Further optimization of the diagnostic management of deep venous thrombosis

eep venous thrombosis of the leg has been recognized since the middle ages.Initially, for lack of other alternatives, clinical symptoms and signs of the disease dominated the diagnostic process of the disease.There was, however, disagreement on the most useful and reliable symptoms and signs to use and even the value of these was questioned.Although venography has been introduced by Bauer in 1940 [1], it did not assume any important role in the diagnosis of clinically suspected deep vein thrombosis until 1969 when Haeger [2] employed it in his study to demonstrate the lack of sensitivity and specificity of the clinical diagnosis in a consecutive series of patients with symptoms and signs of deep vein thrombosis.Since suspected clinical diagnosis of venous thrombosis was objectively verified in only 46% of the patients hospitalized and treated for the disease and no significant difference in frequency of symptoms or signs in patients with and without thrombosis could be established, Haeger concluded that clinical signs could not be used for diagnosis, nor could thrombosis be excluded by their absence.Thus, the need for objective diagnostic tests was established.Ascending contrast venography was the first objective test to be evaluated and is generally regarded as the reference method ("gold standard") for the diagnosis of deep venous thrombosis.Nevertheless, venography is invasive, painful, and can be associated with allergic and other side effects.This, in turn, led to the development and validation of a number of objective, non-invasive diagnostic methods involving in the first stage indirect imaging techniques, such as 125 I-fibrinogen leg scanning, and venous outflow and haemodynamic measurements, such as impedance plethysmography and strain gauge plethysmography; and in the second stage direct imaging techniques, such as compression ultrasonography.Since less than 25% of symptomatic patients actually had thrombosis confirmed by objective tests, such as compression ultrasonography or venography, interest increased in exclusionary tests able to identify, at presentation, those patients with no or little chance of having the condition.Thus, diagnostic methods developed in the third stage included coagulation activation blood tests, such as prothrombin fragments 1+2, thrombin-antithrombin complexes and cross-linked fibrin degradation products (D-dimers); and in the fourth stage re-appreciation and validation of the clinical symptoms and signs of deep venous thrombosis.This thesis focuses on the further optimization of the current methods used in the diagnosis of deep venous thrombosis.To illustrate its position in the field, each chapter will be introduced with a short narration about the work preceding it and leading to its conception and execution.Of those objective diagnostic tests better investigated and more used in clinical practice are impedance plethysmography and compression ultrasonography, the latter alone or combined with pulsed Doppler (Duplex) scanning.At present, impedance plethysmography is still used, in the USA and Canada, but it is recognized that the instrumentation needed is less simple than that used for ultrasonography.Thus, ultrasonography limited to the common femoral and popliteal veins and using compressibility as the sole criterion for abnormality, has emerged as the new gold standard for the diagnosis of symptomatic deep vein thrombosis. D C H A P T E R 1 12Recently, a new compression ultrasonography procedure has been introduced, the so-called comprehensive compression ultrasonography examination, starting from the common femoral vein in the groin and extending all the way down to the ankle, including the entire set of deep calf veins.A number of prospective management studies, in patients with suspicion of deep vein thrombosis, have proven its safety [5].Nonetheless, debate is still ongoing about its place and usefulness among the currently available diagnostic methods.Chapter 6 compares the performance of comprehensive compression ultrasound with that of serial (limited) compression ultrasound alone, or combined with pre-test probability and/or D-dimer.There remains some partially resolved issues regarding the diagnostic management of patients with suspected venous thrombosis.One such issue is the difficulty of diagnosing recurrent disease.Documentation of recurrence usually leads to prolonged, sometimes lifelong, anticoagulant therapy, which is quite a demanding treatment with a considerable risk of bleeding complications.For the purpose of recurrent thrombosis, both invasive and non-invasive techniques could be inaccurate and their results frequently inconclusive.Furthermore, their adequate implementation and interpretation usually requires experienced personnel who might only be available in specialized centres and, even then, may not be present outside the regular working hours.Hence, as an alternative to immediate diagnosis for patients presenting with clinical suspicion of recurrence, a blood sample for D-dimer testing may be obtained at presentation, a single dose of therapeutic low molecular weight heparin administered and the patient requested to return on the following day to complete the diagnostic process.One important aspect for the success of this alternative clinical management model, is the degree of stability of D-dimer levels when measured in plasma stored for 24 hours, usually at 4°C or -20°C.Chapter 7 reports the results of such a scenario for D-dimer samples' storage and, in addition, the performance of two D-dimer assays, MDA and Tinaquant, for the exclusion of recurrent DVT is compared.Another issue of debate is the clinical relevance of a positive family history of venous thromboembolism for selecting patients at a greater risk of having a thrombophilic defect(s) and, hence, in whom a laboratory screening for inherited thrombophilia may be warranted.Thrombophilia is the term used to describe a disturbance of the equilibrium between anti-and pro-coagulants resulting in a state of chronic hypercoagulability.Thrombophilic defects may increase a patient's risk for developing (recurrent) venous thromboembolism.In everyday clinical practice, evaluation of a patient presenting with symptoms of venous thromboembolism would usually involve obtaining a careful medical history, including enquiring about other family members who had experienced similar complaints in the past.However, this is usually not performed with systematic or quantitative methods.The value of thus obtained family history in predicting inherited thrombopilia, at presentation, in patients with suspicion of venous thromboembolism, is quantified in Chapter 8.

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