Radiolabeled peptides in the detection of deep venous thrombosis

Venous thrombosis and pulmonary embolism are major clinical problems that result in significant morbidity and mortality. It is estimated that 600,000 cases of pulmonary embolism occur each year in the United States, resulting in the death of approximately 100,000 patients. Most of these pulmonary emboli arise from deep venous thrombosis (DVT). The clinical diagnosis of DVT is unreliable. Only a third of patients with a clinical suspicion of DVT have objective evidence of the disease, and half of patients with proven DVT do not have any clinical symptoms. Although ascending contrast venography is the present standard for the diagnosis of DVT, duplex ultrasonography, which is increasingly used in combination with color Doppler flow imaging, is accepted as a useful clinical afternative to contrast venography. Both contrast venography and ultrasonography are imaging procedures that detect changes in venous anatomy that are caused by the presence of an intraluminal thrombus that is sufficiently formed either to reduce vascular filling with contrast medium or to resist compression. However, these imaging procedures do not reflect the metabolic activity of the clot, and therefore, they may overestimate the presence of active clots. The sensitivity of ultrasonography is also limited by various disease-related and technical factors. An alternative approach to the diagnosis of acute DVT is to detect a molecular marker of acute DVT that is not present in old, organized DVT. Recent advances in biotechnology permit the use of highly specific synthetic peptide or small molecular markers, which are involved in the acute stages of DVT formation and can be labeled efficiently with 99mTc. 99mTc-apcitide, a glycoprotein (GP IIb/IIIa) receptor antagonist previously known as 99mTc-P280, has been approved recently by the Food and Drug Administration for the clinical detection of acute DVT. Two other agents are currently under clinical investigation: 99mTc-DMP 444, which is another GP IIb/IIIa receptor antagonist, and 99mTc-Fibrin-Binding Domain (FBD), a radio-labeled fibrin-binding domain of fibronectin. Different clinical studies have shown a high diagnostic accuracy with these synthetic 99mTc-labeled peptides in the detection of acute DVT. Although further studies are needed to fully appreciate all of the diagnostic potential of these radiopharmaceuticals, the clinical introduction of 99mTcapcitide scintigraphy will certainly be helpful in expanding the use of nuclear medicine in a specific field in which it used to play a relatively marginal role.     

Diagnosis of deep venous thrombosis of the leg using immunoscintigraphy with 111In-labelled monoclonal antifibrin antibody fragments

Fourteen unselected consecutive patients with clinically suggested deep venous thrombosis were studied using 111In-labelled monoclonal antibody Fab-fragments (59D8) in order to evaluate the accuracy of antifibrin imaging. Scintigrams of the legs were obtained at 1 to 4 h and 20 to 28 h in all patients and in seven dynamic studies were also performed. Contrast medium phlebography used as diagnostic standard revealed thrombosis in six patients who also had increased uptake of the tracer at immunoscintigraphy. Three patients had a positive finding at immunoscintigraphy without thrombosis. Because of the high sensitivity of this method, normal antifibrin images may be used to exclude thrombosis. Phlebography may then be restricted to positive cases to confirm the presence of thrombosis.     

Evaluation of indium-111-labeled antifibrin monoclonal antibody for the diagnosis of venous thrombotic disease

The potential advantage of using 111In-antifibrin (111In-AF) monoclonal antibody for the diagnosis of deep venous thrombosis (DVT) was studied in 44 patients with suspected DVT (27 underwent heparin therapy before 111In-AF injection). All patients had contrast venography (considered as the gold standard) and 111In-AF scintigraphy within 24 hr. Two to 3 mCi of 111In-AF were injected intravenously, and planar scintigraphy of the limbs was recorded within 10 min (17 times), 3 hr (44 times), and 18 hr (39 times). Indium-111-AF images were then interpreted without knowledge of the results of the other examinations. The DVT diagnostic accuracy of 111In-AF was greater when interpretation was based on images recorded at different time periods after injection. Indium-111-AF sensitivity for diagnosis of DVT was 85% (29/34) and was not apparently decreased by heparin therapy. None of the 10 patients with negative contrast venography had a positive 111In-AF scan. The results demonstrate the importance of recording serial images and the excellent accuracy of 111In-AF for diagnosing DVT.     

