The diagnosis and prognosis of venous thromboembolism : variations on a theme - Chapter 1: General introduction and outline of the thesis

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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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Generalintroductionand

outlineofthethesis

NADINES.GIBSONANDHARRYR.BÜLLER 

   

10

G

ENERALINTRODUCTION



Venous thromboembolism is a possibly fatal disease that has been recognized since the middle ages. Since then, numerous researchers have studied this theme to accomplish advances with new variations on the existing practice of the diagnosis, prevention,treatmentandprognosisofthisdisease.

Itwasthe19th_{centuryGermanpathologistRudolfVirchow,whocreatedtheconcept}

that pulmonary embolism and deep venous thrombosis are both manifestations of a singlediseaseentity,calledvenousthromboembolism.Hestated:‘Thedetachmentof largerorsmallerfragmentsfromtheendofthesofteningthrombuswhicharecarried alongbythecurrentofbloodaredrivenintoremotevessels.Thisgivesrisetothevery frequentprocessonwhichIhavebestowedthenameofEmbolia.’1_

Inthe1960’sthediagnosticworkupofpatientswithclinicallysuspectedpulmonary embolism changed significantly when imaging tests, such as contrast venography, pulmonaryangiographyandperfusionlungscanningwereintroduced25_{.Thismajor}

stepforwardinthediagnosisofvenousthromboembolismwascharacterizedbythe possibility to (in)directly visualize thrombi. However, what was not well realized untilthatmoment,wasthatonlyaquarterofclinicallysuspectedpatientsappearedto have the disease. Moreover, the availability of these tests was limited and together withthereluctanceofmanyphysicianstoperforminvasivetestsresultedofteninan incomplete diagnostic workup and anticoagulant treatment without a definitive diagnosis. Despite these limitations, physicians had no alternative diagnostic methods.Inthe1980’s,theintroductionofultrasonography,thatcouldnoninvasively image the deep veins in the leg significantly changed the diagnostic approach6_.

Nevertheless to refute the diagnosis, all patients with suspected venous thromboembolismhadtoundergooneormoreoftheseimagingtests.Thishasledto a revival of the use of information from the medical history, physical examination, and simple blood tests to guide the diagnostic process. With the introduction of clinical decision rules and the Ddimer test (a laboratory assay that indirectly measures blood coagulation), a powerful strategy was created to safely exclude the diseaseinonethirdtohalfofthepatients,withouttheneedforimagingtests.

Albeitwellvalidated,theseclinicaldecisionrulesaresometimesdifficulttocompute andsimplificationmayincreasethebroaderimplementationindailyclinicalpractice. Also the Ddimer assay has gained an important place in the diagnosis of patients withsuspectedpulmonaryembolism.Duetoitsmoderatespecificity,itshouldnotbe used as a screening test, and perhaps other coagulation tests, more specifically

Generalintroductionandoutlineofthethesis



11

C

HAPTER

1

measuring thrombin generation may be helpful to compensate for this shortcoming. On the other hand, how often false negative Ddimer results occur, and what the reasonsare,remainsunclear.

Finally, a dilemma in the diagnostic process has arisen with the ability of new technologyinultrasonographyallowingfullvisualizationofalldeepveinsintheleg, as compared to the traditional method of compression ultrasonography in the groin and popliteal fossa. Regarding the themes prognosis and treatment three pertinent questionshavesurfaced.Thefirstconcernsthesignificanceandthereforetheneedto detect, by either echocardiography or spiral CT, the presence of right ventricular dysfunction in patients who are otherwise hemodynamically stable. This is relevant since the treatment may have to be more aggressive in these patients. Another long termcomplicationofpulmonaryembolismthathascaughtmedicalattentionrecently istheoccurrenceofchronicthromboembolicpulmonaryhypertension.Althoughthe disease is rare in consecutive patients with pulmonary embolism the question is whetherscreeningforthisimportantdiseaseisindicated,inparticularinviewofthe recent advances in the treatment of this disease. Thirdly, the introduction of low molecularweightheparinswithouttheirneedforlaboratorymonitoringhasmadeout of hospital treatment for venous thromboembolism feasible7_{. Although it is widely}

accepted that patients with primary deep venous thrombosis receive out of hospital treatment in the majority of cases this is largely unknown for patients with primary pulmonaryembolism.

