Overview: pulmonary thromboembolism.
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Anticoagulants↗
Biomedical subjects
T W Wakefield
Publications and source records attributed to T W Wakefield.
Current status of pulmonary embolism and venous thrombosis prophylaxis.
Prophylaxis for venous thromboembolism is an area that has received intense study in certain conditions, but less than adequate coverage in other areas. In considering who needs prophylaxis, patients are categorized into levels of risk. Clinical venous thromboembolism can be correlated to these levels of risk. Methods of prophylaxis include pharmacologic, mechanical, and combinations of these. Each category of surgical and medical patient requires specific types of prophylaxis. In certain orthopedic indications, the length of prophylaxis outlasts the inpatient hospital stay and may be as long as 1 month after discharge. Even with the best prophylaxis today, the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) is decreased by only approximately 70% to 80%. Further developments should allow for greater declines in the rates of venous thromboembolism, with its subsequent short-term consequence of pulmonary embolism and lower extremity morbidity and long-term consequence of the disabling syndrome of chronic venous insufficiency (CVI).
Adult↗
Determination of low-molecular-weight heparins and their binding to protamine and a protamine analog using polyion-sensitive membrane electrodes.
A polycation-sensitive membrane electrode based on the ion-exchanger dinonylnaphthalene sulfonate has previously been developed and used as an end-point detector for the determination of unfractionated heparin in whole blood samples via simple potentiometric titration with protamine. Herein, we report the application of the same methodology for the quantitation of a commercial low-molecular-weight heparin (LMWH) preparation (Fragmin) in whole blood samples at concentrations up to 2 U/ml. Further, an analogous polyanion (heparin)-sensitive electrode is used to estimate the binding constants between protamine and various LMWH preparations. The equilibrium constants (Keq) and the number of binding sites per mole of heparin (n) are determined by recasting the data in the form of a Scatchard plot. Results show that the average molecular weight and molecular weight distribution of the LMWH preparation are important parameters affecting their binding with protamine. Comparable binding constants are obtained for the same LMWH preparations titrated with a synthetic protamine analog, [+18RGD] [acetyl-EA(R2A2R2A)4R2GRGDSPA-NH2].
Anticoagulants↗
A multicenter, phase I evaluation of cryopreserved venous valve allografts for the treatment of chronic deep venous insufficiency.
PURPOSE: A phase I feasibility study was conducted to determine whether cryopreserved venous valved segments would remain patent/competent in a short-term period (6 months). METHODS: The target group consisted of 10 patients (C(4-6), E, A(D), P(R)). The exclusion criteria included untreated superficial/perforator venous disease, significant venous or arterial obstruction, hypercoagulability or coagulopathy, and significant preexisting medical conditions. Required preoperative tests were venous duplex, ascending/descending venography, and a physiologic study (eg, APG, blood typing, an ankle/brachial index, and if post-thrombotic, a hypercoagulability work-up). A single-valve transplant was placed below all reflux, aided by anticoagulation with or without a distal arteriovenous fistula. Postoperative assessment included duplex scanning/clinical examination (at 1, 3, and 6 months), descending venogram (at 1 month), and physiologic study (at 1 and 6 months). The primary end point was valve patency/competence, with clinical outcome as a secondary end point. Adverse events were recorded. RESULTS: After eliminating protocol violations, nine patients with superficial femoral (5) or popliteal (4) vein valve transplants were studied. Six-month actuarial results show a patency rate of 67% +/- 16% and 78% +/- 13%, respectively, a primary and secondary competency rate of 56% +/- 17% and 67% +/- 16%, respectively, and a 100% patient survival rate. Clinical outcome averaged 1.1, with healing and/or freedom from ulcer recurrence, in six of nine patients. A postoperative risk of seroma formation (3) and cellulitis (1) exists. CONCLUSION: In patients with few remaining therapeutic options, one can achieve a 6-month assisted patency and competency rate of 78% and 67%, respectively, with an improved clinical outcome.
Actuarial Analysis↗
Neovascularization during venous thrombosis organization: a preliminary study.
