APC resistance due to Factor V Leiden is not related to baseline inflammatory mediators or survival up to 10 years in patients with critical limb ischemia.

To prospectively evaluate the potential influence of resistance to activated protein C (APC-resistance) on the initial inflammatory response, amputation rate and survival during 10 years of follow-up in patients with critical limb ischemia (CLI). Two hundred and fifty-six consecutive CLI patients were analyzed for APC-ratio, the Factor V Leiden mutation and inflammatory mediators and then prospectively followed for 10 years. Inflammatory mediators, amputation rate, morbidity and mortality were compared between patients with and without APC resistance. Of the 256 CLI patients, 35 (14 %) were heterozygotes and 2 (1 %) homozygotes for the Factor V gene mutation, whereas 219 (86 %) patients were non-APC resistant. No significant differences were found between APC resistant and non-APC resistant patients regarding inflammatory mediators. Non-APC resistant patients more often had infrainguinal atherosclerosis (172 [79 %] vs 22 [59 %]; p = 0.017). Amputation rate at 1 year did not differ. Furthermore, there were no significant differences between groups regarding 1-, 3-, 5-, or 10-year survival. APC resistance in patients with CLI was not related to inflammatory activity, and had no impact on limb salvage or rate of amputation or long-term mortality. APC-resistant CLI-patients less frequently had infrainguinal arteriosclerosis, however.

Arterial thrombosis in mice with factor V Leiden mutation.

The factor V Leiden (FVL) mutation has been demonstrated to be associated with the development of venous thrombosis in humans. Whether such a propensity also exists in the arterial circulation remains controversial. In an effort to minimize the variability that clouds the clinical study of arterial thrombosis, we studied FVL-associated arterial thrombosis in an experimental model of homozygous, heterozygous, and wild-type mice. Heterozygous FVL mice were crossbred to C57BL/6J mice over several generations. The genotypes of the resulting three genotype groups (wild type, heterozygous FVL, and homozygous FVL) were blinded to the investigators. Arterial injury was produced with the injection of ferric chloride into an isolated segment of carotid artery. Arterial thrombosis was assessed with an ultrasonic flow probe and the time to occlusion (TTO) was recorded. The carotid artery occluded within 60 minutes of injury in 72 of the animals studied (97.3%). The carotid artery remained patent at 60 minutes in the remaining two animals, both of whom were subsequently found to be genotypically wild type. There was a statistically significant relationship between TTO and genotype (p = .002). TTO was greatest in the wild-type mice (p < .001 vs heterozygous, < .001 vs homozygous) and least in the homozygotes (p < .001 vs heterozygotes). Increased thrombogenicity is present in mice with the FVL mutation and is more prolonged in homozygotes than heterozygotes. These findings provide some corroboration to the clinical studies that suggest an increased risk of arterial events in patients with the FVL mutation.

Initial management and outcome of aortic endograft limb occlusion.

OBJECTIVE: The purpose of this study was to determine the differences in outcome related to initial management of aortic endograft limb occlusion (ELO). METHODS: During a 7-year period, 823 endovascular aneurysm repairs (EVARs) resulted in 25 ELOs in 22 patients. The initial management and outcome of these ELOs were reviewed. Median follow-up after ELO was 24.2 +/- 16.8 months. RESULTS: Initial EVARs included both unsupported unibody (n = 5) and supported modular (n = 17) devices. ELO was significantly more common in the unsupported unibody graft design (P <.024) and with extension of the graft limb to the external iliac artery (P <.001). ELO was managed with an endovascular approach (EVA), including some combination of mechanical thrombectomy (n = 8), angioplasty with or without stenting (n = 8), and thrombolysis (n = 2) in 12 patients and bypass procedures (femoral-femoral bypass, n = 11; axillofemoral bypass, n = 1; and aortofemoral bypass, n = 1) in 13. At 12-month follow-up, freedom from secondary procedures with EVA was 80.2 +/- 17.7% versus 53.2 +/-17.1% with extra-anatomic bypass (EB) (P = NS). Secondary patency was 100% with EVA and 80.6 +/- 14.4% with EB (P = NS). Of the 12 EVAs, there was 1 (8.3%) perioperative mortality with EVA and none with EB. EB failure was directly attributed to donor limb occlusion in 4 of 6 EVAs (67%), and when this occurred it resulted in bilateral lower extremity ischemia. Amputation was required in 2 of 12 (16.7%) EBs versus none of the 12 EVAs (P = NS). EVA never resulted in graft dislodgement or endoleak but did identify an underlying treatable cause in 8 of 12 (67%). CONCLUSION: Both EVA and EB are acceptable management strategies for ELO. The potential risk of graft dislodgement was not observed with an EVA. If EB is employed, assessment of the donor limb and treatment of any underlying lesions is advisable in an attempt to minimize future donor limb occlusion.

