Importance JAMES
of Antithrombin
H. CHESEBRO,
MD, FACC,
Therapy Durhlg Coronary LINA
BADIMON,
Angloplasty pracfdureswith balloons, cutttw or laws all may greatly enlarge the arterial lumen, but luminal diameter may deweax Krause of mural thrombus in 70% to 801, smwAb mwle proliGation, vssoconstrictionor recoil. Thrombi binds to arterial wall matrix and fibrin within a thrambus. Heprin drwdapendmtly decreasesplatelet and thmmbur depositionbut does not eliminate these ewn at high doses.Spedtic tbrombin inhibition started beforeangioplssly experimentally preventsmu. ml thrombw and litits platelet depositionto a singlelayer or less.
Mechanisms of Restenosis Decreasedlumbml diameter atIer angioplasty. Quantitative coronary angiograpby before. immediately after and 3 to 6 months after ~ercutane~w tranrluminal coronary anGoplasty and atherrctomy shows that the minimal~lumkal diameter increases from 0.8 mm before the mocedure to I.5 and 2 mm. respectively, immediately afte; the procedure, but decreasesto a diameter of I .3 and 1.4 mm, respectively, 3 to6 months later (1.2). Today’s challcngc is to maintain the great improvement in minimal luminal diameter achieved immediately after the angioplasty or atbcrcctomy procedure. This decrease in minimal luminal diameter Begins within minutes with both acute platelet-tbmmbus d*position in the plaque fissures. splits and regions of deep ancrial injury (3-71 and with fibrocellular itdimal proliferation that begins with oncogcnc activation within m&es and becameskident over the next 2 to I4 davs when 35% to 50% of smooth muscle cells in the media Bnd intima of the artery are proliferating (8-l I). Mechanisms of dwwed ltmdnal di&r: vwwonstriction and tbrombus. Increased platelet deposition in arterial tbrombus contributes to enhanced vasoconstriction around the angioplasty site (12). Active thrombin binds toarterial wall matrix and fibrin within a thrombus and may contribulc to vasoconstriction through the release of endothelin, one of the most potent vasoconstrictars(13A). The latter two mechanisms may contribute to vasoconstriction. which is maximal I5 to 30 min
PxD,
VALENTIN
Angioplasty
FUSTER,
MD,
FACC
Exprimadaliy, antieoagtdant and antifibrin effects occur at lower antitbrombin bled levels and lower activated partial thmmboplasttn times (1.7 times contml). Becauseplatelolp are so smsttive to thrombin, the hlgber level of thmmbin inhibition required any occur at P speciticlevel (activatedpartial thromboplastin time 2 2 time cantml); this is rwt detked in humans.The durationof Iherapy is nc4deanedin anhpls or humans. Thram. bus and tbrombin may be related to cellular pmliferrdton. (1 Am Cd Cdid 1991;17:968-1008)
after coronary angioplasty in humans and can be prevented with an infusionof intravenous nitmglyccrin (14). Mural thrombus contributing to decreasedhtminal diameter may contribute to an abnomml exercise test within days after coronary angioplasty in patients who later manifest restenosis(8,IS). Contributions to pastangioplasty thrombus. Recent controlled trials (1.16-18) with usual doses of intravenous heparin plus administration of platelet inhibitors have rcduced but not eliminated acute complications of coronary awiorhsty and have not prevented restenosis. This is not su&isiw.hecause these ihcrapies do not prevent mural thrombosisin humansor animals (4-7.12.19). Patients who have a residual stenosis or a significant pressure gradient across rbe stenosis immediately after angioplasty are at higher risk of rcstenasis and early complications (I.20). Similarly, a small luminal diameter immediately before or immediately after angioplastyis the strongat predictor of a small minimal luminal diam& late r&r an&plasty (I). These observations are consistent with the rheology of platelet deposition on the arterial wall; a stenosisenhances platelet deposition within the minimal luminal diameter. Thus, both a thromhogenic substrate of deeply injured arterial wall and a high shearforce (directly related to blood flow velocity and inversely to the third power of the luminal diameter) create the highestrisk of thrombosis(?I).
