Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P280, a synthetic peptide composed of 26 aminoacids, has high affinity (Kd = 100 nM) and specificity for the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor expressed on activated platelets. In this study we investigated the potential usefulness of imaging deep vein thrombosis (DVT) and pulmonary embolism (PE) in humans with 99mTc-P280. In 15 patients (9 men and 6 women; mean age +/- s.d.: 49.2 +/- 14.1) with known DVT and/or PE, serial images were acquired within 24 hours of the injection of approximately 200 micrograms of P280 radiolabelled with 10-23 mCi of 99mTc. P280 was labelled with the ligand exchange method using 99mTc-glucoheptonate. Rapid blood clearance (< or = 5% ID was still circulating in 1 hour) enabled identification of thrombi as early as 60 minutes after the injection, with significant thrombi-to-background ratios (range: 2-4) in 11/15 patients (73%), in 7/9 with DVT, in 2/3 with PE and in 2/3 patients with both DVT and PE. Radiotracer uptake was clearly detectable also in late scans, which confirms that 99mTc-P280 specifically binds to the thrombi through a receptor-mediated mechanism. PE localizations were detectable 3-4 hours after peptide injection, and in 2 cases SPECT enabled the detection of thrombi missed on planar views. Conversely, the test was negative in 4 patients who had the onset of clinical symptoms and the diagnosis of DVT and/or PE more than 40 days before scintigraphy. The lack of 99mTc-P280 uptake in the latter patients suggested that the peptide does not bind to thrombi when thrombogenesis is not active. These preliminary results clearly indicate scintigraphy with 99mTc-P280 to be a suitable, noninvasive and highly specific tool to image fresh clots causing DVT and/or PE. Thus, this technique might overcome the limitations of the imaging procedures currently in use.
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PMID:[Imaging of thromboembolism by scintigraphy with the 99m-technetium-labelled synthetic peptide P280]. 868 69

A hydrazinonicotinamide-functionalized cyclic glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist [cyclo(D-Val-NMeArg-Gly-Asp-Mamb(5-(6-(6-hydrazinonicotin amido)hexanamide))) (HYNICtide)] was labeled with 99mTc using tricine and a water soluble phosphine [trisodium triphenylphosphine-3,3',3"-trisulfonate (TPPTS); disodium triphenylphosphine-3,3'-disulfonate (TPPDS); or sodium triphenylphosphine-3-monosulfonate (TPPMS)] as coligands. Three complexes, [99mTc(HYNICtide)(L)(tricine)] (1, L = TPPTS; 2, L = TPPDS; 3, L = TPPMS), were evaluated in the canine arteriovenous shunt (AV shunt) model and canine deep vein thrombosis imaging (DVT) model. All three agents were adequately incorporated into the arterial and venous portions of the growing thrombus (7.8-9.9 and 0.2-3.7% ID/g, respectively) in the canine AV shunt model. In the canine DVT model all three complexes had thrombus uptake that far exceeded the negative control, [99mTc]albumin. The findings indicate similar incorporation into a venous thrombus (% ID/g = 2.86 +/- 0.4, 3.4 +/- 0.9, and 3.38 +/- 1.1 for complexes 1, 2, and 3, respectively) and similar blood clearance with a t1/2 of approximately 90 min. Gamma camera scintigraphy allowed visualization of deep vein thrombosis in as little as 15 min with the thrombus/muscle ratios being 3.8 +/- 0.8, 2.8 +/- 0.4, and 3.0 +/- 0.8 for complexes 1, 2, and 3, respectively. The visualization of the thrombus improved over time, and the thrombus/muscle ratios were 9.7 +/- 1.9, 13.8 +/- 3.6, and 9.4 +/- 2 for complexes 1, 2, and 3, respectively, at 120 min postinjection. The administration of complexes 1-3 did not alter platelet function, hemodynamics, or the coagulation cascade. Furthermore, complexes 1-3 did not significantly differ in their uptake into the growing thrombus, blood clearance, and target to background ratios. Therefore, all three complexes have the capability to detect rapidly growing venous and arterial thrombi.
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PMID:Biological evaluation of thrombus imaging agents utilizing water soluble phosphines and tricine as coligands when used to label a hydrazinonicotinamide-modified cyclic glycoprotein IIb/IIIa receptor antagonist with 99mTc. 909 55

