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• Heparin and restenosis during percutaneous intervention
  Elijah W Muriithi
  Published on: 6 August 2004

• Published on: 6 August 2004

  Heparin and restenosis during percutaneous intervention

  • Elijah W Muriithi
  • Other Contributors:
    • Philip R Belcher

  Dear Editor,

  The article by Day et al [1]. raises some issues about platelet activation, heparin therapy and acute restenosis after percutaneous coronary intervention that merit further discussion. When compared to other anticoagulants heparin not only has the disadvantage of providing a variable (and unpredictable) anticoagulant response as Day et al. have stated but also has little or no effect on clot...

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  Dear Editor,

  The article by Day et al [1]. raises some issues about platelet activation, heparin therapy and acute restenosis after percutaneous coronary intervention that merit further discussion. When compared to other anticoagulants heparin not only has the disadvantage of providing a variable (and unpredictable) anticoagulant response as Day et al. have stated but also has little or no effect on clot bound thrombin[2]. However, in clinical practice, when prescribed to prevent acute restenosis after percutaneous intervention, heparin has been more reliable and effective than these other anticoagulants and is now the drug of choice during percutaneous and other vascular intervention [3].

  This suggests that the principal benefits conferred by heparin when used for this indication may not be related to its effects on the coagulation cascades. It is therefore possible that the principal mode of action of heparin in this situation is by its effects on platelet activation. This is also suggested by work on the Folts coronary thrombosis model in which cyclic flow reductions due to platelet thrombosis were unaffected by the selective thrombin inhibitor recombinant hirudin [4].

  Platelet activation is a tightly regulated series of events that are initiated by the binding of an agonist to a platelet membrane and culminate in platelet secretion and platelet aggregation. This process can be divided into three phases: (1) shape change, (2) microaggregation (primary aggregation) and (3) macroaggregation (secondary aggregation)[5]. During primary haemostasis macroaggregation is a crucial step as it gives the initial strength to a platelet plug; later, during secondary haemostasis, the platelet plug is reinforced by being consolidated within an enveloping fibrin mesh. It is therefore conceivable that similar events occur during pathological thrombosis.

  Heparin affects platelet activation in at least four ways: (i) Heparin stimulates platelets, probably by a direct action, inducing shape change and microaggregation. [6-7] (ii) In predisposed individuals who have had prior exposure to heparin an immune mediated response may cause intense platelet aggregation.[8-9] (iii) Heparin, in concentrations that vastly exceed those targeted clinically, possibly by a direct action, is a mild inhibitor of platelet macroaggregation.[10-11] (iv) Intravenous heparin even in very low doses causes an almost complete inhibition of platelet macroaggregation.[10-11]

  The inhibitory action of heparin that is of clinical benefit is unlikely to be that observed by Day et al. who used washed platelets which were heparinised in vitro; we state this because several workers, including ourselves, have demonstrated that while intravenous heparinisation, even in low doses, almost completely inhibits platelet macroaggregation, little or no inhibition of platelet macroaggregation is detected even when blood is heparinised in vitro even with much higher doses.[10-13]

  When we studied the relationship between heparin dosage and the inhibition of platelet macroaggregation after intravenous heparinisation, we found that the inhibition of platelet macroaggregation caused by administering 30 U Kg-1 of heparin was almost complete and therefore increasing the dose to 300 U Kg-1 had no additional effect [13]. This suggests that, at all doses currently used in clinical practice, heparin exerts an almost complete inhibition of platelet macroaggregation. We have further demonstrated that the indirect inhibition of platelet macroaggregation is mediated by heparin-releasable endothelial enzymes such as lipoprotein lipase and hepatic lipase;[14] it has also been shown that release of endothelium-anchored lipase does not depend on the molecular weight of the heparin.[15]

  Most interventionalists currently administer heparin as a single dose just before uncomplicated percutaneous intervention; additional post- procedural doses have been associated with a higher risk of bleeding complications while conferring no further reduction in the rate of restenosis [3]. This suggests that heparin may provide better prophylaxis against acute restenosis than it does against later occlusion.

