Thrombosis, antithrombotic agents, and the antithrombotic approach in cardiac disease

To develop a rational approach to antithrombotic therapy, in cardiac disease, a sound understanding is required (1) of the hemostatic processes leading to thrombosis, (2) of the various antithrombotic agents, and (3) of the relative risks of thrombosis and thromboembolism in the various cardiac disease entities. With the understanding of pathogenesis and risk of thrombus formation, a rational approach to the use of antiplatelet and anticoagulant agents can be formulated. Those at high risk of thrombus formation should generally receive a high degree of antithrombotics and, depending on the pathophysiology of the thrombus, may benefit from the concomitant use of antiplatelet and anticoagulant agents. Those with a medium risk of thrombus formation may benefit with the use of an antiplatelet agent alone or anticoagulants alone. Patients at low risk of thrombus formation should not receive antithrombotics. Such rational approach to antithrombotic therapy serves as the basis of this article.     

Introduction to coronary artery stents and their pharmacotherapeutic management

OBJECTIVE: To provide an introduction to coronary artery stents and their pharmacologic management, including anticoagulant therapy and newer antiplatelet regimens. DATA SOURCES: A MEDLINE and current journal search of relevant articles that evaluated coronary stent success rates and anticoagulation or antiplatelet regimens. STUDY SELECTION: Data from the use of primarily the Palmaz-Schatz stent were included. Studies using vitamin K antagonists that are not commercially available in the US were excluded unless they compared an antiplatelet regimen with anticoagulation using the international normalized ratio (INR). DATA SYNTHESIS: Limitations with percutaneous transluminal coronary angioplasty (PTCA), such as ischemic complications and restenosis, have led to the advent of intracoronary stenting. However, the placement of a stent within the coronary artery lumen is associated with a risk of thrombotic events. Despite current postprocedural anticoagulation and antiplatelet regimens, thrombosis occurs at rates ranging from 0.6% to 21%. When anticoagulation is deemed appropriate, it should be used for 1-2 months and the INR should be maintained between 2 and 3.5. Anticoagulation appears to have no effect on the development of restenosis, but has been shown to cause significant hemorrhagic events in 5-13.5% of patients. Newer data continue to define the subsets of patients who may be managed with antiplatelet agents alone. Combinations of aspirin and ticlopidine or aspirin alone may be used to manage patients who fulfill the following criteria: optimal stent placement, high-pressure inflation, and adequate coronary size. CONCLUSIONS: Coronary artery stenting is a novel approach for the management of coronary artery disease, but is associated with the complication of stent thrombosis. Anticoagulation reduces the risk of stent thrombosis, but is associated with bleeding risk. Selected patients may be successfully managed with antiplatelet agents only. More data are needed to better define the optimal antithrombotic regimen.     

The acute coronary ischemic syndromes--the central role of thrombosis

The postulate that thrombotic coronary occlusion was the underlying pathophysiologic event in the acute coronary ischemic syndromes was developed over the years 1912-60. This concept prompted the development of anticoagulant and thrombolytic therapies and the use of acetylsalicylic acid in such patients. A central role for coronary thrombus came to be questioned in the 1970s and the use of anticoagulants dramatically decreased and thrombolytic therapy was little used. Coronary angiographic studies among patients during the early hours of evolving myocardial infarction re-established the etiologic role of coronary thrombosis in the acute coronary ischemic syndromes, and were supplemented by careful autopsy studies. The concepts of meta-analysis lead to more accurate interpretations of earlier randomized, controlled trials of anticoagulant, antiplatelet and thrombolytic therapies. Large clinical trials have provided confirmatory evidence and have established the benefits of antiplatelet and thrombolytic agents in the acute ischemic syndromes. The benefit of long term anticoagulation following myocardial infarction has been demonstrated, although the benefit during the acute in-hospital phase of myocardial infarction is still uncertain. Currently, clinical trials are evaluating new antithrombins, antiplatelet agents, and thrombolytic agents and regimens among patients with unstable angina, acute myocardial infarction, and undergoing angioplasty for complex coronary lesions.     

