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The diagnosis and prognosis of venous thromboembolism : variations on a
theme
Gibson, N.S.
Publication date
2008
Link to publication
Citation for published version (APA):
Gibson, N. S. (2008). The diagnosis and prognosis of venous thromboembolism : variations
on a theme.
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Pulmonaryembolism;areview
NADINES.GIBSONANDHARRYR.BÜLLER
E.E.VANDERWALL,F.VANDERWERFANDF.ZIJLSTRA.CARDIOLOGIE. 2NDED.HOUTEN;BOHNSTAFLEUVANLOGHUM:435442
18
I
NTRODUCTION
The mechanism behind venous thrombus formation has already been formulated in the nineteenth century in the Virchows’ triad, which describes three major elements playing a fundamental role in developing thrombosis: venous stasis, a hypercoagulablestateofbloodandinjuryofthevesselwall1.
However,itisnotwellknownthatRudolfVirchow,aGermanpathologist,wasalso thecreatorofthetheorythatpulmonaryembolismanddeepvenousthrombosisare manifestations of a single disease entity, venous thromboembolism. Embolism is derived from the Greek verb emballein, which means toss. A bloodclot is ‘tossed’ fromadeepveinandrunsviatheheartthroughthepulmonaryartery,toendupin oneormoreofthesmallervesselsofthepulmonaryarterytree. In70%ofthepatientswithpulmonaryembolism,adeepvenousthrombosisisfound inthelegorpelvicveins,whereas50%ofpatientswithdeepvenousthrombosishave (asymptomatic)pulmonaryembolism.
Figure 1. Rudolf Ludwig Karl Virchow
(1821, Schivelbein - 1902, Berlin) was a German doctor, anthropologist, pathologist, biologist and politician.
19 C HAPTER 2
B
ACKGROUND
Epidemiology
Pulmonary embolism is a common disease, with a yearly incidence of 12 per 10002.
The incidence correlates strongly with age, and is 0.05 per 1000 in adolescents, whereasanincidenceof8per1000isobservedintheagecategoryolderthan80.The numberofpatientswithaclinicalsuspicionofpulmonaryembolismwillbefivetimes higher,sinceonly20%ofthesepatientswillhavethedisease.
Natural course
In1960arandomizedtrialwasperformed,whichwouldnotbethinkablenowadays. In this trial patients with pulmonary embolism were randomised into heparin treatment or no treatment to evaluate whether the bleeding risk would counterbalance the possible positive effect of heparin treatment3. Of the 19 patients
thatreceivednotreatment,5developedafatalpulmonaryembolismand5developed a non fatal pulmonary embolism during the first month of observation, versus no eventsinthepatientsthatweretreatedwithheparin.
Withthecurrentanticoagulanttherapythemortalityduetopulmonaryembolismhas decreased from 25% to 23%4. The actual figures may possibly be higher than
generallyaccepted,sincepatientsthatdiedirectlyaftertheacuteonsetofsymptoms areusuallynotincludedinclinicalstudies.
The total mortality after one year is 20%, despite treatment. This is mainly due to comorbiddiseases,likemalignancy,cardiacdiseaseorotherpulmonarydisorders. Itisdifficulttoidentifypatientswithabadprognosis,butbothcardiogenicshockat presentation and right ventricular dysfunction on echocardiography have a distinct correlationwithmortality.
The development of right ventricular dysfunction is the result of a chain reaction of hemodynamic components. Obstruction of a thrombus in the pulmonary artery tree causesanelevatedafterloadintherightventriclewhichcanleadtorightventricular dilatation. The dilatation will counteract the movement of the right ventricle which mayresultinhypokinesia.Furthermoretheventricularseptumwillbulgeintotheleft ventricle,whichinterfereswiththefillingoftheleftventricle.Finally,thiswillcause hypoxemia and vasoconstriction with an increase of the pulmonary vascular resistance.
20
andnotbecauseofembolicobstructionofthepulmonaryarteries.
After three months of treatment, half of the patients will have a normal perfusion scan. Restoration of the perfusion will be mainly due to natural fibrinolysis and recanalisationoftheobstructedbloodvessels.
Clinical presentation
Theclassicpatientwithpulmonaryembolismwillpresentwithacutedyspnoea,chest pain while taking a deep breath, coughing and hemoptysis. However, patients with pulmonary embolism usually have a wide variety of complaints, with nonspecific symptomsthatmatchmanydiseases.
