Recurrent Coronary Thrombosis Research Articles

Abstract 13671: Predicting the Coronary Thrombosis Events Risk in Chinese Patients After Percutaneous Coronary Intervention With Drug Eluting Stents: Risk Model From PROMISE Trial

Introduction: The accurate assessment of individual risk can be of great value to facilitate the prevention of recurrent coronary thrombosis events (CTEs) in patients after percutaneous coronary intervention (PCI) with Drug-Eluting Stents (DES). However, current prediction models in common use were often formulated in white populations and were of limit predicting value in Chinese patients. The current study is aimed at developing and validating a prediction model for recurrent CTEs from 2 contemporary Chinese cohorts of patients after PCI with DES. We formulated a CTEs prediction model from PROMISE trial, a PR ospective O bservational M ulticenter cohort of I schemic and h E morrage risk after PCI. Hypothesis We assessed the hypothesis that the PROMISE model was an effective tool for predicting 2-year CTEs risk in Chinese patients after PCI with DES. Methods 7998 Chinese patients underwent DES-PCI from PROMISE trial with 2-year follow up were used as the derivation cohort to develop the PROMISE model. The external validation was evaluated in one independent Chinese cohort with 3824 participants. Cardiac death, myocardial infarction, definite and probable in-stent thrombosis were defined as CETs. We compared candidate variables between CETs and non-CETs groups. Backward selection with an entry criterion of p<0.05 were used to formulate the model. The model performance was assessed by discrimination C statistics and calibration χ2. We also assessed the internal and external validation. Results Over 2-year follow up in the derivation cohort, 151 patients developed CTEs. Five variables including, previous revascularization, baseline elevated cTNI, left ventricular ejection fraction, residual SYNTAX score after PCI and estimated glomerular filtration rate were finally involved in the PROMISE model. The C statistics of the model was 0.750(95% confidence interval, 0.700-0.799), and the calibration χ2 was 7.2(p=0.612). In the subsequent external validation, the PROMISE model had C statistics of 0.607 (95%CI,0.508-0.706) , and the calibration χ2 was 14.0(p=0.121). Conclusion The PROMISE model had a good internal validation and moderate external validation and it was an effective tool for 2-year CTEs risk prediction in Chinese patients after PCI with DES.

Intracoronary Thrombus in a Patient with Elevated Lp(a) Levels and COVID-19

Lead Author's Financial DisclosuresNothing to disclose.Study FundingNone.Background/SynopsisLp(a) is elevated in 20% of the population and is associated with increased risk for myocardial infarctions and strokes. In patients with COVID-19, Lp(a) is upregulated as a response to the systemic inflammatory infection which can potentially increase the risk for atherothrombotic events. The following case presents the first report of a patient with elevated Lp(a) levels and COVID-19 who presented with an acute MI and evidence for intracoronary thrombus.Objective/Purpose49-year-old male with past medical history of thoracic aortic aneurysm recently diagnosed with COVID-19 presented to ED with chest pain. EKG showed ST-segment elevation in the anterior leads with a 12.7 troponin score. Patient underwent emergent cardiac catheterization that showed 90% ulcerated thrombotic lesion in the proximal LAD. The thrombus was demonstrated by both angiography and IVUS. Thrombectomy, angioplasty, and stenting were performed. There was embolization of thrombus to the distal LAD. Echocardiogram revealed LVEF 55% with apical hypokinesis. He was started on DAPT, statin, and rivaroxaban due to the high risk of recurrent coronary thrombosis. His Lp(a) was 200 nmol/L. (Normal < 75 nmol/L).MethodsN/A.ResultsCases of patients with COVID-19 and elevated Lp(a) presenting with acute MI and intracoronary thrombus have yet to be reported. Elevated Lp(a) level is thought to increase the risk of cardiovascular events and venous thromboembolism through anti-fibrinolytic and pro- atherosclerotic properties. Acute, transient elevations in Lp(a) secondary to IL-6 production have been observed in inflammatory states, such as COVID-19 infections. A cohort study of 146 COVID-19 patients in the Netherlands observed a mean increase in Lp(a) of 16.9mg/dL from baseline over a course of 21 days during hospitalization In a retrospective study of patients admitted with COVID-19, 5.6% of 531 experienced arterial thrombosis, 9 of which suffered myocardial infarction. In patients similar to ours with COVID- 19 and elevated Lp(a), there may be elevated risk of similar events and providers should remain vigilant for potential complications. It is possible that acutely elevated Lp(a) levels contribute to arterial thrombotic events in the coronaries during COVID-19 infection.ConclusionsIn patients presenting with COVID-19 and acute myocardial infarction, we recommend that clinicians measure Lp(a) level and evaluate for intracoronary thrombi to correlate our findings.

