The first 2 mL was discarded. Free-flowing blood was collected in plastic tubes containing 3.8% sodium citrate for a final ratio of 1:9.

Flow Cytometric Assays
Flow cytometric measurements were performed in whole blood by use of a method adapted from Shattil et al¹⁶ and Warkentin et al.¹⁷ The citrated blood was diluted within 15 minutes of being drawn in a 1:4 ratio with a modified Tyrode's buffer solution containing NaCl 137 mmol/L, KCl 2.8 mmol/L, MgCl₂ 1 mmol/L, NaHCO₃ 12 mmol/L, Na₂HPO₄ 0.4 mmol/L, bovine serum albumin 0.35%, HEPES 10 mmol/L, and glucose 5.5 mmol/L, pH 7.4. Then 13 µL of diluted blood was divided into Eppendorff tubes containing 5 µL of a saturating concentration of antibodies and 12 µL of a synthetic pure TRAP (amino acid sequence, SFLLRNPHDKYEPF; provided by Dr Beat Steiner, Hoffmann-La Roche) and of ADP (Sigma Chemical Co) dissolved in Tyrode's buffer solution. The final concentrations of TRAP and of ADP were 0.625 and 0.312 µmol/L, respectively. The samples were incubated for 30 minutes at 26°C without stirring, and further reaction stopped by addition of 500 µL of 1% formaldehyde in Tyrode's buffer solution. The antibodies used were PAC-1, an IgM polyclonal antibody that specifically binds to activated platelet receptor GP IIb/IIIa^{16 17} (Cell Center of Pennsylvania University); CD42b, a murine monoclonal antibody binding GP 1b (Serotec Canada Ltd); and anti-CD62, a murine monoclonal antibody directed against P-selectin expressed on the cell surface (Serotec Canada Ltd).^{18 19} PAC-1 and CD62 were conjugated with FITC and CD42b with PE. Negative murine IgG monoclonal antibodies were also used to assess nonspecific binding.

A total of 5000 platelets from each fixed sample were analyzed within 1 hour of sampling with a Coulter EPICS XL flow cytometer (Coulter Corp). This flow cytometer is equipped with a 100-mV argon laser to produce a laser beam at 488 nm, detecting FITC and PE fluorescence at band-pass filters of 525 and 575 nm, respectively. The platelet population was identified by forward scatter for cell size and by side scatter for cell granularity.²⁰ Double-labeling experiments identified >97% of the particles within the area of interest as positive for CD42b binding. The percentage of fluorescence positive platelets (PL%) and a binding index calculated as mean fluorescence intensity per particle times PL%/100 were obtained in duplicate from the instrument computer system.²¹

Platelet Aggregation Studies
Platelet aggregation was evaluated in PRP by use of a four-channel light transmission aggregometer (Chronolog Corp). The PRP was prepared by centrifugation of whole blood at 1000 rpm for 10 minutes, and the platelet-poor plasma was prepared by centrifugation of the remaining blood at 3000 rpm for an additional 10 minutes. PRP served to set 0% light transmission; platelet-poor plasma, 100% transmission. Platelet aggregation was measured 10 minutes after the addition of TRAP 0.625 µmol/L and of ADP 0.312 µmol/L (final concentration).

Statistical Analyses
The means of duplicate measurements obtained before and after drugs were compared by Student's paired t tests. Results are expressed as mean±SD. A value of P<.05 was considered significant.

	Results

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Platelet Count and Activated Thromboplastin Time
Baseline platelet counts were within the normal range in all patients and unchanged after the intravenous administration of UFH (201±67x10⁶ per 1 mL before and 196±19 x10⁶ per 1 mL after) and of LMWH (221±91x10⁶ and 233±98 x10⁶ per 1 mL, respectively). Heparin prolonged the activated thromboplastin time values from 25.8±2.55 to 51.6±13.26 seconds.

Platelet counts were also unchanged after the addition of UFH in vitro (197±24x10⁶ per 1 mL before and 195±23x10⁶ after), LMWH (197±24x10⁶ and 207±23x10⁶ per 1 mL), and argatroban (197±24x10⁶ and 198±23x10⁶ per 1 mL, respectively).

In Vivo Studies
Table 1 provides the results of the flow cytometric studies in patients with unstable angina administered UFH or LMWH, and Fig 1 the individual responses. UFH consistently resulted in expression of activated GP IIb/IIIa receptor and of P-selectin. This state of activation was manifested in the basal state, with a nearly twofold increase in the number of activated platelets and in the binding index. In the presence of heparin, platelets were also more sensitive to agonist stimulation with ADP, with a 12% increase in the number of platelets expressing activated GP IIb/IIIa (P<.001) and a 67% increase in the number of platelets expressing P-selectin (P<.001). The respective increases with TRAP were 60% (P<.05) and 65% (P<.001). No activation could be detected with LMWH in the basal state; TRAP stimulation, however, was associated with a 65% increase in the number of platelets expressing P-selectin.

