A new way to treat proximal deep venous thrombosis using E-selectin inhibition.

OBJECTIVE: There is an inter-relationship between thrombosis and inflammation. Previously, we have shown the importance of P-selectin in thrombogenesis and thrombus resolution in many preclinical animal models. The role of E-selectin has been explored in rodent models and in a small pilot study of clinical calf vein deep venous thrombosis. The purpose of this study was to determine the role of E-selectin in thrombosis in a primate model of proximal iliac vein thrombosis, a model close to the human condition. METHODS: Iliac vein thrombosis was induced with a well-characterized primate model. Through a transplant incision, the hypogastric vein and iliac vein branches were ligated. Thrombus was induced by balloon occlusion of the proximal and distal iliac vein for 6 hours. The balloons were then deflated, and the primates recovered. Starting on postocclusion day 2, animals were treated with the E-selectin inhibitor GMI-1271, 25 mg/kg subcutaneously, once daily until day 21 (n = 4). Nontreated control animals received no treatment (n = 5). All animals were evaluated by magnetic resonance venography (MRV); evaluation of vessel area by ultrasound, protein analysis, hematology (complete blood count), and coagulation tests (bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thromboelastography) were performed at baseline, day 2, day 7, day 14, and day 21 with euthanasia. In addition, platelet function and CD44 expression on leukocytes were determined. RESULTS: E-selectin inhibition by GMI-1271 significantly increased vein recanalization by MRV vs control animals on day 14 (P < .05) and day 21 (P < .0001). GMI-1271 significantly decreased vein wall inflammation by MRV with gadolinium vein wall enhancement vs control also on day 14 (P < .0001) and day 21 (P < .0001). The thromboelastographic measure of clot strength (maximum amplitude) showed significant decreases in animals treated with GMI-1271 vs controls at day 2 (P < .05) and day 7 (P < .05). Animals treated with GMI-1271 had significant vessel area increase by day 21 vs controls (P < .05) by ultrasound. Vein wall intimal thickening (P < .001) and intimal fibrosis (P < .05) scores were significantly decreased in GMI-1271-treated animals vs controls. Importantly, no significant differences in hematology or coagulation test results were noted between all groups, suggesting that E-selectin inhibition carries no bleeding potential. GMI-1271 did not affect platelet function or aggregation or CD44 expression on leukocytes. In addition, no episodes of bleeding were noted in either group. CONCLUSIONS: This study suggests that E-selectin modulates venous thrombus progression and that its inhibition will increase thrombus recanalization and decrease vein wall inflammation, without affecting coagulation. The use of an E-selectin inhibitor such as GMI-1271 could potentially change how we treat deep venous thrombosis.

Catheter-Directed Thrombectomy for Highly Symptomatic Patients with Iliofemoral Deep Venous Thrombosis not Responsive to Conservative Treatment.

PURPOSE: The use of pharmacomechanical thrombectomy in patients with symptomatic iliofemoral deep venous thrombosis (DVT) not responsive to conservative treatment is under-investigated until now. This prompted us to review and analyze our results (technical/clinical outcome, complications) and compare them to the current literature. MATERIALS AND METHODS: Between 2013 and 2019, 19 patients (14 women and 5 men; mean age: 41.2 years, SD: 18.2) with iliofemoral DVT and excessive pain not responsive to conservative treatment were treated with pharmacomechanical thrombectomy. Patients were followed up for 12 months. Demographics, technical success and clinical outcome data (pain score/Villalta score) were collected. RESULTS: Thrombectomy ± thrombolysis was successful in all cases (n = 19). No major complications were observed. Eight out of nineteen cases developed hematoma at the sheath insertion site not requiring further treatment. Seven out of nineteen cases required additional continuous lysis for complete iliofemoral clot solution. All patients received balloon angioplasty to treat post-thrombotic strictures. In 16/19 cases, stents were placed to preserve iliofemoral caliber and maintain unrestricted iliac venous outflow. Three patients (16%) required re-intervention due to re-thrombosis or in-stent stenosis after 4, 14 days and 4 months, respectively. Symptoms could be improved temporarily or indefinitely in 19 out of 19 patients. 1 year following thrombectomy mean pain score was reduced by 87%, mean Villalta score was 2.6 (SD: 4), and iliofemoral veins were patent in 15/17 patients. CONCLUSION: In symptomatic patients with iliofemoral DVT, refractory to conservative treatment, catheter-directed thrombectomy enables rapid and long-lasting pain relief. High patency rates can be achieved in patients receiving PTA and venous stenting post-thrombectomy.