In vitro verification of antithrombotic effect of recombinant soluble nucleotide triphosphate diphosphohydrolase 1.

PURPOSE: Ecto-ADPase (NTPDase1 or CD39) has been identified on endothelial cells and found to be antithrombogenic, with actions resulting from degradation of adenosine diphosphate (ADP), a thrombogenic molecule secreted by activated platelets at sites of vascular injury. Reasoning that the ADPase activity of CD39 might provide clinical use as an antithrombotic agent, the authors investigate the comparative ability of the agent to inhibit platelet and fibrin deposition. MATERIALS AND METHODS: With use of an in vitro perfusion system, fresh, heparinized human blood was passed over expanded polytetrafluoroethylene grafts at hemodynamic conditions similar to those observed in the human arterial circulation. Three different concentrations of CD39 (30 mcg/mL, 100 mcg/mL, and 300 mcg/mL) were compared with abciximab (4 mcg/mL) and heparin controls. The deposition of radiolabeled platelets and fibrinogen was measured in five perfusions for each treatment group. RESULTS: The addition of soluble CD39 to heparinized blood inhibited platelet deposition to an extent greater than that of heparin alone (P =.04). Effects were similar to those observed with abciximab. The addition of CD39 to heparinized blood did not result in augmentation of fibrin inhibition beyond that observed with heparin alone. The fibrin inhibitory effects of CD39 appeared to be less significant than the fibrin inhibition observed with abciximab, but this difference did not attain statistical significance. CONCLUSION: These results suggest that recombinant CD39 holds potential as antithrombotic agent, with the potential to achieve antiplatelet effects similar to that observed with abciximab.

Nature, frequency, and predictors of secondary procedures after endovascular repair of abdominal aortic aneurysm.

OBJECTIVES: Endovascular stent grafting offers a potentially less invasive option for treatment of abdominal aortic aneurysm. Clinical benefit has been demonstrated with respect to early parameters such as blood transfusion, return of gastrointestinal function, and length of hospital stay. Endovascular repair, however, has been criticized on the basis of inferior long-term outcome. Secondary procedures may be necessary to address durability issues such as migration, high-pressure endoleak, graft limb thrombosis, and degeneration of the stent-fabric structure itself, issues that may compromise the primary goal of aneurysm repair, protection from rupture. METHODS: Between 1996 and 2002, 703 patients underwent endovascular treatment of infrarenal abdominal aortic aneurysm at The Cleveland Clinic Foundation. During this time, five devices were used: Ancure, AneuRx, Excluder, Talent, and Zenith. Outcome was assessed with physical examination, lower extremity arterial studies, plain abdominal radiography, and computed tomography at discharge, at 1, 6, and 12 months postoperatively, and annually thereafter. Secondary procedures were defined as any procedure, exclusive of diagnostic angiography, performed after stent graft implantation, directed at treatment of aneurysm-related events. Multivariable statistical techniques for censored data (Cox proportional hazards modeling) were used to determine baseline parameters associated with need for secondary procedures over follow-up, with calculation of hazards ratio (HR) and 95% confidence interval (CI). RESULTS: Patient follow-up averaged 12.2 +/- 11.7 months. Patient survival was 90% +/- 1.4% at 1 year, 78% +/- 2.6% at 2 years, and 70% +/- 3.8% at 3 years. Aneurysm rupture occurred in 3 patients (0.4%), accounting for rupture risk of 1.4% over the first 2 years of follow-up (Kaplan-Meier method). Overall, 128 secondary procedures were required in 104 patients (15%), with a cumulative risk of 12% +/- 1.5% at 1 year, 24% +/- 2.8% at 2 years, and 35% +/- 4.4% at 3 years after stent graft implantation. Among the secondary procedures, new stent grafts and extensions were placed in 34 patients (27%), embolization of endoleak was performed in 33 patients (26%), and open surgical conversion was undertaken in 11 patients (9%). Periprocedural mortality of secondary procedures was 8% overall, but was 18% for patients undergoing open surgical conversion. Multivariable modeling identified the date the procedure was performed (HR, 1.53 per 3-month period of study; CI, 1.22-1.92; P <.001) and aneurysm size (HR, 1.35 per centimeter of minor axis; CI, 1.13-1.60; P <.001) as independent predictors of need for secondary procedures. CONCLUSIONS: Current endovascular devices are associated with a relatively high rate of complications over mid-term follow-up, culminating in frequent need for secondary remedial procedures. With strict follow-up imaging compliance, however, risk for rupture and aneurysm-related death remain exceedingly low. Newer technology may achieve improved durability and a lower requirement for secondary procedures, while maintaining the minimally invasive nature of presently available devices.