View this table: [in this window] [in a new window]   Table 1. Activated GP IIb/IIIa (PAC-1) and P-Selectin (CD62) Expression on Platelet Surface With Infusion of UFH and of LMWH in Patients With Unstable Angina

View larger version (28K): [in this window] [in a new window]   Figure 1. Percent FITC-positive platelets (PL %) to PAC-1 (activated GP IIb/IIIa) and to CD62 (P-selectin) before and after the administration of therapeutic doses of UFH in patients with unstable angina. Each line represents the data of one patient.

Platelet aggregation increased also twofold during the infusion of heparin. Enoxaparin also increased platelet aggregation; the increase was modest, however, and not statistically significant (Fig 2). Examples of platelet aggregation to ADP and to TRAP before and during an infusion of UFH in a patient with unstable angina are shown in Fig 3.

View larger version (17K): [in this window] [in a new window]   Figure 2. Platelet aggregation (% maximum [max]) to ADP and to TRAP in the patients with unstable angina before and during the infusion of UFH (A) and of enoxaparin (LMWH) (B). ***P<.001 vs before UFH.

View larger version (32K): [in this window] [in a new window]   Figure 3. Typical examples of platelet aggregation to low concentrations of ADP (A) and of TRAP (B) before and during an infusion of UFH in a patient with unstable angina.

In Vitro Studies
The results of the in vitro studies are provided in Table 2, and the individual data points are illustrated in Fig 4. Again, UFH resulted in detectable platelet activation in all individuals studied. The number of platelets binding PAC-1 increased twofold in the basal state, twofold after TRAP stimulation (P<.01), and by 9.3% after ADP stimulation (P<.05). P-selectin expression increased by 57% in the basal state, by 25% after the addition of TRAP, and by 30% after the addition of ADP. By contrast, enoxaparin and argatroban resulted in no increases in these markers of activation. Enoxaparin slightly but significantly decreased P-selectin expression.

View this table: [in this window] [in a new window]   Table 2. Activated GP IIb/IIIa (PAC-1) and P-Selectin (CD62) Expression on Platelet Surface After Addition of UFH, LMWH, and Argatroban in Whole Blood

View larger version (24K): [in this window] [in a new window]   Figure 4. Percent FITC-positive platelets (PL %) to PAC-1 (activated GP IIb/IIIa) and to CD62 (P-selectin) before and after addition of UFH in whole blood to a concentration of 0.25 U/mL. Each line represents the data of one normal individual.

The results of the platelet aggregation studies were consistent (Fig 5), with more than a twofold increase in platelet aggregation after administration of UFH, but no significant changes were noted with enoxaparin and with argatroban. Argatroban nonsignificantly reduced platelet aggregation induced by ADP.

View larger version (21K): [in this window] [in a new window]   Figure 5. Maximum (max) platelet aggregation in PRP in normal individuals after the addition in whole blood of normal saline (control), UFH, enoxaparin (LMWH), and argatroban (ARG). Platelet aggregation to low concentrations of ADP and TRAP is significantly increased in the presence of UFH. *P<.05, **P<.01 vs control.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study documents that therapeutic concentrations of UFH activate platelets in vivo and enhance platelet aggregability. The results observed with flow cytometry and with platelet aggregation studies were very consistent. They were also highly reproducible between individuals, both in vivo, in patients with unstable angina and ex vivo, in normal control subjects. No such pro-proaggregant effects were detected with enoxaparin, an LMWH; argatroban, a direct thrombin inhibitor, had no platelet effects.

Flow cytometry provides a sensitive and direct means to detect surface changes on single platelets. Platelet activation, notwithstanding the stimulus, leads to a configurational change in the integrin membrane receptor GP IIb/IIIa, making it competent to bind fibrinogen and other ligands. PAC-1 is a specific antibody binding the activated expression of the receptor.¹⁶ Platelet activation also results in translocation of P-selectin from the alpha granules to cell surface, where it was detected by a specific monoclonal antibody, anti-CD62.¹⁹ In this study, UFH resulted in detectable activation of the GP IIb/IIIa receptor and expression of P-selectin as manifested by an increase in the total number of activated circulating platelets and a greater binding index. The increase in the total amount of PAC-1–positive circulating platelets was 1.7% in the absence of agonists. This increase was small but statistically significant, suggesting that it could have clinical importance. This pool of activated circulating platelets increased fourfold in the presence of low concentrentions of agonists, from 1.7% to 7.7% with ADP and from 1.7% to 6.1% with TRAP. ADP is released after platelet stimulation, and TRAP mimics the effects of thrombin on the platelet receptor, suggesting that the stimulation with heparin could be important at sites of endothelial injury at which most of the endogenous platelet stimulation occurs.

