2014ESC急性肺栓塞诊断和管理指南(英文版)(3)

In children,studies reported an annual incidence of VTE between 53and57per100000among hospitalized patients,10,11and between

1.4and4.9per100000in the community at large.12,13

2.2Predisposing factors

A list of predisposing(risk)factors for VTE is shown in Web Addenda Table I.There is an extensive collection of predisposing environmen-tal and genetic factors.VTE is considered to be a consequence of the interaction between patient-related—usually permanent—risk factors and setting-related—usually temporary—risk factors.VTE is considered to be‘provoked’in the presence of a temporary or re-versible risk factor(such as surgery,trauma,immobilization,preg-nancy,oral contraceptive use or hormone replacement therapy) within the last6weeks to3months before diagnosis,14and‘unpro-voked’in the absence thereof.PE may also occur in the absence of any known risk factor.The presence of persistent—as opposed to major,temporary—risk factors may affect the decision on the dur-ation of anticoagulation therapy after a?rst episode of PE.

Major trauma,surgery,lower limb fractures and joint replace-ments,and spinal cord injury,are strong provoking factors for VTE.9,15Cancer is a well-recognized predisposing factor for VTE. The risk of VTE varies with different types of cancer;16,17haemato-logical malignancies,lung cancer,gastrointestinal cancer,pancreatic cancer and brain cancer carry the highest risk.18,19Moreover, cancer is a strong risk factor for all-cause mortality following an episode of VTE.20

In fertile women,oral contraception is the most frequent predis-posing factor for VTE.21,22When occurring during pregnancy,VTE is a major cause of maternal mortality.23The risk is highest in the third trimester of pregnancy and over the6weeks of the postpartum period,being up to60times higher3months after delivery,compared with the risk in non-pregnant women.23In vitro fertilization further increases the risk of pregnancy-associated VTE.In a cross-sectional study derived from a Swedish registry,the overall risk of PE(com-pared with the risk of age-matched women whose?rst child was born without in vitro fertilization)was particularly increased during the?rst trimester of pregnancy[hazard ratio(HR)6.97;95%con?-dence interval(CI)2.21–21.96].The absolute number of women who suffered PE was low in both groups(3vs.0.4cases per10000 pregnancies during the?rst trimester,and8.1vs.6.0per10000preg-nancies overall).24In post-menopausal women who receive hormone replacement therapy,the risk of VTE varies widely depend-ing on the formulation used.25

Infection has been found to be a common trigger for hospitaliza-tion for VTE.15,26,27Blood transfusion and erythropoiesis-stimulating agents are also associated with an increased risk of VTE.15,28

In children,PE is usually associated with DVT and is rarely unpro-voked.Serious chronic medical conditions and central venous lines are considered to be likely triggers of PE.29

VTE may be viewed as part of the cardiovascular disease con-tinuum and common risk factors—such as cigarette smoking, obesity,hypercholesterolaemia,hypertension and diabetes melli-tus30–33—are shared with arterial disease,notably atheroscler-osis.34–37However,at least in part,this may be an indirect association,mediated by the effects of coronary artery disease and,

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in the case of smoking,cancer.38,39Myocardial infarction and heart failure increase the risk of PE;40,41conversely,patients with VTE have an increased risk of subsequent myocardial infarction and stroke.42

2.3Natural history

The?rst studies on the natural history of VTE were carried out in the setting of orthopaedic surgery during the1960s.43Evidence collected since this initial report has shown that DVT develops less frequently in non-orthopaedic surgery.The risk of VTE is highest during the?rst two post-operative weeks but remains elevated for two to three months.Antithrombotic prophylaxis signi?cantly reduces the risk of perioperative VTE.The incidence of VTE is reduced with increas-ing duration of thromboprophylaxis after major orthopaedic surgery and(to a lesser extent)cancer surgery:this association has not been shown for general surgery.44,45The majority of patients with symp-tomatic DVT have proximal clots,complicated by PE in40–50%of cases,often without clinical manifestations.44,45

Registries and hospital discharge datasets of unselected patients with PE or VTE yielded30-day all-cause mortality rates between 9%and11%,and three-month mortality ranging between8.6%and 17%.46–48Following the acute PE episode,resolution of pulmonary thrombi,as evidenced by lung perfusion defects,is frequently incom-plete.In one study,lung perfusion scintigraphy demonstrated abnor-malities in35%of patients a year afteracute PE,although the degree of pulmonary vascular obstruction was,15%in90%of the cases.49 Two relatively recent cohort studies covering173and254patients yielded incidences approaching30%.50,51The incidence of con?rmed chronic thromboembolic pulmonary hypertension(CTEPH)after unprovoked PE is currently estimated at approximately1.5%(with a wide range reported by mostly small-cohort studies),with most cases appearing within24months of the index event.52,53