Fast-track thrombolysis protocol: A single-session approach for acute iliofemoral deep venous thrombosis.

OBJECTIVE: Catheter-directed thrombolysis in the treatment of acute iliofemoral deep venous thrombosis (IFDVT) often requires more than one interventional session to yield successful outcomes. Catheter-directed thrombolysis is generally expensive, requiring prolonged hospital stay that may be associated with increased local and systemic hemorrhagic complications. We developed the fast-track thrombolysis protocol (FTTP) to address these issues. The goal of FTTP is to restore patency during the initial session of thrombolysis, thereby minimizing costs and complications associated with prolonged thrombolysis. METHODS: A retrospective analysis of 38 patients treated for acute IFDVT using FTTP at our institution from January 2014 to February 2019 was performed. The protocol includes periadventitial injection of lidocaine at the venipuncture site under ultrasound guidance, contrast venography of the entire target segment, pharmacomechanical rheolytic thrombectomy of the occluded venous segment, tissue plasminogen activator infusion along the occluded segment, balloon maceration of the thrombus, and, if indicated, venous stent placement in areas of significant (≥50%) stenosis refractory to thrombolysis and balloon angioplasty. Once the thrombus was cleared, patients were prescribed oral antithrombotic therapy. RESULTS: Thirty-eight primary FTTPs (45 total interventions) were performed in 38 patients. The median age was 66 years (range, 39-93 years); 60.5% were female. Initial venous access was most often obtained through the popliteal vein, followed by the femoral and great saphenous veins. The mean operative time was 122 minutes (range, 59-249 minutes), and the median volume of tissue plasminogen activator infused was 10 mg (range, 4-20 mg). The median cost per procedure, including devices and medication, was $5374.45. Median postoperative length of stay was 1 day (range, 1-45 days). Successful single-session FTTP, as determined by completion venography, was accomplished in 81.5% (n = 31/38) of cases. The remaining seven cases (18.5%) required one additional session. Of the 38 patients, 30 (79%) required iliac vein stenting. Periprocedural complications consisted of one patient with retroperitoneal hemorrhage that was managed conservatively. No patients experienced rethrombosis within 30 days of FTTP. During the 5-year study period, there were no cases of pulmonary embolism, significant local or systemic hemorrhage, limb loss, or mortality. CONCLUSIONS: FTTP, as presented herein, appears to be a safe, effective, and cost-effective technique in the resolution of acute IFDVT.

Single- versus multiple-stage catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis does not have an impact on iliac vein stent length or patency rates.