Heparin-Platelet Interactions
The interactions between heparin and platelets are complex and only partially known. A stimulating effect was observed in this study in normal individuals as well as in patients, suggesting a true physiological effect. Heparin binds to platelet surface to modify responsiveness.^{4 6 22 23 24} Experimental studies with different concentrations and sources of heparin and different agonists have variously documented platelet activation^{3 4 5 6 7 8 9} or platelet inhibition.^{10 11 12 13 14} When rapidly administered intravenously, UFH reduced platelet counts and prolonged bleeding times,¹⁰ creating a platelet defect.^{13 14 15} In vitro, low doses of heparin are more apt to reduce platelet aggregation, and high doses are more likely to increase it.^{7 9} The proaggregant response is detected with most agonists, including ADP, adrenaline, collagen, and the platelet activating factor.^{3 9} It is more consistently observed with low concentrations of ADP (in the range of 0.15 µmol/L)⁸ and less consistently with higher concentrations (3 and 5 µmol/L).⁹ Similar differential results were observed in our laboratory with low and high concentrations of TRAP; the stimulation observed at low concentrations was not reproduced at the higher concentrations of 2.5 to 10 µmol/L. These findings suggest that the proaggregant effect of UFH is modest and can be overcome with strong platelet stimulation. These findings also could possibly explain why the proaggregant action was detected in most studies only at supratherapeutic concentrations of heparin. The platelet stimulation induced by heparin can be blocked by EDTA and by increasing platelet cyclic adenosine monophosphate content.^{24 25} It does not require fibrinogen because it occurs in washed platelet preparations.⁹ It is not inhibited by blocking cyclooxygenase and does not require ADP.⁸ In the presence of antithrombin III, heparin inhibits all platelet activities induced by thrombin, including secretion, increases in cytosolic calcium, and aggregation.⁷ The thrombin receptor peptide used in this study mimics the effects of thrombin on the receptor,²⁶ yet its platelet effects were potentiated and not inhibited by heparin. This observation is consistent with the indirect effect of heparin to inhibit thrombin-induced platelet aggregation, requiring a cofactor. Because the heparin–antithrombin III complex has limited effects on thrombin bound to fibrin,²⁷ heparin may stimulate platelets within or in the vicinity of the blood clot to paradoxically entertain local thrombogenic stimulation. Although circulating thrombin is inactivated by antithrombin III, fibrin-bound thrombin is relatively inaccessible to inhibition by the heparin–antithrombin III complex. Therefore, platelet activation, although weak systematically and counteracted by the anticoagulant effect, may become very significant at the site of thrombus formation.

Enoxaparin and Argatroban
The platelet effects of heparin vary with the molecular weight of heparin and with the affinity for antithrombin III; similarly, the hemorrhagic and antithrombotic properties of the various heparins can be dissociated.^{1 3 10 28 29} LMWHs with a low affinity for the antithrombin stimulate platelet and high-affinity LMWHs lose their sparing effect when antithrombin III is removed from the plasma.^{8 30 31} These observations suggest a preferential binding site of heparin for antithrombin III and a less avid site for binding platelets. The binding of LMWH with antithrombin III can therefore minimize the platelet effects. Such is not the case for the high-molecular-weight fractions with an excess of binding sites. The absence of a detectable effect of enoxaparin in our study, except after stimulation with TRAP, which is a strong agonist, is compatible with this concept. Different responses could be observed with other LMWHs with a different affinity for antithrombin III or with different doses. Argatroban is a direct thrombin inhibitor requiring no cofactor for its effects. It was not associated with any detectable platelet activity in this study.

Study Limitations
An alternative explanation for the platelet activation detected in this study could be the unstable state of the patients. Unstable angina can be associated with an elevation of platelet factor 4 and thromboglobulin,^{32 33} increased production of thromboxane A₂,³⁴ and thrombin generation.³⁵ This explanation is unlikely in our study because no activation was detected in the acute phase before the initiation of heparin and because all patients were stable on treatment. Furthermore, the activation was reproducible in the heparin patients and absent in the two other groups without standard heparin. Samplings in the study were also performed at the same hour of the day to minimize the effects of circadian variation in platelet function and in coagulant activity.^{30 36} An artifactual platelet activation related to blood manipulation is also unlikely, considering the reproducibility of the results before and after heparin and before and after enoxaparin. Each patient served as his or her own control in the in vivo study, and the ex vivo studies were performed by addition of heparin, enoxaparin, or argatroban in blood obtained from one single vein puncture.