The mechanism of arterial thrombosis, including coronary thrombosis, is different from that of thrombosis which occurs at sites of blood stasis such as deep venous thrombosis. Considering the onset of arterial thrombus formation, soluble coagulant factors may not play important roles for its onset since they are diluted by the effect of blood flow and cannot reach high enough concentrations to form insoluble fibrin. Platelets, which can stick to damaged vascular lumen even in the presence of shearing effects of blood flow, may play a crucial role in the onset of arterial thrombus formation. Thus, the mechanism of platelet thrombus formation should be assessed in the presence of blood flow. However, current dogma that fibrinogen binding to activated GP IIb/IIIa is the final common pathway for platelet thrombus formation was developed by using the function assay system of aggregometer, in which the effects of blood flow were not seriously considered. We are proposing in this review that plasma ligand protein of von Willebrand factor (vWF) and its interactions with platelet GP lb and GP IIb/IIa, which become apparent only in assays systems under influence of high shear rates of flow condition such as flowchambers or coneplate viscometers, are the key events leading to the onset of arterial thrombosis. A better understanding of the vWF-mediated mechanism of platelet thrombus formation is important for the development of better clinical tools to prevent ischemic heart disease as well as for a complete understanding of the mechanism of coronary thrombosis.
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PMID:Coronary thrombosis. Effects of blood flow on the mechanism of thrombus formation. 992 90

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.
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PMID:Radiolabeled peptides in the detection of deep venous thrombosis. 1133 Jul 82

The established indication for Tc99m apcitide scintigraphy is for detecting deep venous thrombosis. However, due to its mechanism of binding to GP IIb/IIIa receptors on activated platelets, it can be used to image acute cerebral thrombosis. I report a patient with an acute ischaemic stroke, with right leg swelling, referred for Tc99m apcitide scintigraphy to show of deep venous thrombosis. There was no abnormal uptake in the legs but there was in the left parieto-occipital region. This correlated with the clinical and CT data, indicating an acute ischaemic stroke in this area.
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PMID:Detection of acute cerebral ischaemia with Tc-99m apcitide scintigraphy. 1238 29

Deep vein thrombosis (DVT) is a low flow pathology often prevented by vascular compression to increase blood movement. We report new heterotypic adhesive interactions of normal erythrocytes operative at low wall shear rates (gamma(w)) below 100 s(-1). Adhesion at gamma(w) = 50 s(-1) of washed red blood cells (RBCs) to fibrinogen-adherent platelets was 4-fold less (P <.005) than to collagen-adherent platelets (279 +/- 105 RBC/mm(2)). This glycoprotein VI (GPVI)-triggered adhesion was antagonized (> 80% reduction) by soluble fibrinogen (3 mg/mL) and ethylenediaminetetraacetic acid (EDTA). RBC-platelet adhesion was reduced in half by antibodies against CD36 or GPIb, but not by antibodies against GPIIb/IIIa, von Willebrand factor (VWF), thrombospondin (TSP), P-selectin, beta(1), alpha(v), or CD47. Adhesion of washed RBCs to fibrinogen-adherent neutrophils was increased 6-fold in the presence of 20 microM N-formyl-Met-Leu-Phe to a level of 67 RBCs per 100 neutrophils after 5 minutes at 50 s(-1). RBC-neutrophil adhesion was diminished by anti-CD11b (76%), anti-RBC Landsteiner-Wiener (LW) (ICAM4; 40%), or by EDTA (> 80%), but not by soluble fibrinogen or antibodies against CD11a, CD11c, CD36, TSP, beta(1), alpha(v), or CD47. RBC adhesion to activated platelets and activated neutrophils was prevented by wall shear stress above 1 dyne/cm(2) (at 100 s(-1)). Whereas washed RBCs did not adhere to fibrin formed from purified fibrinogen, adhesion was marked when pure fibrin was precoated with TSP or when RBCs were perfused over fibrin formed from recalcified plasma. Endothelial activation and unusually low flow may be a setting prone to receptor-mediated RBC adhesion to adherent neutrophils (or platelets/fibrin), all of which may contribute to DVT.
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PMID:Adhesion of normal erythrocytes at depressed venous shear rates to activated neutrophils, activated platelets, and fibrin polymerized from plasma. 1239 14

Excessive coagulation and impaired fibrinolysis lead to many hemostatic disorders, which enhance the risk of development of life-threatening cardiovascular diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism, belonging to the most important factors influencing morbidity and mortality in civilized societies. The adverse events induced by currently used drugs, the need for regular monitoring of coagulation parameters, inconvenient, in some cases, route of administration stimulate further search for novel, effective and safe methods of therapies of these disorders. In this paper, we describe those new agents which are now under experimental and clinical study, such us prostanoids, nitroaspirin, GP IIb/IIIa receptor antagonists, thienopyridine derivatives, collagen-GPVI and von Willebrand factor-GPIb-IX contact blockers, direct thrombin inhibitors, inhibitors of thrombin-platelet interactions, factor VII inhibitors and tissue factor-factor VII contact blockers. Based on the available literature, we discuss the possible role of these agents in the future prevention and treatment of thromboembolic diseases.
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PMID:Progress in pharmacotherapy of thrombosis. 1458 10