BACKGROUND: Incomplete venous thrombolysis and residual nonstented iliac vein disease are known predictors of recurrent deep venous thrombosis (DVT). Controversy exists as to whether the number of thrombolysis sessions affects total stent treatment length or stent patency. The goal of this study was to evaluate the outcomes of patients who underwent single vs multiple catheter-directed lysis sessions with regard to stent extent and patency. METHODS: Consecutive patients who underwent thrombolysis and stenting for acute iliofemoral DVT between 2007 and 2018 were identified and divided into two groups on the basis of the number of treatments performed (one vs multiple sessions). Operative notes and venograms were reviewed to determine the number of lytic sessions performed and stent information, including size, location, total number, and length treated. End points included total stent length, 30-day and long-term patency, and post-thrombotic syndrome (Villalta score ≥5). The χ2 comparisons, logistic regression, and survival analysis were used to determine outcomes. RESULTS: There were 79 patients who underwent lysis and stenting (6 bilateral interventions; mean age, 45.9 ± 17 years; 48 female). Ten patients (12 limbs) underwent single-stage treatment with pharmacomechanical thrombolysis, and the remaining 69 (73 limbs) had two to four operating room sessions combining pharmacomechanical and catheter-directed thrombolysis. Patients who underwent a single-stage procedure were older and more likely to have a malignant disease. These patients received less tissue plasminogen activator compared with the multiple-stage group (17.2 ± 2.2 mg vs 27.6 ± 11.6 mg; P = .008). Average stent length was 8.8 ± 5.2 cm for the single-stage group vs 9.2 ± 4.6 cm for the multiple-stage group (P = .764). Patients who underwent a single-stage procedure had no difference in average length of stay from that of patients who underwent multiple sessions (8.5 days vs 5.9 days; P = .269). The overall 30-day rethrombosis rate was 7.3%. Two-year patency was 72.2% and 74.7% for the single and multiple stages, respectively (P = .909). The major predictors for loss of primary patency were previous DVT (hazard ratio [HR], 5.99; P = .020) and incomplete lysis (HR, 5.39; P = .014) but not number of procedures (HR, 0.957; P = .966). The overall post-thrombotic syndrome rate was 28.4% at 5 years and was also not associated with the number of treatment sessions. CONCLUSIONS: Single- vs multiple-stage thrombolysis for DVT is not associated with a difference in extent of stent coverage. Patency rates remain high for iliac stenting irrespective of the number of lytic sessions, provided lysis is complete and the diseased segments are appropriately stented.

Evaluation of anticoagulant and antiplatelet therapy after iliocaval stenting: Factors associated with stent occlusion.

OBJECTIVE: Iliocaval stenting has gained increased use over recent years for a variety of indications, including May-Thurner syndrome (MTS), post-thrombotic syndrome (PTS), and acute deep vein thrombosis (DVT). METHODS: A retrospective review of 155 patients undergoing iliocaval venous stenting at a large teaching hospital was performed. Clinical and procedural data, mode and duration of anticoagulation or antiplatelet therapy, and outcomes were recorded. RESULTS: Forty-five patients were treated for MTS, 49 for PTS. and 61 for acute DVT. The median follow-up was 19 months (interquartile range, 9-30 months). Primary patency rates were 97.8% in the MTS group, 85.7% in PTS, and 85.2% for the acute DVT group. Stent restenosis or occlusion occurred in one patient with MTS (2.2%), seven patients with PTS (14%), and nine patients with acute DVT (15%). An ipsilateral DVT recurred in 7 patients with PTS (14%) and 15 patients with acute DVT (25%). The stents that occluded had a tendency toward longer length (162.2 vs 125.2 mm; P = NS) and extension into the common femoral vein (18.8 vs 5.3%; P = NS). The patent stent group had statistically larger nominal diameter stents (P = .013). The duration of anticoagulation did not seem to be a significant factor in stent patency. CONCLUSIONS: Stent diameter has a significant influence on iliocaval stent patency rates.

Posterior tibial vein approach to catheter-directed thrombolysis for iliofemoral deep venous thrombosis.