Significance of Results
The platelet effects of heparin have received relatively little attention in clinical practice except in the syndromes of heparin-induced thrombocytopenia. This situation occurs 5 days after the onset of therapy or earlier in patients previously exposed to heparin. None of the normal volunteers in this study had previously received heparin, and patients with unstable angina were studied early after the initiation of heparin and had normal platelet counts. The platelet stimulating effects observed with UFH were only modest, and the clinical relevance of the observation is unknown. This study was not designed to study the consequences of the platelet stimulation. The proaggregant effects, however, were reproducible and much amplified in the presence of ADP and of TRAP, suggesting that they could be important at the site of thrombus formation at which platelet stimulation occurs. It can be hypothesized that the platelet effect of standard heparin could lead to paradoxical stimulation of thrombosis in some clinical circumstances and contribute to the therapeutic failure of heparin in conditions such as failure of reperfusion and infarct extension in acute myocardial infarction and refractory ischemia and rebound reactivation after heparin discontinuation in unstable angina.³¹ Prevention of this platelet activation could therefore enhance the antithrombotic potential of heparin and its clinical effectiveness. Aspirin used in patients with unstable angina in this study did not prevent the activation. The more potent inhibitors of platelet aggregation, such as the inhibitors of the platelet membrane receptor GP IIb/IIIa, may have some effects; characterization of their effects in the presence and absence of heparin may help researchers understand some of the mechanisms for their clinical benefits. Alternatively, the use of LMWH or of a direct thrombin inhibitor could be advantageous. Knowledge of the exact site of the heparin effects on platelets could also be of help in the design of target specific therapy.

	Selected Abbreviations and Acronyms

 

D = dalton FITC = fluorescein isothiocyanate LMWH = low-molecular-weight heparin PE = phycoerythrin PRP = platelet-rich plasma TRAP = thrombin receptor agonist peptide UFH = unfractionated heparin

	Acknowledgments

 
We thank Marta Ghitescu and Jacinthe Rivard for their assistance in performing the various platelet assays.

Received May 23, 1997; revision received September 3, 1997; accepted September 30, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Hirsh J, Levine MN. Low molecular weight heparin. Blood. 1992;79:1–17.[Free Full Text]

2. Markwardt F, Kaiser B, Novak G. Studies on antithrombotic effects of recombinant hirudin. Thromb Res. 1989;54:377–388.[Medline] [Order article via Infotrieve]

3. Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Farreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest. 1980;65:64–73.

4. Eika C. Inhibition of thrombin-induced aggregation of human platelets in heparin. Scand J Haematol. 1971;8:216–222.[Medline] [Order article via Infotrieve]

5. Ellisson N, Edmunds LH, Colman RW. Platelet aggregation following heparin and protamine administration. Anesthesiology. 1978;48:65–68.[Medline] [Order article via Infotrieve]

6. Thomson C, Forbes CD, Prentice CRM. The potentiation of platelet aggregation and adhesion by heparin in vitro and in vivo. Clin Sci Mol Med. 1973;45:485–494.[Medline] [Order article via Infotrieve]

7. Eika C. On, the mechanism of platelet aggregation induced by heparin, protamine, and polybrene. Scand J Haematol. 1972;9:248–257.[Medline] [Order article via Infotrieve]

8. Eika C. The platelet aggregating effect of eight commercial heparins. Scand J Haematol. 1979;9:480–482.

9. Westwick J, Scully MF, Poll C, Kakkar VV. Comparison of low molecular weight heparin and unfractionated heparin on activation of human platelets in vitro. Thromb Res. 1986;42:435–447.[Medline] [Order article via Infotrieve]

10. Holmer E, Lindhal U, Backstrom G, Thunberg L, Sandberg H, Soderstrom G, Andersson LO. Anticoagulant activities and effects on platelet of a heparin fragment with high affinity for antithrombin. Thromb Res. 1980;18:861–869.[Medline] [Order article via Infotrieve]

11. O'Brien JR, Shoobridge SM, Finch Wj. Comparison of the effect of heparin and citrate on platelet aggregation. J Clin Pathol. 1969;2:28–31.

12. Besterman EMM, Gillett MPT Heparin effects on plasma lecithin formation and platelet aggregation. Atherosclerosis. 1973;17:503–513.[Medline] [Order article via Infotrieve]

13. Heiden D, Mielke CH Jr, Rodvien R. Impairment by heparin of primary haemostasis and platelet (14C)5-hydroxytryptamine release. Br J Haematol. 1977;36:427–436.[Medline] [Order article via Infotrieve]

14. Fernandez F, N'Guyen P, Van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. Hemorrhagic doses of heparin and other glycosaminoglycans induce a platelet defect. Thromb Res. 1986;43:491–495.[Medline] [Order article via Infotrieve]

15. Kelton JG, Hirsh J. Bleeding associated with antithrombotic therapy. Sem Hematol. 1980;17:259–291.[Medline] [Order article via Infotrieve]

16. Shattil SJ, Cunningham M, Hoxie JA. Detection of activated platelets in whole blood using activation-dependent antibodies and flow cytometry. Blood. 1987;70:307–315.[Abstract/Free Full Text]

17. Warkentin TE, Powling MJ, Hardisty RM. Measurements of fibrinogen binding to platelets in whole blood by flow cytometry: a micromethod for the detection of platelet activation. Br J Haematol. 1990;76:387–394.[Medline] [Order article via Infotrieve]