PURPOSE: Thrombus organization after venous thromboembolism leading to recanalization occurs at a variable rate. The angiogenic chemokine interleukin-8 (IL-8) has been found in thrombus months after thrombus initiation. We hypothesize that thrombus organization involves neovascularization and leukocyte influx and that IL-8 administered at thrombus induction will promote thrombus organization. METHODS: A group of rats underwent inferior vena caval occlusive thrombosis. At thrombus induction and every 24 hours, the rats were administered IL-8 (1 microgram) or serum albumin. The rats were killed at either day 4, day 8, or day 12, and, at death, colloidal carbon was perfused via the heart. The inferior vena cava was isolated, measured, weighed, and formalin fixed. The sections were stained with anti-polymorphonuclear leukocyte antibody, the endothelial marker factor VIII-related antigen, and with hematoxylin and eosin. Thrombus neovascularization (colloidal carbon) with morphometric analysis was normalized to the total thrombus area. In addition, the rats underwent perfusion with fluorescein isothiocyanate dextran (molecular weight, 150,000) at death to correlate with colloidal carbon perfusion, and thrombus fluorescence was determined. RESULTS: Thrombus cellularity initially involved neutrophils, followed by monocytes. Significantly more neutrophils, monocytes, and cells that were defined as spindle shaped (fibroblasts and endothelial cells) were noted in the animals treated with IL-8. Neovascularization was significantly increased at day 4 in the animals treated with IL-8 versus the animals treated with serum albumin and was corroborated with a significant increase in thrombus fluorescein isothiocyanate dextran fluorescence at day 4 in the rats treated with IL-8. Colloidal carbon perfusion was noted within vascular channels without extravasation and colocalized with factor VIII-related antigen. CONCLUSION: This study shows that thrombus organization involves neovascularization and that IL-8 augments thrombus organization.
Animals↗
Developments in diagnosis and classification of venous disorders: non-invasive diagnosis.
PURPOSE: This review examines the many techniques that have been used for the non-invasive diagnosis of acute and chronic venous disease and was conducted by members of the Committee on Research of the American Venous Forum. It proposes to identify those techniques with the greatest clinical potential, to suggest algorithms for the clinical application of non-invasive techniques in the identification of acute deep venous thrombosis and chronic venous insufficiency, and to identify areas of deficient knowledge and potential areas for future research initiatives. METHODS: Review of pertinent clinical and research material. RESULTS: Impedance plethysmography and ultrasonic imaging are the primary non-invasive tools used in the diagnosis of acute deep venous thrombosis. At present, ultrasonic imaging techniques are recommended on the basis of greater diagnostic accuracy in recent comparative clinical trials. Data would suggest that serial evaluation should probably be viewed as the preferred option for symptomatic patients with a negative initial examination and the presence of risk factors or physical findings suggesting a proximal deep venous obstruction/thrombosis. Chronic venous disease is the result of valvular incompetence, with or without associated venous obstruction. Duplex imaging can be used to determine the location and extent of reflux; however, there are reported procedural variations in the performance and interpretation of such studies. Recent innovations in air plethysmography may provide a means of quantifying volume changes, and permit an objective characterization of venous reflux and calf pump efficiency. CONCLUSIONS: There are still significant questions that need to be answered by well-designed research initiatives. Research applications that incorporate non-invasive diagnostic techniques may involve the diagnosis, treatment and natural history of acute deep venous obstruction/thrombosis and chronic venous insufficiency, assessment prior to and following venous reconstruction, and the basic science aspects of acute and chronic venous disease. At present, a lack of common standards is, by far, the greatest impediment to an organized research approach to venous disease.
Acute Disease↗
IL-10 regulates thrombus-induced vein wall inflammation and thrombosis.
Vein wall inflammation associated with venous thrombosis is mediated by an imbalance in proinflammatory as compared with antiinflammatory molecules. We hypothesize that IL-10 is an important antiinflammatory cytokine that influences vein wall inflammation and thrombus propagation during venous thrombosis. To test this hypothesis a model of inferior vena caval thrombosis was used. Studies were performed at sacrifice 2 days after thrombus induction and included leukocyte morphometrics, myeloperoxidase activity, vein wall permeability, thrombus weight, and IL-10 ELISA analysis from the vein wall. IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, while supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. Interestingly, a low 2.5-microg rIL-10 dose given at time of initiation of thrombosis most significantly decreased inflammation. Thrombus weight was importantly diminished by reconstitution of IL-10. These studies support an important role for IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis.