OBJECTIVE: Deep venous thrombosis (DVT) remains a significant cause of morbidity in the American population. Catheter-directed thrombolysis for acute iliofemoral DVT is an effective therapy not only to restore venous patency but also to reduce the development of post-thrombotic syndrome (PTS), especially in patients with extensive thrombosis involving the iliac and femoral venous segments. We hypothesized that delivery of thrombolytics through an access site in a vein distal to the segments containing thrombus would provide the greatest short- and long-term therapeutic clinical benefit with similar safety and efficacy. METHODS: All patients treated at a single institution between 2009 and 2016 undergoing mechanical and chemical thrombolysis for iliofemoral DVT were retrospectively reviewed. Patients were divided into groups by access site, including contralateral and ipsilateral femoral vein, popliteal vein, and posterior tibial vein (PTV). Preoperative demographics, intraoperative data, and postoperative outpatient charts were analyzed. Primary end points included evidence of incompetence after the procedure by duplex ultrasound assessment and development of complications of PTS as defined by the Villalta scale. RESULTS: Fifty-eight patients underwent mechanical and chemical thrombolysis, and 51 patients met the inclusion criteria. Thrombolysis access was through PTV (n = 27), popliteal vein (n = 20), or femoral vein (n = 4). More patients were female (55%), and the mean age was 57 years. Forty patients had unilateral DVT, whereas 11 patients had bilateral involvement. After lysis, 44 patients underwent percutaneous venous angioplasty and 11 patients underwent venous stenting in the acute setting. Although not statistically significant, mean operative times were slightly longer in the posterior tibial approach (156.7 minutes vs 130.6 minutes; P = .08), and mean fluoroscopy time was higher in the posterior tibial group (18.1 minutes vs 14.3 minutes; P = .17). Overall 90-day morbidity was 9.8%, and no deaths were recorded. Patency of the deep venous system was similar between the posterior tibial and the popliteal or femoral approach (95% vs 88%; P = .29); 21.6% developed symptoms of PTS. There was no difference for development of PTS between posterior tibial and popliteal or femoral approaches (22% vs 20.8%; P = .52). There was no difference in development of chronic nonocclusive DVT (37% vs 35%; P = .61). Median follow-up was 8.7 months (range, 0.4-58.9 months). CONCLUSIONS: The PTV approach to catheter-directed thrombolysis is a safe and sensible option for the treatment of iliofemoral and femoropopliteal DVT. A larger cohort will be necessary to demonstrate superiority of tibial vein access in the treatment of iliofemoral DVT with popliteal involvement.

Thrombolysis for Management of Phlegmasia Cerulea Dolens in the First Trimester of Pregnancy.

BACKGROUND: Pregnancy is a hypercoagulable state associated with a fivefold increase in the risk of venous thromboembolism. Thrombolysis is the preferred level of care for patients with acute iliofemoral deep vein thrombosis (DVT); however, most studies exclude pregnant patients, highlighting the lack of data regarding the efficacy and safety of thrombolytic therapy for mother and fetus. METHODS: We describe the successful use of thrombolytic therapy in conjunction with ultrasound to remove a large ileofemoral DVT in a first-trimester patient with phlegmasia cerulea dolens. The procedure was performed safely for both mother and fetus. RESULTS: No radiation or contrast dye was used, and intravascular ultrasound confirmed patency of the entirety of the venous system. She delivered a healthy term baby after the procedure and had no further sequalae. CONCLUSION: Thrombolysis with intravascular ultrasound may be considered in first-trimester pregnant patients with threatened limb due to DVT.

Antiplatelet Therapy is Associated with Stent Patency After Iliocaval Venous Stenting.

PURPOSE: To examine the effectiveness of antithrombotic medications to prevent venous stent malfunction for iliocaval occlusive disease. MATERIALS AND METHODS: A retrospective analysis was performed on 62 patients who underwent technically successful endovascular iliocaval stent placement between May 2008 and April 2017. Clinical records were reviewed for demographic information, procedure details, post-stenting antithrombotic prophylaxis and stent patency on follow-up. Stent malfunction was defined as > 50% stenosis or occlusion at follow-up. Risk factors for stent malfunction were assessed with univariable and multiple Cox proportional hazard models. RESULTS: The median follow-up period was 11.6 months (range 0.1-76.4). Overall primary and secondary cumulative patency rates at 12 months were 70.0% and 92.4%, respectively. After stent placement, 97% of patients received anticoagulation with warfarin, enoxaparin or a factor Xa inhibitor. In addition, 61% received antiplatelet prophylaxis with aspirin, clopidogrel or a combination. In multiple Cox regression analysis, post-stenting antiplatelet use remained significantly associated with primary stent patency (HR = 0.28, P = 0.022). CONCLUSION: After iliocaval venous stenting, stent patency was best predicted by concomitant antiplatelet and anticoagulation therapy rather than anticoagulation alone. This novel finding warrants further research underlying mechanisms leading to venous stent thrombosis, and has implications for optimal medical management after venous stenting.