Can Prolactinemia Cause Coronary Thrombosis

AbstractThere is an increasing trend of myocardial infarction (MI) among the young population. There exist various causes for this trend, as the pathogenesis of increased MI could be atheromatous, nonatheromatous, or hypercoagulable, and involve substance misuse. Here, we report a case of a 32-year-old female patient presented with coronary thrombosis; on evaluation, she was found to have hyperprolactinemia with no other causes of coronary thrombosis. Hyperprolactinemia is a rare cause of recurrent coronary thrombosis. Prolactin levels are even elevated in MI but they return to normal values in 2 to 4 weeks; however, this patient experienced a persistent elevation of prolactin levels with no signs of pituitary adenoma, so there is a possibility that elevated prolactin levels could cause coronary thrombosis.

GLS-409, an Antagonist of Both P2Y1 and P2Y12, Potently Inhibits Canine Coronary Artery Thrombosis and Reversibly Inhibits Human Platelet Activation

Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Previous evidence from our group, obtained in a preclinical model of recurrent platelet-mediated thrombosis, demonstrated that GLS-409, a diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12 ADP receptors, may be a novel and promising antiplatelet drug candidate. However, the salutary antiplatelet effects of GLS-409 were accompanied by a trend toward an unfavorable increase in bleeding. The goals of this study were to: 1) provide proof-of-concept that the efficacy of GLS-409 may be maintained at lower dose(s), not accompanied by an increased propensity to bleeding; and 2) establish the extent and kinetics of the reversibility of human platelet inhibition by the agent. Lower doses of GLS-409 were identified that inhibited in vivo recurrent coronary thrombosis with no increase in bleeding time. Human platelet inhibition by GLS-409 was reversible, with rapid recovery of platelet reactivity to ADP, as measured by platelet surface activated GPIIb-IIIa and platelet surface P-selectin. These data support the concept that GLS-409 warrants further, larger-scale investigation as a novel, potential therapy in acute coronary syndromes.

GLS-409, a Synergistic Inhibitor of Both P2Y1 and P2Y12: Efficacy in a Canine Model of Recurrent Coronary Thrombosis and Reversibility of Human Platelet Inhibition