18. Hsu-Lin SC, Berman CL, Furie BC, August D, Furie B. A platelet membrane glycoprotein expressed during platelet activation. J Biol Chem. 1984;259:9121–9126.[Abstract/Free Full Text]

19. McEver RP, Martin MN. A monoclonal antibody to a membrane glycoprotein binds only to activated platelet. J Biol Chem. 1984;259:9799–9804.[Abstract/Free Full Text]

20. Jackson CW, Jennings LK. Heterogeneity of fibrinogen receptor expression on platelets activated in normal plasma with ADP: analysis by flow cytometry. Br J Haematol. 1989;72:407–414.[Medline] [Order article via Infotrieve]

21. Hjemdahl P, Chronos NA, Wilson DJ, Bouloux P, Goodal AH. Epinephrine sensitizes human platelets in vivo and in vitro as studied by fibrinogen binding and P-selectin expression. Arterioscler Thromb. 1994;14:77–84.[Abstract/Free Full Text]

22. Goldstad G, Solumn N, Krutnes MB. Heparin binding platelet proteins demonstrated by crossed affinity immunoelectrophoresis. Br J Haematol. 1983;53:563–566.[Medline] [Order article via Infotrieve]

23. Sobel M, Adelman B. Characterization of platelet binding of heparins and other glycosaminoglycans. Thromb Res. 1988;50:815–826.[Medline] [Order article via Infotrieve]

24. Horne MK. Heparin binding to normal and abnormal platelets. Thromb Res. 1988;51:135–144.[Medline] [Order article via Infotrieve]

25. Saba HI, Saba SR, Blackburn CA, Hartmann RC, Mason RG. Heparin neutralization of PGI₂. Science. 1979;205:499–501.[Abstract/Free Full Text]

26. Coughlin SR, Vu TKH, Hung DT, Wheaton VI. Characterization of a functional thrombin receptor: issues and opportunities. J Clin Invest. 1992;89:351–355.

27. Weitz J, Huboda M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86:385–391.

28. Carter CJ, Kelton JG, Hirsh J, Gent M. Relationship between the antithrombotic and the anticoagulant effects of low molecular weight heparin. Thromb Res. 1981;21:169–174.[Medline] [Order article via Infotrieve]

29. Cade JF, Buchanan MR, Boeu B, Ockelford P, Cater CJ, Cerskus AL, Hirsh J. A comparison of the antithrombotic and hemorraghic effects of low molecular weight heparin fractions. Thromb Res. 1984;35:613–625.[Medline] [Order article via Infotrieve]

30. Ogawa H, Yasue H, Oshima S, Okumura K, Matsuyama K, Obata K. Circadian variation of plasma fibrinopeptide A level in patients with variant angina. Circulation. 1989;80:1617–1626.[Abstract/Free Full Text]

31. Théroux P, Waters D, Lam J, Juneau M, McCans, J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med. 1992;327:141–145.[Abstract]

32. Melina G, Colivicchi F, Bevilacqua E, Mangnanimi S, Melina D. Blood pressure variations, hemorheological determinants, and platelet aggregation in hypertensive patients with unstable angina. Clin Exp Hypertens. 1995;17:1145–1156.

33. al-Nozha M, Gader AM, al-Momen AK, Noah MS, Jawaid M, Arafa M. Haemostatic variables in patients with unstable angina. Int J Cardiol. 1994;43:269–277.[Medline] [Order article via Infotrieve]

34. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med. 1986;315:983–989.[Abstract]

35. Théroux P, Latour JG, Leger-Gauthier C, De Lara J. Fibrinopeptide A and platelet factor levels in unstable angina pectoris. Circulation. 1987;75:156–162.[Abstract/Free Full Text]

36. Tofler GH, Berzinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514–1518.[Abstract]

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				H. L. Dauerman Coronary Intervention Without a Safety Net J. Am. Coll. Cardiol., October 14, 2008; 52(16): 1299 - 1301. [Full Text] [PDF]

				L. T. Newsome, R. S. Weller, J. C. Gerancher, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: II. Perioperative Considerations and Management Anesth. Analg., August 1, 2008; 107(2): 570 - 590. [Abstract] [Full Text] [PDF]

				D. Sibbing, G. Busch, S. Braun, S. Jawansky, A. Schomig, A. Kastrati, I. Ott, and N. von Beckerath Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention Eur. Heart J., June 2, 2008; 29(12): 1504 - 1509. [Abstract] [Full Text] [PDF]

				P. M. Ho, E. D. Peterson, L. Wang, D. J. Magid, S. D. Fihn, G. C. Larsen, R. A. Jesse, and J. S. Rumsfeld Incidence of Death and Acute Myocardial Infarction Associated With Stopping Clopidogrel After Acute Coronary Syndrome JAMA, February 6, 2008; 299(5): 532 - 539. [Abstract] [Full Text] [PDF]