Theoccurrenceofsomecommonsignsandsymptomsofpulmonaryembolismisas follows:dyspnoea73%,pleuriticpain44%,cough34%,hemoptysis13%,tachypnoea 54%andtachycardia24%5.
Thecombinationofcomplaintsismainlyduetotheextentofthrombusobstructionin the pulmonary artery tree. Large thrombi at the bifurcation of the main pulmonary artery or the lobar branches may cause hemodynamic instability or even circulatory collapse. Smaller thrombi that are localized more distal are more likely to produce pleuritic chest pain or no complaints at all. Altogether, symptoms and signs of pulmonary embolism are highly variable, nonspecific, and common among patients withandwithoutpulmonaryembolism.
Becauseoftheabovementionedpatternofcomplaints,thephysicalexaminationwill be of little help in the majority of the patients. Crepitation or crackles can be heard with auscultation, caused by pleurital friction rub. Moreover, a loud pulmonary componentofthesecondheartsoundmayindicatepulmonaryhypertensionsandan elevatedcentralvenouspressureisasignofrightventricularoverload.Ifthephysical examination shows a red, swollen, tender leg, or if other signs of deep venous thrombosisarepresent,thediagnosisofvenousthromboembolismwillbeverylikely.
Risk factors
Thecausesofpulmonaryembolismarediverse.Bothhereditaryandacquiredfactors cancontributetoanelevatedriskforpulmonaryembolism(Table1).
Patients with cancer have a hypercoagulable state, and pulmonary embolism can signalthefirstappearanceofamalignancy.However,aroutineaggressivesearchfor malignancyinallpatientsdoesnotappeartobewarranted.
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2
Table 1. Risk factors for pulmonary embolism.
Oral contraceptives are the most important cause of pulmonary embolism in young women, due to their widespread use6. Within the first months of use the risk of
pulmonaryembolismisespeciallyincreased,buttheriskdoespersistafterthisperiod. Secondgenerationcontraceptiveshaveamorefavorablethrombosisriskprofilethan thirdgenerationproducts,butallareassociatedwithanincreasedriskforpulmonary embolism.
The expressiontrombophilia can be used for inherited and acquired changes in the coagulation cascade that increase the risk of pulmonary embolism (Figure 2). Trombophiliameansatendencyfordevelopingvenousthromboembolism,whichcan be caused by either physiological coagulation inhibitors, prothrombotic mutations andacquiredprothromboticchanges.
Deficiencies of the naturally occurring anticoagulants protein C and protein S decrease the inhibition of factors Va en VIIIa, which causes a hypercoagulable state. AntithrombinisamajorinhibitorofthrombinandfactorXa,anddeficiencyleadsto lessdownregulationofthrombinandfactorXageneration.
The Factor V Leiden and prothrombin mutation are prothrombotic mutations. The firstisanautosomaldominantconditionthatpreventsefficientinactivationoffactor V.WhenfactorVremainsactive,itfacilitatesoverproductionofthrombinleadingto excess fibrin generation and excess clot formation. In patients with a prothrombin mutation an elevated plasma level of the clotting protein prothrombin has been described. Malignancy Surgery Immobilisation Trauma Oral anticonceptives
Hormon ereplacement therapy History of VTE
Pregnancy
Post partum period Increasing age
22
Figure 2. A survey of the coagulation cascade in the human body.
XIa
Xa (+Va) IIa (trombine) Fibrine Tissue factor + VIIa
Antitrombine
IXa (+VIIIa) Geactiveerd proteïne-C(+ proteïne S)
If a defect appears in the vascular wall, subendothelial tissue factor will be exposed to blood which is the primary physiological event in initiating clotting. Tissue factor than complexes with factor VII, and activates factor X into factor Xa. Factor Xa converts prothrombin into thrombin with the help of factor Va, and thrombin converts fibrinogen into fibrin (thick arrows).
A first positive feed back loop consists of indirect factor X activation, via factor IXa with the help of factor VIIIa (triangle of arrows). The second feed back loop consist of factor XI activation by thrombin, which leads tot further factor IX and factor X activation (circle of arrows)
Negative feed back is established by activated protein C, in association with protein S that inactivates factors VIIIa and Va. Furthermore, antithrombin inactivates factors IIa and Xa (dotted arrows).
