| | Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliteransReceived 24 February 2006; accepted 25 June 2006. published online 23 August 2006. BackgroundThis study investigated the efficacy and safety of autologous bone marrow-mononuclear cells (ABMMNC) implantation in patients with critical limb ischemia (CLI) due to thromboangiitis obliterans (Buerger’s disease). MethodsThe study comprised 28 patients (25 men and 3 women) with a median age of 44 years (range, 25-54 years) who had thromboangiitis obliterans and unilateral critical limb ischemia, defined as ischemic rest pain in a limb with or without nonhealing ulcers. The patients received multiple injections of erythrocyte-depleted and volume-reduced ABMMNC into the gastrocnemius muscle, the intermetatarsal region, and the feet dorsum (n = 26) or forearm (n = 2) vs saline injections into the less ischemic contralateral limbs. The patients were nonresponders to previous Iloprost infusion and smoking cessation ≥6 months and were not candidates for nonsurgical or surgical revascularization. Primary end points were the total healing of the most important lesion while avoiding major or minor amputation, the relief of rest pain without the need for analgesics from baseline to 6 months’ follow-up, and the safety and feasibility of the treatment. Secondary end points were the changes in ankle-brachial pressure index and peak walking time, the angiographic evidence of collateral vessel formation or remodeling, and the quality-of-life assessment. Two investigators blinded for treatment assignment performed image analyses. ResultsUnilateral intramuscular administration of ABMMNC was not associated with any complications. The mean follow-up time was 16.6 ± 7.8 months (range, 7.6 to 33.8 months). Only one patient required toe amputation during follow-up. A change in the ankle-brachial pressure index >0.15 was achieved in 8 patients at 3 months and in 14 patients at 6 months compared with baseline values. At 6 months, patients demonstrated a significant improvement in rest pain scores (P < .0001), peak walking time (P < .0001), and quality of life (P < .0083). Total healing of the most important lesion was achieved in 15 patients (83%) with ischemic ulcers, and relief of rest pain without the need of narcotic analgesics improved in all patients. Digital subtraction angiography studies before and 6 months after the ABMMNC implantation showed vascular collateral networks had formed across the affected arteries in 22 patients (78.5%). ConclusionsABMMNC implantation could be a safe alternative to achieve therapeutic angiogenesis in patients with thromboangiitis obliterans and critical limb ischemia refractory to other treatment modalities.
Since the first detailed and accurate description by Leo Buerger in 1908, the cause of thromboangiitis obliterans (TAO, Buerger’s disease) has remained unknown, and the treatment modalities have been unsatisfactory in this type of nonatherosclerotic, segmental, inflammatory vasculitis. The only way to prevent the progression of the disease is to abstain from all tobacco products; otherwise, the disease spontaneously leads to tissue loss and major amputations. Patients may continue to have claudication or Raynaud’s phenomenon even after the complete discontinuation of tobacco use, however.1 The effectiveness of surgical sympathectomy remains unclear.2 Revascularization is frequently not feasible because of the diffuse segmental involvement and distal nature of the disease. Therapeutic angiogenesis by using cellular therapeutic strategies may be useful in these patients.3
Bone marrow–derived endothelial progenitor cells (EPCs) or angioblasts isolated from peripheral blood were shown to have incorporated into the sites of active angiogenesis and were identified as a key factor for re-endothelialization.4 EPCs contribute to tissue vascularization during embryonic and postnatal physiologic processes.5, 6 Recent findings suggest that growth and development of new blood vessels in the adult are not restricted to angiogenesis but encompass vasculogenesis as well.7, 8
In a clinical setting, Tateishi-Yuyama et al9 have recently established that implantation of autologous bone marrow-mononuclear cells (ABMMNC), including EPCs, into ischemic limbs increases collateral vessel formation.9 In addition, recent publications have described beneficial effects of ABMMNC10, 11 and autologous peripheral blood mononuclear cells (APBMNC)12, 13, 14, 15 in the setting of critical limb ischemia (CLI) in humans. The aim of this study, therefore, was to evaluate the feasibility, safety, reproducibility, and efficacy of ABMMNC implantation in patients with CLI due to TAO.