Prevention of carotid artery thrombosis by oral platelet GPIIb/IIIa antagonist in dogs

BACKGROUND AND PURPOSE: Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/ IIIa antagonist, DMP728, in an electrically induced carotid artery thrombosis model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke. METHODS: Anesthetized dogs were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline or DMP728 (0.1 to 1.0 mg/kg PO). Thrombus formation (platelet-rich aggregate with fibrous coating and a few erythrocytes) by anodal electrolytic stimulation (300 microA) to the intimal surface of the right carotid artery was initiated 120 minutes after oral DMP728 administration and continued for 180 minutes. Whole blood cell counts, ex vivo platelet aggregation, and template bleeding time were determined at different time points throughout the study. RESULTS: DMP728 administered at 0.1 to 1.0 mg/kg PO exhibited dose-dependent antithrombotic efficacy in this model. DMP728 was shown to be significantly effective in inhibiting ex vivo platelet aggregation and in inhibiting thrombosis at 0.3 to 1.0 mg/kg PO. The antiplatelet, antithrombotic effects of DMP728 were demonstrated without any significant changes in the different hemodynamic or coagulation parameters. These data demonstrated the oral antithrombotic efficacy of DMP728 in dogs. CONCLUSIONS: Platelet GPIIb/IIIa blockade with an orally active antagonist was shown to be safe and effective in the prevention of carotid artery occlusive thrombosis.     

Circulating lupus coagulants. A paradox in vascular pathology]

Lupus anticoagulants (LA) are acquired inhibitors of coagulation related to the antiphospholipid antibodies. Paradoxically, these anticoagulants do not expose patients to the risk of hemorrhage but, on the contrary, to a thrombotic risk. The association in a patient of an antiphospholipid antibody and a clinical manifestation (thrombosis or equivalent) defines the antiphospholipid syndrome. This syndrome is termed primary or secondary according to whether it appears as an isolated disorder or is associated with an identified disease, frequently autoimmune (systemic lupus erythematous or lupus related syndrome). Clinical complications of LA are arterial or venous thrombosis at various sites. They are frequently recurrent, and deep venous thrombosis of leg, oculo-cerebral ischemic lesions and heart valve complications have all been well documented. Thrombosis of the microcirculation can cause tissue or organ disfunction, the most characteristic effect being repeated abortions. Laboratory demonstration of LA is difficult when the inhibitor is weak, and this should be completed by tests for other antiphospholipid antibodies. Clinical studies are necessary to assess the thrombotic risk of the LA in different clinical conditions and to evaluate the need and type of antithrombotic treatment. The LA are heterogeneous and only a small proportion of patients with LA will develop thrombosis. New tests capable of predicting the thrombotic risk, bases on the physiopathological mechanisms with which LA interfere in vivo, are currently being investigated.     

Acute coronary syndromes: 2. Antiplatelet agents

Therapies with novel antiplatelet agents and anticoagulants are the focus of current research. When used separately or in combination, these agents prevent generation of thrombin by activated platelets. The new therapies, in conjunction with judicious use of fibrinolytic drugs and mechanical interventions, are revolutionizing the management of patients with acute coronary syndromes.     

Thrombolytic agents and anticoagulants

The medical and scientific communities, appreciating the pivotal role of thrombosis in the evolution and expression of atherosclerotic coronary artery disease, have embarked upon intense efforts to develop safe, effective, and affordable thrombolytic agents and anticoagulants. With an understanding that more is not always better, these new compounds, mutants, and derivatives will be designed specifically to impair, neutralize, or enhance several key components of well-characterized thrombotic and fibrinolytic processes. If efforts continue at the current pace, one or more "designer" thrombolytics and anticoagulants will be ready for Phase II or Phase III clinical trials in the near future.     

Laboratory assessment of antithrombotic therapy: what tests and if so why?

