Early changes in deep vein diameter and biochemical markers associated with thrombi formation after spinal cord injury in mice.
ABSTRACT Spinal cord injury (SCI) is associated with the development of deep venous thrombosis (DVT) in the lower limbs and, hence, with rapidly increasing risks of cardiovascular and pulmonary complications soon after trauma. However, specific mechanisms underlying DVT formation following SCI are poorly understood. Here, we studied in mice, employing in vivo confocal microscopy, changes in deep vein size over 4 weeks after spinal cord transection (Tx). Changing levels of biochemical markers that may be associated with DVT formation were also examined. The results showed decreased concentrations of cholesterols, triglycerides, and low-density lipoprotein (LDL), but not of high-density lipoproteins (HDL) and platelets. Concentrations of creatinine, bilirubin, glucose, albumin, total protein and uric acid did not significantly change. In turn, the femoral and saphenous veins underwent a large increase (>1.5-fold) in diameter throughout the entire period studied. Overall, this study reveals that a profound change in deep vein size and, an unsuspected decrease in triglyceride and LDL levels, occur as early as at one week post-Tx in mice. This indicates, given the well-documented risk of DVT formation soon after SCI, that deep vein enlargement, but not lipoprotein level changes, may constitute an early event contributing to venous stasis and thrombi formation in paralyzed individuals.
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ABSTRACT: We tested the hypothesis that a venous thromboembolism to the pulmonary arterial system (pulmonary embolism [PE]) would cause an inflammatory response within the pulmonary arterial (PA) wall marked by elevated cytokines and chemokines and an influx of inflammatory cells. Experimental PE was induced in 70 rats and confirmed with angiography and O(2) saturation depression, and an additional 70 rats underwent sham operations. PA and lung tissue were removed at 3 hours and at 1, 2, 4, 6, 8, and 14 days (n = 10 per time point), were analyzed for proinflammatory cytokines and chemokines, and underwent histologic analysis. Data were analyzed with analysis of variance and the unpaired Student t test. Average gross PE resolution was 40% at 2 days, 90% at 4 days, and 100% at 6 days. Only monocyte chemoattractant protein-1 levels were greater in affected PAs compared with sham PAs at 3 hours, 1 day, and 2 days (137 +/- 13 pg/mg protein, 285 +/- 40 pg/mg protein, and 249 +/- 36 pg/mg protein versus 101 +/- 6 pg/mg protein, 150 +/- 36 pg/mg protein, and 92 +/- 3 pg/mg protein; P <.01 for all). Keratinocyte-derived chemokine, tissue necrosis factor, interleukin-10, nitric oxide, P-selectin, and E-selectin levels were not elevated. Neutrophils infiltrated the PA wall beginning at 3 hours, peaked at 2 days (69.4 +/- 21.7 per five high-power fields; P <.01), and returned to baseline by 8 days after PE. Macrophages peaked at 1 day after PE (29.3 +/- 6.9; P <.01) and returned to baseline by 4 days after PE. PE also was associated with a significantly increased intima to media ratio (P <.05), apparent at 4 days after PE and persisting through 14 days. PE is associated with an early influx of polymorphonuclears and macrophages and monocyte chemoattractant protein-1 elevation within the PA wall. These are temporally associated with thrombus resolution and intimal hyperplasia. These factors may mediate these two processes after PE. This offers targets for further study with the hopes of minimizing the pathophysiologic response to PE.Journal of Vascular Surgery 10/2002; 36(3):581-8. · 2.88 Impact Factor
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ABSTRACT: An animal model. To test the natural sequence of venous thrombosis and pulmonary thromboembolism experimentally. Veterans Administration Hospital, USA. In dogs, a venous thrombosis was induced in a isolated segment of the internal jugular vein by a 5 min exposure to sodium morrhuate and then re-establishing venous patency. A tracer, (125)I human fibrinogen, was administered through another vein 1 h prior to the end of each experiment when a blood sample, the venous thrombus, and the lungs were removed. Thrombi were described by age, weight, histology, and fibrin uptake (thrombus to blood radioactivity ratio, g/g). Pulmonary emboli (PE) were identified by autoradiography of lung slices or by microscopic examination of lung sections.Results:Venous thrombosis developed in all experiments, duration 1-64, median 5 h (n=12). Histologically, younger thrombi were characterized by platelet aggregates surrounded by polymorphonuclear leukocytes (PMN), and uniform fibrin deposit; the older thrombi by platelet ghost cells, fewer PMN leukocytes, and broken fibrin strands and loops (n=6). Pulmonary thromboemboli were imaged as 'hot spots' in six of six experiments in which lung slices were autoradiographed and were identified microscopically in six of six experiments in which lung sections were taken. The number of PE diagnosed microscopically did not correlate with the age of the corresponding thrombus but was directly related to fibrin uptake (n=5, r=0.99, P<0.01). An animal model for venous thrombosis that generates pulmonary thromboembolism has been described.Spinal Cord 11/2005; 43(11):635-9. · 1.90 Impact Factor
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ABSTRACT: Deep vein thrombosis (DVT) occurs with high prevalence in association with a number of risk factors, including major surgery, trauma, obesity, bed rest (> 5 days), cancer, a previous history of DVT, and several predisposing prothrombotic mutations. A novel murine model of DVT was developed for applications to preclinical studies of transgenically constructed prothrombotic lines and evaluation of new antithrombotic therapies.A transient direct-current electrical injury was induced in the common femoral vein of adult C57BI/6 mice. A non-occlusive thrombus grew, peaking in size at 30 min, and regressing by 60 min, as revealed by histomorphometric volume reconstruction of the clot. Pre-heparinization greatly reduced clot formation at 10, 30, and 60 min (p < 0.01 versus non-heparinized). Homozygous FactorV Leiden mice (analogous to the clinical FactorV Leiden prothrombotic mutation) on a C57Bl/6 background had clot volumes more than twice those of wild-types at 30 min (0.121 +/- 0.018 mm3 vs. 0.052 +/- 0.008 mm3, respectively; p < 0.01). Scanning electron microscopy revealed a clot surface dominated by fibrin strands, in contrast to arterial thrombi which showed a platelet-dominated structure. This new model of DVT presents a quantifiable approach for evaluating thrombosis-related murine transgenic lines and for comparatively evaluating new pharmacologic approaches for prevention of DVT.Thrombosis and Haemostasis 09/2005; 94(3):498-503. · 6.09 Impact Factor