AngioJet血栓清除装置治疗急性下肢深静脉血栓形成初步临床应用

目的 探讨AngioJet血栓机械性清除装置治疗急性下肢深静脉血栓形成(DVT)的效果和安全性.方法 回顾性分析2014年7月至2015年10月收治的55例急性下肢DVT患者临床资料,其中23例接受AngioJet血栓清除装置治疗(A组),32例接受置管溶栓治疗(B组).评价两组患者治疗期间应用尿激酶总量、溶栓时间、住院时间、消肿率及并发症发生情况.结果 A、B组患者尿激酶总用量分别为(106.09±61.92)×104 U、(204.38±108.27)×104 U,溶栓时间分别为(3.00±2.35)d、(5.11±2.57)d,住院时间分别为(7.39±0.94)d、(9.19±2.26)d,差异均有统计学意义(P值分别为0.001、0.003、0.001);患肢消肿率分别为(76.60±19.07)％、(73.59±25.22)％,并发症发生率分别为4.35％(1/23)、6.25％ (2/32),差异无统计学意义(P值均＞0.05).结论 AngioJet血栓机械性清除装置治疗急性下肢DVT可明显提高血栓清除效率,减少尿激酶用量,缩短药物溶栓时间及住院治疗时间,且疗效良好,值得临床上进一步推广应用.     

An in vitro model for the scintigraphic detection of thrombi using a 99Tcm-labelled antifibrin monoclonal antibody

Because of their specific targeting properties, monoclonal antibodies have found widespread use in nuclear medicine. In this paper, a method is described for the evaluation of immunoscintigraphic parameters for the detection of thrombi, using a 99Tcm-labelled antifibrin monoclonal antibody (designated as Y22). An in vitro model was developed to evaluate the effects of various environmental conditions on uptake by plasma clots of 99Tcm-Tc-Y22 in circulating plasma on a gamma camera. The clots became visible as hotspots after approximately 1 h of circulation of 99Tcm-Y22 containing citrated plasma at 37 degrees C. Circulation of 99Tcm-fibrinogen, 99Tcm-HSA or 99Tcm-control MoAb did not show visible uptake by the clots under the same conditions. At 37 degrees C, 99Tcm-Y22 accumulated approximately four times faster than at 20 degrees C. Heparin did not affect binding of the antibody to clots. To assess the feasibility of thrombus detection in vivo, an extracorporeal rat thrombus model was used. A thrombus in a shunt between a carotid artery and a jugular vein became visible 1 h after injection of the labelled Y22 and, more clearly, after 3 h.     

Deep venous thrombosis: detection by high-resolution real-time ultrasonography

High-resolution real-time ultrasonography was performed in 11 patients with clinically suspected deep venous thrombosis (DVT) of the lower extremity. Contrast venography was performed in all patients within 24 hours of sonographic examination. The common femoral vein at the groin and the popliteal vein in the popliteal fossa were evaluated for presence or absence of intraluminal soft-tissue mass (thrombi), compressibility of the veins, and response to performance of the Valsalva maneuver. Of the 11 patients, six were shown to have DVT by contrast venography. In all six cases there was complete agreement between sonography and contrast venography as to the presence or absence of thrombi in the common femoral vein or the popliteal vein.     

Deep vein thrombosis: scintigraphic diagnosis with In-111-labeled monoclonal antifibrin antibodies

Fifty-two patients suspected of having deep vein thrombosis under-went scintigraphy with an indium-111-labeled monoclonal antifibrin antibody. Venography disclosed deep vein thrombosis in 31 patients. With the whole limb considered an anatomic entity, antifibrin antibody scintigrams obtained 2 hours after injection had a specificity and sensitivity of 81% and 84%, respectively. A higher sensitivity (92%) was found for a subgroup of patients (n = 44) with symptoms for less than 10 days. Regional sensitivities for all patients and for the subgroup, respectively, were 92% and 100% in the calf, 82% and 94% in the popliteal region, 63% and 71% in the thigh, and only 18% and 13% in the pelvis. Additional imaging performed 6 hours and 21 hours after injection in 12 patients and quantitative analysis done from scintigrams with and without blood-pool (technetium-99m human serum albumin) correction did not improve sensitivity. In-111-antifibrin antibody scintigraphy is an accurate method for diagnosis of acute established deep vein thrombosis of the calf and popliteal region; its sensitivity in the thigh is lower, and it is not feasible for diagnosis in the pelvic area.     