Prevention and Treatment of Restenosis Pretreatment with hepnrin and protongedanticoagulation. In patients with unstable angina. there is strong evidence that pretreatmentwith a continuousheparin infusion for a mean of 3 to 4 and up to 7 days before coronary angioplasty significantly increasesthe incidence of uncomplicatedprocedural successand reduces the likelihood of acute occlusion and angiograpbicallyevident mural thrombus (22-24).
Figure 1. Disarbance of thrombur by mecbanieel breakage, ~ponteneousembolization or pharmacolnnic thrombotvris PX~~ICI active thmmbin
bound io fibrin. Tixombin acrivete\ ptaletetr. activatesfactor Y to VJ (which leadsto yeneralion of n?xe thrombin by way of the prothrombina complex). convens fibrinogen to fibrin
I
and fibrin 11 and xetrwtes factor Xl,, to Xllla (which cross links fibrin). The formation of the prothrombinasecomplen acceleretestne generetion of thrombin by 278.033 times a singlefactor
alone128).Theser:ambinedprocew~ stimulated bv rhrombin orodocee wtent stirnutusfor thromb&is. He&in mnayonly dew and not prevent continued thrombosis becauseplatelet factor 4 secretedfrom aggregatingplatelets neutralizes hepain, fibrin II monomerinhibits the action of hepatio-antitbrombinIII and factor Xa within the pr&hmmbindse complex is protected from inhibition by Lparin-antithrombin 111. Reproduced with permission from Webrreret al. 14%
Angiosraphicelly in 66% of pat&s
evident mural rhrombus can be eliminated
with prolonged anticoagulant therapy initidlv with herarin and if necessary followed hv wa.farin for a t&a of7’days or as long 88 30 days (25). it has long been known that preexisting mural ihrombus identified by angiography (which underestimates the true incidence) is a major risk factor for acute occlusion and complications of angioplasty (26). A major reason for the high risk of acute occlusion. emergency bypass surgery. failed angioplasty. acute myncardial infarction and death after angioplasty in the presence of preexisting thrombus appears to be the high thrombngenicity of residual thrumbus, which id even more thrombagenic than deeply injured ertery (27). Residual thrombus that is disturbed mechanically with e catheter. spnntaneously by embolization or pharnwcologically with thrombalysis exposes active thmmbin bound to fibrin within the thrombus and thus accelerates thrombosis (Fig. II (28.29). Rrvtntii cd posbutgioplpstr ~terial lhrnmbw role of heparin and hirudbt therapy. Possibilities for preventing arterial thrombosis include the major mechanisms of platelet activation. such as thromboxane A,. sermonin. thrombin. collagen and adenosine diphosphate (ADP) (30). Using a pig model of balloon angioplasty with deep arterial injury, we investigated various mechanisms of platelet inhibition for the reduction of platelet deposition and elimination of mural thrombosis after deep arterial injury. Neither thromboxane A, receptor inhibition nor serotonin receptor inhibition. nor bath, con prevent arterial thrombosis or lessen the amount of platelet deposition in deeply injured arteries that occurs with nlacebo (31). However. studies 132.33) of six increasinr steady state doses of unfractionated heparin showed a dosedependent decrease in platelet deposition and mural thrombosis that we hypothesized es due in thrombin inhibition. We proved this hypothesis with use of the specific thmmbin receptor inhibitor hirudin. which rotally inhibited arterial
thrombosis and limited oletelet deposition to a sin&
layer when used alone witbou~ adjuncti~e therapy (Fig. 2,. Thus. thrombosis after deep arterial injury in viva is mediated predominantly by thrombin activation of platelets (28). Srrndy
stur~ blood levels of hepmin or hirudin
can be
nchiered wirh un inmrcwenor~sbofus injerrion plus a simalranews i&ion
(4.32). This is critical to mainlain therapeutic
blood levels with these medications. which have a very short half-life of
of Antithrombin
H. CHESEBRO,
MD, FACC,
Therapy Durhlg Coronary LINA
BADIMON,
Angloplasty pracfdureswith balloons, cutttw or laws all may greatly enlarge the arterial lumen, but luminal diameter may deweax Krause of mural thrombus in 70% to 801, smwAb mwle proliGation, vssoconstrictionor recoil. Thrombi binds to arterial wall matrix and fibrin within a thrambus. Heprin drwdapendmtly decreasesplatelet and thmmbur depositionbut does not eliminate these ewn at high doses.Spedtic tbrombin inhibition started beforeangioplssly experimentally preventsmu. ml thrombw and litits platelet depositionto a singlelayer or less.
