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Diagnostics in Venous Thromboembolism: From Origin to Future Prospects Giuseppe Lippi, MD1 Elisa Danese, PhD2 Emmanuel J. Favaloro, PhD FFSc (RCPA)3 Martina Montagnana, MD2 Massimo Franchini, MD4
of Parma, Parma, Italy 2 Clinical Biochemistry Section, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy 3 Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, Westmead Hospital, Westmead, New South Wales, Australia 4 Department of Hematology and Transfusion Medicine, Azienda Ospedaliera Carlo Poma, Mantova, Italy
Address for correspondence Giuseppe Lippi, MD, Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Via Gramsci 14, 43126 - Parma, Italy (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:374–381.
Abstract
Keywords
► venous thromboembolism ► deep vein thrombosis ► pulmonary embolism ► diagnosis ► D-dimer
Venous thromboembolism (VTE) is a prevalent and life-threatening condition that requires an accurate and timely diagnosis. The current diagnostic approach to this condition, entailing an efficient integration of clinical judgment, diagnostic imaging, and laboratory testing, is the result of decades of scientific and medical research. This article aims to present and discuss the major breakthroughs that have occurred in the diagnostic imaging of both deep vein thrombosis and pulmonary embolism, along with the various biological markers that have emerged from the laboratory bench and which have only marginally migrated to the bedside. Despite decades of research, the current diagnostic armamentarium for an efficient diagnosis of VTE remains suboptimal, and some wiggle room remains for the development of more efficient diagnostic tools, which may include thrombus-targeted molecular imaging, infrared thermal imaging, thrombin generation, and proteomics.
Venous thromboembolism (VTE), which typically comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), has an estimated prevalence of 0.1 to 0.2% in the general population, which gradually increases with aging, from 1 per 100,000 in the young up to 1 per 100 in elderly subjects aged 80 years and older.1,2 A higher frequency of VTE cases has also been reported in hospitalized patients, and mainly due to the prevailing prothrombotic factors such as immobilization, infections, cancer, and surgery in this population.3 Approximately 90% of pulmonary emboli originates from the lower extremities, while upper extremity DVT embolization is less common, although the increasing use of central venous access devices has recently contributed to increase its frequency.4 Depending on the different epidemiological approaches, it has been estimated that the mortality rate of VTE ranges
from 10 to 30%, with the vast majority of deaths occurring in patients with PE,1 which is hence currently regarded as the third most common cause of vascular death only preceded by myocardial infarction and stroke, as well as the leading preventable cause of death in hospitalized patients.5,6 Indeed, the overall world-wide morbidity and mortality burden associated to thrombosis is very significant, and VTE causes a major burden of disease across all socioeconomic classes and low-, middle-, and high-income countries. 7 The current diagnostic approach to VTE, entailing an efficient integration of clinical judgment,8 diagnostic imaging,9,10 and laboratory testing,11 is the result of decades of scientific and medical research, which is outlined in subsequent sections of this article.
published online April 14, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Hot Topics VII; Guest Editor: Emmanuel J. Favaloro, PhD, FFSc (RCPA).
DOI http://dx.doi.org/ 10.1055/s-0034-1544003. ISSN 0094-6176.
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1 Laboratory of Clinical Chemistry and Hematology, Academic Hospital
History of Diagnostic Imaging in Deep Vein Thrombosis Christian Doppler, an Austrian mathematician and physicist, in 1841 originally discovered that the frequency of a wave depends on both the relative speed of source and observer.12 The first application of the Doppler principle in clinical medicine has been then attributed to the work of H. P. Kalmus, who described in 1954 how flow velocity in fluids could be determined by measuring the phase difference between an upstream and downstream ultrasonic wave. In 1959, Franklin et al first developed a flowmeter that could be mounted directly on blood vessels.13 In the same year, it was also reported that the Doppler frequency shift could be used for detection of blood velocity patterns12 and, shortly afterward, a team of scientists from the University of Washington published their work on a flowmeter, which was successfully used to record blood flow through intact vessels in dogs.13 Later, in 1964, D. W. Baker and H. F. Stegall developed the first Doppler instrument intended for transcutaneous measurement of blood flow velocity in man using the continuous wave Doppler principle.14 In the following year, it was demonstrated that continuous wave Doppler ultrasonography had applications and provided good results in visualizing occlusive clots without extensive collaterals (►Fig. 1).15 The first pulsed-wave Doppler, consisting of intermittent (pulsed) bursts of ultrasound at a frequency called the pulse repetition frequency, was produced in 1970.16 Around the mid-1970s, ultrasonic angiography (consisting of a pulsed ultrasonic flow detector and a B-scanner) was successfully used in the diagnosis of DVT.17 A major breakthrough occurred when Talbot18 and Cronan19 combined B-mode imaging and pulse Doppler together, to describe the cardinal signs of DVT on ultrasound. Finally, additional data were obtained by the use
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of color Doppler ultrasound in the mid-1980s, which allowed detection and visualization of movement toward and away from the added ultrasound transducer.20,21 Before the 1970s, the diagnosis of DVT had been mostly performed by venography, through injection of dyes into a vein, which allowed visualization of the vein on X-ray. This method was subsequently largely replaced by noninvasive medical approaches such as impedance plethysmography.22,23 This technique measures the change in blood volume by registering small electrical resistance variations of leg or arm while a thigh cuff is inflated.24 Accordingly, the blood volume varies in direct relationship with the electrical conductance and inversely with the resistive electrical impedance of the conductor.25 Although the history of impedance plethysmography dates back to 1932, when Atzler and Lehmann observed changes in the capacitance between two parallel plates kept across the human chest, this technique was only introduced for the diagnosis of DVT 50 years later by Wheeler et al, who described its principles and clinical applications.26,27 Initially, the method was based on the maximum respiratory effort, and then modified by replacing the respiratory approach with the occlusive pneumatic thigh cuff technique.28,29 This method has remained virtually unchanged up to date. The computed tomography venography, which was developed during the 1990s, is a method which provides direct imaging of the veins immediately after helical computed tomographic pulmonary angiography, without injection of additional contrast material or with less contrast media than conventional venography.30 The technique was originally reported by Stehling et al in 1994,31 and has rapidly found broad application in DVT diagnostics along with magnetic resonance imaging (MRI) venography.32–36
Fig. 1 The brief history of diagnostics of venous thromboembolism.