Introduction. Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor inhibitor is a mainstay of pharmacological therapy in acute coronary syndromes. GLS-409 is a novel diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12platelet ADP receptors.Aims. 1) Determine the minimal dose of GLS-409 for in vivo inhibition of recurrent coronary thrombosis in a canine model. 2) Characterize the effects of the minimal antithrombotic dose of GLS-409 on the bleeding time. 3) Determine the extent and kinetics of the reversibility of platelet inhibition by GLS-409.Methods. (1) Canine Model of Recurrent Coronary Thrombosis. Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h post-injury + stenosis, dogs were randomized to receive either GLS-409 or matched volumes of vehicle (saline). Three doses of GLS-409 were assessed: A) 0.054 mg/kg bolus + 0.00018 mg/kg/min infusion maintained for 2 hours; B) 1/10th bolus + 1/10th infusion; C) 1/100th bolus + 1/100th infusion. Coronary blood flow was monitored throughout the 2 hours post-treatment. Primary endpoints were: (i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); and (ii) template bleeding time. (2) Reversibility of platelet inhibition following 30 minutes exposure to GLS-409. Sodium citrate 3.2% anticoagulated whole blood from healthy human volunteers (n=9) was treated with 80% inhibitory dose of GLS-409 for 30 minutes and assessed for recovery of response to ADP by flow cytometric analysis of platelet surface P-selectin and activated GPIIb-IIIa (reported by binding of the activation-dependent monoclonal antibody, PAC-1), at specified times before and after 300-fold dilution in drug-free, platelet-poor plasma.Results. (1) All dogs developed spontaneous episodes of recurrent thrombosis following coronary injury + stenosis. In the saline control group, there was no change in coronary patency during the 2 hour treatment period versus the pretreatment phase. Administration of GLS-409 at Doses A and B was associated with significant increases in % flow-time area, while Dose C had no significant effect on patency (Figure A). GLS-409 at Doses A and B which effectively inhibited recurrent coronary thrombosis, had no effect on the template bleeding time.(2) Incubation of human whole blood with GLS-409 for 30 min at room temperature, produced strong, concentration-dependent inhibition of the ADP-stimulated increases in platelet surface P-selectin and activated GPIIb-IIIa; 80% inhibition was obtained with 1.56 nM GLS-409. Blood exposed for 30 minutes to the 80% inhibitory concentration of GLS-409, then diluted 300-fold in drug-free, platelet-poor plasma (thereby reducing GLS-409 to 0.0052 nM, final concentration) showed a time-dependent recovery of reactivity to ADP as measured by both platelet surface P-selectin and activated GPIIb-IIIa (Figure B). However, while ADP-stimulated activated GPIIb-IIIa fully recovered within 60 min to levels seen in vehicle-treated samples, ADP-stimulated P-selectin response recovered to only 75% of the response seen in the vehicle-treated control (Figure B).Conclusions. (1) GLS-409 improved coronary patency in this canine model of recurrent coronary thrombosis without an accompanying increase in the bleeding time. (2) The time required after exposure of platelets to GLS-409 in whole blood for 50% recovery of ADP-stimulated PAC-1 reactivity (~26 min) is longer than published (J Thromb Haemost . 2017. 10.1111/jth.13627) recovery times after exposure to cangrelor (1.8 min), ticagrelor (4.4 min), and ticagrelor active metabolite (6.3 min), suggesting a slower off-rate for GLS-409. Incomplete reversibility of ADP-stimulated P-selectin following exposure to GLS-409 is similar to published results for cangrelor, but different from ticagrelor, both of which are selective for P2Y12. This relatively slow reversibility of GLS-409 inhibition offers another explanation, in addition to its dual specificity for P2Y1 and P2Y12, for the presently-described high potency of GLS-409 observed in the animal model. These properties suggest that GLS-409 could become a useful addition to the current drugs used in acute coronary syndromes. Further evaluation of the potential clinical utility of GLS-409 is warranted. [Display omitted] DisclosuresMichelson:Ionis: Research Funding; Sysmex: Research Funding; Baxalta: Research Funding; GLSynthesis: Research Funding; Eisai: Research Funding; Elsevier: Patents & Royalties; Ironwood: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratory: Consultancy; Pfizer: Research Funding. Yanachkov:GLSynthesis: Employment. Yanachkova:GLSynthesis: Employment. Wright:GLSynthesis: Employment. Przyklenk:GLSynthesis: Research Funding. Frelinger:Pfizer: Research Funding; Ionis: Research Funding; Sysmex: Research Funding; Baxalta: Research Funding; GLSynthesis: Research Funding; Ironwood: Research Funding.

Abstract 19210: Remote Ischemic Conditioning, Applied During Recurrent Coronary Thrombosis Mimicking Unstable Angina, Improves Coronary Patency

Evidence from our group revealed that the benefits of preconditioning ischemia extend beyond infarct size reduction via up-regulation of cardioprotective signaling. We found that brief antecedent ischemia: i) attenuates molecular indices of platelet activation-aggregation (i.e., P-selectin expression, fibrinogen binding); and thus ii) improves arterial patency in models mimicking unstable angina. However, two issues limit potential translation of this endogenous anti-platelet effect: the conditioning stimulus was applied directly to the heart, as a pretreatment . Our current aim was to establish whether brief ischemia applied at a remote site (skeletal muscle), after the onset of recurrent coronary thrombosis, would improve subsequent coronary patency. Methods: Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h after injury + stenosis, dogs received: i) remote ischemic conditioning (RIC: 4 5-min episodes of bilateral hindlimb ischemia); or ii) a time-matched sham-control period. Coronary blood flow was monitored throughout the 1 h before treatment and for 2 h after the RIC/sham stimulus. Primary endpoints were: i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); and ii) % duration of total thrombotic occlusion (flow=0). Results: Both groups displayed poor coronary patency during the 1 h pretreat period: flow-time area averaged 31-32%, and duration of total thrombotic occlusion was 19-25%. Patency remained unchanged in controls throughout the protocol. In contrast, RIC evoked an immediate attenuation of recurrent thrombosis: flow-time area was increased to 63±10% (p&lt;0.01) and duration of total occlusion was reduced to 4% (p=0.11). Conclusion: Remote ischemic conditioning, applied during episodes of recurrent platelet-mediated thrombosis mimicking unstable angina, improves subsequent coronary patency.