Mechanisms of Restenosis Decreasedlumbml diameter atIer angioplasty. Quantitative coronary angiograpby before. immediately after and 3 to 6 months after ~ercutane~w tranrluminal coronary anGoplasty and atherrctomy shows that the minimal~lumkal diameter increases from 0.8 mm before the mocedure to I.5 and 2 mm. respectively, immediately afte; the procedure, but decreasesto a diameter of I .3 and 1.4 mm, respectively, 3 to6 months later (1.2). Today’s challcngc is to maintain the great improvement in minimal luminal diameter achieved immediately after the angioplasty or atbcrcctomy procedure. This decrease in minimal luminal diameter Begins within minutes with both acute platelet-tbmmbus d*position in the plaque fissures. splits and regions of deep ancrial injury (3-71 and with fibrocellular itdimal proliferation that begins with oncogcnc activation within m&es and becameskident over the next 2 to I4 davs when 35% to 50% of smooth muscle cells in the media Bnd intima of the artery are proliferating (8-l I). Mechanisms of dwwed ltmdnal di&r: vwwonstriction and tbrombus. Increased platelet deposition in arterial tbrombus contributes to enhanced vasoconstriction around the angioplasty site (12). Active thrombin binds toarterial wall matrix and fibrin within a thrombus and may contribulc to vasoconstriction through the release of endothelin, one of the most potent vasoconstrictars(13A). The latter two mechanisms may contribute to vasoconstriction. which is maximal I5 to 30 min
PxD,
VALENTIN
Angioplasty
FUSTER,
MD,
FACC
Exprimadaliy, antieoagtdant and antifibrin effects occur at lower antitbrombin bled levels and lower activated partial thmmboplasttn times (1.7 times contml). Becauseplatelolp are so smsttive to thrombin, the hlgber level of thmmbin inhibition required any occur at P speciticlevel (activatedpartial thromboplastin time 2 2 time cantml); this is rwt detked in humans.The durationof Iherapy is nc4deanedin anhpls or humans. Thram. bus and tbrombin may be related to cellular pmliferrdton. (1 Am Cd Cdid 1991;17:968-1008)
after coronary angioplasty in humans and can be prevented with an infusionof intravenous nitmglyccrin (14). Mural thrombus contributing to decreasedhtminal diameter may contribute to an abnomml exercise test within days after coronary angioplasty in patients who later manifest restenosis(8,IS). Contributions to pastangioplasty thrombus. Recent controlled trials (1.16-18) with usual doses of intravenous heparin plus administration of platelet inhibitors have rcduced but not eliminated acute complications of coronary awiorhsty and have not prevented restenosis. This is not su&isiw.hecause these ihcrapies do not prevent mural thrombosisin humansor animals (4-7.12.19). Patients who have a residual stenosis or a significant pressure gradient across rbe stenosis immediately after angioplasty are at higher risk of rcstenasis and early complications (I.20). Similarly, a small luminal diameter immediately before or immediately after angioplastyis the strongat predictor of a small minimal luminal diam& late r&r an&plasty (I). These observations are consistent with the rheology of platelet deposition on the arterial wall; a stenosisenhances platelet deposition within the minimal luminal diameter. Thus, both a thromhogenic substrate of deeply injured arterial wall and a high shearforce (directly related to blood flow velocity and inversely to the third power of the luminal diameter) create the highestrisk of thrombosis(?I).
