Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparison With Low-Molecular-Weight Heparin and With a Direct Thrombin Inhibitor
To the Editor:
We read with interest the article by Xiao and Theroux1 on “Platelet Activation With Unfractionated Heparin at Therapeutic Concentrations and Comparisons With a Low-Molecular-Weight Heparin and a Direct Thrombin Inhibitor.” They found that platelets of patients with unstable angina were hyperresponsive during treatment with unfractionated heparin (UFH). Moreover, aggregation to ADP and thrombin receptor agonist peptide (TRAP) was enhanced after addition of UFH ex vivo to blood of normal volunteers. In contrast, when a low-molecular-weight heparin (LMWH) or a direct thrombin inhibitor (argatroban) was added, platelet aggregation induced by TRAP had no detectable effects. However, argatroban reduced maximum platelet aggregation induced by ADP.
We performed similar studies ex vivo and in vitro on platelet aggregation in platelet-rich plasma (PRP) induced by ADP and collagen in the presence of commercial hog mucosal UFH (Liquemin, Roche), LMWHs (LMWH Hepar Laboratory; Enoxaparin, Rhone-Poulenc Rorer), and the direct thrombin inhibitor hirudin (Boehringer Mannheim).2 3 4 In agreement with Xiao and Theroux, UFH added to PRP at therapeutic concentration or after injection of healthy volunteers with a bolus of 5000 IU induced enhanced platelet aggregation by ADP at different final concentrations (0.8 to 2 μmol/L). Such an effect was still present 60 minutes after the bolus injection. Moreover, LMWH, either injected as a bolus or added in vitro, minimally affected or did not affect platelet aggregation induced by ADP. In contrast, when collagen was the aggregating agent, both UFH and LMWH showed an inhibitory effect, although UFH seemed to be more powerful.2 3
Finally, and more importantly, hirudin at a final concentration of 2 μg/mL reduced ADP-induced aggregation by 50% and did not have any effect when collagen was the aggregating agent. Moreover, when we added 2 thrombolytic agents, urokinase and recombinant tissue plasminogen activator, to PRP, this pattern was not modified.4
Powerful direct antithrombin agents like hirudin or argatroban could play a role in preventing the reocclusion of coronary arteries in the early phase of reperfusion, during thrombolytic therapy, by inhibiting both thrombin released by the residual thrombus and ADP-induced platelet activation. In contrast, the heparins could have a more important action in the subsequent phase after successful thrombolysis, when platelets interact with exposed subendothelial collagen. However, because platelets play a crucial role in the failure of thrombolysis, the new antiplatelet inhibitors could be better drugs for increasing the speed of reperfusion and preventing reocclusion.5
- Copyright © 1999 by American Heart Association
Xiao Z, Théroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation. 1998;97:251–256.
Paolini R, Sbarai A, Toffoli S, Rampin E, Vianello A, Luzzatto G, Girolami A, Sasahara AA, Cella G. Effect of thrombolytic agents on platelet aggregation in presence of heparins and hirudin. Hematol Rev.1995;9:205–212.
Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation. 1998;97:211–218.