Multiple intra-abdominal venous thrombosis in ulcerative colitis: role of MDCT for detection

Patients with ulcerative colitis are at increased risk for venous thrombosis. We report herein the case of a 28-year-old woman who developed multiple intraabdominal venous thrombosis, including partial Budd-Chiari syndrome in association with intracranial venous thrombosis and pulmonary embolism during the relapse of a known ulcerative colitis. Multidetector-row computed tomography (MDCT) allowed depiction of multiple intraabdominal sites of thrombosis including right and medial hepatic veins, left portal vein, splenic vein and left ovarian vein and demonstrated complete resolution of the multiple thrombi after anticoagulant therapy. The association of partial Budd-Chiari syndrome with other thrombi involving portal, splenic and ovarian veins in association with ulcerative colitis, has, to our knowledge never been reported yet. In addition, the potential role of MDCT in the detection of possible multiple thrombosis in patients with ulcerative colitis has never been emphasized.     

Augmentation in lower extremity sonography for the detection of deep venous thrombosis

OBJECTIVE: The purpose of our study was to evaluate the usefulness of venous flow augmentation with duplex sonography in the evaluation of deep venous thrombus of the lower extremities. CONCLUSION: The augmentation component of the lower extremity sonogram rarely provides additional information in the diagnosis of deep venous thrombus. In our large series, no deep venous thromboses were discovered with augmentation. Factors such as the lack of usefulness and patient discomfort may justify removal of augmentation from the routine study. However, augmentation should still be applied as a diagnostic tool in difficult or uncertain cases.     

经颈静脉AngioJet治疗有溶栓禁忌的急性下肢深静脉血栓形成24例

【摘要】 目的 探讨AngioJet血栓清除系统治疗有溶栓禁忌的急性下肢深静脉血栓形成（DVT）的效果及经颈静脉途径特点。方法 对24例有溶栓禁忌的急性DVT患者施行经右颈静脉途径DSA造影、下腔静脉滤器置入、AngioJet血栓抽吸、经皮腔内血管成形（PTA）、支架植入、取出滤器。观察血栓抽吸疗效及手术相关并发症。 结果 24例患者AngioJet血栓清除治疗均获得成功。其中21例（87%）血栓清除为Ⅲ级,3例（13%）为Ⅱ级。19例（79%）置入下腔静脉滤器并全部取出。7例（29%）伴有髂静脉受压综合征患者接受PTA,其中3例（43%）植入支架。所有患者均出现不同程度血红蛋白尿,22例48 h内消失,2例72 h内恢复正常,均未出现大出血、肾衰竭等严重并发症。术后随访6～12个月,1例失访,1例复发。 结论 经颈静脉途径AngioJet血栓清除系统治疗有溶栓禁忌的急性DVT安全可行,疗效好,并发症少。     

Deep venous thrombosis evaluation with limited-flip-angle, gradient- refocused MR imaging: preliminary experience

Sixteen patients (17 lower extremities) were prospectively examined with venography and limited-flip-angle, gradient-refocused magnetic resonance (MR) imaging for the presence or absence of deep venous thrombosis. Thrombosed vessels showed decreased-to-absent signal intensity, while patent vessels had high signal intensity. In 16 of 17 extremities, MR images allowed accurate detection and localization of the thrombi found with venography. In the remaining extremity, MR imaging allowed correct identification of thrombus in the iliac and femoral veins but incorrectly demonstrated clot in the calf and popliteal veins. MR imaging with limited-flip-angle, gradient-refocused pulse sequences appears to be a sensitive, noninvasive means of detecting deep venous thrombosis.     