Takentogether,‘Variations onaTheme’canbeusedasametaphorforthedifferent aspectsofvenousthromboembolismthatarediscussedbelow,tofurtherimproveour understandingofthediagnosis,prognosisandtreatmentofthisdiseaseentity.

O

UTLINEOFTHETHESIS



This thesis consists of two parts. The first focuses on the diagnosis of venous thromboembolism and in the second part prognostic and therapeutic aspects are addressed.

In Chapter 2 an overview of pulmonary embolism is presented, consisting of the various diagnostic strategies that have been evaluated, as well as the etiology, best prevention and treatment and finally prognosis of this disease. The Wells clinical decisionrule,probablyoneofthebestrulesforassessingtheclinicalprobabilitywas furthervalidatedinChapter3,togetherwiththederivationofasimplifiedvariationof

12

thisrule.Chapter4focusesonthevalidationofthissimplifiedclinicaldecisionrulein anotherlargecohortofpatientswithsuspectedpulmonaryembolism.Towhatdegree decision rules and Ddimer assays are really integrated in the daily clinical routine and whether physicians are influenced by the information of an abnormal Ddimer result when scoring the decision rule is evaluated by means of a questionnaire in Chapter5.InChapter6weassessedhowoftenfalsenegativeDdimersoccurinall comers with pulmonary embolism, and in those with a likely clinical probability for the disease. Chapter 7 focuses on the clinical usefulness of the measurement of the prothrombinfragment1+2inpatientspresentingwithclinicallysuspectedpulmonary embolism, and whether this test had additional diagnostic utility to the widely applied Ddimer assay. The findings of a large partly randomized clinical followup studyinpatientswithsuspecteddeepvenousthrombosisarepresentedinChapter8. AfterexclusionwiththehelpofanunlikelyclinicalprobabilityandanormalDdimer, patients were randomized to undergo either the clinical two point compression ultrasoundinthegroinandpoplitealfossa,orasinglefullassessment,fromthegroin downtothedistalveinsinthecalf.

The second part of this thesis evaluates aspects of the prognosis and treatment of venous thromboembolism. Chapter 9 is a review on the prognostic value of right ventricular dysfunction diagnosed with echocardiography and spiral CT. In particular, it focuses on the diagnostic utility of these methods and calculates the possible advantages and disadvantages with more aggressive treatment. Whether screening for chronic thromboembolic pulmonary hypertension in consecutive patients with previous pulmonary embolism is useful is evaluated in Chapter 10. In the last chapter, Chapter 11, the treatment strategies employed by Dutch internists and pulmonologists in daily clinical practice investigated by chart review of consecutivepatientsinfourteenhospitalsintheNetherlandsaredescribed.

Generalintroductionandoutlineofthethesis



R

EFERENCELIST



1. Virchow RLK. Cellular Pathology. London: John Churchill; 1978:204-7.

2. Sasahara AA, Stein M, Simon M, Littmann D. Pulmonary angiography in the diagnosis of thromboembolic disease. N Engl J Med. 1964;270:1075-1081.

3. Haeger K. Problems of acute deep venous thrombosis. I. The interpretation of signs and symptoms. Angiology. 1969;20:219-223.

4. Wagner HN, Jr., Sabiston DC, Jr., McAfee JG, Tow D, Stern HS. Diagnosis of massive pulmonary embolism in man by radioisotope scanning. N Engl J Med. 1964;271:377-384. 5. Williams JR, Wilcox C, Andrews GJ, Burns RR. Angiography in pulmonary embolism.

JAMA. 1963;184:473-476.

6. Lensing AW, Prandoni P, Brandjes D et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320:342-345.

7. Othieno R, Abu AM, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007;CD003076.