Animals↗
Ultrasound echogenicity in experimental venous thrombosis.
This study characterizes the echogenicity of experimentally induced venous thrombosis. Venous duplex imaging (Diasonics Spectra) was performed of the rat (n 12) and primate (n 3) inferior vena cava (IVC). Thrombosis was induced by IVC ligation at the level of the renal veins (rat, baboon) or balloon occlusion (baboon) of the IVC at the renal vein and iliac vein bifurcation level. Sham-treated rats served as controls. B-mode images were stored for off-line computer analysis. Fixed depth gain control curves allowed for measuring gain-corrected echogenicity units over the IVC in both a longitudinal and transverse orientation. In rat studies, thrombus was removed at time of euthanasia and dissolved, allowing for fibrin monomer determination using a chromogenic assay. Echogenicity values generally increased over time in both rat and primate studies. Significant differences between ligated and sham-treated rats were noted at each time point measured (6 h, 2 days, and 6 days after IVC ligation) and fibrin monomer values correlated (p < 0.05) with echogenicity units. In primate studies, echogenicity values significantly were different from baseline values at all time points measured (6 h, 2 days, 6 days, and 13 days after thrombus induction). Duplex ultrasound can be used to quantitate thrombus echogenicity, which correlates to fibrin content. Such measurement may potentially allow for improved thrombus age determination and the noninvasive quantitation of thrombus progression/resolution.
Animals↗
Low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis.
PURPOSE: Venous thrombosis results in a vein wall inflammatory response initiated by thrombus. Although anticoagulation with standard heparin (SH) and low-molecular-weight heparin (LMWH) is known to limit further thrombosis, their anti-inflammatory properties are poorly defined. The anti-inflammatory properties of these heparins were studied. METHODS: Sprague-Dawley rats were divided into groups and underwent inferior vena caval (IVC) ligation just below the renal level producing IVC thrombosis. One hour before ligation, animals received subcutaneous SH or LMWH at either high or low dose; normal saline (NS) was used as control. Six hours after ligation, animals were killed, and the IVCs were analyzed for clot presence, vein wall morphometrics, and vein wall permeability (VP) to define injury. RESULTS: Animals in both low-dose groups had no measurable anticoagulation, whereas those in both high-dose groups were adequately anticoagulated. There were statistically less IVC neutrophils for all groups compared with the control group, with low-dose LMWH showing the least cells (low-dose LMWH, 16 +/- 3; high-dose LMWH, 37 +/- 10; low-dose SH, 37 +/- 6; high-dose SH, 32 +/- 9; NS control, 63 +/- 2). Similar results were noted for total inflammatory cells. The lowest VP was noted for low-dose LMWH. CONCLUSION: Although both SH and LMWH inhibited vein wall neutrophils and total inflammatory cells, low-dose LMWH was most effective limiting neutrophil extravasation and was the only intervention to decrease VP below control levels. This occurred without preventing thrombus formation or causing a state of anticoagulation. Low-dose LMWH possesses anti-inflammatory properties distinct from its anticoagulant properties.
Animals↗
Acute respiratory distress after deep cervical plexus block.
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Acute Disease↗
Differential effects of novel protamine variants on myocyte contractile function with left ventricular failure.
