Accuracy and safety of 99mTc-labeled anti-D-dimer (DI-80B3) Fab’ fragments (ThromboView®) in the diagnosis of deep vein thrombosis: A phase II study

doi:10.1016/j.thromres.2012.05.011

Thrombosis Research

Volume 130, Issue 3, September 2012, Pages 381-389

https://doi.org/10.1016/j.thromres.2012.05.011 Get rights and content

Abstract

Background

The assessment of patients with suspected deep vein thrombosis (DVT) remains challenging despite current diagnostic algorithms. ^99mTc-labelled DI-DD3B6/22-80B3 Fab´ fragments (^99mTc-DI-80B3, ThromboView®) is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect DVT. This test has an anatomic component to locate DVT and a functional component to differentiate acute (newly formed) thrombus from inactive (old) thrombus.

Methods

In a multi-centre prospective cohort trial we investigated the diagnostic accuracy and safety of ^99mTc-DI-80B3 in consecutive patients with suspected DVT who had the diagnosis confirmed or excluded by venography.

Results

We enrolled 94 patients with suspected DVT of whom 12 did not have ^99mTc-DI-80B3 imaging, leaving 82 patients for the safety analysis. Of these patients, there were 16 with non-evaluable imaging (11 venography, 7 ^99mTc-DI-80B3, both in two patients) leaving 66 patients for the accuracy analysis. ^99mTc-DI-80B3 imaging was well-tolerated: 2 patients developed urticaria; none developed serious adverse events. For proximal DVT, the sensitivity (84.2%; 95% confidence interval [CI]: 62.4–94.5) and specificity (97.6%; CI: 83.3–99.4) were highest when the combined 0.25-hour and 3-hour ^99mTc-DI-80B3 images were used. The accuracy was lower for distal DVT, irrespective of the images used. There were insufficient patients to comment on the accuracy of ^99mTc-DI-80B3 imaging for suspected recurrent DVT.

Conclusions

^99mTc-DI-80B3 (ThromboView®) is a novel diagnostic modality for patients with suspected DVT with a promising accuracy and safety profile that justifies additional clinical development in diagnostic accuracy and clinical management studies.

Introduction

Despite advances in the assessment of patients with suspected lower limb deep vein thrombosis (DVT), the diagnosis of DVT remains challenging [1]. Recommended diagnostic algorithms, which typically incorporate a clinical prediction guide, D-dimer, and venous ultrasound, have limitations in at least three patient groups [1]. The first is patients with a moderate-to-high clinical suspicion for DVT and a normal venous ultrasound, in whom up to 10% will have DVT [2]. The second is patients with suspected recurrent DVT in whom venous ultrasound may not distinguish old from new disease [3]. The third is obese or edematous patients in whom venous ultrasound is technically difficult. In these patients, additional imaging with venography, computed tomography or magnetic resonance imaging may be required to identify DVT [4], [5]. However, venography and computed tomography are avoided in patients with renal insufficiency or contrast dye allergy and magnetic resonance imaging is not widely available.

^99mTc-labelled DI-DD3B6/22-80B3 Fab´ fragments (ThromboView®), hereafter referred to as ^99mTc-DI-80B3, is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect acute venous thromboembolism [6]. After intravenous injection, ^99mTc-DI-80B3 binds to the cross-linked “D” domains of fibrin in thrombi; this binding is visualized by gamma scintigraphy of both legs [7]. ^99mTc-DI-80B3 has unique properties as a diagnostic test because it combines an anatomic component, by identifying the location of DVT, and a functional component, by identifying acute (newly formed) DVT and differentiating it from old (inactive) DVT. These properties would enable ^99mTc-DI-80B3 to identify non-occlusive proximal DVT or distal DVT, which may be undetected with venous ultrasound, to differentiate an old thrombus from new DVT in patients with suspected recurrence, and to be used in obese or edematous patients in whom venous ultrasound may be difficult to interpret. Furthermore, ^99mTc-DI-80B3 does not require administration of intravenous contrast dye and is mostly non-invasive, requiring only an injection of radiolabelled monoclonal antibody (DI-80B3) into a peripheral vein.