The risk of developing a first event of pulmonary embolism in patients with an antithrombindeficiency,oraproteinCorSdeficiency,is8to10foldincreased,and3 to 5 fold in patients with a factor V Leiden or prothrombin mutation7. In those
patientswithacombinationoftwoormoretrombophiliadefects(doublehit),therisk fordevelopingpulmonary embolismincreasesevenmore.Theriskfordevelopinga recurrent pulmonary embolism after a first pulmonary embolism is not or only weaklyrelatedtothepresenceofthrombophilia.
An acquired form of thrombophilia is the anti phospholipid syndrome. This syndrome occurs when autoimmune antibodies are produced against phospholipids and cardiolipin. These antibodies are often seen in patients with autoimmune
23
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Table 2. Differential diagnosis of pulmonary embolism.
Pulmonary causes Cardiac causes Thoracic causes Others
Pneumothorax Angina pectoris Musculoskeletal pain Stomach complaints Pneumonia Myocardial infarction Rib fracture Hyperventilation Atelectasis Pericarditis Costochondritis
Astma Aneurysma dissecans
COPD Heart failure
Pulmonary oedema Pericard tamponade Malignancy Pulmonary hypertension
disorders like systemic lupus erythematodes (SLE), but may also be observed in patientswithoutthesedisorders.
A definite diagnosis of the antiphospholipid syndrome can be made when the antibodies are present on a minimum of two occasions in combination with (recurrent)arterialorvenousthrombosisorrecurrentmiscarriages.Todatetheexact mechanismisunknown.
D
IAGNOSIS
A correct diagnosis or exclusion of pulmonary embolism is of utmost importance, becausepulmonaryembolismisassociatedwithasubstantialmorbidityandmortality ifuntreated,whereasanticoagulanttreatmentisassociatedwithanincreasedbleeding risk(Table2).
Electrocardiography, chest radiograph and arterial blood gas
Electrocardiography (ECG), chest radiograph and arterial blood gas are often performed in patients with acute chest pain that are suspected of pulmonary embolism.However,thevalueofthesetestsindiagnosingpulmonaryembolismare restricted.
ECG is especially of importance for the diagnosis or exclusion of an alternative diagnosis, for example a myocardial infarction or pericarditits8. Abnormalities on
ECGthatcanbeseeninpatientswithpulmonaryembolism,arenonspecificsignsof right ventricular dysfunction and tachycardia. The abnormalities most commonly observed are nonspecific STsegment and Twave changes, which are also seen in patientswithrightventricularstrainduetoothercauses.
24
Radiographic abnormalities resembling cardiomegaly, atelectasis or parenchymal abnormalitiesaresimilarlycommoninpatientswithpulmonaryembolismasinthose without the disease9. However, chest radiograph is of value for diagnosing an
alternativediagnosis,suchasapneumothoraxorpneumonia.
Arterial blood gas analysis usually shows hypoxemia, hypocapnia, and respiratory alkalosis in patients with pulmonary embolism. However, in patients with massive pulmonary embolism hypotension and respiratory collapse can cause hypercapnia andarespiratoryandmetabolicacidosis.
Anarterialbloodgasanalysiscanbeofuseindecidingwhetherornotsupplemental oxygenshouldbeadministered.
Takentogether,ECG,chestXrayandarterialbloodgasareofusefordrawingupa differential diagnosis, but additional testing is necessary to diagnose or exclude the disease.
Ventilation-perfusion scan and pulmonary angiography
Aventilationperfusionscanevaluatesthecirculationofairandbloodinthelungsof apatient.Theperfusionscandepictshowwellthebloodcirculateswithinthelungs, whereastheventilationscanestimatestheabilityofairtoreachallpartsofthelungs. If after intravenous injection of radioactive labelled albumin a perfusion defect is shown, the ventilation scan has to be performed, upon which the patients inhales a gaseous radionuclide xenon or technetium. With a normal perfusion scan, a pulmonaryembolismcanbesafelyexcluded.However,ifamismatchisshownonthe lobarorsegmentallevelsofthelungs,apulmonaryembolismisdiagnosed10.