BACKGROUND: Protamine administration can cause left ventricular (LV) dysfunction, which may have clinical significance in the setting of congestive heart failure (CHF). Protamine variants have recently been constructed with heparin reversal capacity similar to protamine. The purpose of this study was to examine the potential differential effects of these protamine variants on isolated myocyte contractile function in normal myocytes and in myocytes after the development of CHF. METHODS: Contractile function was measured by means of computer-aided videomicroscopy in myocytes from five normal pigs and five pigs with CHF induced by rapid pacing (240 beats/min for 3 weeks). Myocyte contractility was examined in the presence of 40 micrograms/ml native protamine or one of three protamine variants: (1) reduced charge (+18) and lysine substituted for arginine; (2) lysine-substituted variant with glutamic acid substituted for the initial proline; or (3) arginine-rich peptide with a terminal arginine-glycine-aspartic acid (RGD) amino acid sequence. RESULTS: In the presence of native protamine, myocyte percent shortening fell from baseline in both the normal (2.86 +/- 0.15 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.01 +/- 0.06 versus 2.07 +/- 0.05, p < 0.05). With both of the lysine-substituted protamine variants, percent shortening fell from baseline in the normal group (3.42 +/- 0.20 for arginine and 3.74 +/- 0.20 for glutamic acid versus 4.58 +/- 0.08, p < 0.05), and was unchanged in the CHF group (1.94 +/- 0.13 versus 2.07 +/- 0.05, p = 0.34 for arginine; and 1.96 +/- 0.10 versus 2.07 +/- 0.05, p = 0.31, for glutamic acid). However, with the arginine/RGD variant, percent shortening fell from baseline in both the normal (2.86 +/- 0.23 versus 4.58 +/- 0.08, p < 0.05) and the CHF groups (1.32 +/- 0.10 versus 2.07 +/- 0.05, p < 0.05). CONCLUSIONS: Specific changes in the primary and secondary structures of protamine had different effects on myocyte contractile function. Furthermore, the negative effects of lysine-substituted protamine variants on myocyte contractility were less pronounced in both CHF and normal myocytes. Thus protamine variants may be of clinical use, particularly in the setting of preexisting LV dysfunction.
Animals↗
A novel protamine variant reversal of heparin anticoagulation in human blood in vitro.
PURPOSE: Protamine reversal of heparin anticoagulation during cardiovascular surgery may cause severe hypotension and pulmonary hypertension. A novel protamine variant, [+18RGD], has been developed that effectively reverses heparin anticoagulation without toxicity in canine experiments. Heretofore, human studies have not been undertaken. This investigation hypothesized that [+18RGD] would effectively reverse heparin anticoagulation of human blood in vitro. METHODS: Fifty patients who underwent anticoagulation therapy during vascular surgery had blood sampled at baseline and 30 minutes after receiving heparin (150 IU/kg). Activated clotting times were used to define specific quantities of [+18RGD] or protamine necessary to completely reverse heparin anticoagulation in the blood sample of each patient. These defined amounts of [+18RGD] or protamine were then administered to the heparinized blood samples, and percent reversals of activated partial thromboplastin time, thrombin clotting time, and antifactor Xa/IIa levels were determined. In addition, platelet aggregation assays, as well as platelet and white blood cell counts were performed. RESULTS: [+18RGD] and protamine were equivalent in reversing heparin as assessed by thrombin clotting time, antifactor Xa, antifactor IIa levels, and white blood cell changes. [+18RGD], when compared with protamine, was superior in this regard, as assessed by activated partial thromboplastin time (94.5 +/- 1.0 vs 86.5 +/- 1.3% delta, respectively; p < 0.001) and platelet declines (-3.9 +/- 2.9 vs -12.8 +/- 3.4 per mm3, respectively; p = 0.048). Platelet aggregation was also decreased for [+18RGD] compared with protamine (23.6 +/- 1.5 vs 28.5 +/- 1.9%, respectively; p = 0.048). CONCLUSIONS: [+18RGD] was as effective as protamine for in vitro reversal of heparin anticoagulation by most coagulation assays, was statistically more effective at reversal than protamine by aPTT assay, and was associated with lesser platelet reductions than protamine. [+18RGD], if less toxic than protamine in human beings, would allow for effective clinical reversal of heparin anticoagulation.
Aged↗
Limb asymmetry in titanium Greenfield filters: clinically significant?