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History of Diagnostic Imaging in Pulmonary Embolism Before the development of objective diagnostic standards in the second half of the past century (i.e., electrocardiogram and chest radiograph), the diagnosis of PE was essentially based on clinical judgment.37 The availability of more sophisticated diagnostic procedures has greatly assisted physicians to diagnose PE in recent years.38 The imaging approaches to diagnose PE currently entail pulmonary angiography, ventilation/perfusion scanning, computed tomography angiography, and MRI.39–41 Pulmonary angiography was first described by Robb and Steinberg in 1939,42 and its development greatly facilitated the diagnosis of PE and also provided opportunities to understand its underlying pathophysiological processes. Although pulmonary angiography is still considered the reference test for establishing the presence or absence of PE,43 its invasiveness and limited availability greatly limits the routine use. Moreover, the procedure has some technical limitations for visualization of peripheral embolization and is also plagued by a large variation in interobserver agreement.44,45 For these reasons, this diagnostic procedure is indicated for those patients where noninvasive tests are inconclusive.46 Ventilation/perfusion lung scintigraphy is a noninvasive technique originally developed nearly 50 years ago.47 This method allows the visualization of pulmonary perfusion through intravenous injection of isotopically labeled microaggregates of human albumin. Although a normal perfusion scan virtually rules out PE, an abnormal perfusion scan is substantially nonspecific. Due to the significant rate of “positive” but nondiagnostic results, the use of lung scintigraphy has dramatically declined over the past 15 years, largely replaced by CT angiography.48 Since the first report in 1978 of diagnosis of PE using CT,49 this imaging technology has greatly evolved, gradually assuming the role of the leading imaging modality in patients with suspected PE.43 Wide variations in both sensitivity (0.53–1.00) and specificity (0.73–1.00) have been reported in the literature on the performance of single-detector CT angiography.50 In this respect, multidetector CT angiography appears more sensitive than single-detector CT angiography, thus allowing exclusion of PE without additional compression ultrasonography of the leg.51,52 Notably, a meta-analysis analyzing 23 studies with 4,657 patients with a negative CT angiography who did not receive anticoagulation treatment showed a 3-month rate of subsequent VTE of 1.4% (95% confidence interval [CI], 1.1–1.8) and a 3-month rate of fatal PE of 0.51% (95% CI, 0.33–0.76), comparing favorably with the results observed after a standard invasive contrast pulmonary angiogram.53 In recent years, gadolinium-enhanced MRI angiography has also emerged as an alternative diagnostic imaging modality due to its avoidance of exposure to ionizing radiation.54,55 This technology, first developed in the 1970s,56 reached a sensitivity of 0.78 and a specificity of 0.99 in technically adequate images, according to a recent multicenter prospective study.57 Magnetic resonance angiography is, Seminars in Thrombosis & Hemostasis
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however, an expensive, limited, and time-consuming resource, and should hence be considered only in centers where it is routinely performed and only in patients for whom standard tests are contraindicated.
History of Biomarkers in Venous Thromboembolism The investigation of potential biomarkers of VTE began in earnest in 1945, when Seegers et al demonstrated that plasmin digested fibrinogen consisted of two major electrophoretic fragments called α- and β-fibrinogen.58 Almost one decade later, Nussenzweig et al performed the first comprehensive evaluation of plasmin–fibrinogen interactions and classified the fractions resulting from fibrinogen cleavage, as A, B, C, D, and E fragments based on the order of their elution from the ion exchange chromatographic column.59 Afterward, two further intermediate cleavage fragments named X and Y were recognized by Marder et al,60 who also provided the missing step for making physiochemical characterization of fibrin degradation products (FDP) match with the threedimensional structures previously provided by electron microscopy.61 In 1973, two independent research groups first identified a unique fragment of exclusive fibrin derivation, which was originally named “Double D.”62,63 This fragment was characterized as containing two D domains instead of the single one typically found after fibrinogen digestion.64 The D domains were then shown to originate from two adjacent fibrin molecules, held together by the cross-linked γ-chain remnants of the originating fibrin.65 Meanwhile, it was also demonstrated that this peptide, which was eventually called “D-dimer” is frequently associated with an E domain in a noncovalent manner, thus forming an electrophoretically stable D-dimer–E complex, the D2E entity.66 D-dimer was originally presumed to represent the largest soluble fragment derived from cross-linked insoluble fibrin. However, this assumption was rapidly discredited in 1979 by Graeff and coauthors, who showed that higher molecular weight and large cross-linked FDP called X-oligomers were the predominant FDP fraction in vivo.67 The evidence that the formation of FDP in the circulation represents the most tangible demonstration of ongoing fibrinolysis in blood prompted researchers to develop immunologic assays for qualitative (i.e., positive/negative) FDP measurement ex vivo. These first assays lacked specificity, as they were mostly based on polyclonal antibodies against fibrinogen and its fragments,68 so that they could not adequately distinguish between fibrinogen and FDPs. In the early 1980s, a new generation of monoclonal antibodies became available,69 which were used to specifically bind to epitopes on D-dimer fragments that are absent on fibrin, fibrinogen, and non– cross-linked fragments of fibrin, thus enabling higher specificity in the assessment of D-dimer as a biomarker of fibrin formation and stabilization.70 Although additional biomarkers emerged at that time (i.e., fibrinopeptide A [FPA] and soluble fibrin) and gained limited popularity for a period of time as biomarkers of a prethrombotic state, the short
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mentioning here, however, that some technical problems still plague D-dimer testing in clinical laboratories, and these substantially include a poor harmonization due to the lack of a reference material and a reference method,87 and the potential analytical interference from hemolysis88 or heterophilic antibodies.89 Thus, there will be occasions in which D-dimer results from a patient with or without thrombosis will be positive with one method, but negative with another, or may be positive or negative on one sample, but not on another.90
Future Perspectives Despite decades of basic and applied research, the current diagnostic armamentarium for an efficient diagnosis of VTE remains suboptimal. The use of D-dimer or ultrasound of the proximal veins in patients with suspected DVT,91 along with D-dimer, CT pulmonary angiography, or ventilation-perfusion scanning when CT pulmonary angiography is inconclusive in patients with suspected PE,92 have enormously improved the diagnostic efficiency, but several cases remain still undiagnosed. These particularly include DVT patients with small and distal thrombosis, as well as patients with peripheral (military) pulmonary embolization.93 In these cases, the level of thrombosis, or the “remoteness” of the thrombosis, leads to plasma levels of D-dimer that are indistinguishable from the normal “background” level (typically < 500 ng/mL as fibrinogen equivalent units). Here, it may also be worth noting that normal physiological “wear and tear” processes are always in progress in all of us, and so D-dimer levels in plasma are never “zero.” It can also be concluded that some wiggle room remains for further research on this issue, and for the development of more sensitive markers of thrombus formation or lysis (►Table 1).