A disadvantage of this test is that besides the limited availability, more than half of the patients will have a nondiagnostic test result. The test is nondiagnostic if only subsegmentaldefectsareshown,orifperfusionandventilationdefectsarematched, which can be observed by consolidation caused by an infection. The prevalence of pulmonaryembolisminthepatientswithanondiagnosticscanisstill25%,therefore, additionaltestingisnecessarytoexcludeordiagnosethediseaseinthissubgroupof patients. Todate,pulmonaryangiographyisassumedtobethegoldstandardfordiagnosing pulmonaryembolism.Duetoitsinvasivecharacterandtheexpertisethatisrequired for performing this test, it is usually only performed in patients in whom the ventilationperfusion scan is nondiagnostic, and in whom ultrasound of the venous
25
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2
system of the legs does not show a deep venous thrombosis. Angiography is performedbyinjectionofintravenousioniccontrastmaterialinthepulmonaryartery via a catheter, to view intraluminal filling defects, caused by thrombi in the pulmonaryarterytree11.
Among diagnostic algorithms that include previously mentioned imaging tests, it usually takes over 72 hour to diagnose or exclude the disease. In the last decade a greatdealofefforthasbeeninvested,toimprovethediagnosticprocedure.Withthe combinationofaclinicalprobabilitytest,aDdimertestandaspiralCTscan,asafe andefficientdiagnosticstrategyhasbeendevelopedthatcanbecompletedwithin24 hours12.
Clinical probability test, D-dimer and spiral CT
Nowadays,thediagnosticstrategyforpatientsthatpresentwithsignsandsymptoms of pulmonary embolism consists of an estimation of the probability for having the disease, based on the history and the physical examination. In case of a low or an unlikelyclinicalprobability,anadditionalbloodtestisperformed,theDdimerassay. The estimation of the probability is also called, the pretest probability, and can be measured by a clinical decision rule. A widely excepted decision rule is the ‘Wells rule’, which assigns points to seven elements, to generate a score that resembles the pretestprobability(Figure3)13.
The blood test that is used in patients with a low pretestprobability to exclude the diseaseisaDdimerassay.Itmeasuresfibrindegradationproductsthatareproduced by fibronolysis. These degradation products can be observed in increased concentrationsinpatientswiththrombosis,butaswellinnumerousothersituations, for example in patients with malignancy or an infection, after an operation, during pregnancy, or in the elderly. Therefore this assay is especially sufficient to exclude pulmonaryembolism,butnottodiagnosethedisease,sinceanabnormalDdimerisa nonspecifictestresult14. Inabout30%ofthepatientsthecombinationofanunlikelyclinicalprobabilityanda normalDdimertestresultisobserved.Inthesepatientspulmonaryembolismcanbe safelyexcluded,andtheuseofextensiveimagingtestscanberestrained.Inpatients
26
Signs and symptoms of pulmonary embolism (PE) Clinical decision rule (CDR)
CDR 4 CDR > 4
D-dimer (DD) DD 0.5 mg/l DD > 0.5 mg/l
No PE Spiral CT Spiral CT
Figure 3. The diagnostic strategy for patients with clinically suspected pulmonary embolism.
with a likely clinical probability or with an abnormal Ddimer, additional imaging testing has to be performed. The strength of this diagnostic strategy lies in the combinationofhighefficiencytogetherwitheaseofuseindailyclinicalpractice.
Inthosepatientsthatrequireadditionaltesting,usuallyaspiralCTscanisperformed. Nonioniccontrastmaterial isinjected,andpulmonary embolismisdiagnosedifthe contrast material outlines an intraluminal filling defect or if a vessel is totally occludedbylowattenuationmaterialonatleasttwoadjacentslices.Anadvantageof thespiralCTscanisthepossibilityofimaginganalternativediagnosis.
The spiral CTscan had gained widespread popularity in the last decades for diagnosingpulmonaryembolism,attheexpenseofthepulmonaryangiography.Asa consequencetheexpertisetoperformanangiographywithsufficientexperiencewill decline.
The seven items of the Wells clinical decision rule Score Clinical signs & symptoms deep venous thrombosis 3
Tachycardia (>100/min) 1.5
Immobilization or surgery in the previous four weeks 1.5 Previous deep venous thrombosis/pulmonary embolism 1.5
Hemoptysis 1 Malignancy 1 An alternative diagnosis is less likely than pulmonary embolism 3
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T
REATMENT
The patient’s clinical status has to be taken into account when choosing the appropriate treatment. Those patients with a normal blood pressure should initially be treated with low molecular weight heparin (LMWH), a pentasaccharide, or unfractionatedheparin,followedbyvitaminKantagonists.Inpatientswithmassive pulmonary embolism, that present with cardiogenic shock thrombolytic therapy is indicated15.
