Use of Radiolabeled Peptides to Image Deep Venous Thrombosis and ...

INVITED COMMENTARY

Use of Radiolabeled Peptides to Image Deep Venous Thrombosis and Pulmonary Embolism imaging modalities. Basically, 2 objec he development of radiophannaceu tive methods are used: contrast venog ticals to image acute deep venous raphy (CV) and sonography, which are thrombosis (DVT) and pulmonary em based on the detection of changes in bolism (PE) has sparked the interest of the venous anatomy associated with many nuclear medicine researchersfor the presence of an intraluminal throm years. At present, the development of bus that, if sufficiently formed, either radiolabeled peptides able to bind to reduces the vascular filling or resists to fresh thrombi is an appealing subject of the compression. CV, although consid study. Knight et al. (1), who have made ered the gold standard, is associated great efforts in this field, describe the with considerable patient discomfort potential use of @“@Tc-labeled bitistatin and is time consuming, expensive, and in the imaging of both DVT and PE. inadequate in >30% of cases (4,6). CV This study, done in an animal model, also has extreme intraobserver variabil posespotential for using @Tc-labeled ity (4) and is not reliable in differentiat bitistatin in humans. However, these ing recurrent, acute DVT from the preliminary results still require confir sequelae of old DVT (4,8). mation in clinical studies. Sonography (real-time B-mode with Bitistatin, an amino acid polypeptide compression and pulsed-wave Doppler isolated from viper venom, has great flow) is used increasingly in combina avidity for the surface receptors of the tion with color Doppler flow imaging integrin family, known as glycoprotein and has an increased sensitivity in the llbfIHa (OP llbfIlla) (2). These OP detection of DVT in the leg, although it receptors are highly expressed by acti is less accurate in the calves (9,10). vated platelets, which gain the ability Sonography, like CV, has some draw to bind fibrinogen and other platelets. backs: differential diagnosis of recur Conversely, they are not expressed by rent, acute DVT versus late sequelae; resting platelets (3). Thus, these recep and low sensitivity in asymptomatic tors may be considered as a molecular patients or in detecting thrombi located marker of acute thrombi. The diagnosis of DVT and PE is not in the calves of obese patients or those having orthopedic casts, swollen limbs, a trivial problem because of the signifi cant prevalence of these 2 diseases. or duplication of femoral veins (9—13). The prevalence of DVT is as high as In addition, there are at least 5 main 2—5 millioncasesperyearintheUnited reasons why accurate diagnosis of both States, whereas the prevalence of PE DVT and PE requires a prompt diagno has been estimated to be 500,000— sis. First, in approximately one third of 600,000 cases per year (4,5). Such the cases ofPE, death occurs so quickly that there is little opportunity for diag figures are comparable with those in Western Europe. The clinical diagnosis nosis and treatment (4). Second, ap of DVT is extremely inaccurate; in proximately 30% of the two thirds of fact, only one half of patients with patients who survive a first episode of whereas8% will signs and symptoms consistent with PE will dieuntreated, DVT are confirmed to have disease by die in spite of treatment (4). Third, between 70% and 90% of PEs are Received Dec. 21, 1999; revisionaccepted Jan. derived from acute DVT of the lower 13,2000. For correspondenceor reprintscontact:Pietro extremities (5,14). Fourth, acute DVT Muto, MD, Via Posillipo, 56, 80132, Napoli, Italy. causes postphlebitic syndrome (venous

RADIOLABELED

PEPTIDES

TO IMAGE

DVT

hypertension, which leads to edema, pigmentation, and ulceration of the leg) in 25%—65%of cases (15—17).There fore, the prevention of such morbid conditions clearly ameliorates the qual ity of life. Fifth, anticoagulation, which is the usual treatment