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis.

Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype. To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

The Success of Clopidogrel Treatment for Recurrent Coronary Thrombosis in a Patient With Aortic and Mitral Valve Replacement

The Success of Clopidogrel Treatment for Recurrent Coronary Thrombosis in a Patient With Aortic and Mitral Valve Replacement

Effect of adenosine A2 receptor stimulation on platelet activation–aggregation: Differences between canine and human models

IntroductionAdenosine A2 agonists improve arterial patency in experimental models of recurrent thrombosis, an effect purportedly triggered by stimulation of platelet A2 receptors and subsequent down-regulation of platelet function. However: (i) there is no direct evidence to substantiate this premise; and (ii) given the recognized differences among species in platelet signaling, it is possible that the mechanisms of A2 receptor stimulation may be model-dependent. Accordingly, we applied an integrated in vivo and in vitro approach, using both canine and human models, to test the hypothesis that the anti-thrombotic effects of A2 agonist treatment are due in part to inhibition of platelet activation. MethodsIn Protocol 1, recurrent coronary thrombosis was triggered in anesthetized dogs by application of a stenosis at a site of arterial injury. Coronary patency and flow cytometric indices of platelet activation (P-selectin expression; formation of heterotypic aggregates) were compared in dogs pre-treated with the A2 agonist CGS 21680 versus controls. In Protocols 2 and 3, blood samples were obtained from dogs and human volunteers. In vitro aggregation and platelet activation (assessed by impedance aggregometry and flow cytometry, respectively) were quantified in paired aliquots pre-incubated with CGS versus vehicle. ResultsIn the canine models, CGS improved in vivo coronary patency and attenuated in vitro aggregation but, contrary to our hypothesis, did not evoke a down-regulation in platelet activation. In contrast, in human blood samples, CGS attenuated both in vitro aggregation and flow cytometric markers of platelet activation–aggregation. ConclusionThe mechanisms contributing to the anti-thrombotic effect of A2 agonist treatment are species-dependent: adenosine A2 receptor stimulation inhibits platelet activation in human, but not canine, models.

Preconditioning ischemia attenuates molecular indices of platelet activation-aggregation.

Previous studies have shown that ischemic preconditioning (PC) not only limits infarct size, but also improves arterial patency in models of recurrent thrombosis. We hypothesize that this enhanced patency is presumably because of a PC-induced attenuation of platelet-mediated thrombosis. However, there is, at present, no direct evidence that PC acts on the platelets per se and favorably down-regulates platelet reactivity. Our goal was to test the concept that PC ischemia attenuates molecular indices of platelet activation-aggregation. Anesthetized dogs were randomly assigned to receive 10 min of PC ischemia followed by 10 min of reperfusion or a time-matched control period. Spontaneous recurrent coronary thrombosis was then initiated in all dogs by injury + stenosis of the left anterior descending coronary artery. Coronary flow was monitored for 3 h poststenosis, and molecular indices of platelet activation-aggregation were quantified by whole blood flow cytometry. Coronary patency was, as expected, better-maintained following injury + stenosis in the PC group vs. controls (53% +/- 5%* vs. 23% +/- 5% of baseline flow, respectively; *P < 0.05). Moreover, PC was accompanied by: (i) a significant down-regulation of platelet-fibrinogen binding and formation of neutrophil-platelet aggregates (112% +/- 14%* vs. 177% +/- 21% and 107% +/- 8%* vs. 155% +/- 19% of baseline values in PC vs. control groups); and (ii) a trend towards a reduction in platelet P-selectin expression (148% +/- 12% vs. 190% +/- 21% of baseline; *P < 0.05 and P = 0.09 vs. control). These data provide novel, direct evidence in support of the concept that ischemic PC attenuates molecular indices of platelet activation-aggregation.