A critical review is given of the tests available for the assessment of the action of anticoagulants, such as heparins, oral anticoagulants and direct thrombin inhibitors, in patients under antithrombotic therapy. The principle of action and the performance of the thromboplastin time (PT), the activated partial thromboplastin time (aPTT), the whole blood clotting time, the thrombin time, the ecarin clotting time and the endogenous thrombin potential (ETP) is discussed, as well as the evidence behind the accepted therapeutic ranges. The two most common tests, PT and aPTT, respond in an essentially different way to clinically effective anticoagulation with heparin and with oral anticoagulants. This means that they covariate with, but do not themselves represent the essential parameter influenced by anticoagulation. The experimental basis for the widely accepted two times prolongation of the aPTT as an indicator for adequate anticoagulation is shown to be meagre in the case of unfractionated heparin and lacking for the other anticoagulants. Common sources for error in the interpretation of anti-factor Xa- and anti-thrombin activity of heparins are indicated. Extensive experience with new tests like the ecarin clotting time and the ETP is still lacking. On the basis of preliminary data and in view of the importance of the enzymatic action of thrombin in the pathogenesis of thrombosis, the ETP is considered a possible candidate for a common parameter to assess different types of anticoagulants.     

New NO donors with antithrombotic and vasodilating activities, part 25. Hydroxylamine derivatives

Twelve ethoxycarbonyl or phenylsulfonyl derivatives as prodrugs of hydroxylamine or phenylhydroxylamine were prepared and tested for antiplatelet (in vitro, Born test) antithrombotic (in vivo thrombosis model), and antihypertensive (in vivo, SHR rats) effects. In the Born test N,N-bisphenylsulfonylhydroxylamine (10) was most active (IC50 = 11 mumol/L). The N-ethoxycarbonyl-phenylhydroxylamine (7) was the most potent antithrombotic compound. It inhibited the thrombus formation in mesenteric arterioles of rats by 39% after a single p.o. dose of 60 mg/kg. Compound 7 lacked any antihypertensive activity. It, therefore, had been possible to separate completely the antithrombotic activities from antihypertensive properties in suitable hydroxylamine derivatives.     

Thrombolytic therapy of acute myocardial infarct--current status and new developments

Timely initiation of thrombolytic therapy can achieve coronary reperfusion, a reduction in infarct size, a preservation of left ventricular function and a reduction in mortality. It is therefore an established procedure in acute myocardial infarction. The major drawback is an increased rate of bleeding. As a consequence thrombolytic therapy is at present withheld from many patients with contraindications. Other problems include relative inefficacy of presently available thrombolytic agents and early reocclusion of primarily successfully reperfused vessels. New approaches to optimize the risk/benefit ratio for the patient and to make thrombolytic therapy available to more patients include new antithrombin and antiplatelet agents as adjunctive therapy, synergistic combinations of plasminogen activators, mutants of t-PA and prourokinase, chimeric molecules and antibody-targeted thrombolysis.     

Deep venous thrombosis in pregnant women

The main risk factors for deep vein thrombosis in pregnancy and after delivery are preeclampsia, operative delivery, adiposity, prolonged bed rest, and haemostatic defects (antithrombin, protein C and protein S deficiencies), activated protein C resistance, lupus anticoagulant/antiphospholipid antibodies. Hyperhomocystinaemia is a general risk factor for deep vein thrombosis. The clinical diagnosis of deep vein thrombosis is difficult and must be confirmed by imaging techniques. Positive D-dimer has high sensitivity, but low specificity to detect acute thrombosis. Standard treatment is unfractionated heparin intravenously for 7-10 days, followed by subcutaneous injections. Anticoagulant treatment is prolonged for 6-12 weeks after delivery, usually with warfarin. During pregnancies associated with high risk of thrombosis, low molecular heparin prophylaxis is given during pregnancy and 6-12 weeks after delivery. Thrombosis in pregnancy must be followed by adequate investigation for an underlying thrombotic predisposition.     

Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families

Deficiency of the naturally occurring anticoagulant proteins, such as antithrombin, protein C and protein S, and activated protein C resistance due to the factor V Leiden gene mutation is associated with inherited thrombophilia. So far, no direct comparison of the thrombotic risk associated with these genetic defects is available. In this study, we wish to compare the lifetime probability of developing thrombosis, the type of thrombotic symptoms, and the role of circumstantial triggering factors in 723 first- and second-degree relatives of 150 index patients with different thrombophilic defects. We found higher risks for thrombosis for subjects with antithrombin (risk ratio 8.1, 95% confidence interval [CI], 3.4 to 19.6), protein C (7.3, 95% CI, 2.9 to 18.4) or protein S deficiency (8.5, 95% CI, 3. 5 to 20.8), and factor V Leiden (2.2, 95% CI, 1.1 to 4.7) than for individuals with normal coagulation. The risk of thrombosis for subjects with factor V Leiden was lower than that for those with all three other coagulation defects (0.3, 95% CI, 0.1 to 1.6), even when arterial and superficial vein thromboses were excluded and the analysis was restricted to deep vein thrombosis (0.3, 95% CI, 0.2 to 0.5). No association between coagulation defects and arterial thrombosis was found. The most frequent venous thrombotic manifestation was deep vein thrombosis with or without pulmonary embolism (90% in antithrombin, 88% in protein C, 100% in protein S deficiency, and 57% in factor V Leiden), but a relatively mild manifestation such as superficial vein thrombosis was common in factor V Leiden (43%). There was a predisposing factor at the time of venous thromboembolism in approximately 50% of cases for each of the four defects. In conclusion, factor V Leiden is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiency. In addition, individuals with factor V Leiden develop less severe thrombotic manifestations, such as superficial vein thrombosis.     

Efficacy of local inhibition of procoagulant activity associated with small-diameter prosthetic vascular grafts

PURPOSE: Graft procoagulant activity is determined by thrombin (IIa) and activated factor X (Xa) that binds to thrombus. Thrombus-associated factor Xa and thrombin are resistant to antithrombin III-dependent therapy (heparin). To avoid complications and costs associated with systemic administration, we evaluated whether locally applied antithrombotic agents inhibit prosthetic graft procoagulant activity under no-flow and low-flow conditions. METHODS: Four-millimeter-diameter collagen-coated grafts were preclotted in recalcified human plasma, washed, immersed in antithrombotic agents (either 100 nm hirudin, 20 microns D-Phe-L-Pro-L-Arg chloromethylketone, 5 microns tick anticoagulant peptide or 5 or 10 micrograms/ml tissue factor pathway inhibitor) or saline solution, and extensively rewashed. Grafts were exposed to recalcified plasma either in multiwell plates or underwent perfusion at 1 ml/min flow rate. Fibrinopeptide A, which reflects fibrin elaboration, was measured as a marker of thrombin activity. RESULTS: Inhibitors reduced fibrinopeptide generation at 8 minutes by 55% (tissue factor pathway inhibitor), 57% (hirudin), or 63% (tick anticoagulant peptide and D-Phe-L-Pro-L-Argchloromethylketone) compared with the control agents (p < 0.05). Under low-flow conditions tissue factor pathway inhibitor and hirudin reduced fibrinopeptide generation at 13 minutes by 61% and 49%, respectively, when compared with control agents (p < 0.05). CONCLUSIONS: Graft-associated inhibitors targeted at factors IIa, Xa, or tissue factor/VIIa/Xa complex effectively reduce procoagulant activity on prosthetic grafts. The success of local application of antithrombotic agents in attenuating early fibrin formation suggests that this strategy could favorably influence acute graft patency, and we speculate these agents may improve long-term graft patency as well.     