for acute DVT

and PE, is associated with risks: major bleeding in 2%—7% ofcases and throm

bocytopeniain 1% of patientswho received intravenous heparmn(18). Identification of an accurate and prompt diagnostic method that exploits biochemical and functional changes between acute thrombi and other condi tions is extremely important and has undergone extensive investigation. liii tially, WIn-labeled monoclonal antibod ies raised against these receptors were investigated (19,20). The lack of a significant clinical impact in the man agement of patients with both DVT and PE led to further studies. The evidence that OP HbfIlla also binds to peptides and proteins that contain the tripeptide sequence arginyl-glycyl-aspartate (ROD) enabled the development ofsynthetic pep tides containing such specific sequences that@once labeled, could be used for the imaging of fresh thrombi. Some of these have been characterized in animal mod els and phase I studies in humans (3,21,22). These peptides are labeled with @‘@Tc, which increases

their favorable

pharmacokinetic profile, enabling rapid localization of fresh thrombi as early as 30 mm after intravenous administra tion. Different labeling procedures have been proposed and executed to ensure proper specific activities without lower ing the affinity of peptides for target receptors. Oenerally, small peptides are modified by incubation with triamine monothiol, propyleneamine oxime, tet ramine, and hydrazinonicotinamide (23). This latter method has been used

AND

PE

•Muto

and

Lastoria

1065

by Knight et al. (1) to label bitistatin using @Tc-glucoheptonate as an inter mediate. This labeling prOcedUre, which ensures favorable biodistribution pa rameters in animals without loss of reactivity, enabled high lesion-to back ground ratios, which averaged 18: 1 for DVT to blood, 34: 1 for PE to lung, and 284: 1 for DVT to muscle. These find ings were significantly higher than those reported under similar conditions for other synthetic peptides raised against

OP llb/Illa receptors and labeled with The evidence that radiolabeled syn thetic peptides have a role in the imag ing of fresh thrombi has been well documented. Nevertheless, the clinical impact of peptide scintigraphy must be fully evaluated. Available data suggest that this approach is extremely accu rate for prompt diagnosis of DVT or for differential diagnosis ofrecurrent, acute DVT from late sequalae of previous episodes. DVT imaging by radiola

beled peptide scintigraphyis easily performed in the nuclear medicine labo ratory, without requiring specific de vices or manipulating biologic fluids and cells. The test is well tolerated by patients and is risk free. The images are diagnostic 1 h after injection, and inter pretation is uncomplicated. The test provides unique information on the

biochemicaland functionalprofileof the fresh thrombus. However, multicen ter studies with larger series of patients are needed to offer solid statistical data to referring physicians with specific clinical questions. The increasing number of radiola

THE Joui@i.

12. Lansing AWA, Doris J, McGrath FP. et al. A comparison of compression ultrasound with color Doppler ultrasound for the diagnosis of symptom less postoperative deep vein thrombosis. Arch in tern Med. 1997:157:765—768.

13. ScreatonNJ. GillardJH, BermanLH, KempPM.

Pietro Muto

SecondoLastoria National Cancer Institute Napoli. Italy

2000:41:1056—1064. 2. Niewiarowski 5, McLane MA. Kloczewiak M, Stewart GJ. Disintegrins and other naturally occur ring antagonists of platelet fibrinogen receptors. SeminHenaatol.1994:31:289-300. 3. Lister-James J, Knight LC. Maurer AH. Bush LR. Moyer BR, Dean RT. Thmmbus imaging with a technetium-99m-labeled, activated platelet receptor

binding peptide. JNucl Med. 1996:37:775—781. thrombo

sis and pulmonary embolism. Circulation. 1996;96: 2212—2245. 5. Moser KM. Venous thromboembolism.

14. Hull RD. Hirsh J. Carter 0. et al. Pulmonaiy angiography. ventilation lung scanning. and venog raphy for clinically suspected pulmonary embolism Med. 1983:98:891—899.

1. Knight LC, Baidoo KE. Romano 1€.Gabriel JL, Maurer AN. Imaging pulmonary emboli and deep venous thrombi with @Tc-bitistatin,a platelet

4. Hirshi. HOakJ. Managementofdeepvein

Duplicated superficial femoral veins: a source of error in the sonographic investigation of deep vein thrombosis. Radiology. l998;206:397-40l.

with abnormalperfusionlung scan. Ann intern

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