PURPOSE: The purpose of this study was to determine the outcomes for patients with titanium Greenfield vena caval filters (TGFs) and, in particular, to evaluate the effect of filter leg distribution on recurrent pulmonary embolism (PE) and caval occlusion. METHODS: Physical examination, abdominal plain films, and duplex ultrasound examinations of the inferior vena cava and lower extremities were obtained annually and recorded in a Filter Database. RESULTS: Seven hundred eighty-three TGFs have been placed since 1989. Follow-up was available for 373 patients, or 65% of the surviving patients, over 1 to 84 months (mean, 33 months). Asymmetry was identified in 42 placements (5%), and 35 of these patients had at least one follow-up examination. The overall incidence of recurrent PE was 3.2% (12 of 373), whereas the caval patency rate was 97.8% (265 of 271). These outcomes were not significantly different for patients who had asymmetric filters (p = 0.1 and 0.18, respectively). CONCLUSIONS: Filter leg distribution does not appear to be associated with an increased incidence of recurrent PE or caval occlusion. These data support earlier in vitro findings. The long-term results with the TGF are comparable with the results of the original stainless steel Greenfield filter.
Female↗
"Bull's-eye" sign on gadolinium-enhanced magnetic resonance venography determines thrombus presence and age: a preliminary study.
PURPOSE: Venous thrombosis is associated with a significant inflammatory response, which can be visualized by gadolinium magnetic resonance venography (MRV). Gadolinium extravasates into tissue during inflammation, producing perithrombus enhancement on magnetic resonance scanning. This study determines (1) whether gadolinium enhancement occurs during deep venous thrombosis (DVT); and (2) whether this enhancement changes with time and can therefore establish the age of thrombus. METHODS: Patients with a diagnosis of iliofemoral DVT by duplex ultrasound who were referred for MRV to document central thrombus extent were studied. T1 weighted images were obtained before and after gadolinium injection (0.1 mmol/kg); repeat scans were obtained up to 3 months thereafter. At the level of maximum thrombus, measurements of signal intensity were made at the periphery (rim), and the center of the thrombosed vein, as well as the contralateral normal vein, on images after gadolinium enhancement. Rim-center vein signal intensity ratios were then calculated and followed. RESULTS: A total of 39 scans were obtained in 14 patients (eight men, six women). The thrombosed veins were enlarged, with a peripheral rim of enhancement ("bull's-eye" sign). The rim-center ratio for thrombosed veins (2.16 +/- 0.18) was different from that of normal veins (0.66 +/- 0.10; n = 39; p < 0.001). For all acute studies (< or = 14 days) the rim-center ratio was 2.38 +/- 0.17 (n = 31), whereas for all chronic studies (> 14 days) the rim-center ratio was 1.29 +/- 0.44 (n = 8; p = 0.001). Among patients who underwent both early and late studies, the rim-center ratio dropped significantly, from 2.33 +/- 0.20 acutely to 1.29 +/- 0.44 in chronic studies (n = 8; p = 0.03). One patient with active malignancy had a paradoxic increase in rim-center ratio over time and a clinical recurrence of symptoms, suggesting active thrombosis. CONCLUSIONS: We conclude that (1) a pattern of peripheral gadolinium enhancement (bull's-eye sign) is seen around acutely thrombosed veins on gadolinium-enhanced MRV, facilitating DVT diagnosis; and (2) the ratio of signal intensity at the rim versus the center of the thrombosed vein may be a good discriminator of acute compared with chronic DVT, which may help direct therapy.
Acute Disease↗
Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis.
PURPOSE: Venous thrombosis and inflammation are interrelated. P-selectin contributes to activation of leukocyte-mediated inflammation. Therefore, we hypothesized that the neutralization of P-selectin would decrease vein wall inflammation and thrombosis. METHODS: Twelve baboons underwent infrarenal inferior vena caval balloon occlusion to induce thrombosis. Two groups of four baboons received neutralizing intravenous anti-P-selectin antibody (PSab) GA6 or CY1748 before occlusion and at days 2 and 4. Four baboons received saline control injections. One baboon per group was killed at days 2, 6, and 13, and at 2 months. Analysis included phlebography, ultrasound, gadolinium (Gd)-enhanced magnetic resonance venography (reflecting vein wall inflammation), and histologic, morphometric, and protein evaluation of the vein wall. Thrombus presence or absence was assessed. RESULTS: By day 2 in PSab baboons, vein wall Gd enhancement was decreased in the mid-inferior vena cava and the right iliac vein (p < 0.05; GA6 vs control baboons), normalizing by 2 months. The mid-inferior vena cava revealed fewer neutrophils and total leukocytes in PSab baboons; however, for GA6 in the right iliac vein these decreases were not present despite the absence of Gd enhancement; they were decreased with CY1748. PSab baboons demonstrated significantly less thrombus than control baboons (p < 0.01, GA6 and CY1748 vs control baboons). CONCLUSIONS: Anti-P-selectin antibody decreases vein wall inflammation and thrombus formation. Inhibition of P-selectin may be useful in venous thrombosis prophylaxis.