A distinction is needed, however, between the D-dimer that is measured in the plasma/whole blood, which has poor specificity for DVT, and the D-dimer that is used with ^99mTc-DI-80B3 imaging. Whereas plasma/whole blood D-dimer testing often yields false positive results due to co-morbid illness such as cancer or non-thrombotic causes of leg swelling such as cellulitis, ^99mTc-DI-80B3 overcomes this limitation by providing anatomic images of D-dimer-rich acute thrombi when the plasma/whole blood D-dimer is positive, thereby distinguishing elevated D-dimer due to thrombotic and non-thrombotic causes. Based on these promising characteristics, we investigated the diagnostic accuracy and safety of ^99mTc-DI-80B3 in patients with suspected first or recurrent DVT.

Section snippets

Study Design

We undertook a multi-centre, phase II, prospective cohort trial with two aims: i) to investigate the diagnostic accuracy (sensitivity and specificity) of ^99mTc-DI-80B3 in patients with suspected DVT who had DVT confirmed or excluded by a reference standard test (venography); and ii) to investigate the safety of ^99mTc-DI-80B3 over a 90-day follow-up period. This study was approved by the Institutional Review Boards of all participating hospitals and all study patients provided written informed

Patient Population

We enrolled 94 patients with suspected leg DVT. The derivation of patients used for the safety and efficacy analyses is shown in Fig. 1. There were 82 patients who had ^99mTc-DI-80B3 imaging and were included in the safety analysis; these patients’ characteristics are shown in Table 1. Of these 82 patients, there were 16 with non-evaluable imaging studies (11 venography, 7 ^99mTc-DI-80B3, both in two patients), thereby leaving 66 patients for the accuracy analysis.

Suspected First DVT

There were 53 such patients in

Discussion

There are three principal findings from this study. Firstly, in patients with suspected first DVT ^99mTc-DI-80B3 imaging based on the combined 0.25-hour and 3-hour images has adequate sensitivity (84.2%) and specificity (97.6%) to diagnose and exclude proximal DVT, which is considered the most clinically important type of DVT. The high specificity suggests that this imaging modality can confirm DVT when other imaging tests are inconclusive. The 0.25-hour (blood pool) image allows the reader to

Conflict of Interest Statement

All co-authors have declared any potential conflicts of interests.

Acknowledgments

The Steering Committee consisted of Drs. James Douketis (Chair), Philip Comp, Paul Eisenberg (consultant to AGEN Biomedical Ltd.), Jeff Ginsberg, Tim Morris, and Richard White. The Data Safety and Monitoring Committee consisted of Drs. Robin Roberts (Chair) and Jeff Weitz. The Venography Adjudication Committee consisted of Drs. Jack Hirsh (Chair), Graham Turpie, Clive Kearon, and Jeff Weitz. The ^99mTc-DI-80B3 Adjudication Committee consisted of Drs. Paul Thomas, Fred Khafagi, and Sam

References (19)

D.J. Brotman et al.
Limitations of D-dimer testing in unselected patients with suspected venous thromboembolism
Am J Med
(2003)
D.B. Rylatt et al.
An immunoassay for human D dimer using monoclonal antibodies
Thromb Res
(1983)
E. Lamoyi et al.
Preparation of F(ab')2 fragments from mouse IgG of various subclasses
J Immunol Methods
(1983)
A. Trotti et al.
CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment
Semin Radiat Oncol
(2003)
T.A. Morris et al.
Pulmonary emboli imaging with (99m)Tc-labelled anti-D-dimer (DI-80B3) Fab' followed by SPECT
Heart Lung Circ
(2011)
S.M. Bates 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)
H. Heijboer et al.
Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis
Acta Radiol
(1992)
M. Bettman et al.
Leg phlebography; the incidence, nature, and modification of undesirable side-effects
Radiology
(1977)
H. Bounameaux et al.
Venous thromboembolism: contemporary diagnostic and therapeutic aspects
Vasa
(2008)

There are more references available in the full text version of this article.

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Regular ArticleAccuracy and safety of 99mTc-labeled anti-D-dimer (DI-80B3) Fab’ fragments (ThromboView®) in the diagnosis of deep vein thrombosis: A phase II study

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study Design

Patient Population

Suspected First DVT

Discussion

Conflict of Interest Statement

Acknowledgments

Am J Med

Thromb Res

J Immunol Methods

Semin Radiat Oncol

Heart Lung Circ

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

Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis

Acta Radiol

Leg phlebography; the incidence, nature, and modification of undesirable side-effects

Radiology

Venous thromboembolism: contemporary diagnostic and therapeutic aspects

Vasa

Regular Article
Accuracy and safety of ^99mTc-labeled anti-D-dimer (DI-80B3) Fab’ fragments (ThromboView®) in the diagnosis of deep vein thrombosis: A phase II study