Editor's Choice - Factors Associated with Long-Term Outcome in 191 Patients with Ilio-Femoral DVT Treated With Catheter-Directed Thrombolysis.

OBJECTIVE: To identify factors associated with long-term treatment success after catheter-directed thrombolysis (CDT) for acute deep venous thrombosis (DVT) involving the ilio-femoral vein. MATERIAL AND METHODS: This was a non-randomised observational cohort study. From 1999 to 2013, 191 consecutive patients (203 limbs) attending a tertiary vascular centre at Gentofte University Hospital, Denmark underwent CDT. All patients had ultrasonically verified acute ilio-femoral DVT with open distal popliteal vein and calf veins. Patients were seen in the outpatient clinic 6 weeks, 3, 6, and 12 months, and annually thereafter following the DVT. Successful outcome was defined as patent deep veins without reflux on Duplex ultrasound scanning (DUS). Data were collected prospectively as per protocol and analysed retrospectively. RESULTS: Median age was 27 years (range 14-74 years) and overall median lysis time was 56 h (range 22-146 h). A stent was placed in 106 limbs (52%). Six patients had major bleeding. The median follow-up was 5 years (range 1 month-14.3 years). The cumulative rate of patients with deep patent veins without reflux at 7 years was 79%. Multivariate Cox regression analyses showed that symptom duration >2 weeks (hazard ratio (HR) 2.78, 95% CI 1.14-6.73) and chronic post-thrombotic lesions (HR 19.3, 95% CI 7.29-51.2) were significantly associated with poorer outcome, while the pulse-spray technique (HR 0.15, 95% CI 0.05-0.48) was associated with better outcome. Age, gender, side, IVC atresia, stenting, and lysis duration did not affect outcome. CONCLUSION: In this observational study of CDT for ilio-femoral DVT it was demonstrated that symptom duration less than 2 weeks, absence of chronic post-thrombotic lesions and use of the pulse-spray technique for CDT resulted in better primary patency including normal valve function in the long term.

Endovascular Thrombolysis in the Management of Iliofemoral Thrombosis in Children: A Multi-Institutional Experience.

PURPOSE: To evaluate technical feasibility, complications, and clinical outcomes of endovascular thrombolysis for iliofemoral thrombosis at two tertiary-care children's hospitals. MATERIALS AND METHODS: Institutional review board-approved retrospective review from March 2003 through June 2013 showed that venous thrombolysis for iliofemoral thrombosis was performed in 57 children (64 limbs) with a median age of 16.1 years (mean age, 14.5 y; range, 1.0-17.8 y). Techniques included catheter-directed thrombolysis (CDT), percutaneous mechanical thrombectomy (PMT), and pharmacomechanical catheter-directed thrombolysis (PCDT) with adjunctive angioplasty and/or stent placement. Villalta and modified Villalta scales were applied retrospectively to follow-up data to assess postthrombotic syndrome (PTS). RESULTS: Technical success (≥ 50% thrombolysis) rate was 93.7%: grade III (100%) in 19 limbs, grade II (50%-99%) in 41 limbs, and grade I (< 50%) in four limbs. Techniques included CDT with PCDT (32.8%) or PMT (35.9%), CDT alone (26.6%), PCDT alone (4.7%) or with adjunctive angioplasty (54.7%), and stent placement (6.3%). Mean duration of CDT was 36.5 hours (range, 2.9-89.6 h). There was one major complication (1.8%) of bleeding requiring transfusion. Minor complications (ie, bleeding) occurred in seven patients (12.2%). Median follow-up was 1.5 years (range, 30 d to 7 y). Seven patients underwent repeat thrombolysis for recurrent thrombosis. The PTS rate was 59.3% per modified Villalta scale but only 2.1% per Villalta scale. CONCLUSIONS: Endovascular thrombolysis is technically feasible and safe for iliofemoral thrombosis in children. Variable results were seen with two scales to assess PTS, suggesting an acute need for standardization of outcome measurement in children.