Acute Disease↗
Pathogenesis of venous thrombosis: a new insight.
Venous thrombosis and thrombophlebitis have long been observed to result in painful inflammation around the affected veins. The full extent of the synergistic interaction between thrombosis and the inflammatory response and how this leads to the later sequelae of chronic venous insufficiency is only now beginning to be understood. Venous thrombosis is known directly to elicit an inflammatory response in the thrombus and vein wall. Leukocytes including neutrophils and monocytes roll, adhere, activate and extravasate into the vein wall based on a vein wall cytokine/chemokine gradient producing an inflammatory response. Such a response leads to amplification of thrombus formation through mechanisms such as the elaboration of tissue factor on the surface of monocytes and the release of cathespin G from activated neutrophils (distrupting the endothelial cell barrier), exposing the thrombogenic subendothelial vein wall collagen. Selectins such as P-selectin and the proinflammatory cytokine tumor necrosis factor appear important in this vein wall response. Inhibition of inflammation before the initiation of the thrombotic event may decrease the detrimental vein wall changes that contribute to vein wall and vein valve damage and thrombus formation.
Chemokines↗
Research and clinical issues in chronic venous disease.
The purpose of this study was to summarize the current issues in chronic venous disease by reviewing of the literature relating to the condition. The review was conducted by members of the Committee on Research of the American Venous Forum and includes the Committee's venous disease and current/future directions. Progress in the understanding and management of chronic venous problems has lagged behind that in arterial disease, despite the large number of patients affected. The complex pathophysiology of venous problems, lack of accepted evaluation standards and lack of prosthetic conduits are some of the factors which contribute to this. New information in these areas has laid the foundation for advances in both operations and non-operative therapy. In conclusion, many opportunities for clinical and basic research in the area of chronic venous disease are available. Application of basic science techniques, including those of molecular biology, will lead to new insights into pathophysiology of chronic venous syndrome. Developments in technology, classification and basic science suggest multiple new potentials therapeutic approaches in the next decade.
Blood Vessel Prosthesis Implantation↗
Hemodynamically significant atherosclerotic renal artery stenosis: MR angiographic features.
PURPOSE: To identify magnetic resonance (MR) angiographic features of hemodynamically significant renal artery stenosis. MATERIALS AND METHODS: Forty-seven patients underwent MR angiography of the renal arteries, including T1-weighted spin-echo and three-dimensional gadolinium-enhanced spoiled gradient-echo and three-dimensional phase-contrast pulse sequences, followed by renal revascularization. Thirty-five patients (52 arteries) were identified who benefited from renal revascularization, which indicated that they had hemodynamically significant renal artery stenoses. Kidney length, cortical thickness, parenchymal enhancement, and poststenotic dilatation were measured. Arteries were also examined for signal drop-out (dephasing) on phase-contrast angiograms; dephasing was considered severe if the stenotic artery appeared occluded on phase-contrast angiograms. RESULTS: Poststenotic dilatation of greater than 20% was present in 36 (59%) of 52 hemodynamically significant renal artery stenoses, and severe dephasing was present in 45 (87%) of 52. In patients with unilateral hemodynamically significant stenosis or occlusion, mean ischemic kidney length was reduced to 9.3 cm compared with 10.7 cm for the contralateral normal kidney (P = .009), mean parenchymal thickness was reduced (1.2 vs 1.7 cm; P < .001), and mean parenchymal enhancement was 15% less on the ischemic side (P = .05). Severe dephasing on phase-contrast angiograms was present in nine (75%) of 12 unilateral hemodynamically significant stenoses but in only one contralateral normal renal artery (P < .001). CONCLUSION: MR angiography depicts features of renal artery stenosis that are markers of hemodynamic significance.
Adult↗