Anticoagulant therapy
Theinitialtherapywith(lowmolecularweight)heparin,orapentasaccharideshould beadministeredforatleast5days,andpreferablyuntilthevitaminKantagonisthas reached a therapeutic level. With unfractionated heparin treatment, frequent monitoring of the activated partial thromboplastin time (APTT) is necessary to accomplish a therapeutical range, which is 1.5 to 2 times the control value of the APTT.
Heparin is an indirect thrombin inhibitor which complexes with antithrombin and converts it into a 1000 fold more rapid inactivor of several coagulation factors, especiallyfactorXaandIIa(thrombin).
Nowadays low molecular weight heparin (LMWH) is often preferred above unfractionatedheparin.Duetothestablefarmacokineticprofile,monitoringbymeans of the antifactor Xa, is only necessary in those patients with an altered metabolism (severe renal insufficiency, morbid obesity or pregnancy). Furthermore the subcutaneous delivery makes treatment at home possible, although outpatient therapy for pulmonary embolism is not well established. The dosage of LWMH is basedonthepatient’sweight16.
Vitamin K antagonists, coumarin derivates, inhibit the production of vitamin K dependent coagulation factors prothrombin, factor VII, IX and X. The therapeutic rangeismeasuredbytheInternationalNormalizedRatio(INR),basedonthepartial thromboplastintime.IntheNetherlandstheThromboticServicesareresponsiblefor maintainingtheINRinthetherapeuticrange,andadjustingthedosage,ifnecessary. VitaminKantagonistsarecontraindicatedinpatientswithliverorrenalinsufficiency, hemorrhagic diathesis, severe thrombopenia, severe hypertension, recent bleeding events and hypersensitivity for coumarin derivates. During the first term of pregnancy there is a risk of developing teratogenic abnormalities with vitamin K
28
antagonisttreatment,andafter36weeksbleedingcomplicationsduringandafterthe delivery may occur. Therefore LMWH is a safe alternative in pregnant patients. Vitamin K antagonists are not contraindicated during lactation, since they have no anticoagulant effect on the infant. Moreover, in the Netherlands all neonates receive vitaminKsuppletion17.
A complication of unfractionated heparin and in small amounts of LMWH, is the development of a heparin induced thrombocytopenia (HIT). At least five days after initiating heparin therapy, antibodies appear, that cause platelet aggregation, with thrombocytopeniaasaconsequence.Theseaggregatesincreasetheriskofvenousand arterial thrombosis. In patients suspected of HIT, the heparin treatment should be stopped and HIT antibodies have to be measured. Treatment with vitamin K antagonistsmaycauseworseningofthromboticcomplications,includingvenouslimb gangreneandskinnecrosis,andshouldthereforenotbeinitiated.Patientsshouldbe treated with alternative anticoagulant therapy, for example danaparoid, a pentasaccharideorthedirectthrombininhibitorsbivalirudinandlepirudin18.
Thrombolytic therapy
VitaminKantagonistsandheparinarenonthrombolyticagents.Theypreventfurther thrombus deposition and establish thrombus stabilization and endogenous lysis. In patients with massive pulmonary embolism and cardiogenic shock, a rapid lysis of the clot by thrombolytic therapy is necessary. Thrombolytic agents activate plasminogentoformplasmin,resultingintheacceleratedlysisofthrombi.Examples arestreptokinase,alteplaseorurokinase,whichincreasetheendogenousfibrinolysis considerably. The restraint for using thrombolytic therapy is caused by a high bleedingrisk,withariskofseverebleedingof6to8%.Incaseofseverebleeding,the thrombolytictherapyshouldbediscontinuedimmediately,andfreshfrozenplasma, fibrinogen,andcryoprecipitateinhighdosageshouldbeadministered.
However, thrombolytic therapy is justified in those patients with cardiogenic shock, since the risk of dying of the disease counterbalances the bleeding risk. There is insufficientevidencethathemodynamicstablepatientswithsignsofrightventricular dysfunctionshouldbetreatedwiththrombolysis.