Prevention and Treatment of Restenosis Pretreatment with hepnrin and protongedanticoagulation. In patients with unstable angina. there is strong evidence that pretreatmentwith a continuousheparin infusion for a mean of 3 to 4 and up to 7 days before coronary angioplasty significantly increasesthe incidence of uncomplicatedprocedural successand reduces the likelihood of acute occlusion and angiograpbicallyevident mural thrombus (22-24).
Figure 1. Disarbance of thrombur by mecbanieel breakage, ~ponteneousembolization or pharmacolnnic thrombotvris PX~~ICI active thmmbin
bound io fibrin. Tixombin acrivete\ ptaletetr. activatesfactor Y to VJ (which leadsto yeneralion of n?xe thrombin by way of the prothrombina complex). convens fibrinogen to fibrin
I
and fibrin 11 and xetrwtes factor Xl,, to Xllla (which cross links fibrin). The formation of the prothrombinasecomplen acceleretestne generetion of thrombin by 278.033 times a singlefactor
alone128).Theser:ambinedprocew~ stimulated bv rhrombin orodocee wtent stirnutusfor thromb&is. He&in mnayonly dew and not prevent continued thrombosis becauseplatelet factor 4 secretedfrom aggregatingplatelets neutralizes hepain, fibrin II monomerinhibits the action of hepatio-antitbrombinIII and factor Xa within the pr&hmmbindse complex is protected from inhibition by Lparin-antithrombin 111. Reproduced with permission from Webrreret al. 14%
Angiosraphicelly in 66% of pat&s
evident mural rhrombus can be eliminated
with prolonged anticoagulant therapy initidlv with herarin and if necessary followed hv wa.farin for a t&a of7’days or as long 88 30 days (25). it has long been known that preexisting mural ihrombus identified by angiography (which underestimates the true incidence) is a major risk factor for acute occlusion and complications of angioplasty (26). A major reason for the high risk of acute occlusion. emergency bypass surgery. failed angioplasty. acute myncardial infarction and death after angioplasty in the presence of preexisting thrombus appears to be the high thrombngenicity of residual thrumbus, which id even more thrombagenic than deeply injured ertery (27). Residual thrombus that is disturbed mechanically with e catheter. spnntaneously by embolization or pharnwcologically with thrombalysis exposes active thmmbin bound to fibrin within the thrombus and thus accelerates thrombosis (Fig. II (28.29). Rrvtntii cd posbutgioplpstr ~terial lhrnmbw role of heparin and hirudbt therapy. Possibilities for preventing arterial thrombosis include the major mechanisms of platelet activation. such as thromboxane A,. sermonin. thrombin. collagen and adenosine diphosphate (ADP) (30). Using a pig model of balloon angioplasty with deep arterial injury, we investigated various mechanisms of platelet inhibition for the reduction of platelet deposition and elimination of mural thrombosis after deep arterial injury. Neither thromboxane A, receptor inhibition nor serotonin receptor inhibition. nor bath, con prevent arterial thrombosis or lessen the amount of platelet deposition in deeply injured arteries that occurs with nlacebo (31). However. studies 132.33) of six increasinr steady state doses of unfractionated heparin showed a dosedependent decrease in platelet deposition and mural thrombosis that we hypothesized es due in thrombin inhibition. We proved this hypothesis with use of the specific thmmbin receptor inhibitor hirudin. which rotally inhibited arterial
thrombosis and limited oletelet deposition to a sin&
layer when used alone witbou~ adjuncti~e therapy (Fig. 2,. Thus. thrombosis after deep arterial injury in viva is mediated predominantly by thrombin activation of platelets (28). Srrndy
stur~ blood levels of hepmin or hirudin
can be
nchiered wirh un inmrcwenor~sbofus injerrion plus a simalranews i&ion
(4.32). This is critical to mainlain therapeutic
blood levels with these medications. which have a very short half-life of
