Q J Med 2001; 94: 179-185
© 2001 Association of Physicians
Review |
Current trends in the management of thromboembolic events
From the Thrombosis Research Institute, London, and 1 Ashford Hospital, Middlesex, UK
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Introduction |
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 Top Introduction Thrombosis in ischaemic heart...Medical therapy for the...Venous thrombosisReferences |
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Thrombus formation on a disrupted atherosclerotic plaque is the main pathogenetic mechanism for the acute coronary syndromes of myocardial infarction and unstable angina. Myocardial infarction results from an acute total occlusion of the artery, while unstable angina is secondary in most cases to mural thrombus formation. Thrombus formation has also been implicated in chronic atherosclerotic disease progression, and in restenosis following coronary angioplasty. Therapeutic measures to treat thrombus rely on the ability of drugs either to prevent thrombus extension, to dissolve its fibrin component, or to prevent further platelet aggregation.
Following arterial vessel wall injury, platelets adhere to the subendothelial collagen. Glycoprotein Ib on the platelet membrane is the primary receptor for this single layer of platelets, and it binds von Willebrand factor as its extracellular ligand. Platelet aggregation involves activation of several different pathways leading to exposure of the glycoprotein IIb/IIIa receptor on the platelet. These receptors bind either fibrinogen or von Willebrand factor, leading to platelet- platelet interaction and the formation of a white platelet thrombus. The luminal component of thrombus is a mixture of platelets and fibrin. The occlusive tail of the thrombus is composed of red blood cells and fibrin (red thrombus).
Both plaque disruption and erosion of a plaque involve the presence of an inflammatory process at the site of thrombus formation. This inflammatory process consists primarily of activated macrophages and T lymphocytes.
Thrombus formation depends on at least three factors: (i) the depth of vessel wall injury and the thrombogenicity of the exposed plaque; (ii) the prothrombotic state; and (iii) haemodynamic factors that promote vasoconstriction and stasis of blood flow.
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Thrombosis in ischaemic heart disease |
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Traditionally, plaque rupture has been considered to result mainly from the physical pressure exerted upon the plaque surface. The plaque's vulnerability to rupture depends upon the size and consistency of its atheromatous core. Davies et al.1 found a direct relationship between core size and risk of plaque rupture in the aorta, and suggested that plaques with a core occupying more than 40% of the plaque area were particularly vulnerable to rupture. While collagen synthesis by smooth muscle cells tends to stabilize plaques, ‘soft’ plaques with a core lacking supporting collagen and consisting predominantly of extracellular lipids have an increased risk of rupture.2 The lipid composition of the atheroma is also important. Cores containing liquid cholesteryl esters are softer than those containing crystalline cholesterol.3 Another determinant of plaque rupture is the composition and strength of the fibrous cap. Caps rich in collagen tend to be stable, whereas those with diminished collagen content and reduced cap thickness are more prone to rupture.1 The role of inflammation in plaque rupture has attracted much interest recently. Disruption of the fibrous cap often occurs at sites of ongoing inflammation, as indicated by the presence of activated macrophages. Moreno et al.4 examined plaque tissue obtained by atherectomy, and found that 14% of plaques from patients with unstable angina and non-Q wave myocardial infarction were infiltrated by macrophages, compared with 3% of plaques from patients with stable angina. Increased numbers of circulating activate T cells have also been found in patients with unstable angina.5 C-reactive protein is an acute-phase reactant, levels of which increase dramatically in response to infections or trauma. There is an increasing amount of evidence that the level of C-reactive protein is an independent predictor of future cardiac events, further strengthening the arguments in favour of a role for inflammation in promoting plaque rupture.6,7
Exposure of the interior of a lipid-rich plaque could be a potent stimulus to thrombus formation. It has been suggested that tissue factor, which is present in the adventitia of normal vessels, might be an important stimulus for thrombus formation within atherosclerotic plaques following plaque disruption.8 Tissue factor protein is readily demonstrable in atherectomy specimens of culprit lesions in patients with unstable angina.9 Particularly in patients with de novo lesions, tissue factor is frequently demonstrable and could lead to activation of both intrinsic and extrinsic coagulation pathways. Activated macrophages, the dominant inflammatory cell in unstable plaques, express tissue factor.10
The coagulability of the blood may also contribute to the amount of thrombus formation. Thrombosis is a complex balance between pro- and anticoagulant and between pro- and antifibrinolytic mechanisms. For blood to flow normally throughout the body, it is necessary for a relatively antithrombotic state to be mantained. In pathological situations in which thrombus develops, one or more pertubations can usually be demonstrated. High levels of catecolamines from smoking or stress can activate platelets, causing vasoconstriction and vessel injury.11
Increased fibrinogen levels are independently associated with the risk of myocardial infarction in prospective epidemiological studies.12 Elevations in factor VII coagulant activity13 and possibly lipoprotein a, have also been associated with an increased risk of thrombosis.14 Impaired fibrinolysis as detected by increased levels of plasminogen activator inhibitor is associated with recurrent myocardial infarction.15 Whatever the mechanism involved, activation of the coagulation system or an increase in one or more of its procoagulant factors, and/or decrease in fibrinolytic activity are commonly noted before or following acute coronary syndromes. Merlini et al.16 have shown that months after clinical stabilization of patients who presented with acute coronary syndromes, persistent activation of the coagulation system was detectable by elevation of peptide fragments (F1+2), indicative of ongoing thrombin generation.