P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor.

OBJECTIVE: Aptamers are oligonucleotides targeting protein-protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low-molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT. APPROACH AND RESULTS: Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti-P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti-P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed. CONCLUSIONS: The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.

Fibrinolytic activity of endothelial cells from different venous beds.

BACKGROUND: Little is known about the molecular biology of endothelial cells from different venous vascular beds. As a result, our treatment of deep vein thrombosis and pulmonary artery embolism remain identical. As an initial step in understanding venous thromboembolic disease in the trauma and surgical patients, this study sought to investigate the balance between coagulation and fibrinolysis in the pulmonary and deep venous vascular beds and how trauma might influence this balance. MATERIALS AND METHODS: Confluent human iliac vein endothelial cells (HIVECs) and human pulmonary artery endothelial cells (HPAECs), were cultured in the absence or presence of tumor necrosis factor (TNFα; 10 ng/mL) for 24 h. The expression of mediators of coagulation and fibrinolysis were determined by Western blot analysis, and plasminogen activator activity was determined by a fibrin clot degradation assay. RESULTS: After TNFα stimulation, there was decreased expression of endothelial protein C receptor and thrombomodulin in both HIVECs and HPAECs. TNFα stimulation increased urokinase plasminogen activator expression in both HIVECs and HPAECs. There was an increase in the expression of tissue plasminogen activator and plasminogen activator inhibitor-1 in response to TNFα in HPAECs, but not in HIVECs. There was significantly greater clot degradation in the presence of both the conditioned media and cell extracts from HIVECs, when compared with HPAECs. CONCLUSIONS: HPAECs and HIVECs react differently in terms of fibrinolytic potential when challenged with a cytokine associated with inflammation. These findings suggest that endothelial cells from distinct venous vascular beds may differentially regulate the fibrinolytic pathway.

The role of short-term oxygen administration in the prevention of intimal hyperplasia.

OBJECTIVE: Intimal hyperplasia (IH) is the cause of most failed arteriovenous fistulas (AVFs), resulting in repeat procedures and leading to increased utilization of scarce health care resources. Our laboratory has previously demonstrated the role of supplemental oxygen in preventing IH and smooth muscle cell proliferation (SMCp) at an artery-to-graft anastomosis and at the deployment site of an intra-arterial stent. This study examines the effect of supplemental oxygen in preventing IH and SMCp in an AVF in a rabbit model. METHODS: Ninety-six rabbits were randomized into four groups: group 1, control; group 2, no surgery with supplemental oxygen; group 3, AVF without supplemental oxygen; and group 4, AVF with supplemental oxygen. Rabbits receiving supplemental oxygen received 30% oxygen for up to 42 days. Specimens were collected in all groups at days 1, 3, 7, 21, 42, and 90. IH and SMCp were measured at the AVF site as well as in the artery and vein proximal and distal to the AVF. RESULTS: IH was first noted at day 7 and significantly increased through day 90 at all locations in the nonoxygen-supplemented groups. No significant IH was noted in the oxygen-supplemented group at any location or any time point. SMCp was noted at day 3 through day 21 in the nonoxygen-supplemented group, whereas almost no SMCp was noted in the oxygen-supplemented group at any location or time point. CONCLUSIONS: Without oxygen supplementation, SMCp begins at day 3 and is no longer noted at day 21 after creation of an AVF, whereas IH begins by day 7 and increases at least through day 90 after creation of an AVF. Forty-two days of 30% supplemental oxygen inhibits IH and SCMp after creation of an AVF. These data suggest a role for the short-term administration of low-dose O2 to prevent both IH and SMCp after creation of an AVF that may prolong patency and function.