Fragment E1 labeled with I-123 in the detection of venous thrombosis

Fragment E1, which has been shown to have specific binding affinity for thrombi in an animal model, was investigated in humans for its safety and ability to bind to venous thrombi. Human Fragment E1 was labeled with I-123 and administered intravenously to patients with proved or suspected deep vein thrombosis. The vascular distribution of radioactivity was documented by obtaining gamma camera images of the patients' legs for 30 minutes following administration of I-123-Fragment E1. All patients (n = 5) with documented venous thrombi had rapid localization of labeled Fragment E1 in the area of thrombus. Patients without evidence of thrombi (n = 5) showed no focal localization, although two of these patients showed diffuse uptake along the length of the veins, due to superficial phlebitis. Analysis of blood samples in four patients indicated that disappearance of Fragment E1 from the circulation was more rapid in individuals with thrombosis (t 1/2 = 20 min) than in individuals without thrombosis (t 1/2 = 90 min), and a radiolabeled species of high molecular weight was found in patients with thrombosis but was absent from patients without thrombosis. These early results suggest that radiolabeled Fragment E1 is a safe and potentially valuable agent for the rapid detection of venous thrombosis.     

A new method for 99Tcm-labelling of proteins with an application to clot detection with an antifibrin monoclonal antibody

A new method is described for labelling proteins with 99Tcm. Labelling of fibrinogen resulted in a radiochemical yield of about 80%. After clotting this 99Tcm-labelled fibrinogen with trombin, an equal percentage of the radioactivity was found in the clot illustrating the retained biological behaviour of this labile protein after our labelling procedure. Labelling of a monoclonal antibody (MoAb) directed against fibrin resulted in a labelling percentage of about 70%. Immunoreactivity of this antifibrin (Y22) is hardly affected by the procedure as demonstrated by a double-sandwich enzyme immunoassay (EIA). Perfusion experiments on a gamma camera in which a plasma clot in a glass chamber was perfused with plasma containing 99Tcm-labelled Y22 revealed an excellent uptake of activity by the clot within 2 h. Finally an animal experiment is presented which showed clear visualization of the thrombi in the jugular vein and the abdomen of a rabbit by scintigraphy after the administration of 99Tcm-labelled antifibrin (Y22).     

Tc-99m antifibrin Fab' fragments for imaging venous thrombi: evaluation in a canine model

An antifibrin antibody (T2G1s) Fab' fragment labeled with technetium-99m was tested for its ability to produce images of fresh thrombi in dogs. In gamma camera images, all thrombi were evident by 2-4 hours after injection. Mean thrombus-to-blood and thrombus-to-muscle ratios averaged 4.0 and 69 at four hours after injection and increased to 24 and 270, respectively, by 24 hours after injection. When compared with I-125 fibrinogen injected into the same dogs, Tc-99m-antifibrin Fab' had lower absolute uptake in thrombus but higher thrombus-to-blood ratios due to a faster rate of disappearance from the blood. The primary route of excretion was through the kidneys. Tc-99m-antifibrin Fab' was highly stable in vivo, with an average of 82% of the circulating radioactivity able to bind to fibrin at 4 hours after injection. When compared with an In-111-labeled Fab fragment of antifibrin antibody 59D8, thrombus-to-blood and thrombus-to-muscle ratios were slightly higher for the Tc-99m-labeled antibody, and the blood disappearance rate was slightly faster. The absolute uptake in thrombus, however, was not significantly different, and the thrombus was visualized at about the same time after injection. These studies suggest that Tc-99m T2G1s Fab' is a potential agent for detecting thrombi in a clinical setting.     

Prospective study of echography versus phlebography in the detection of sural venous thrombosis]

Among all noninvasive techniques, high-resolution ultrasonography used alone has rarely been used for the diagnosis of thrombosis in the calf. Nineteen patients with suspected AVT were examined with ultrasonography and phlebography during 4 months. For each patient, a sonogram and a phlebogram were taken within less than 24 hours and interpreted independently. The sonographic exploration with a high-resolution (5 MHz) transducer covers all deep trunks and muscular veins (soleus or gastrocnemius muscles). The positivity criterion is the persistence of a hypoechogenic endoluminal image under moderate compression. According to the phlebographic data, 65% of the patients present with thrombosis. Ultrasonography has a sensitivity of 95% and a specificity of 99% for the study of the deep trunks. Ultrasonography screens more thromboses than phlebography (23 cases versus 17). On a whole, ultrasonography seems to be more sensitive than phlebography for the diagnosis of recent sural thrombosis.     