Duration of treatment
ThedurationoftreatmentwithvitaminKantagonistsdependsonthecircumstances in which the embolism was formed, the presence of risk factors or if it is a first or recurrent episode. Three to six months of treatment is adequate for patients with a
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first provoked episode of pulmonary embolism, with the presence of an apparent temporaryriskfactor.
In those patients with pulmonary embolism without risk factors, an idiopathic pulmonary embolism, treatment of 6 to 12 months is advised. In high risk patients, with recurrent spontaneous venous thromboembolism, long term treatment is advised, provided the increased risk of bleeding is counterbalanced by the positive effect of treatment. Therefore the patient’s opinion on the bleeding and recurrence riskshouldbetakenintoaccountinthedecisionoftreatmentduration.Afteroneyear oftreatment2to8%ofpatientshavemajorbleedingevents,whichwillleadtoafatal bleedingin0.25%ofthepatients.
In patients with malignancy, treatment should be given for an indefinite period if metastatic disease is present or the patient is receiving chemotherapy, or until the cancer is resolved. It is advisable to reevaluate frequently the riskbenefit ratio of ongoing anticoagulant therapy in individual patients, taking into consideration the overallclinicalstatusofthepatientandthequalityoflife.
New anticoagulants
Although pulmonary embolism can be treated efficiently and safe with the current therapy, some aspects of the treatment are still open for improvement, especially thoseaspectswhichmaketheadministrationofthetherapymoreconvenientforthe patient. With the improved understanding of the coagulation system down to the molecularlevel,newanticoagulantshavebeendevelopedinthelastdecade.Theaim wastodevelopanovelanticoagulantwhichissuitablebothfortheinitialaswellas for the chronic treatment phase, and which requires no laboratory monitoring. The patientcanthenbetreatedwithjustoneagent,anddoesnotneedINRmonitoring. These new antithrombotic agents can be divided into the direct thrombin inhibitors, andthefactorXainhibitors.Themostimportantsimilarityinthesenewagentsisthe absenceoftheneedtomonitortheeffectoftheagentwithlaboratorytests19.
Thrombininhibitorsbinddirecttotheactivepartofthrombin.Ximelagatranwasthe mostpromisingdrugofthedirectthrombininhibitors,withaneffectivereductionof the risk of a new venous thromboembolism episode. Furthermore, the bleeding complications were comparable to the treatment with vitamin K antagonists. Unfortunately there was a high incidence of hepatotoxicity, which resulted in withdrawalofthisagentfromthemarket.
30
TheorallyactivefactorXainhibitorsinhibitfactorXadirectlybybindingtoitsactive site without requiring the action of antithrombin. Due to the ease of use of these agents,theymaybeagoodsubstitutedrugforthevitaminKantagonists.
Pentasaccharides are indirect factor Xa inhibitors. They consist of at least five saccharide units, and have a sequence derived from the minimal antithrombin binding region of heparin. When the pentasaccharide binds on this region a conformational change in antithrombin increases the ability of antithrombin to inactivate factor Xa. The pentasaccharide fondaparinux appeared to be as effective andsafeintheinitialtreatmentofpulmonaryembolismasheparin20.Withahalflife
of 17 hours, fondaparinux is administered once daily. Idraparinux is a longer acting analogueoffondaparinux,andcanbeadministeredonceaweekbecauseofthehalf life of 80 to 130 hours. A disadvantage of this longer half life is the difficulty of counteractingtheanticoagulanteffectofthedrugwhenableedingeventoccurs,due totheabsenceofareversingagent.
Thefuturewilltellwhichoftheseagentsoffersthemostfavourablebalancebetween effectiveness,safety,convenienceandcosteffectiveness.
Inferior vena caval filter
Inferiorvenacavalfiltersallowbloodto pass through the caval vein while preventing large emboli from traveling from the pelvis or lower extremities to the lung. Patients at high risk for recurrence pulmonary embolism in whom anticoagulant treatment is contraindicated, due to an increased bleeding risk, and those with recurrent pulmonary embolism, despite adequate anticoagulant therapy are eligible for a caval filter insertion. Disadvantages of the caval filter are the increased risk for deep venous thrombosis, and the possibility of developing of a vena cava
31 C HAPTER 2
P
ROGNOSIS
Thenaturalcourseofpulmonaryembolismdiffers widely.Therefore,itisofutmost importance to identify those patients in the acute phase that are at risk for severe morbidity or even mortality. These patients may benefit from more aggressive therapy,suchasthrombolysisorsurgicalremovalofthethrombus(thrombectomie). Persistent hypotension or a cardiogenic shock are widely accepted indications for thrombolytictherapy.Right ventricular dysfunction and biomarkers
Studiesinnormotensiveandhypotensivepatientshaveshownthatrightventricular dysfunction, with a prevalence of 30 to 40%, is associated with a twofold increased risk of pulmonary embolism related mortality. However, the impact of right ventriculardysfunctiononthemortalityinonlynormotensivepatientsappearstobe modest,withapulmonaryembolismrelatedmortalityof4to5%.