Methods  Definitions TAO was diagnosed by using the clinical criteria previously defined by Shionoya17 and modified by Olin,1 including (1) smoking history, (2) age of onset <45 years, (3) infrapopliteal arterial occlusive disease documented by noninvasive vascular testing, (4) objective evidence of medium or small arterial disease by angiography, (5) upper limb involvement or phlebitis migrans, (6) absence of atherosclerotic risk factors other than smoking at the time of initial diagnosis, (7) exclusion of autoimmune diseases, diabetes mellitus, proximal source of emboli, and hypercoagulable states. Inclusion criteria were (1) unilateral CLI, defined as ischemic rest pain in a limb with or without nonhealing ulcers, (2) unresponsive clinical condition to smoking cessation 6 months before ABMMNC implantation, (3) unresponsive clinical condition to previous intravenous infusion of iloprost, (4) unsuitable vessel lesions for nonsurgical or surgical revascularization, (5) unhealed trophic lesions despite intensive wound care for 6 months for patients presented with ischemic ulcers, and (6) signed, informed consent. Patients were not enrolled in the study if any of the following exclusion criteria were met: (1) concomitant cause for arterial occlusive disease, including diabetes mellitus, atherosclerosis, connective tissue, or thrombotic diseases; (2) detection of proximal source of emboli including atrial fibrillation; (3) previous or current history of neoplasia or other comorbidity that could impact the patient’s survival; (4) primary hematologic disease, including hypercoagulable states; (5) detection of proliferative retinopathy; (6) entrapment syndromes; (7) thoracic outlet syndrome; (8) current ethanol abuse or cocaine, amphetamine, and cannabis ingestion; and (9) detection of osteomyelitis. The Research Ethics and Scientific Committee of the Medical Faculty, University of Ankara, approved the study protocol and all subjects gave informed consent. Baseline evaluation On admission, complete laboratory tests and serologic profile were obtained for all patients, including complete blood count with differential, liver function, renal function, fasting blood glucose, urine analysis, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, anticentromere antibody, antiphospholipid antibodies, Scl-70, fibrinogen, complement measurements, serum homocysteine, hypercoagulability screen (protein C, protein S, and antithrombin III plasma levels, and factor V Leiden, and prothrombin 20210A gene mutation analysis), chest radiograph, electrocardiogram, and transthoracic echocardiography. Safety was evaluated in the study by adverse event monitoring, physical examinations, laboratory tests, resting electrocardiograms, and ophthalmologic examinations. All the patients underwent a routine preharvest examination and work-up by an experienced hematologist from the Stem Cell Transplantation Unit. Aspirin and clopidogrel were discontinued 5 to 7 days before ABMMNC implantation. All patients underwent a standard vascular examination that included measurement of ankle-brachial pressure index (ABPI) assessed with duplex ultrasonography. They underwent a validated progressive treadmill protocol, with a reduced initial speed (1.6 km/h),18 in which they continued walking until they reached claudication pain or another clinical indication for stopping the test. Claudication onset time, claudication distance, peak walking time, and distance were recorded. Those who previously had below-knee amputation were asked to walk with their prosthesis at a self-selected velocity over an increasing walking distance. A 10-cm visual analog scale (VAS) was recorded monthly by the patients for pain, where 0 was no pain at all and 10 was the most severe pain ever experienced for ischemic and control limbs. Appropriate systemic antibiotic therapy was prescribed for patients with trophic ulcers as determined by microbiologic quantitative tissue cultures and sensitivity results. Before the patient was considered for cellular therapy, local wound care and surgical débridement were applied until three-culture negative microbiologic results were achieved. Ischemic ulcers were documented by digital color photography. Intra-arterial digital subtraction angiography Digital subtraction angiography (DSA) (Multistar Plus/T.O.P., Siemens AG, Forchheim, Germany) of both upper and lower extremities was performed for all patients at baseline and at the 6-month follow-up. The amount and the force of low-osmolality nonionic contrast injection and the position of the catheter tip (5F, Weinberg, pigtail, Digiflex, Boston Scientific Corp, Watertown, Mass) was strictly fixed for DSA studies to obtain identical imaging conditions. To evaluate proximal vasculature, contrast media injection doses were as follows: 2 frames/s per 2 mL (total dose, 4 mL) for the superficial femoral artery, 2 frames/s per /3 mL (total dose, 6 mL) for the popliteal artery, 2 frames/s per 4 mL (total dose, 8 mL) above the knee, and 2 frames/s per 5 mL (total dose, 10 mL) distal to the knee. For evaluation, each leg was divided into 14 segments. Angiographic mapping of both lower limbs and comparison of all the evaluated segments were reviewed by two independent radiologists blinded to the treated extremity. The angiographic scores for the formation of new collateral vessel formation were assessed as +0 (no collateral development), +1 (slight), +2 (moderate), and +3 (rich), as described previously.9 Vascular Quality of Life Questionnaire The King’s College Hospital’s Vascular Quality of Life Questionnaire (VascuQol) was used to assess QOL at baseline, and at 3 and 6 months after the procedure.19 The 25-item questionnaire was related to pain, other symptoms, activity, social, and emotional items. The total VascuQol score was also scored 1 to 7 (all the item scores divided by 25) for each evaluation. Bone marrow harvest and isolation of mononuclear cells The stem cell transplantation team collected bone marrow from both spina iliaca posterior superior at prone position under general anesthesia approximately 2 hours before the ABMMNC implantation. The collected bone marrow (653.2 ± 77.3 mL) was immediately transferred to the