Thrombocytosis and coronary disease. Report of a case

We report the case of a young male with an inferior myocardial infarction who was treated with fibrinolytic agents and displayed a good evolution. The only cardiovascular risk factor that this patient had was an idiopathic thrombocytosis with abnormal platelet hyperreactivity tests. The angiogram showed an eccentric lesion of 60% in the left main coronary artery. A week later, after treatment based on anticoagulants and antithrombotic agents the angiogram was normal, and the lesion had disappeared. The association between these conditions is discussed the therapeutic approach is also discussed. A review of the literature is conducted.     

A double-blind randomized comparison of combined aspirin and ticlopidine therapy versus aspirin or ticlopidine alone on experimental arterial thrombogenesis in humans

No randomized study comparing the effect of combined ticlopidine and aspirin therapy versus each drug alone in reducing poststenting thrombotic complications has been performed. To compare these three antiplatelet regimens versus placebo, we conducted a double-blind randomized study using an ex vivo model of thrombosis. Sixteen healthy male volunteers were assigned to receive for 8 days the following four regimens separated by a 1-month period: aspirin 325 mg/d, ticlopidine 500 mg/d, aspirin 325 mg/d + ticlopidine 500 mg/d, and placebo. At the end of each treatment period, native nonanticoagulated blood was drawn directly from an antecubital vein over collagen- or tissue factor (TF)-coated coverslips positioned in a parallel-plate perfusion chamber at an arterial wall shear rate (2, 600 s-1 ) for 3 minutes. Thrombus, which formed on collagen in volunteers treated by placebo, were rich in platelets and poor in fibrin. As compared with placebo, aspirin and ticlopidine alone reduced platelet thrombus formation by only 29% and 15%, respectively (P > .2). In contrast, platelet thrombus formation was blocked by more than 90% in volunteers treated by aspirin + ticlopidine (P < .01 v placebo or each treatment alone). Furthermore, the effect of the drug combination therapy was significantly larger than the sum of the two active treatments (P < .05). Thrombus, which formed on TF-coated coverslips in volunteers treated by placebo, were rich in fibrin and platelets. Neither of the three antiplatelet treatments significantly inhibited fibrin deposition and platelet thrombus formation on this surface (P > .2). Thus, the present study shows that combined aspirin and ticlopidine therapy dramatically potentiates the antithrombotic effect of each drug alone, but that the antithrombotic effect of the combined treatment depends on the nature of the thrombogenic surface.     

Inhibition of experimental neointimal hyperplasia and thrombosis depends on the type of vascular injury and the site of drug administration

BACKGROUND: Heparin inhibits vascular smooth muscle cell proliferation in tissue culture and limits neointimal hyperplasia after experimental arterial injury but has been ineffective in reducing clinical restenosis. We examined how this discrepancy might reflect suboptimal drug-tissue interactions and/or differences in the vascular response to injury. METHODS AND RESULTS: Intravenous infusion was compared with local administration of heparin to injured rabbit iliac arteries either from drug-impregnated polymeric controlled release matrices in the perivascular space or from drug-releasing endovascular stents. Occlusive thrombosis, seen in 42% of control stent-bearing arteries, and partial thrombosis were virtually eliminated by heparin delivery from any route. Intimal area 14 days after balloon withdrawal denudation alone was reduced to an equal extent by continuous systemic heparin or by perivascular heparin for the first 3 days. In contrast, endovascular stents produced more exuberant neointimal hyperplasia, the inhibition of which required continuous rather than only early heparin administration. Neither perivascular delivery limited to the first 3 days nor stent-based delivery reduced neointimal hyperplasia as effectively. CONCLUSIONS: The antiproliferative and antithrombotic effects of heparin differ markedly, depending on the type of arterial injury and the mode of drug administration. Different forms of injury may require different therapies, and complications of arterial intervention such as excessive neointimal hyperplasia and thrombosis may demand alternate therapeutic regimens. Duration, dose, and site of delivery rather than frank resistance to therapy may explain why experimentally effective antiproliferative and antithrombotic agents fail clinically.     