Theragnostics and Beyond The use of theragnostics, which is a treatment strategy that combines therapeutics with diagnostics, is prepotently emerging in several areas of clinical medicine, including diagnostics and therapy of thrombotic disorders.94 More specifically, recent technical innovations are considerably improving the array of therapeutic agents for treatment of thrombotic and occlusive disorders, most notably entailing thrombus-targeted fibrinolytic therapy with tissue- and
Table 1 Innovative thromboembolism
techniques
for
diagnosing
venous
1. Thrombus-targeted molecular imaging a. Radioiodinated monoclonal antibodies b. Small molecules with fibrin affinity c. Nanoparticles 2. Infrared thermal imaging 3. Thrombin generation 4. Proteomics
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half-life of these peptides was incompatible with the criteria of a reliable VTE diagnostics. Therefore, it became soon clear that the only robust test in this area was D-dimer, as Gaffney had already perceived as far back as 1972.71 It is also noteworthy that a variety of additional biomarkers were discovered and tested over the past three decades. These substantially included soluble fibrin monomers, thrombin– antithrombin complex, plasmin-antiplasmin complex, fibrinopeptide, prothrombin fragment 1 þ 2, thrombus precursor protein, activated protein C–protein C inhibitor complex, and myeloperoxidase. Nonetheless, none of them made it through the clinical practice for a variety of reasons, including lower analytical sensitivity, necessity of more cumbersome or time consuming procedures, as well as the higher costs compared with D-dimer.72 In the late 1980s, D-dimer testing was introduced in diagnosis and management of a variety of thrombosis-related clinical conditions, including disseminated intravascular coagulation (DIC), VTE, ischemic cardiopathy, stroke, and thrombolytic therapy. Merits and pitfalls have been recognized for all these applications,73 leading to the conclusion that the only clinical advantage of a D-dimer assay appeared to be the exclusion of DVT/PE or DIC when the level of D-dimer was normal.74–77 The main reason being that D-dimers become elevated in a variety of disorders and diseases, so that a positive D-dimer is nonspecific. Once the use of D-dimer was recognized as the biochemical gold standard for ruling out VTE or DIC, increasing efforts have been made to validate assays that could be usable in the clinical and laboratory practice. In the 1990s, several assays based on monoclonal antibodies to various preparations of D-dimer have been developed, which were essentially based on three major techniques: latex agglutination assays, wholeblood erythrocyte agglutination assay, and enzyme-linked immunosorbent assays (ELISAs).75 The available information about the use of the various commercially available D-dimer assays in the diagnostic approach of clinically suspected VTE in distinct patient populations and clinic situations were first reviewed in 1997 by Bounameaux et al,78 and then updated by the same research group in 2008.79 These and other authors80 concluded that the ELISA D-dimer assays and automated latex immunoturbidimetric tests showed much higher sensitivity than the whole-blood agglutination assay (up to 1.00 compared), and a greater accuracy attributable to the lower interobserver variability.81 As such, after more than 20 years from its first introduction in clinical practice, D-dimer testing is still considered the mainstay in the laboratory diagnostic approach of patients with suspected VTE across multiple health-care settings.11 Convincing evidence has also recently emerged that D-dimer values may be effectively used for predicting the risk of recurrent thrombosis82,83 or embolization in patients with atrial fibrillation.84 Another important breakthrough, which will probably contribute to increase the clinical effectiveness of D-dimer testing, is represented by the use of age-adjusted diagnostic thresholds,85 which is justified by the fact that D-dimer values gradually increases with aging.86 It is worth
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fibrin-specific immunoconjugates, fibrinolytic-bearing red blood cells, or nanoparticles.95 Initial evidence about the possibility of ex vivo thrombus detection was published in the late 1980s, when radioiodinated conjugates of antifibrin monoclonal antibodies were successfully used to identify vascular thrombosis in animal models.96 These techniques were then applied to the human model. In particular, the results of a preliminary phase I trial, in which 26 patients with acute lower limb DVT were injected with a radiolabeled monoclonal Fab’ fragment with affinity and specificity for D-dimer,97 showed that efficient localization of thrombosis could be achieved as early as 30-minute postinjection with no relevant side effects other than mild hypertension, modest increase of lactate dehydrogenase, and alanine transaminase. In a subsequent phase II study including 82 patients with suspected DVT,98 the injection of the same radiolabeled monoclonal Fab’ fragment allowed to diagnose proximal DVT with 0.84 sensitivity and 0.98 specificity, respectively. However, the accuracy for diagnosing distal DVT was overall lower (0.41 sensitivity and 0.90 specificity, respectively), so it was concluded that additional studies combining improved training for image readers and better timing of images acquisition are needed. Interestingly, specific nanoparticles have also been developed, which locally accumulated in the site of thrombosis, thus allowing the direct (rather than indirect, in terms of “filling defect”) CT visualization of both the presence and extent of primary and recurrent thrombi.99 Likewise, fibrinspecific contrast agents have also been developed for the accurate quantification of fibrin content, which were proven effective to reliably visualize thrombus localization and size by means of MRI100,101 or PET.102 Therefore, emerging evidence suggests that thrombus-targeted imaging using radioiodinated monoclonal antibodies, small molecules or nanoparticles,103 may be regarded as an appealing technique for more accurate identification (with up to 1.00 sensitivity), origin detection, and molecular, spatial, and temporal characterization (i.e., age, composition, stability) of venous clots, even those with the smallest extension and peripheral localization.104,105 Some drawbacks should be considered, however. These typically include the costs, which are currently much higher than those of conventional imaging techniques, along with the longer time required for performing the tests compared with the current gold standards (i.e., ultrasound and CT).
Thrombin Generation Another appealing perspective is represented by thrombin generation assays in plasma, platelet poor plasma, or whole blood.108 Thrombin generation is sensitive to both pro- and anticoagulant processes, and it can hence be used for general characterization of a broad range of thrombotic and bleeding disorders. Recent evidence suggests that these techniques may provide useful information for diagnosing VTE and predicting recurrence.109 In particular, thrombin generation of patients with DVT shows higher endogenous thrombin potential and peak height compared with the reference population.110 As for thrombus-targeted molecular imaging, however, the current assay formats are not suited for a rapid and efficient diagnosis of VTE, and additional refinements would be needed before they can replace D-dimer testing in the diagnostic algorithms of suspected VTE.