Recurrent Coronary Thrombosis, Factor V Leiden, Primary Antiphospholipid Sydrome, and HIV

We describe a 54-year-old man who was HIV-positive, admitted for cardiogenic shock complications inferior myocardial infarction. He was treated with primary percutaneous transluminal angioplasty (PCTA) and stent deployment in mid right coronary artery. After a few days thrombotic occlusion of the stent occurred, and the problem recurred during implantation of a new stent in the course of a second PTCA. We detected coinheritance of factor V Leiden, primary antiphospholipid syndrome and antithrombin deficiency. We discuss the role of these coagulation disorders in acute myocardial infarction as well as the treatment and course of the coronary syndrome in this context.

Does GPIIb/IIIa Inhibition Do More Than Prevent Recurrent Coronary Thrombosis?

Opening coronary arteries does not result necessarily in return of myocardial function. Resolution of ST elevation also correlates with return of

The challenge of acute coronary syndromes

I n t roduc t ion Acute coronary syndromes (ACS) pose multiple challenges to physicians, cardiologists, internists, and emergency department physicians, as well as to general practitioners. General practitioners are responsible for early recognition of ACS among patients with chest discomfort and identification of patients who require hospital admission; cardiologists and other specialists prescribe initial and subsequent medical therapy and select patients for immediate, early, or elective revascularisation by percutaneous techniques (balloon angioplasty, stent) or bypass surgery. A systematic approach may guide the physicians to meet these challenges (table). The term ACS encompasses a spectrum of patients who present with chest discomfort or other symptoms caused by myocardial ischaemia. The unification of these manifestations of coronary artery disease under a single term reflects the understanding that these are caused by a similar pathophysiology, characterised by erosion, fissuring, or rupture of a pre-existing plaque, leading to intravascular thrombosis and impaired myocardial blood supply? The presence or absence of mechanical obstruction by the plaque and its contents, the amount and extent of associated thrombus formation, and the degree of collateral circulation determine the outcome of patients, particularly whether myocardial ischaemia recovers fully or results in minor or major myocardial necrosis. The common pathophysiology of different clinical presentations of ACS logically requires a similar therapeutic approach. In the 1970s, attention focused on management of lifethreatening arrhythmias. Coronary care units were introduced to detect and treat such arrhythmias by pacemakers (A-V block) or defibrillation (ventricular fibrillation). 2-~ Defibrillators were also introduced in ambulances. Antiarrhythmic drugs were also introduced to prevent ventricular fibrillation. Subsequently, attention shifted to measures to reduce myocardial oxygen consumption with [3-blockers, nitrates, and calcium antagonists. ' These agents prevented progression to myocardial infarction in patients with unstable angina, and improved outcome in selected patients with evolving infarction." In the past 10 years, reperfusion therapy has been introduced, supported by intensive antithrombotic and anticoagulant therapy. The value of reperfusion therapy with coronary occlusion (evolving infarction) by thrombolytic therapy or direct angioplasty has been well established. 9-n However, the indications for, and opt imum timing of, percutaneous or surgical coronary intervention in the spectrum of patients with unstable angina are still debated. H

Nitric Oxide and Prostacyclin Are Involved in Antithrombotic Action of Captopril in Venous Thrombosis in Rats