				G. Montalescot, M. Cohen, G. Salette, W. J. Desmet, C. Macaya, P. E.G. Aylward, Ph. G. Steg, H. D. White, R. Gallo, S. R. Steinhubl, et al. Impact of anticoagulation levels on outcomes in patients undergoing elective percutaneous coronary intervention: insights from the STEEPLE trial Eur. Heart J., February 2, 2008; 29(4): 462 - 471. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): 652 - 726. [Full Text] [PDF]

				G. Li, A. C. Keenan, J. C. Young, M. J. Hall, Z. Pamuklar, E. M. Ohman, S. R. Steinhubl, and S. S. Smyth Effects of Unfractionated Heparin and Glycoprotein IIb/IIIa Antagonists Versus Bivalirdin on Myeloperoxidase Release From Neutrophils Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1850 - 1856. [Abstract] [Full Text] [PDF]

				E. N. Deliargyris, B. Upadhya, L. G. Melton, C. Thompson, M. Fisher, D. A. Gabriel, G. J. Dehmer, and D. C. Sane Unfractionated Heparin Reduces the Anti-Platelet Effects of Abciximab but not Eptifibatide During PCI Clinical and Applied Thrombosis/Hemostasis, October 1, 2006; 12(4): 458 - 464. [Abstract] [PDF]

				H. Dent, Z. Lekic, and M. Vicenzi Unfractionated heparin and coronary artery stenting. Br. J. Anaesth., October 1, 2006; 97(4): 582 - 582. [Full Text] [PDF]

				G. Montalescot, H. D. White, R. Gallo, M. Cohen, P. G. Steg, P. E.G. Aylward, C. Bode, M. Chiariello, S. B. King III, R. A. Harrington, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N. Engl. J. Med., September 7, 2006; 355(10): 1006 - 1017. [Abstract] [Full Text] [PDF]

				C. M. Dyke, N. G. Smedira, A. Koster, S. Aronson, H. L. McCarthy II, R. Kirshner, A. M. Lincoff, and B. D. Spiess A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study J. Thorac. Cardiovasc. Surg., March 1, 2006; 131(3): 533 - 539. [Abstract] [Full Text] [PDF]

				M. S. Williams and L. S. Ng'alla Heparin Therapy Leads to Platelet Activation and Prolongation of PFA-100 Closure Time Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4): 273 - 280. [Abstract] [PDF]

				M. Di Nisio, S. Middeldorp, and H. R. Buller Direct Thrombin Inhibitors N. Engl. J. Med., September 8, 2005; 353(10): 1028 - 1040. [Full Text] [PDF]

				A. M. Dyszkiewicz-Korpanty, E. P. Frenkel, and R. Sarode Approach to the Assessment of Platelet Function: Comparison between Optical-based Platelet-rich Plasma and Impedance-based Whole Blood Platelet Aggregation Methods Clinical and Applied Thrombosis/Hemostasis, January 1, 2005; 11(1): 25 - 35. [Abstract] [PDF]

				K. A. Tanaka, F. Szlam, N. Katori, N. Sato, J. D. Vega, and J. H. Levy The Effects of Argatroban on Thrombin Generation and Hemostatic Activation In Vitro Anesth. Analg., November 1, 2004; 99(5): 1283 - 1289. [Abstract] [Full Text] [PDF]

				G. Montalescot, J.P. Collet, M.L. Tanguy, A. Ankri, L. Payot, R. Dumaine, R. Choussat, F. Beygui, V. Gallois, and D. Thomas Anti-Xa Activity Relates to Survival and Efficacy in Unselected Acute Coronary Syndrome Patients Treated With Enoxaparin Circulation, July 27, 2004; 110(4): 392 - 398. [Abstract] [Full Text] [PDF]

				M. A. Blazing, J. A. de Lemos, H. D. White, K. A. A. Fox, F. W. A. Verheugt, D. Ardissino, P. M. DiBattiste, J. Palmisano, D. W. Bilheimer, S. M. Snapinn, et al. Safety and Efficacy of Enoxaparin vs Unfractionated Heparin in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Who Receive Tirofiban and Aspirin: A Randomized Controlled Trial JAMA, July 7, 2004; 292(1): 55 - 64. [Abstract] [Full Text] [PDF]

				J R S Day, I S Malik, A Weerasinghe, M Poullis, I Nadra, D O Haskard, K M Taylor, and R C Landis Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention Heart, July 1, 2004; 90(7): 794 - 799. [Abstract] [Full Text] [PDF]

				Z. Xiao and P. Theroux Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome J. Am. Coll. Cardiol., June 2, 2004; 43(11): 1982 - 1988. [Abstract] [Full Text] [PDF]