Haemodynamic factors such as vasoconstriction also promote the formation or extension of thrombus. In Prinzmetal angina, transient coronary spasm is followed by elevation of fibrinopeptide A, a marker of increased thrombin activity.17 Vasoconstriction at the site of disruption may predispose to occlusion by promoting stasis of blood, with the formation of a red, fibrin-rich clot.
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Medical therapy for the treatment of intracoronary thrombus |
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Once a thrombus has formed, there are several strategies to dissolve or prevent extension of the blood clot. The goal of thrombotic strategies in unstable angina is to prevent the extension of the thrombus and the development of total coronary occlusion. In acute myocardial infarction, on the other hand, the goal is generally to re-open the artery as quickly as possible and to keep it patent.
Unfractionated heparin
Unfractionated heparin (UFH) by i.v. infusion reduces symptomatic and silent ischaemic episodes in patients with unstable angina,18 but, individually, most randomized controlled studies have not shown significant advantage from the combination of UFH plus aspirin over aspirin alone in preventing myocardial infarction or death.19,20 In a meta-analysis of six randomized studies (total 1353 patients), the incidence of death or myocardial infarction was 7.9% during treatment with aspirin plus UFH vs. 10.4% with aspirin alone, consistent with a 33% reduction in relative risk.21 Although the 95%CIs were compatible with no or modest effect, the balance of evidence is probably in favour of a small but clinically worthwhile benefit from UFH in the first few days of treatment. Studies are needed to clarify the optimum duration of therapy (2–7 days). Cessation of UFH has sometimes been associated with a ‘rebound’ increase in ischaemic events.22 In randomized trials, the overall incidence of major bleeding was 1.5% with aspirin plus UFH, compared with 0.4% with aspirin alone.21
Intravenous heparin becomes a potent anticoagulant once it binds plasma antithrombin III. This binding is inhibited by platelet factor 4, secreted by activated platelets, which can diminish the efficacy of heparin.
Low-molecular-weight heparins
These limitations of UFH may be overcome by using low-molecular-weight heparins (LMWHs) which have less affinity for plasma proteins and endothelial cells. The LMWHs have numerous advantages over UFH, including a higher affinity for factor Xa (critical in thrombin production), greater induction of the coagulation inhibitor tissue factor production inhibitor (TFPI), a more predictable dose- response relationship, and a longer plasma half-life with dose-independent clearance kinetics. LMWHs are also relatively resistant to neutralization by platelet factor 4, and have a lower affinity for platelets, which may translate to less microvascular bleeding.
LMWHs have proved to be particularly useful for patients with acute coronary syndromes. In such patients, dalteparin was more effective than placebo in the FRISC study, but with only similar efficacy to UFH in the FRIC study.23,24 The incidence of a combined clinical endpoint with heparin was significantly reduced by more than half with nadroparin.25 Similarly, enoxaparin sodium was shown to be more effective than UFH in the TIMI 11 B trial and in the ESSENCE study.26,27 In these two studies, enoxaparin sodium has been shown to reduce the risk of death, myocardial infraction, and urgent revascularization when compared with UFH.26,27
There has been relatively little research into LMWHs in acute myocardial infarction (AMI) patients with ST segment elevation. However, Baird et al.28 studied 300 AMI patients who had received thrombolytic treatment and who were subsequently randomized to either UFH or enoxaparin. The combined incidence of death, myocardial infarction, or readmission for acute coronary syndrome was significantly reduced, from 36.4% to 25.4%, in the patients treated with enoxaparin.28
Other antithrombin agents
A number of direct-acting antithrombins are also under investigation. Unlike heparin, these inhibitors can act on circulating thrombin as well as on the relatively resistant, fibrin-bound thrombin in the coronary thrombus. However, this theoretical advantage has not yet been translated into additional clinical benefit; the TIMI 9 B and Gusto II B studies, for example, have shown similar efficacy for hirudin and heparin.29,30 At present, other studies are needed to conclude that these drugs are clinically useful in patients with myocardial ischaemia.