Saline-jet aspiration thrombectomy catheter. Clinical results in patients with venous thrombosis

PURPOSE: To evaluate hydraulic thrombectomy using a saline-jet aspiration thrombectomy catheter in the treatment of venous thrombosis. MATERIAL AND METHODS: Ten patients underwent 12 hydraulic thrombectomy procedures using 2.7 or 4.0 mm catheters. The site of the thrombus was either central, peripheral or in portal veins. The age of the thrombi was between 2 and 60 days (mean 19.7 days). The efficacy of hydraulic thrombectomy was evaluated based on the aspirated thrombus ratio (ATR), i.e. the volume of the thrombus aspirated divided by the volume of the thrombus before thrombectomy. ATR was estimated by comparing the angiograms of the lesion before and after thrombectomy. RESULTS: Soft thrombi were usually rapidly removed. ATR was >2/3 in 3, 2/3-1/3 in 2, 1/3-0 in 4, and 0 in 1 patient. The activation time of the injector was 23-224 s (mean 102 s) and the volume of aspirated blood was 30-680 ml (mean 250 ml). Compensatory infusion of saline was performed for blood loss, and 400 ml of packed red blood cells was transfused in 1 patient. No complications of the hydraulic thrombectomy were observed. Thrombolysis or additional treatment were performed in 9 patients. CONCLUSION: Hydraulic thrombectomy using this catheter can contribute to the treatment of venous thrombosis.     

Follow-up MRI in dural arteriovenous malformations involving the cavernous sinus: emphasis on detection of venous thrombosis

Summary Six patients with a dural arteriovenous malformation (dural AVM) involving the cavernous sinus were followed up with magnetic resonance imaging in order to assess change in the lesions. Spin-echo (SE) imaging of three patients in whom the AVM appeared to have closed at least 1 month earlier (two of them spontaneously, and one after external carotid artery embolization) showed neither apparent flow void in the involved cavernous sinus nor evidence of venous thrombosis. SE images of the other three patients who had not been cured by external carotid artery embolization (two of whom were examined within a week of treatment), detected persisting arteriovenous shunts, including high-flow cortical venous drainage, seen as flow void. Two-dimensional time-of-flight MR angiography (2D TOF MRA) was performed simultaneously in three patients. Whereas shunting blood and the normal cavernous sinus were of high intensity, presumed thrombosed cavernous sinuses were isointense with stationary brain tissue. SE imaging can confirm the resolution of arteriovenous shunts, but poorly delineates ver acute and chronic thrombosis of the draining veins. In contrast, 2D TOF MRA directly demonstrates flowing blood, permitting the diagnosis of venous thrombosis; it should be included in follow-up of a dural AVM involving the cavernous sinus when venous thrombosis is suspected.     

Criteria for detection of deep venous thrombosis by 99Tcm-plasmin test

Criteria for the interpretation of 99Tcm-plasmin test results were systematically investigated in 353 patients with suspected deep venous thrombosis (DVT). Scintillation detector measurements were made at 12 points on each leg after intravenous injection of 99Tcm-porcine plasmin. Phlebography was used as a reference method. The criteria were chosen to obtain the highest possible sensitivity (98 to 100%). On this assumption, the specificity reached 66 to 69%, when using the two most efficient criteria. These criteria involved a comparison between count rates at three adjacent points of the leg suspected of having DVT, and count rates at the three corresponding points of the other leg. Comparison between measurements performed at 5 and 30 min after the injection showed a higher sensitivity of the test at the 30 min measurement. The specificity decreased when the results from both 5 and 30 min measurements were combined. Further increase in specificity could only be achieved at the cost of decreased sensitivity. The suggested criteria seem to be the most efficient for this kind of radionuclide test and improved test-efficiency has to await more thrombus-specific radiopharmaceuticals.