				E. I. Lev, D. Hasdai, E. Scapa, A. Tobar, A. Assali, J. Lahav, A. Battler, J. J. Badimon, and R. Kornowski Administration of eptifibatide to acute coronary syndrome patients receiving enoxaparin or unfractionated heparin: Effect on platelet function and thrombus formation J. Am. Coll. Cardiol., March 17, 2004; 43(6): 966 - 971. [Abstract] [Full Text] [PDF]

				E. H. Kincaid, M. L. Monroe, D. L. Saliba, N. D. Kon, W. G. Byerly, and M. G. Reichert Effects of preoperative enoxaparin versus unfractionated heparin on bleeding indices in patients undergoing coronary artery bypass grafting Ann. Thorac. Surg., July 1, 2003; 76(1): 124 - 128. [Abstract] [Full Text] [PDF]

				A. M. Lincoff, J. A. Bittl, R. A. Harrington, F. Feit, N. S. Kleiman, J. D. Jackman, I. J. Sarembock, D. J. Cohen, D. Spriggs, R. Ebrahimi, et al. Bivalirudin and Provisional Glycoprotein IIb/IIIa Blockade Compared With Heparin and Planned Glycoprotein IIb/IIIa Blockade During Percutaneous Coronary Intervention: REPLACE-2 Randomized Trial JAMA, February 19, 2003; 289(7): 853 - 863. [Abstract] [Full Text] [PDF]

				G. C. Wong, R. P. Giugliano, and E. M. Antman Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention JAMA, January 15, 2003; 289(3): 331 - 342. [Abstract] [Full Text] [PDF]

				D. L. Bhatt, B. I. Lee, P. J. Casterella, M. Pulsipher, M. Rogers, M. Cohen, V. E. Corrigan, T. J. Ryan Jr, J. A. Breall, J. W. Moses, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: Results of the coronary revascularization using integrilin and single bolus enoxaparin study J. Am. Coll. Cardiol., January 1, 2003; 41(1): 20 - 25. [Abstract] [Full Text] [PDF]

				P. Kujath, C. Eckmann, and F. Misselwitz Low-Molecular-Weight Heparin in Arterial Reconstructive Surgery: A Double-Blind, Randomized Dose-Finding Trial Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 337 - 345. [Abstract] [PDF]

				G Niccoli and A P Banning Heparin dose during percutaneous coronary intervention: how low dare we go? Heart, October 1, 2002; 88(4): 331 - 334. [Abstract] [Full Text] [PDF]

				M. Mirabet, D. Garcia-Dorado, J. Inserte, J. A. Barrabes, R.-M. Lidon, B. Soriano, M. Azevedo, F. Padilla, L. Agullo, M. Ruiz-Meana, et al. Platelets activated by transient coronary occlusion exacerbate ischemia-reperfusion injury in rat hearts Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1134 - H1141. [Abstract] [Full Text] [PDF]

				A. K.C. Chan, J. Rak, L. Berry, P. Liao, M. Vlasin, J. Weitz, and P. Klement Antithrombin-Heparin Covalent Complex: A Possible Alternative to Heparin for Arterial Thrombosis Prevention Circulation, July 9, 2002; 106(2): 261 - 265. [Abstract] [Full Text] [PDF]

				G. Fragasso, P. M. Piatti, L. Monti, A. Palloshi, C. Lu, G. Valsecchi, E. Setola, G. Calori, G. Pozza, A. Margonato, et al. Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: Evaluation of the protective role of the metabolic modulator trimetazidine J. Am. Coll. Cardiol., February 6, 2002; 39(3): 413 - 419. [Abstract] [Full Text] [PDF]

				E.M. Antman, M. Cohen, C. McCabe, S.G. Goodman, S.A. Murphy, and E. Braunwald Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE Eur. Heart J., February 2, 2002; 23(4): 308 - 314. [Abstract] [Full Text] [PDF]

				R. Corti, V. Fuster, and J.J. Badimon Strategy for ensuring a better future for the vessel wall Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A31 - A41. [Abstract] [PDF]

				S.R Mehta, J.W Eikelboom, H.-J Rupprecht, B.S Lewis, M.K Natarajan, C Yi, J Pogue, and S Yusuf Efficacy of hirudin in reducing cardiovascular events in patients with acute coronary syndrome undergoing early percutaneous coronary intervention Eur. Heart J., January 2, 2002; 23(2): 117 - 123. [Abstract] [Full Text] [PDF]

				M. A. Lauer, P. L. Houghtaling, J. G. Peterson, C. B. Granger, D. L. Bhatt, S. K. Sapp, M. L. Simoons, R. A. Harrington, E. J. Topol, and A. M. Lincoff Attenuation of Rebound Ischemia After Discontinuation of Heparin Therapy by Glycoprotein IIb/IIIa Inhibition With Eptifibatide in Patients With Acute Coronary Syndromes: Observations From the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Circulation, December 4, 2001; 104(23): 2772 - 2777. [Abstract] [Full Text] [PDF]