Endovascular repair of abdominal aortic aneurysms: device-specific outcome.

OBJECTIVES: Endovascular repair of abdominal aortic aneurysms, while advantageous because of its minimally invasive nature, falls short of achieving the long-term durability of traditional open surgical repair. Problems such as device migration, continued sac pressurization from endoleak, and graft limb thrombosis culminate in a high rate of secondary procedures and failure to protect against aneurysm rupture. While prior studies hint at a correlation between these postprocedural events and specific device design, a single comparative analysis that correlates device attributes with clinical outcome has not been performed. METHODS: Over 6 years ending in 2002, 703 patients underwent endovascular treatment of infrarenal abdominal aortic aneurysms. During this time, five devices were used, ie, Ancure, AneuRx, Excluder, Talent, and Zenith, and six device-specific groups were analyzed; the Zenith group was subdivided into those placed as part of the multicenter trial (Zenith-MCT) and those under a sponsor-investigator investigational device exemption trial (Zenith-SIT). Results were assessed with the Kaplan-Meier method for censored data, and the log-rank test was used to ascertain differences between device groups. RESULTS: While overall survival was diminished in the Zenith-SIT group (P =.046), risk for aneurysm-related death was similar in all groups (P =.336), averaging 2% or less at 12 months. Among the total cohort of patients, freedom from rupture was 98.7% +/- 0.9% at 24 months, without demonstrable differences between groups (P =.533). There were no statistically significant differences in rate of secondary procedures, conversion to open repair, or migration. There were, however, significant differences in risk for graft limb occlusion and rate of endoleak between groups. Limb occlusion occurred most often with Ancure devices (11% +/- 4.6% at 12 months, P =.009). Endoleak of any type was most common with Excluder devices (64% +/- 11% at 12 months, P =.003), a finding directly related to increased frequency of type II leaks in that group (58% +/- 11% at 12 months, P =.001). While there were no differences in frequency of type I or type III endoleak, a trend toward increased risk for microleak was observed with AneuRx devices (4.0% +/- 1.3%, P =.054), and more modular separations were observed with Zenith devices (3.5% +/- 2.3%, P =.032). Shrinkage at 12 months correlated with frequency of endoleak in the device groups, and was most common in the two Zenith groups (54% +/- 7.3% in the Zenith-MCT group and 56% +/- 7.8% in the Zenith-SIT group) and the Talent group (52% +/- 9.7%) and was least in the Excluder group (15% +/- 7.9% at 12 months, P <.001). By contrast, sac growth occurred most often in the Zenith-SIT group (13% +/- 4.5% at 12 months, P =.034), possibly as a result of the challenging aortoiliac anatomy frequently present in these patients. CONCLUSIONS: There are significant differences in frequency of limb occlusion and endoleak between groups with different endovascular devices. Knowledge of these and other differences is instructional in development of next-generation endovascular devices, incorporating design features linked to satisfactory outcome while abandoning those associated with device failure.