[99mTcO] apcitide (99mTcO(P246)), the technetium complex of the 13 amino acid, apcitide, cyclo-(D-Tyr-Apc-Gly-Asp-Cys)-Gly-Gly-Cys(Acm)-Gly-Cys(Acm)-Gly-Gly-Cys-NH2, where Apc is L-[S-(3-aminopropyl)]cysteine (an arginine mimetic) and Acm is the acetamidomethyl protecting group, has high affinity and selectivity for the GPIIb/IIIa receptor that is expressed on the membrane surface of activated platelets and plays an integral role in platelet aggregation and thrombus formation. Bibapcitide, a 26 amino acid, bis-succinimidomethyl ether-linked dimer of the peptide apcitide has been formulated as a single-vial, lyophilized kit having the trade name AcuTect. When sterile, nonpyrogenic sodium pertechnetate (99mTcO4-) in 0.9% sodium chloride is added to the AcuTect radiopharmaceutical kit and the resulting kit is heated, [99mTcO] apcitide forms. This is the first radiopharmaceutical to target acute deep vein thrombosis (DVT) in the lower extremities. We report here the preparation, purification, and isolation of the 99Tc complex of apcitide and its characterization to determine the mode of binding of Tc to apcitide. [99TcO] apcitide was prepared, on the macroscopic level, by reaction of [99TcOCl4]- with apcitide, purified by preparative HPLC and isolated as a trifluoroacetate salt. [99TcO] apcitide can also be formed from the reaction of bibapcitide and 99TcO4- in the presence of Sn(II) and glucoheptonate at 80 degrees C, conditions that mimic the radiopharmaceutical kit preparation. FTIR data show a Tc=O stretch at 961.2 cm(-1), in the range observed for anionic [TcVO]3+ amide thiolate complexes. The mass spectral data is in agreement with the formula, [C51H73O20N17S5Tc]-, consistent with retention of Acm groups and the Tc binding in the Gly11-Gly12-Cys13 region of the peptide. Despite significant spectral overlap due to numerous similar amino acids, all protons of apcitide and [99TcO] apcitide were unambiguously assigned. The observation of two nonequivalent Acm groups and the observation of only 10 NH-CH cross-peaks in the TOCSY and COSY spectra of [99TcO] apcitide (NH-CH cross-peaks were absent for Gly11-Gly12-Cys13), compared to all 13 cross-peaks found in apcitide, provided compelling evidence to support the 99Tc binding to the terminal Gly11-Gly12-Cys13 region of apcitide.
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PMID:Preparation and characterization of [99TcO] apcitide: a technetium labeled peptide. 1510 74

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 x 10(-7). In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband's daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event.
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PMID:Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation. 1549 23

The importance of genetic thrombophilic factors in the development of venous thromboembolism has been increasingly recognized. Factor V Leiden (FVL), prothrombin gene mutation G20210A (FII G20210), genetic variant C677T of the methylentetrahydrofolate reductase (MTHFR), as well as the polymorphism A2 (PlA2) in platelet glycoprotein IIb/IIIa were recently discussed. We analyzed the contribution of genetic thrombophilic factors to the pathogenesis of pulmonary embolism (PE) and their association with the early onset and recurrence of PE using DNA analysis methods. In this case control trial we found thrombophilic genetic variants in 58.8% of 51 patients with PE. FVL was found in 23.5% of the patients versus 7.1% of the 98 controls (p=0.01), PlA2 IIb/IIIa was found in 35.3% vs. 14.3% (p=0.03), and FII G20210A was found in 5.9% vs. 2.0% (NS). Patients with recurrent PE had a very high prevalence of genetic factors, 70.4%. High prevalence of FVL was found in patients under 45 years of age: 39.3% (OR=14.23, 95% CI=1.58-330.03, p=0.01) as well as in patients with recurrent incidence (37%, OR=7.647, 95% CI=2.27-26.44, p=0.001). FVL was also significantly higher in the subgroup of patients with PE combined with deep venous thrombosis (OR=6.500, 95% CI=1.81-23.76, p=0.002) in comparison with patients with isolated PE (OR=2.261, 95% CI=0.50-9.69). The carriers of FVL are at higher risk for early and recurrent PE events. High prevalence of PlA2 in PE patients evidently shows the impact of this polymorphism in PE development. A different treatment should be considered in carriers of thrombophilic defects.
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PMID:Impact of thrombophilic genetic factors on pulmonary embolism: early onset and recurrent incidences. 1809 19


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