  Regarding the role of the platelet in restenosis: as the authors point out, restenosis results from a combination of smooth muscle proliferation, recoil and incorporation of thrombus; platelets are thought to play significant roles in all three processes. It is however likely that acute restenosis, both after percutaneous intervention and coronary artery bypass grafting, is largely the result of thrombosis [16].

  On the basis of the above arguments we propose that the principal way in which heparin retards thrombosis, and hence acute restenosis, is by its lipase mediated actions that prevent the formation of the platelet plug, upon which fibrin would be laid, rather than by its antithrombin III- mediated inhibition of thrombin.

  The observations by previous workers that increased bleeding times after intravenous heparin correlate with lipase release [17], but are independent of heparin’s effect on plasma coagulation [12], raise the possibility that the bleeding diathesis associated with heparin therapy may also be more closely linked to heparin’s effects on platelet activation than they are to heparin’s anticoagulant properties.

  Refernces

  (1). Day JRS, Malik IS, Weerasinghe A, et al. Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention Heart 2004;90:794-799.

  (2). Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990;86:385-91.

  (3). Smith SCJr, Dove JT, Jacobs AK, et al. ACC/AHA Guidelines for Percutaneous Coronary Intervention (Revision of the 1993 PTCA Guidelines) A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty) Endorsed by the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 2001;37:2239i-lxvi

  (4). Belcher PR, Drake-Holland AJ, Hynd JW, et al. Failure of recombinant hirudin to influence intracoronary thrombosis in the dog. Clin Sci (London) 1996;90:363-8

  (5). Pedvis LG, Wong T, Frojmovic MM. Differential inhibition of the platelet activation sequence: shape change, micro- and macro-aggregation, by a stable prostacyclin analogue (Iloprost). Thromb Haemost 1988;59:323- 328.

  (6). Thomson C, Forbes CD, Prentice CR. The potentiation of platelet aggregation and adhesion by heparin in vitro and in vivo. Clin Sci Mol Med 1973;45:485-94.

  (7). Kappa JR, Fisher CA, Addonizio VPJ. Heparin-induced platelet activation: the role of thromboxane A2 synthesis and the extent of platelet granule release in two patients. J Vasc Surg 1989;9:574-579

  (8). Chong BH, Fawaz I, Chesterman, CN et al. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989:73:235-240.

  (9). Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular- weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330-1335.

  (10). Besterman EM and Gillett MP. Heparin effects on plasma lysolecithin formation and platelet aggregation. Atherosclerosis 1973;17:503-13.

  (11). Belcher PR, Muriithi EW, Milne EM et al. Heparin, Platelet Aggregation, Neutrophils And Cardiopulmonary Bypass. Thromb Res 2000;98:249-56.

  (12). Heiden D, Mielke, CHJ Rodvien R. Impairment by heparin of primary haemostasis and platelet [14C]5- hydroxytryptamine release. Br J Haematol 1977;36:427-436.

  (13). Muriithi EW, Belcher PR, Day SP et al. Heparin induced platelet dysfunction and cardiopulmonary bypass. Ann Thorac Surg 2000;69:1827-32.

  (14). Muriithi EW, Belcher PR, Day SP et al. Lipolysis generates platelet dysfunction after in vivo heparin administration. Clin Sci (Lond) 2002;103:433-40.

  (15). Nasstrom B, Stegmayr BG, Olivecrona G et al. Lower plasma levels of lipoprotein lipase after infusion of low molecular weight heparin than after administration of conventional heparin indicate more rapid catabolism of the enzyme. J Lab Clin Med 2003;142:90-9.

  (16). Schoen FJ, Padera RF Jr. Cardiac Surgical Pathology. In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. 2nd Edition New York: McGraw-Hill, 2003:119-185.

  (17). Barrowcliffe TW, Merton RE, Gray E et al. Heparin and bleeding: an association with lipase release. Thromb Haemost 1988;60:434-436.

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  Conflict of Interest:
  None declared.

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