Conclusion
Thrombus formation is considered the major cause of acute coronary syndromes. However, in the future years, we will learn more concerning the interrelationships between thrombus formation, atherosclerosis, inflammation, and coagulation disorders. This understanding should produce improved methods for therapy and prevention.
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Venous thrombosis |
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Each year, venous thrombosis occurs in about 1:1000 people in developed countries (31). This disorder commonly manifests as deep-vein thrombosis (DVT) of the leg, and if embolization occurs, as pulmonary embolism (PE). The incidence of thrombosis increases with age, from 1 : 100 000/year in childhood to nearly 1 : 100/year in old age.31
Until recently, the investigation of thrombosis has lagged behind that of bleeding disorders. Our improved understanding of the coagulation system now allows identification of patients whose thrombotic tendency is due to congenital deficiency of coagulation inhibitor proteins, and the development of molecular markers of coagulation activation. The recognition of the importance of tissue factor (TF), the discovery of the tissue factor pathway inhibitor (TFPI), and the need to explain the clinical effects of various coagulation factor deficiencies, have prompted revision of the blood coagulation cascade.32 There are several significant features of this revised scheme. First, TF has assumed the role of major physiological activator of coagulation; FXII, the initiator of the ‘intrinsic’ system, is no longer regarded as a coagulation factor. Indeed, FXII may be more important as a fibrinolytic activator, and its deficiency may be a risk factor for thrombosis. Secondly, FXI is placed at the terminal end of the cascade, where it acts as an alternative substrate for thrombin.33 Finally, TFPI-regulated feedback inhibition of the TF-FVIIa complex explains the need for the intrinsic coagulation pathway. The TF-factor VII pathway seems to be responsible for the rapid generation of thrombin sufficient to cause local platelet aggregation and activation of the critical cofactors V and VIII. Continuing haemostasis, however, certainly requires ongoing generation of factor Xa through the actions of factors VIII and IX, which explains the clinical importance of these clotting factors.
Acquired risk factors for thrombosis include immobilization, surgery, trauma, pregnancy, lupus anticoagulant, malignant disease, and female hormones. Since protein C, protein S and antithrombin are the main natural inhibitors of the procoagulant system, a heterozygous deficiency of these proteins leads to excessive thrombin formation.34 Over the past 5 years, several abnormalities in the clotting system that predispose to venous thrombosis have been discovered, including resistance to activated protein C due to a mutation in clotting factor V, factor V Leiden.35 When factor V has a mutation at one of the cleavage sites for activated protein C, it is less sensitive to the natural anticoagulant protein C/protein S system and therefore there is a resistance to activated protein C and increased risk of DVT. Similarly, high concentrations of clotting factor VIII are related to increased risk of thrombosis.36 Finally, hyperhomocysteinaemia is an abnormality that has been associated with venous thrombosis in several studies37,38 and in meta-analysis.39
Prophylaxis and treatment for venous thromboembolism
Many randomized double-blind studies have shown that, in patients undergoing major abdominal, gynaecological or chest surgery, prophylaxis using the currently available LMWH preparations is at least as effective as UFH (5000 units s.c. every 8 or 12 h) in preventing DVT.40,41
In one meta-analysis of 17 randomized studies (involving 6878 patients), the incidences of both DVT (5.3% with LMWH vs. 6.7% with UFH) and PE (0.31% vs. 0.70%) were significantly lower in patients receiving LMWH than in those given UFH.42 In a second, larger meta-analysis (25 studies, 9863 patients), there was no significant advantage in favour of LMWH.43 Neither analysis found any significant difference between the LMWHs and UFH in the incidence of major bleeding. One later study, in 3809 patients undergoing abdominal surgery, found that wound haematoma, severe bleeding, or re-operation to control bleeding were significantly more common in those receiving UFH (5000 units s.c. twice daily) than in those given prophylaxis with dalteparin (2500 IU s.c. once daily).43
Initial treatment of patients with DVT has until recently required admission to hospital and continous i.v. infusion (or 12-hourly s.c. injection) of UFH, in a dose-adjusted regimen according to the activated partial thromboplastin time (APTT), until the patient has been stabilized on warfarin (usually about 5–7 days).