Proteomics The traditional coagulation tests such as FDP and D-dimer are indeed useful for identifying major prothrombotic abnormalities, but their diagnostic specificity is still suboptimal for distinguishing VTE from other clinical conditions characterized by concomitant activation of blood coagulation and fibrinolysis.111 It is hence predictable that large-scale study of proteins, along with the investigation of their structure and function, would be effective to target entire biological pathways or suggestive pathophysiological interactions, which may assist the early and accurate diagnosis of VTE. The use of proteomics for studying clot phenotype and platelet proteome is hence regarded as an appealing perspective in the field of venous thrombosis, in which several cellular and plasma components interplay during the development and complication of DVT and/or PE. Some promising results were published over the past decades,112 although the complete movement from the bench to the bedside remains challenging.
Conclusion VTE is a life-threatening condition that requires an accurate and timely diagnosis. The current diagnostic approach to this condition, that is the result of decades of scientific and medical research, includes diagnostic imaging of both DVT and PE, along with biological markers such as D-dimer. Although representing major advances over the years, this armamentarium provides a suboptimal approach for the diagnosis of VTE. The development of more efficient diagnostic tools may improve diagnosis and thus clinical outcomes in the future.
Infrared Thermal Imaging Infrared thermal imaging (IRTI) is a technique based on the use of naturally emitted infrared radiation from the skin surface, with diagnostic applications in a large number of human diseases.106 As regard to VTE, Deng et al recently studied nine rabbits, which had one femoral vein embolized (the contralateral served as a nonembolized control).107 The use of IRTI allowed DVT detection in all animals, and it was hence concluded that this technique might be regarded as a reliable screening tool for the efficient and rapid screening of DVT. Seminars in Thrombosis & Hemostasis
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tomography in suspected pulmonary embolism. N Engl J Med 2005;352(17):1760–1768 Righini M, Le Gal G, Aujesky D, et al. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008;371(9621):1343–1352 Moores LK, Jackson WL Jr, Shorr AF, Jackson JL. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 2004;141(11):866–874 Meaney JF, Weg JG, Chenevert TL, Stafford-Johnson D, Hamilton BH, Prince MR. Diagnosis of pulmonary embolism with magnetic resonance angiography. N Engl J Med 1997;336(20):1422–1427 Oudkerk M, van Beek EJ, Wielopolski P, et al. Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Lancet 2002;359(9318): 1643–1647 Geva T. Magnetic resonance imaging: historical perspective. J Cardiovasc Magn Reson 2006;8(4):573–580 Stein PD, Chenevert TL, Fowler SE, et al; PIOPED III (Prospective Investigation of Pulmonary Embolism Diagnosis III) Investigators. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med 2010;152(7):434–443, W142-3 Seegers WH, Nieft ML, Vandenbelt JM. Decomposition products of fibrinogen and fibrin. Arch Biochem 1945;7:15–19 Nussenzweig V, Seligmann M, Pelmont J, Grabar P. The products of degradation of human fibrinogen by plasmin. I. Separation and physicochemical properties. Ann Inst Pasteur (Paris) 1961; 100:377–389 Marder VJ, Shulman NR, Carroll WR. High molecular weight derivatives of human fibrinogen produced by plasmin. I. Physicochemical and immunological characterization. J Biol Chem 1969;244(8):2111–2119 Hall CE, Slayter HS. The fibrinogen molecule: its size, shape, and mode of polymerization. J Biophys Biochem Cytol 1959;5(1): 11–16 Gaffney PJ. Subunit relationships between fibrinogen and fibrin degradation products. Thromb Res 1973;2(3):201–207 Kopec M, Teisseyre E, Dudek-Wojciechowska G, Kloczewiak M, Pankiewicz A, Latallo ZS. Studies on the “Double D” fragment from stabilized bovine fibrin. Thromb Res 1973;2:283–291 Dudek GA, Kloczewiak M, Budzyński AZ, Latallo ZS, Kopeć M. Characterisation and comparison of macromolecular end products of fibrinogen and fibrin proteolysis by plasmin. Biochim Biophys Acta 1970;214(1):44–51 Schwartz ML, Pizzo SV, Hill RL, McKee PA. Human Factor XIII from plasma and platelets. Molecular weights, subunit structures, proteolytic activation, and cross-linking of fibrinogen and fibrin. J Biol Chem 1973;248(4):1395–1407 Hudry-Clergeon G, Paturel L, Suscillon M. Identification of a (D-D)...E complex in degradation products of bovine fibrin stabilized by factor XIII [in French]. Pathol Biol (Paris) 1974;22 (Suppl):47–52 Graeff H, Hafter R, Bachmann L. Subunit and macromolecular structure of circulating fibrin from obstetric patients with intravascular coagulation. Thromb Res 1979;16(3-4):313–328 Donati MB. Assays for fibrinogen-fibrin degradation products in biological fluids: some methodological aspects. Thromb Diath Haemorrh 1975;34(3):652–660 Rylatt DB, Blake AS, Cottis LE, et al. An immunoassay for human D dimer using monoclonal antibodies. Thromb Res 1983;31(6): 767–778 Gaffney PJ, Perry MJ. Unreliability of current serum fibrin degradation product (FDP) assays. Thromb Haemost 1985;53(3): 301–302
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markers for the diagnosis of venous thromboembolism: the past, present and future. J Thromb Thrombolysis 2010;30(4): 459–471 Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011;57(9):1256–1262 Lippi G, Mengoni A, Manzato F. Plasma D-dimer in the diagnosis of deep vein thrombosis. JAMA 1998;280(21):1828–1829 Bates SM. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Hemost 2012;38(7):673–682 Franchini M, Lippi G, Manzato F. Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation. Thromb J 2006;4:4 Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost 2010;36(4):458–467 Bounameaux H, de Moerloose P, Perrier A, Miron MJ. D-dimer testing in suspected venous thromboembolism: an update. QJM 1997;90(7):437–442 Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008;6(7):1059–1071 Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009;113(13):2878–2887 Di Nisio M, Squizzato A, Rutjes AW, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007;5(2):296–304 Douketis J, Tosetto A, Marcucci M, et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ 2011;342:d813 Kyrle PA, Eichinger S. Clinical scores to predict recurrence risk of venous thromboembolism. Thromb Haemost 2012;108(6): 1061–1064 Danese E, Montagnana M, Cervellin G, Lippi G. Hypercoagulability, D-dimer and atrial fibrillation: an overview of biological and clinical evidence. Ann Med 2014;46(6):364–371 Lippi G, Favaloro EJ, Cervellin G. A review of the value of D-dimer testing for prediction of recurrent venous thromboembolism with increasing age. Semin Thromb Hemost 2014;40(6): 634–639 Lippi G, Bonfanti L, Saccenti C, Cervellin G. Causes of elevated D-dimer in patients admitted to a large urban emergency department. Eur J Intern Med 2014;25(1):45–48 Dempfle CE. D-dimer: standardization versus harmonization. Thromb Haemost 2006;95(3):399–400 Lippi G, Avanzini P, Zobbi V, Ippolito L. Influence of mechanical hemolysis of blood on two D-dimer immunoassays. Blood Coagul Fibrinolysis 2012;23(5):461–463 Lippi G, Ippolito L, Tondelli MT, Favaloro EJ. Interference from heterophilic antibodies in D-dimer assessment. A case report. Blood Coagul Fibrinolysis 2014;25(3):277–279 Lippi G, Favaloro EJ, Franchini M. Dangers in the practice of defensive medicine in hemostasis testing for investigation of bleeding or thrombosis: Part I—Routine coagulation testing. Semin Thromb Hemost 2014;40(7):812–824 Bates SM, Jaeschke R, Stevens SM, et al; American College of Chest Physicians. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(2, Suppl):e351S–e418S Lapner ST, Kearon C. Diagnosis and management of pulmonary embolism. BMJ 2013;346:f757 Lippi G, Franchini M, Targher G, Favaloro EJ. Help me, Doctor! My D-dimer is raised. Ann Med 2008;40(8):594–605 Lippi G. Wisdom of theragnostics, other changes. MLO Med Lab Obs 2008;40(1):6
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thrombus-targeted fibrinolysis. Semin Thromb Hemost 2013; 39(1):48–58 Knight LC. Imaging thrombi with radiolabelled anti-fibrin monoclonal antibodies. Nucl Med Commun 1988;9(10):823–829 Macfarlane D, Socrates A, Eisenberg P, et al. Imaging of deep venous thrombosis in patients using a radiolabelled anti-D-dimer Fab’ fragment (99mTc-DI-DD3B6/22-80B3): results of a phase I trial. Eur J Nucl Med Mol Imaging 2009;36(2):250–259 Douketis JD, Ginsberg JS, Haley S, et al. Accuracy and safety of (99m)Tc-labeled anti-D-dimer (DI-80B3) Fab’ fragments (ThromboView®) in the diagnosis of deep vein thrombosis: a phase II study. Thromb Res 2012;130(3):381–389 Kim DE, Kim JY, Sun IC, et al. Hyperacute direct thrombus imaging using computed tomography and gold nanoparticles. Ann Neurol 2013;73(5):617–625 Vymazal J, Spuentrup E, Cardenas-Molina G, et al. Thrombus imaging with fibrin-specific gadolinium-based MR contrast agent EP-2104R: results of a phase II clinical study of feasibility. Invest Radiol 2009;44(11):697–704 Andia ME, Saha P, Jenkins J, et al. Fibrin-targeted magnetic resonance imaging allows in vivo quantification of thrombus fibrin content and identifies thrombi amenable for thrombolysis. Arterioscler Thromb Vasc Biol 2014;34(6):1193–1198 Ciesienski KL, Yang Y, Ay I, et al. Fibrin-targeted PET probes for the detection of thrombi. Mol Pharm 2013;10(3):1100–1110
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imaging: a novel technique for imaging venous thromboemboli. Thromb Haemost 2003;89(5):773–782 van Langevelde K, Srámek A, Vincken PW, van Rooden JK, Rosendaal FR, Cannegieter SC. Finding the origin of pulmonary emboli with a total-body magnetic resonance direct thrombus imaging technique. Haematologica 2013;98(2):309–315 Ring EF, Ammer K. Infrared thermal imaging in medicine. Physiol Meas 2012;33(3):R33–R46 Deng F, Tang Q, Zheng Y, Zeng G, Zhong N. Infrared thermal imaging as a novel evaluation method for deep vein thrombosis in lower limbs. Med Phys 2012;39(12):7224–7231 Tripodi A. A(nother) test meant to fill the gap between in vivo and ex vivo hemostasis. Clin Chem 2014;60(9):1137–1140 Ten Cate H. Thrombin generation in clinical conditions. Thromb Res 2012;129(3):367–370 ten Cate-Hoek AJ, Dielis AW, Spronk HM, et al. Thrombin generation in patients after acute deep-vein thrombosis. Thromb Haemost 2008;100(2):240–245 Hayward CP, Webert KE. Expert approaches to common bleeding and thrombotic problems, part II. Semin Thromb Hemost 2013; 39(2):113–116 Lippi G, Favaloro EJ, Plebani M. Proteomic analysis of venous thromboembolism. Expert Rev Proteomics 2010;7(2):275–282
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95 Lippi G, Mattiuzzi C, Favaloro EJ. Novel and emerging therapies:
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Diagnostics in Venous Thromboembolism: From Origin to Future Prospects Giuseppe Lippi, MD1 Elisa Danese, PhD2 Emmanuel J. Favaloro, PhD FFSc (RCPA)3 Martina Montagnana, MD2 Massimo Franchini, MD4
of Parma, Parma, Italy 2 Clinical Biochemistry Section, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy 3 Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, Westmead Hospital, Westmead, New South Wales, Australia 4 Department of Hematology and Transfusion Medicine, Azienda Ospedaliera Carlo Poma, Mantova, Italy
Address for correspondence Giuseppe Lippi, MD, Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Via Gramsci 14, 43126 - Parma, Italy (e-mail: [email protected]).
Semin Thromb Hemost 2015;41:374–381.
Abstract
Keywords
► venous thromboembolism ► deep vein thrombosis ► pulmonary embolism ► diagnosis ► D-dimer
Venous thromboembolism (VTE) is a prevalent and life-threatening condition that requires an accurate and timely diagnosis. The current diagnostic approach to this condition, entailing an efficient integration of clinical judgment, diagnostic imaging, and laboratory testing, is the result of decades of scientific and medical research. This article aims to present and discuss the major breakthroughs that have occurred in the diagnostic imaging of both deep vein thrombosis and pulmonary embolism, along with the various biological markers that have emerged from the laboratory bench and which have only marginally migrated to the bedside. Despite decades of research, the current diagnostic armamentarium for an efficient diagnosis of VTE remains suboptimal, and some wiggle room remains for the development of more efficient diagnostic tools, which may include thrombus-targeted molecular imaging, infrared thermal imaging, thrombin generation, and proteomics.