The long-term administration of captopril to patients with a left ventricular dysfunction after myocardial infarction reduces the rate of recurrent coronary thrombosis. Thus, in the present study we investigated the influence of angiotensin-converting enzyme inhibitors (ACE-Is) on experimental venous thrombosis in normotensive rats and the involvement of NO and PGI2 in this effect. Animals were treated with captopril (1.5, 5 or 25 mg/kg twice daily, CAP), enalapril (15 mg/kg once daily, ENA) or distilled water for 10 days, per os. After ligation of the vena cava the thrombus weight decreased in both CAP and ENA treated rats. The effect was most pronounced in animals given the highest dose of CAP (p<0.0001 vs. control) and was significantly stronger than observed in ENA treated animals (CAP vs. ENA p<0.01). The mean blood pressure measured by the "tail cuff" method and platelet aggregation were not altered by either of the ACE-Is. The antithrombotic activity of CAP was reduced by indomethacin (2.5 mg/kg, s.c.) and independently by the NO-synthase inhibitor N(G)-nitro L-arginine methyl ester (3 mg/kg i.v. bolus + 3 mg/kg/h i.v. infusion, L-NAME). In the latter case CAP regained its antithrombotic properties in rats pretreated with L-Arginine (300 mg/kg i.v. + 300 mg/kg/h i.v.) before administration of L-NAME (p<0.05 vs. control). Moreover, the concomitant administration of indomethacin and L-NAME failed to completely abolish the antithrombotic action of captopril. Similar effects were observed in respect to the incidence of venous thrombosis. Our study documents a novel and important effect of ACE-Is on the vein thrombotic process and demonstrates the involvement of NO and PGI2 in this phenomenon.

Relationship between serum angiotensin-converting enzyme activity and plasma plasminogen activator inhibitor activity in patients with recent myocardial infarction

Background An elevated level of angiotensin-converting enzyme (ACE) has been demonstrated to increase the risk of myocardial infarction. Plasminogen activator inhibitor (PAI) is the most important physiological inhibitor of tissue plasminogen activator in plasma. An elevated level of PAI has been reported to be associated with decreased fibrinolytic capacity and to constitute a marker of the risk for recurrent coronary thrombosis. Methods We measured the serum ACE activity and plasma PAI activity in 34 patients with recent myocardial infarction, and evaluated the correlation between these two values by linear regression analysis. We also administered captopril (37.5 mg/day) to 17 of these patients and placebo to the other 17 patients at random, and compared the changes in PAI activity and ACE activity in these two groups over a 1-month period. Results There was a significant correlation between the serum ACE activity and the plasma PAI activity at baseline in the patients (r = 0.498, P < 0.01). The captopril-treated patients showed significantly reduced PAI activity (P < 0.01), and a concomitant decrease in ACE activity. Conclusion These results suggest that elevated ACE activity is associated with impaired fibrinolysis and that treatment with an ACE inhibitor improves the fibrinolytic function in patients with recent myocardial infarction. The results also suggest that the renin-angiotensin system plays a role in the increased risk of ischemic cardiovascular events when it is activated, and in the reduction of risk of recurrent myocardial infarction by ACE inhibition.

DTTX30, a combined thromboxane receptor antagonist and thromboxane synthetase inhibitor, prevents coronary thrombosis in anesthetized dogs.

Combined thromboxane A2 receptor blockade and thromboxane synthetase inhibition facilitates local prostacyclin production at the site of platelet activation thereby providing a potent antithrombotic effect. The efficacy of DTTX30, a combined thromboxane A2 receptor blocker-thromboxane synthetase inhibitor, in inhibiting recurrent coronary thrombosis was evaluated in vivo using a canine model of unstable angina pectoris. Pentobarbital-anesthetized dogs (total of 25) were used in which acute damage of the proximal left circumflex coronary artery, together with mechanical stenosis, produced an occlusive thrombosis. When the platelet plug was removed by rubbing the vessel, the occlusion returned reproducibly for at least 2 hours in control studies. To evaluate the antithrombotic efficacy of DTTX30, a reproducible pattern of occlusive coronary thrombi was first established over a period of one hour. Thereafter, DTTX30 (0.12 mg/kg i.v. bolus plus 0.29 mg/kg/hr), acetylsalicylic acid (ASA, 5 mg/kg, i.v. bolus), vapiprost (1.0 mg/kg i.v. bolus plus 1.0 mg/kg/ hr), or vehicle was administered and observations continued for one additional hour. At the end of the one hour observation period, epinephrine (0.3 microgram/kg/min i.v.) was infused (with continued DTTX30, vapiprost or vehicle infusion) and observations were continued for an additional 30 min. DTTX30 eliminated the recurrent arterial thrombus formation in all dogs without significant systemic or left ventricular hemodynamic effects. Infusion of epinephrine to further provoke thrombus formation produced a significant enhancement of left ventricular pressure development (LV dP/dt) and arterial diastolic and systolic pressures but failed to initiate thrombus formation. DTTX30 inhibited fully collagen-induced platelet aggregation ex vivo and produced an approximate 3-fold prolongation of the sublingual bleeding time. ASA eliminated thrombus formation in 4 of 5 dogs, but the additional prothrombotic stimulus of epinephrine infusion produced recurrent thrombus formation in all dogs. Collagen-induced platelet aggregation ex vivo was inhibited by acetylsalicylic acid, but sublingual bleeding time was unaffected. Vapiprost inhibited arterial thrombus formation in all dogs, but thrombus formation returned with the addition of epinephrine. There was a tendency for prolonged bleeding times with vapiprost administration and collagen-induced platelet aggregation ex vivo was effectively inhibited. These studied indicate that the combined inhibition of the thromboxane A2 receptor together with inhibition of thromboxane synthetase provides superior antithrombotic activity in vivo than does thromboxane A2 receptor blockade alone (vapiprost) or inhibition of cyclooxygenase (ASA). Thrombus formation even with the additional stimulation of epinephrine was inhibited by DTTX30 but neither vapiprost nor ASA was effective in this setting.