Iliac vessel wall thickness in menstrual and hormone treated and untreated postmenopausal women.

OBJECTIVE: To assess iliac vessel wall thickness in different groups of women. METHOD: Three groups of women were menopausal and were classified by hormone replacement therapy (HRT) (n = 32), atherosclerotic risk factors (n = 14) and an untreated group of postmenopausal women (n = 29), two groups of menstrual women, above 35 years (N = 35) and below 35 years (n = 16). In these groups of women, a 3.5 MHz ultrasound was used to assess the combined vessel wall thickness of the right iliac artery inner wall and vein outer wall. RESULTS: The iliac vessel wall thickness was found significantly high in the menopausal group of women possessing high risk factors for atherosclerosis (4.3 ± 0.08 mm) and the untreated menopausal group of women (3.9 ± 0.08 mm) compared to the other three groups (p < 0.0001) (Mann-Whitney U test). The vessel wall thickness of the HRT group was 2.96 ± 0.09 mm, the older menstrual group 2.61 ± 0.07 mm, and 2.0 ± 0.06 mm in the young menstrual group. The HRT group had a significantly thicker iliac vessel wall compared to the young menstrual group (p < 0.001). CONCLUSION: These results confirm the significant impact of high risk factors, such as smoking, hyperlipidaemia and diabetes, on the vessel wall thickness due to accelerated atherosclerosis. This study also suggests that the oestrogenaemic state of a woman may affect the health of the vessel wall.

Mechanosensitive transient receptor potential vanilloid type 1 channels contribute to vascular remodeling of rat fistula veins.

OBJECTIVE: We previously showed that matrix metalloproteinases (MMPs) contribute to tremendous blood flow-induced venous wall thickening during the maturation of an arteriovenous fistula (AVF). However, how veins in the fistula sense a dramatic change in the blood flow remains unknown. Because mechanosensitive transient receptor potential vanilloid channels (TRPVs) are present in the endothelium, we examined whether the Ca2+-permeable TRPVs play a role in remodeling of fistula veins. METHODS: The fistula veins were generated at femoral AVF of Wistar rats. Changes in the hemodynamics and the width and internal radius of the iliac vein were studied at 3, 7, 14, and 28 days, then the iliac vein was removed and examined for changes in wall thickness and protein or mRNA expression by immunofluorecent stain, Western blot, or real time PCR. Changes in MMP2 activity was examined by gelatin zymography. Two ligatures were performed in iliac vein to prevent venodilatation to confirm the effect of dramatic changes in hemodynamics on TRPV expression. The specific role of TRPV was studied in another group of fistula veins given with capsazepine via a subcutaneous mini-osmotic pump for 28 days. RESULTS: The fistula veins demonstrated high flow/wall shear stress (WSS), wall thickening, and venodilatation compared with control veins. The WSS increase was positively correlated with upregulation of TRPV1, but not TRPV4. Narrowing fistula veins prevented TRPV1 upregulation, indicating that high flow directly upregulates TRPV1. We examined the underlying signaling components and found that enhanced Ca2+/calmodulin-dependent protein kinase II (CaMK II) activity upregulated endothelial nitric oxide synthase (eNOS) and downregulated arginase I in the fistula veins. These changes were reversed by a CaMK II inhibitor. The relative levels of eNOS and arginase I activity consequently augmented NO formation, which coincided with an increase in MMP2 activity. Chronic inhibition of TRPV1 in the fistula veins by capsazepine showed no effect on high flow and TRPV1 expression, but markedly attenuated WSS, which was concomitantly associated with attenuation of CaMK II activity, NO-dependent MMP2 activation, and remodeling. CONCLUSION: These findings indicate that TRPV1 is essential in the remodeling of AVFs and that WSS leads to TRPV1 upregulation, which then enhances remodeling, therefore, inhibition of TRPV1 pathway may prolong the lifespan of an AVF by decreasing WSS and vein wall remodeling.

Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation.

P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n = 3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n = 3); and iii) primates receiving no treatment (n = 3). PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.