Venous thromboembolism (VTE), which typically comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), has an estimated prevalence of 0.1 to 0.2% in the general population, which gradually increases with aging, from 1 per 100,000 in the young up to 1 per 100 in elderly subjects aged 80 years and older.1,2 A higher frequency of VTE cases has also been reported in hospitalized patients, and mainly due to the prevailing prothrombotic factors such as immobilization, infections, cancer, and surgery in this population.3 Approximately 90% of pulmonary emboli originates from the lower extremities, while upper extremity DVT embolization is less common, although the increasing use of central venous access devices has recently contributed to increase its frequency.4 Depending on the different epidemiological approaches, it has been estimated that the mortality rate of VTE ranges
from 10 to 30%, with the vast majority of deaths occurring in patients with PE,1 which is hence currently regarded as the third most common cause of vascular death only preceded by myocardial infarction and stroke, as well as the leading preventable cause of death in hospitalized patients.5,6 Indeed, the overall world-wide morbidity and mortality burden associated to thrombosis is very significant, and VTE causes a major burden of disease across all socioeconomic classes and low-, middle-, and high-income countries. 7 The current diagnostic approach to VTE, entailing an efficient integration of clinical judgment,8 diagnostic imaging,9,10 and laboratory testing,11 is the result of decades of scientific and medical research, which is outlined in subsequent sections of this article.
published online April 14, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Issue Theme Hot Topics VII; Guest Editor: Emmanuel J. Favaloro, PhD, FFSc (RCPA).
DOI http://dx.doi.org/ 10.1055/s-0034-1544003. ISSN 0094-6176.
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1 Laboratory of Clinical Chemistry and Hematology, Academic Hospital
History of Diagnostic Imaging in Deep Vein Thrombosis Christian Doppler, an Austrian mathematician and physicist, in 1841 originally discovered that the frequency of a wave depends on both the relative speed of source and observer.12 The first application of the Doppler principle in clinical medicine has been then attributed to the work of H. P. Kalmus, who described in 1954 how flow velocity in fluids could be determined by measuring the phase difference between an upstream and downstream ultrasonic wave. In 1959, Franklin et al first developed a flowmeter that could be mounted directly on blood vessels.13 In the same year, it was also reported that the Doppler frequency shift could be used for detection of blood velocity patterns12 and, shortly afterward, a team of scientists from the University of Washington published their work on a flowmeter, which was successfully used to record blood flow through intact vessels in dogs.13 Later, in 1964, D. W. Baker and H. F. Stegall developed the first Doppler instrument intended for transcutaneous measurement of blood flow velocity in man using the continuous wave Doppler principle.14 In the following year, it was demonstrated that continuous wave Doppler ultrasonography had applications and provided good results in visualizing occlusive clots without extensive collaterals (►Fig. 1).15 The first pulsed-wave Doppler, consisting of intermittent (pulsed) bursts of ultrasound at a frequency called the pulse repetition frequency, was produced in 1970.16 Around the mid-1970s, ultrasonic angiography (consisting of a pulsed ultrasonic flow detector and a B-scanner) was successfully used in the diagnosis of DVT.17 A major breakthrough occurred when Talbot18 and Cronan19 combined B-mode imaging and pulse Doppler together, to describe the cardinal signs of DVT on ultrasound. Finally, additional data were obtained by the use
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of color Doppler ultrasound in the mid-1980s, which allowed detection and visualization of movement toward and away from the added ultrasound transducer.20,21 Before the 1970s, the diagnosis of DVT had been mostly performed by venography, through injection of dyes into a vein, which allowed visualization of the vein on X-ray. This method was subsequently largely replaced by noninvasive medical approaches such as impedance plethysmography.22,23 This technique measures the change in blood volume by registering small electrical resistance variations of leg or arm while a thigh cuff is inflated.24 Accordingly, the blood volume varies in direct relationship with the electrical conductance and inversely with the resistive electrical impedance of the conductor.25 Although the history of impedance plethysmography dates back to 1932, when Atzler and Lehmann observed changes in the capacitance between two parallel plates kept across the human chest, this technique was only introduced for the diagnosis of DVT 50 years later by Wheeler et al, who described its principles and clinical applications.26,27 Initially, the method was based on the maximum respiratory effort, and then modified by replacing the respiratory approach with the occlusive pneumatic thigh cuff technique.28,29 This method has remained virtually unchanged up to date. The computed tomography venography, which was developed during the 1990s, is a method which provides direct imaging of the veins immediately after helical computed tomographic pulmonary angiography, without injection of additional contrast material or with less contrast media than conventional venography.30 The technique was originally reported by Stehling et al in 1994,31 and has rapidly found broad application in DVT diagnostics along with magnetic resonance imaging (MRI) venography.32–36
Fig. 1 The brief history of diagnostics of venous thromboembolism.
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History of Diagnostic Imaging in Pulmonary Embolism Before the development of objective diagnostic standards in the second half of the past century (i.e., electrocardiogram and chest radiograph), the diagnosis of PE was essentially based on clinical judgment.37 The availability of more sophisticated diagnostic procedures has greatly assisted physicians to diagnose PE in recent years.38 The imaging approaches to diagnose PE currently entail pulmonary angiography, ventilation/perfusion scanning, computed tomography angiography, and MRI.39–41 Pulmonary angiography was first described by Robb and Steinberg in 1939,42 and its development greatly facilitated the diagnosis of PE and also provided opportunities to understand its underlying pathophysiological processes. Although pulmonary angiography is still considered the reference test for establishing the presence or absence of PE,43 its invasiveness and limited availability greatly limits the routine use. Moreover, the procedure has some technical limitations for visualization of peripheral embolization and is also plagued by a large variation in interobserver agreement.44,45 For these reasons, this diagnostic procedure is indicated for those patients where noninvasive tests are inconclusive.46 Ventilation/perfusion lung scintigraphy is a noninvasive technique originally developed nearly 50 years ago.47 This method allows the visualization of pulmonary perfusion through intravenous injection of isotopically labeled microaggregates of human albumin. Although a normal perfusion scan virtually rules out PE, an abnormal perfusion scan is substantially nonspecific. Due to the significant rate of “positive” but nondiagnostic results, the use of lung scintigraphy has dramatically declined over the past 15 years, largely replaced by CT angiography.48 Since the first report in 1978 of diagnosis of PE using CT,49 this imaging technology has greatly evolved, gradually assuming the role of the leading imaging modality in patients with suspected PE.43 Wide variations in both sensitivity (0.53–1.00) and specificity (0.73–1.00) have been reported in the literature on the performance of single-detector CT angiography.50 In this respect, multidetector CT angiography appears more sensitive than single-detector CT angiography, thus allowing exclusion of PE without additional compression ultrasonography of the leg.51,52 Notably, a meta-analysis analyzing 23 studies with 4,657 patients with a negative CT angiography who did not receive anticoagulation treatment showed a 3-month rate of subsequent VTE of 1.4% (95% confidence interval [CI], 1.1–1.8) and a 3-month rate of fatal PE of 0.51% (95% CI, 0.33–0.76), comparing favorably with the results observed after a standard invasive contrast pulmonary angiogram.53 In recent years, gadolinium-enhanced MRI angiography has also emerged as an alternative diagnostic imaging modality due to its avoidance of exposure to ionizing radiation.54,55 This technology, first developed in the 1970s,56 reached a sensitivity of 0.78 and a specificity of 0.99 in technically adequate images, according to a recent multicenter prospective study.57 Magnetic resonance angiography is, Seminars in Thrombosis & Hemostasis
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however, an expensive, limited, and time-consuming resource, and should hence be considered only in centers where it is routinely performed and only in patients for whom standard tests are contraindicated.