Potential Antithrombotic and Fibrinolytic Properties of the Angiotensin Converting Enzyme Inhibitors.

As a class of therapeutic agents, the ACE inhibitors have proven to have long-term mortality benefit when used after myocardial infarction and among patients with symptomatic congestive heart failure. Clinical trial data also indicate that the use of ACE inhibitors is associated with reduced rates of recurrent coronary thrombosis, an observation that raises the possibility that the renin-angiotensin system may be directly involved in the thrombotic process and that the ACE inhibitors may have valuable fibrinolytic and/or antithrombotic effects. Recent in vitro and in vivo studies of angiotensin II and its interactions with the fibrinolytic system, particularly with the primary inhibitor of intravascular fibrinolysis, plasminogen activator inhibitor type 1 (PAI-1), provide substantial support for this hypothesis. In addition, a series of cross-sectional studies have described a genetic linkage between a common ACE gene polymorphism (DD) and the prevalence of clinical cardiovascular events, an intriguing finding as this polymorphism may account for much of the population variability in plasma ACE levels. Taken together, the totality of available clinical and experimental findings support the possibility of a direct linkage between the ACE system and vascular thrombosis that merits further prospective evaluation.

Role of Heparin in Coronary Thrombolysis

Although the benefits of coronary thrombolysis are well established, the optimal therapeutic strategy for ensuring rapid and sustained coronary artery patency remains controversial. The available data suggest that the success of coronary thrombolysis depends not only on the induction of clot lysis, but also on the extent to which procoagulant activity that promotes recurrent thrombosis is inhibited. Procoagulant activity increases almost immediately in patients treated with fibrinolytic agents, and persistent increases in thrombin activity have been associated with recurrent coronary thrombosis. Heparin administered intravenously appears to markedly attenuate the thrombin activity associated with thrombolysis and, in patients treated with tissue plasminogen activator (t-PA), prevents early recurrent coronary thrombosis. The results of clinical trials of coronary thrombolysis indicate that conjunctive treatment of patients with heparin improves survival compared with treatment with fibrinolytic agents alone. Although recent clinical trials in which patients were treated with streptokinase suggested that 12,500 units of heparin administered subcutaneously twice daily decreases mortality, this dosage regimen does not induce therapeutic levels of anticoagulation within the first 24 h in most patients. The failure to achieve early therapeutic anticoagulation may account for the lack of mortality benefit in trials in which patients given t-PA were treated with conjunctive subcutaneous heparin therapy. Thus, the available experimental and clinical data suggest that intravenous heparin should be given to patients treated with fibrinolytic agents for acute myocardial infarction.

Effect of choline as a lipotropic agent in the treatment of human coronary atherosclerosis.

Over a 3-year period the lipotropic agent choline was effective in significantly reducing the mortality rate due to recurrent coronary thrombosis with myocardial infarction in a series of 115 patients with proven coronary atherosclerosis.