The risk of recurrence of VTE has been reviewed in detail.54–56 Based on historical data,the cumulative proportion of patients with early recurrence of VTE(on anticoagulant treatment)amounts to 2.0%at2weeks,6.4%at3months and8%at6months;more recent,randomized anticoagulation trials(discussed in the section on acute phase treatment)indicate that recurrence rates may have dropped considerably recently.The rate of recurrence is highest during the?rst two weeks and declines thereafter.During the early period,active cancer and failure to rapidly achieve therapeutic levels of anticoagulation appear to independently predict an increased risk of recurrence.56,57

The cumulative proportion of patients with late recurrence of VTE (after six months,and in most cases after discontinuation of anticoa-gulation)has been reported to reach13%at1year,23%at5years, and30%at10years.56Overall,the frequency of recurrence does not appear to depend on the clinical presentation(DVT or PE)of the?rst event,but recurrent VTE is likely to occur in the same clinical form as the index episode(i.e.if VTE recurs after PE,it will most likely be PE again).Recurrence is more frequent after multiple VTE epi-sodes as opposed to a single event,and after unprovoked VTE as opposed to the presence of temporary risk factors,particularly surgery.58It is also more frequent in women who continue hormone intake after a VTE episode,and in patients who have suffered PE or proximal vein thrombosis compared to distal(calf) vein thrombosis.On the other hand,factors for which an independ-ent association with late recurrence have not been de?nitely estab-lished include age,male sex,59,60a family history of VTE,and an increased body mass index.54,56Elevated D-dimer levels,either during or after discontinuation of anticoagulation,indicate an increased risk of recurrence;61–63on the other hand,single thrombo-philic defects have a low predictive value and anticoagulation manage-ment based on thrombophilia testing has not been found to reduce VTE recurrence.64,65

2.4Pathophysiology

Acute PE interferes with both the circulation and gas exchange.Right ventricular(RV)failure due to pressure overload is considered the primary cause of death in severe PE.

Pulmonary artery pressure increases only if more than30–50% of the total cross-sectional area of the pulmonary arterial bed is occluded by thromboemboli.66PE-induced vasoconstriction, mediated by the release of thromboxane A2and serotonin,contri-butes to the initial increase in pulmonary vascular resistance after PE,67an effect that can be reversed by vasodilators.68,69Anatomical obstruction and vasoconstriction lead to an increase in pulmonary vascular resistance and a proportional decrease in arterial compliance.70

The abrupt increase in pulmonary vascular resistance results in RV dilation,which alters the contractile properties of the RV myocar-dium via the Frank-Starling mechanism.The increase in RV pressure and volume leads to an increase in wall tension and myocyte stretch. RV contraction time is prolonged,while neurohumoral activation leads to inotropic and chronotropic stimulation.Together with sys-temic vasoconstriction,these compensatory mechanisms increase pulmonary artery pressure,improving?ow through the obstructed pulmonary vascular bed,and thus temporarily stabilize systemic blood pressure(BP).71The extent of immediate adaptation is limited,since a non-preconditioned,thin-walled right ventricle (RV)is unable to generate a mean pulmonary artery pressure above40mm Hg.

The prolongation of RV contraction time into early diastole in the left ventricle leads to leftward bowing of the interventricular septum.72The desynchronization of the ventricles may be exacer-bated by the development of right bundle-branch block.As a result,left ventricular(LV)?lling is impeded in early diastole,and this may lead to a reduction of the cardiac output and contribute to systemic hypotension and haemodynamic instability.73

As described above,excessive neurohumoral activation in PE can be the result both of abnormal RV wall tension and of circulatory shock.The?nding of massive in?ltrates in the RV myocardium of patients who died within48hours of acute PE may be explained by high levels of epinephrine released as a result of the PE-induced‘myo-carditis’.74This in?ammatory response might explain the secondary haemodynamic destabilization which sometimes occurs24–48 hours after acute PE,although early recurrence of PE may be an alter-native explanation in some of these cases.75

Finally,the association between elevated circulating levels of bio-markers of myocardial injury and an adverse early outcome indicates

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