History of Biomarkers in Venous Thromboembolism The investigation of potential biomarkers of VTE began in earnest in 1945, when Seegers et al demonstrated that plasmin digested fibrinogen consisted of two major electrophoretic fragments called α- and β-fibrinogen.58 Almost one decade later, Nussenzweig et al performed the first comprehensive evaluation of plasmin–fibrinogen interactions and classified the fractions resulting from fibrinogen cleavage, as A, B, C, D, and E fragments based on the order of their elution from the ion exchange chromatographic column.59 Afterward, two further intermediate cleavage fragments named X and Y were recognized by Marder et al,60 who also provided the missing step for making physiochemical characterization of fibrin degradation products (FDP) match with the threedimensional structures previously provided by electron microscopy.61 In 1973, two independent research groups first identified a unique fragment of exclusive fibrin derivation, which was originally named “Double D.”62,63 This fragment was characterized as containing two D domains instead of the single one typically found after fibrinogen digestion.64 The D domains were then shown to originate from two adjacent fibrin molecules, held together by the cross-linked γ-chain remnants of the originating fibrin.65 Meanwhile, it was also demonstrated that this peptide, which was eventually called “D-dimer” is frequently associated with an E domain in a noncovalent manner, thus forming an electrophoretically stable D-dimer–E complex, the D2E entity.66 D-dimer was originally presumed to represent the largest soluble fragment derived from cross-linked insoluble fibrin. However, this assumption was rapidly discredited in 1979 by Graeff and coauthors, who showed that higher molecular weight and large cross-linked FDP called X-oligomers were the predominant FDP fraction in vivo.67 The evidence that the formation of FDP in the circulation represents the most tangible demonstration of ongoing fibrinolysis in blood prompted researchers to develop immunologic assays for qualitative (i.e., positive/negative) FDP measurement ex vivo. These first assays lacked specificity, as they were mostly based on polyclonal antibodies against fibrinogen and its fragments,68 so that they could not adequately distinguish between fibrinogen and FDPs. In the early 1980s, a new generation of monoclonal antibodies became available,69 which were used to specifically bind to epitopes on D-dimer fragments that are absent on fibrin, fibrinogen, and non– cross-linked fragments of fibrin, thus enabling higher specificity in the assessment of D-dimer as a biomarker of fibrin formation and stabilization.70 Although additional biomarkers emerged at that time (i.e., fibrinopeptide A [FPA] and soluble fibrin) and gained limited popularity for a period of time as biomarkers of a prethrombotic state, the short
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mentioning here, however, that some technical problems still plague D-dimer testing in clinical laboratories, and these substantially include a poor harmonization due to the lack of a reference material and a reference method,87 and the potential analytical interference from hemolysis88 or heterophilic antibodies.89 Thus, there will be occasions in which D-dimer results from a patient with or without thrombosis will be positive with one method, but negative with another, or may be positive or negative on one sample, but not on another.90
Future Perspectives Despite decades of basic and applied research, the current diagnostic armamentarium for an efficient diagnosis of VTE remains suboptimal. The use of D-dimer or ultrasound of the proximal veins in patients with suspected DVT,91 along with D-dimer, CT pulmonary angiography, or ventilation-perfusion scanning when CT pulmonary angiography is inconclusive in patients with suspected PE,92 have enormously improved the diagnostic efficiency, but several cases remain still undiagnosed. These particularly include DVT patients with small and distal thrombosis, as well as patients with peripheral (military) pulmonary embolization.93 In these cases, the level of thrombosis, or the “remoteness” of the thrombosis, leads to plasma levels of D-dimer that are indistinguishable from the normal “background” level (typically < 500 ng/mL as fibrinogen equivalent units). Here, it may also be worth noting that normal physiological “wear and tear” processes are always in progress in all of us, and so D-dimer levels in plasma are never “zero.” It can also be concluded that some wiggle room remains for further research on this issue, and for the development of more sensitive markers of thrombus formation or lysis (►Table 1).