Device induced thromboembolism in a bovine in vitro coronary stent model

The potential of a new bovine in vitro model to evaluate various aspects of device induced thromboembolism was studied using two test modes. First, the effect of an antithrombotic drug on stent induced thromboembolism was assessed. The antithrombotic potential of an antiplatelet agent was compared with that of the other conventional antithrombotic agents (aspirin, dipyridamole) used in the past with this in vitro model. Stent associated thrombus was assessed gravimetrically at the end of the experiment. Emboli were assessed continuously using a light scattering microemboli detection system. Second, the sensitivity of the model to flow induced thromboembolism was studied using a combination of surface roughness and stenosis. Thrombus was assessed visually, and emboli were assessed as described earlier. The results show that 1) this in vitro model is sensitive to the action of antithrombotic drugs, and to the effect of hemodynamics on thromboembolism; 2) the antiplatelet drug used in this study was effective in attenuating thromboembolism; 3) a stenosis in combination with roughness produced more emboli than roughness alone; and 4) the model was useful for the study of physical and biochemical aspects of thromboembolism.     

Antithrombotic therapy after cerebral ischemia

Following cerebral ischaemia a recurrent stroke must be avoided in most patients by means of antithrombotic agents. Based on the results reviewed here of new therapy studies, we discuss the presently available antithrombotic treatment options for prophylaxis in ischaemic stroke. TASS (Ticlopidine Aspirin Stroke Study) and CATS (Canadian American Ticlopidine Study) are two multicentre studies investigating the effect of ticlopidine, a new antiplatelet agent of the thienopyridine family, compared to acetylsalicylic acid (ASA) respectively placebo, in the secondary prophylaxis of ischaemic stroke. A significant relative risk reduction of ticlopidine against ASA (21%) and against placebo (28.1%) was shown. CAPRIE (Clopidogrel vs. Aspirin in Patients with Risk of Ischemic Events) evaluated clopidogrel and ASA in the secondary prophylaxe of stroke, myocardial infarction and peripheral vascular occlusive disease. Clopidogrel has been shown to be as effective as ticlopidine compared to ASA in the secondary prevention of vascular disease but had the advantage of a far less severe side effect profile as ticlopidine. ESPS 2 (2nd European Stroke Prevention Study) compared dipyridamole and ASA alone and in combination against placebo in stroke prevention. The combination of agents showed a 24.4% relative risk reduction to suffer ischaemic stroke as opposed to placebo. The ranking of heparin and heparinoids in the secondary prevention of ischaemic stroke has not been completely established but seems to diminish according to recently published data from three major trials. The American TOAST study (Trial of Org 10172 in Acute Stroke Treatment) failed to prove any advantage of intravenous Orgaran compared to placebo. In IST (International Stroke Trial) and CAST (Chinese Acute Stroke Trial) the benefits of heparin are invalidated by a higher bleeding rate of patients on intravenous heparin therapy. Furthermore, the results of IST have to be judged critically because of significant methodical inadequacies. When applying antithrombotic agents, therapeutic effect and presumed better outcome should be weighed against the risk of associated bleedings. The indication for an antithrombotic treatment should be reevaluated in regular control examinations and the possibility of a less aggressive treatment should be considered.     

The role of intracoronary stents in the prevention of restenosis--facts and fallacies

Ten years after the first stents were implanted in human coronary arteries by Dr Sigwart, stenting has proved itself to be a highly effective solution to acute or threatened closure associated with failed balloon angioplasty, and in the prevention of restenosis. Despite these salutary and exciting outcomes, there remain a number of issues of deep-seated concern including stent thrombosis and anticoagulation-related bleeding complications. Recently, these two latter problems have been largely rectified by evolving technical refinements in stent implantation and the use of less aggressive post-stent antithrombotic regimens. The technology, however, has also created a new, potentially complex situation-that of stent overuse and the implantation of stents for non evidence-based indications.