The biomarkers BNP, troponin I and troponin T appear to have prognostic value in patients with pulmonary embolism. The elevated pressure in the pulmonary artery and the right ventricle can cause micro infarctions in the right ventricular wall and myocardialcelldamage.Troponinmayleakoutofthecellswithin12hoursafterthe onsetofpulmonaryembolismandtheriseofBNPappearsalreadyafterafewhours duetoventricularmyocytestretch22.
There is no sufficient evidence that more aggressive therapy will improve the prognosis of normotensive patients with right ventricular dysfunction or elevated biomarkers.Futurestudieshavetoshow,whetherastrategycanbedesignedwith,for example,thecombinationofrightventriculardysfunctionandseveralbiomarkersfor ariskstratificationforpoorprognosis.
Recurrent thrombosis
Thehighestriskforrecurrentvenousthromboembolismoccursdirectlyaftertheacute onsetofpulmonaryembolism,andismainlyinfluencedbythecircumstancesthatled topulmonaryembolism.Therecurrentriskafteranidiopathicpulmonaryembolism is 12 to 18% within two years of the diagnosis, whereas this risk after pulmonary embolismduetosurgeryoratemporaryriskfactorisverylow.32
than for recurrent pulmonary embolism, and is therefore limited in predicting the recurrencerisk.
Difficulties in diagnosing a recurrent pulmonary embolism are frequently observed, since50%ofthepatientswillhaveresidualthrombosisonimagingtests.Thismakesit difficulttodistinguishbetweenoldandnewabnormalities23.
Chronic thromboembolic pulmonary hypertension
Chronic thromboembolic pulmonary hypertension is an important complication of pulmonary embolism, which causes progressive complaints of exertional dypsnoea. Although the exact hemodynamic evolution of the disease has not been fully established, the hypertension appears to be a result of insufficient thrombus resolution,whichmaycausechangesinthesmallresistancevesselsoftheperipheral pulmonaryvascularbedwhichwillleadtoincreasedpulmonaryarterypressure. Pulmonaryhypertensionisdiagnosedifpulmonaryarterypressureexceeds25mmHg at rest, or 30mmHg on exertion, observed with right heart catheterization and pulmonaryangiography.
The incidence of chronic thromboembolic pulmonary hypertension appears to be below1%.Thedisorderhoweveristhoughttobeunderdiagnosed.Theprognosisis poor,withatwoyearssurvivaloflessthan20%ifnottreatedinthosepatientswitha meanpulmonaryarterypressureexceeding50mmHg.
Chronic thromboembolic pulmonary hypertension can be treated by thromboendarterectomy, but only in the patients with emboli in the proximal pulmonary arteries. This surgical intervention has a high mortality rate of 10% in specialized clinical centers with expertise. On the other hand, the prognosis and qualityoflifeimprovesignificantlyifthesurgeryissuccessful24.
C
ONCLUSION
In the last decade the diagnosis of pulmonary embolism has been optimized. Diagnostic strategies have been developed that can safely diagnose or rule out pulmonary embolism within 24 hours, with a simple combination of a clinical decisionrule,aDdimertestandaspiralCTscan.Furthermoreitislikelythatinthe coming years the treatment of pulmonary embolism will consist of an oral agent, without the need for monitoring and differentiation between the initial phase and longtermtreatment.
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Concerning the prognosis of pulmonary embolism some issues remain unclear. Is it possible to develop a risk stratification that estimates the risk for severe morbidity and mortality? And how do we treat normotensive patients with right ventricular dysfunction?
Hopefully these questions will be answered in the future along with further optimization of treatment and implementation of improved diagnostic strategies in dailyclinicalpractice.
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