Theragnostics and Beyond The use of theragnostics, which is a treatment strategy that combines therapeutics with diagnostics, is prepotently emerging in several areas of clinical medicine, including diagnostics and therapy of thrombotic disorders.94 More specifically, recent technical innovations are considerably improving the array of therapeutic agents for treatment of thrombotic and occlusive disorders, most notably entailing thrombus-targeted fibrinolytic therapy with tissue- and
Table 1 Innovative thromboembolism
techniques
for
diagnosing
venous
1. Thrombus-targeted molecular imaging a. Radioiodinated monoclonal antibodies b. Small molecules with fibrin affinity c. Nanoparticles 2. Infrared thermal imaging 3. Thrombin generation 4. Proteomics
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half-life of these peptides was incompatible with the criteria of a reliable VTE diagnostics. Therefore, it became soon clear that the only robust test in this area was D-dimer, as Gaffney had already perceived as far back as 1972.71 It is also noteworthy that a variety of additional biomarkers were discovered and tested over the past three decades. These substantially included soluble fibrin monomers, thrombin– antithrombin complex, plasmin-antiplasmin complex, fibrinopeptide, prothrombin fragment 1 þ 2, thrombus precursor protein, activated protein C–protein C inhibitor complex, and myeloperoxidase. Nonetheless, none of them made it through the clinical practice for a variety of reasons, including lower analytical sensitivity, necessity of more cumbersome or time consuming procedures, as well as the higher costs compared with D-dimer.72 In the late 1980s, D-dimer testing was introduced in diagnosis and management of a variety of thrombosis-related clinical conditions, including disseminated intravascular coagulation (DIC), VTE, ischemic cardiopathy, stroke, and thrombolytic therapy. Merits and pitfalls have been recognized for all these applications,73 leading to the conclusion that the only clinical advantage of a D-dimer assay appeared to be the exclusion of DVT/PE or DIC when the level of D-dimer was normal.74–77 The main reason being that D-dimers become elevated in a variety of disorders and diseases, so that a positive D-dimer is nonspecific. Once the use of D-dimer was recognized as the biochemical gold standard for ruling out VTE or DIC, increasing efforts have been made to validate assays that could be usable in the clinical and laboratory practice. In the 1990s, several assays based on monoclonal antibodies to various preparations of D-dimer have been developed, which were essentially based on three major techniques: latex agglutination assays, wholeblood erythrocyte agglutination assay, and enzyme-linked immunosorbent assays (ELISAs).75 The available information about the use of the various commercially available D-dimer assays in the diagnostic approach of clinically suspected VTE in distinct patient populations and clinic situations were first reviewed in 1997 by Bounameaux et al,78 and then updated by the same research group in 2008.79 These and other authors80 concluded that the ELISA D-dimer assays and automated latex immunoturbidimetric tests showed much higher sensitivity than the whole-blood agglutination assay (up to 1.00 compared), and a greater accuracy attributable to the lower interobserver variability.81 As such, after more than 20 years from its first introduction in clinical practice, D-dimer testing is still considered the mainstay in the laboratory diagnostic approach of patients with suspected VTE across multiple health-care settings.11 Convincing evidence has also recently emerged that D-dimer values may be effectively used for predicting the risk of recurrent thrombosis82,83 or embolization in patients with atrial fibrillation.84 Another important breakthrough, which will probably contribute to increase the clinical effectiveness of D-dimer testing, is represented by the use of age-adjusted diagnostic thresholds,85 which is justified by the fact that D-dimer values gradually increases with aging.86 It is worth
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fibrin-specific immunoconjugates, fibrinolytic-bearing red blood cells, or nanoparticles.95 Initial evidence about the possibility of ex vivo thrombus detection was published in the late 1980s, when radioiodinated conjugates of antifibrin monoclonal antibodies were successfully used to identify vascular thrombosis in animal models.96 These techniques were then applied to the human model. In particular, the results of a preliminary phase I trial, in which 26 patients with acute lower limb DVT were injected with a radiolabeled monoclonal Fab’ fragment with affinity and specificity for D-dimer,97 showed that efficient localization of thrombosis could be achieved as early as 30-minute postinjection with no relevant side effects other than mild hypertension, modest increase of lactate dehydrogenase, and alanine transaminase. In a subsequent phase II study including 82 patients with suspected DVT,98 the injection of the same radiolabeled monoclonal Fab’ fragment allowed to diagnose proximal DVT with 0.84 sensitivity and 0.98 specificity, respectively. However, the accuracy for diagnosing distal DVT was overall lower (0.41 sensitivity and 0.90 specificity, respectively), so it was concluded that additional studies combining improved training for image readers and better timing of images acquisition are needed. Interestingly, specific nanoparticles have also been developed, which locally accumulated in the site of thrombosis, thus allowing the direct (rather than indirect, in terms of “filling defect”) CT visualization of both the presence and extent of primary and recurrent thrombi.99 Likewise, fibrinspecific contrast agents have also been developed for the accurate quantification of fibrin content, which were proven effective to reliably visualize thrombus localization and size by means of MRI100,101 or PET.102 Therefore, emerging evidence suggests that thrombus-targeted imaging using radioiodinated monoclonal antibodies, small molecules or nanoparticles,103 may be regarded as an appealing technique for more accurate identification (with up to 1.00 sensitivity), origin detection, and molecular, spatial, and temporal characterization (i.e., age, composition, stability) of venous clots, even those with the smallest extension and peripheral localization.104,105 Some drawbacks should be considered, however. These typically include the costs, which are currently much higher than those of conventional imaging techniques, along with the longer time required for performing the tests compared with the current gold standards (i.e., ultrasound and CT).
Thrombin Generation Another appealing perspective is represented by thrombin generation assays in plasma, platelet poor plasma, or whole blood.108 Thrombin generation is sensitive to both pro- and anticoagulant processes, and it can hence be used for general characterization of a broad range of thrombotic and bleeding disorders. Recent evidence suggests that these techniques may provide useful information for diagnosing VTE and predicting recurrence.109 In particular, thrombin generation of patients with DVT shows higher endogenous thrombin potential and peak height compared with the reference population.110 As for thrombus-targeted molecular imaging, however, the current assay formats are not suited for a rapid and efficient diagnosis of VTE, and additional refinements would be needed before they can replace D-dimer testing in the diagnostic algorithms of suspected VTE.
Proteomics The traditional coagulation tests such as FDP and D-dimer are indeed useful for identifying major prothrombotic abnormalities, but their diagnostic specificity is still suboptimal for distinguishing VTE from other clinical conditions characterized by concomitant activation of blood coagulation and fibrinolysis.111 It is hence predictable that large-scale study of proteins, along with the investigation of their structure and function, would be effective to target entire biological pathways or suggestive pathophysiological interactions, which may assist the early and accurate diagnosis of VTE. The use of proteomics for studying clot phenotype and platelet proteome is hence regarded as an appealing perspective in the field of venous thrombosis, in which several cellular and plasma components interplay during the development and complication of DVT and/or PE. Some promising results were published over the past decades,112 although the complete movement from the bench to the bedside remains challenging.
Conclusion VTE is a life-threatening condition that requires an accurate and timely diagnosis. The current diagnostic approach to this condition, that is the result of decades of scientific and medical research, includes diagnostic imaging of both DVT and PE, along with biological markers such as D-dimer. Although representing major advances over the years, this armamentarium provides a suboptimal approach for the diagnosis of VTE. The development of more efficient diagnostic tools may improve diagnosis and thus clinical outcomes in the future.
Infrared Thermal Imaging Infrared thermal imaging (IRTI) is a technique based on the use of naturally emitted infrared radiation from the skin surface, with diagnostic applications in a large number of human diseases.106 As regard to VTE, Deng et al recently studied nine rabbits, which had one femoral vein embolized (the contralateral served as a nonembolized control).107 The use of IRTI allowed DVT detection in all animals, and it was hence concluded that this technique might be regarded as a reliable screening tool for the efficient and rapid screening of DVT. Seminars in Thrombosis & Hemostasis
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