				W. B. Batchelor, K. W. Mahaffey, P. B. Berger, E. Deutsch, S. Meier, V. Hasselblad, E. T. Fry, P. S. Teirstein, A. M. Ross, C. A. Binanay, et al. A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: the ATLAST trial J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1608 - 1613. [Abstract] [Full Text] [PDF]

				D. P. Chew, D. L. Bhatt, A. M. Lincoff, D. J. Moliterno, S. J. Brener, K. E. Wolski, and E. J. Topol Defining the Optimal Activated Clotting Time During Percutaneous Coronary Intervention : Aggregate Results From 6 Randomized, Controlled Trials Circulation, February 20, 2001; 103(7): 961 - 966. [Abstract] [Full Text] [PDF]

				J. W. Eikelboom, S. S. Anand, S. R. Mehta, J. I. Weitz, C. Yi, and S. Yusuf Prognostic Significance of Thrombocytopenia During Hirudin and Heparin Therapy in Acute Coronary Syndrome Without ST Elevation : Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Study Circulation, February 6, 2001; 103(5): 643 - 650. [Abstract] [Full Text] [PDF]

				J. Ph. Collet, G. Montalescot, L. Lison, R. Choussat, A. Ankri, G. Drobinski, I. Sotirov, and D. Thomas Percutaneous Coronary Intervention After Subcutaneous Enoxaparin Pretreatment in Patients With Unstable Angina Pectoris Circulation, February 6, 2001; 103(5): 658 - 663. [Abstract] [Full Text] [PDF]

				S. G. Goodman, A. Barr, A. Sobtchouk, M. Cohen, G. J. Fromell, L. Laperriere, C. Hill, A. Langer, and for the Canadian Efficacy and Safety of Subcutaneo Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q-wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1507 - 1513. [Abstract] [Full Text] [PDF]

				E. Braunwald, E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) J. Am. Coll. Cardiol., September 1, 2000; 36(3): 970 - 1062. [Full Text] [PDF]

				G. Montalescot, J. P. Collet, L. Lison, R.e. Choussat, A. Ankri, E. Vicaut, K. Perlemuter, F. Philippe, G.e. Drobinski, and D. Thomas Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina J. Am. Coll. Cardiol., July 1, 2000; 36(1): 110 - 114. [Abstract] [Full Text] [PDF]

				S. Kaul and P. K. Shah Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1699 - 1712. [Abstract] [Full Text] [PDF]

				T. Matsuo and K. Kario Direct Detection of Heparin-Induced Platelet Aggregation Circulation, December 21, 1999; 100 (25): e155 - e155. [Full Text] [PDF]

				C. Perrault, N. Ajzenberg, P. Legendre, G. Rastegar-Lari, D. Meyer, J. A. Lopez, and D. Baruch Modulation by Heparin of the Interaction of the A1 Domain of von Willebrand Factor With Glycoprotein Ib Blood, December 15, 1999; 94(12): 4186 - 4194. [Abstract] [Full Text] [PDF]

				E. M. Antman, M. Cohen, D. Radley, C. McCabe, J. Rush, J. Premmereur, and E. Braunwald Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non-Q-Wave Myocardial Infarction : TIMI 11B-ESSENCE Meta-Analysis Circulation, October 12, 1999; 100(15): 1602 - 1608. [Abstract] [Full Text] [PDF]

				H. L. Messmore JR Heparin-Induced Thrombocytopenia: Historical Review Clinical and Applied Thrombosis/Hemostasis, October 1, 1999; 5(1_suppl): S2 - S6. [Abstract] [PDF]

				T. J. Anderson Assessment and treatment of endothelial dysfunction in humans J. Am. Coll. Cardiol., September 1, 1999; 34(3): 631 - 638. [Full Text] [PDF]

				E. De Candia, R. De Cristofaro, and R. Landolfi Thrombin-Induced Platelet Activation Is Inhibited by High- and Low-Molecular-Weight Heparin Circulation, June 29, 1999; 99(25): 3308 - 3314. [Abstract] [Full Text] [PDF]

				G. Cella, A. Girolami, and A. A Sasahara Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparison With Low-Molecular-Weight Heparin and With a Direct Thrombin Inhibitor Circulation, June 29, 1999; 99(25): 3323 - 3326. [Full Text] [PDF]

				T. Bachetti, E. Pasini, E. Clini, G. Cremona, and R. Ferrari High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats Circulation, June 8, 1999; 99(22): 2861 - 2863. [Abstract] [Full Text] [PDF]

				J. P. Bossavy, K. S. Sakariassen, K. Rubsamen, C. Thalamas, B. Boneu, and Y. Cadroy Comparison of the Antithrombotic Effect of PEG-Hirudin and Heparin in a Human Ex Vivo Model of Arterial Thrombosis Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1348 - 1353. [Abstract] [Full Text] [PDF]

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