Three large randomized studies (double-blind or with independent blinded assessement of outcome), involving a total of 736 inpatients with proven DVT,44–46 and several smaller studies, have shown that initial treatment with LMWH is at least as effective and safe as conventional i.v. UFH. Patients assigned to LMWH received a fixed, weight-adjusted dose (tinzaparin, nadroparin, enoxaparin)44–46 by s.c. injection for 6–10 days. Warfarin was started after 2–10 days and continued for at least 3months. The pooled results from these three studies,44–46 showed that initial treatment with LMWH reduced the incidence of symptomatic recurrent venous thromboembolism more effectively than UFH during the first 15 days of therapy (0.8% vs. 3.2%; p=0.02) and over the period of anticoagulation as a whole (2.9% vs. 6.4%; p=0.006).47 Meta-analysis of these and other studies also found lower mortality in patients given LMWH, relative to those given UFH, chiefly because of unexplained better survival in the subgroup of patients with cancer.47,48 In most studies, the incidence of major bleeding did not differ between the treatments,49 but two meta-analyses have found significant advantage from use of LMWH.47,48
Treatment with LMWH outside hospital
In two large studies, a total of 900 patients with proximal DVT were randomized to receive UFH, given in hospital by i.v. infusion, or a fixed, weight-adjusted s.c. dose of LMWH,50,51 administered wholly or partly at home by the patient, a nurse or relative. All patients started warfarin within 48 h of randomization. Up to two-thirds of those screened were excluded from the studies because of co-existing disorders that required hospital admission or increased the risk of bleeding, and short life expectancy. In these studies, which used independent, blinded assessement of outcome events over 3months, there were no significant differences between the treatment groups in terms of symptomatic recurrence of thromboembolism, mortality or incidence of major bleeding, nor in the time to achieve anticoagulant control with warfarin. Patients randomized to LMWH spent an average of 3–5.4 fewer days in hospital than those receiving UFH.50,51
Treatment of pulmonary embolism
In a European study, 612 patients with symptoms and signs of PE were randomized to conventional therapy with i.v. UFH or to tinzaparin in a fixed, weight-adjusted s.c. dose, each for a mean of 7 days; warfarin was started on day 1–3.52 About two-thirds of all patients received therapeutic doses of UFH for a mean of 18 h before randomization. Patients with massive PE, requiring thrombolytic therapy or embolectomy, were excluded; nonetheless, 28% of randomized patients had clinical features of major embolism (cyanosis, syncope, acute right ventricular strain) and nearly half had 50% pulmonary vascular obstruction on perfusion scan. During the first 8 days, nine patients in each group died or had recurrent thromboembolism or major bleeding; during 90 days of anticoagulant therapy, these events occurred in 18 (5.9%) patients (12 deaths) initially given tinzaparin and 22 (7.1%) of those given UFH (14 deaths); the differences were not significant.
Dosage and administration
In patients at moderate risk of venous thromboembolism, prophylaxis with LMWH is given in a fixed, once-daily dose, beginning 1–2 h before surgery and continued for 5–10 days or until the patient is mobile or the risk diminishes. In patients considered at high risk of venous thromboembolism, a higher fixed dose is suggested, beginning up to 12 h before or on the evening before surgery.
For the treatment of DVT or PE, LMWH is given for 5–6 days and until the patient is established on warfarin (which should be begun on day 1), with INR>2.0 for at least 2 consecutive days. Dalteparin and tinzaparin are given once daily, enoxaparin every 12 h, all three at a weight-adjusted dose.
Conclusion
Low-molecular-weight heparins are an important addition to the range of treatments available for the prevention and treatment of venous thromboembolism. They simplify treatment and require less monitoring by blood tests than conventional UFH. For prophylaxis in patients undergoing orthopaedic surgery appears to be significant clinical advantage from the use of LMWH. For these patients, use of LMWH might also be more cost-effective. Extended prophylaxis with LMWH reduces the incidence of late DVT in patients undergoing hip surgery. For the initial treatment of established DVT, use of LMWH in a fixed, weight-adjusted subcutaneous dose is at least as effective and safe as intravenous therapy with UFH in a dose adjusted by laboratory monitoring. It is much simpler to use and probably reduces overall treatment costs. Out-patient treatment with LMWH is now possible for patients with DVT. In hospital, treatment with LMWH has been shown to be an effective alternative to UFH in patients with PE.
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Notes |
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Address correspondence to Dr F. De Lorenzo, Thrombosis Research Institute 1B Manresa Road, Chelsea, London SW3 6LR
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References |
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