Hemapheresis Unit. Using this schedule, we targeted total mononuclear cells of 1 × 10e8-9/mL while avoiding unnecessary red blood cell (RBC) implantation and higher harvest volumes. The harvest material was processed on COBE Spectra (Gambro BCT, Lakewood, Colo) using the bone marrow processing program and software version 5.1. After RBC depletion and volume reduction using a continuous flow cell separator in a closed system,20 we achieved 91% ± 2% RBC depletion and concentrated ABMMNC to a final volume and concentration of 59.9 ± 9.2 mL and 1.69 ± 0.89 × 10e9/mL total mononuclear cells, respectively. The total number of implanted CD34+ cells was 53.1 ± 35.9 × 10e6. Cytofluorimetric analysis of implanted stem cells was 99% viable and included 97.5 ± 2.2 percentage of CD45+ cells. Cultures of cell preparations were tested and proved negative for bacterial and fungal contamination. ABMMNC implantation Within 2 hours of the bone marrow collection, the ABMMNCs were implanted into the leg with CLI by means of multiple intramuscular injections into the gastrocnemius muscle, intermetatarsal region, and around the trophic lesions. ABMMNC injections were commenced 4 to 5 cm proximal to the obstructive lesion and continued distally in all patients. General anesthesia was preferred if débridement was required for ischemic ulcers and mild sedation was used for isolated ABMMNC implantation. In eligible patients, control treatment with normal saline into the less ischemic contralateral limb was also performed during each procedure. We used 22-gauge spinal needle and a 7-cm grid to implant about 1 mL of ABMMNC into each injection site (3 to 4 cm deep and oblique) for a total of 54 ± 7 sites (range, 41 to 70). Follow-up Clinical, operative, and follow-up data were recorded prospectively in a computerized database. Three (10.7%) of 28 patients were taking lipid-lowering medication on their initial evaluation in the outpatient clinic (Table). All patients were treated with aspirin (300 mg daily), statin (if total cholesterol concentrations were >150 mg/dL), and L-arginine (500 mg daily). Patients were required to be on this medication regimen 6 months before entry into the study, and the drugs used were not changed throughout the study. The patients were seen in the outpatient clinic every 2 weeks postoperatively for evaluation of pain scores, QOL assessment using VascuQol scores, and trophic lesions. Repeat digital subtraction angiography was performed at 6-months. Six-month follow-up was completed in all patients. Statistical analysis For the study to support the working hypothesis, it needed to have the power of being able to show significant improvements in the total healing of the ischemic ulcer, while avoiding major or minor amputation, and the total relief of rest pain without the need for analgesics. We determined from the data reported by Tateishi-Yuyama9 and our feasibility study21 that 25 subjects in treatment groups with 90% power and a P < .05 were required to be detected to have a significant clinical improvement. Because of the small sample size and nonnormal distribution of the variables, nonparametric tests were used to measure the differences. We performed the Friedman test to find the differences among the groups, and the Wilcoxon signed test to find which group created these differences. In the Wilcoxon signed-rank test, the Bonferroni adjustment for the significance levels was used. To compare the significance of three pairs of the variables ABPI, VAS pain score, peak walking time, and claudication onset time for baseline and 3 and 6 months, we used .05/3 (.0167) significance level, and for VascuQol scores, .05/6 (.0083) significance level for 6 different pairs of comparison. Data were analyzed using SPSS 11.5 (SPSS Inc, Chicago, Ill) for Windows (Microsoft Corp, Redmond, Wash). Results Since 2000, the ratio of new patients with TAO to the new patients with arteriosclerosis obliterans has been 1:4 at our outpatient clinic. During the study period, 52 patients with TAO (46 men, 6 women) were admitted to the Heart Center at the University of Ankara; of these, 32 were graded as Rutherford II-III, and 28 were included in the study protocol. Four patients who were not included in the study did not want to participate after receiving detailed information about the possible side effects of cellular therapy, and 18 patients were graded as Rutherford I and excluded from the study. All subjects were smokers and presented with ischemic rest pain or trophic lesions, or both. Mean age at disease onset was 33 years (range, 20 to 45 years), and mean age at initial evaluation was 42 years (range, 25 to 54 years). The disease involved the infrapopliteal arteries in 28 patients (100%) and the upper extremities in 9 patients (32%) (Table). Procedural data The same surgical team performed all procedures. The mean total bone marrow harvesting time was 35.7 ± 6.1 minutes (range, 27 to 50 minutes) and the mean total procedural time for ABMMNC implantation was 32.5 ± 4.4 minutes (range, 22 to 39 minutes). In each injection, approximately 2 million cells were delivered in a volume of 1 mL. All necrotic and devitalized tissues were eradicated with surgical debridement in 18 patients (64.2%) with ischemic ulcers. Safety data No patient experienced periprocedural complications and ABMMNC implantation was well tolerated. No patient received a transfusion after bone marrow harvest. Before discharge, however, three patients (10.7%) who were diagnosed with iron deficiency–induced hypochromic microcytic anemia were treated by oral iron replacement therapy for 3 months. All patients with rest pain were discharged on the second day of hospitalization as specified by the protocol. For patients with trophic lesions, hospital stay after ABMMNC was 26.4 ± 14.6 days (range, 7 to 52 days). All patients remained free of retinopathy observed in funduscopic examinations and teratoma formation. The levels of C-reactive protein, white blood cells, and fibrinogen at baseline and follow-up were not significantly different. Follow-up evaluations Mean follow-up after ABMMNC implantation was 16.6 ± 7.8 months (range, 7.6 to 33.8 months), and follow-up was 100% complete. At the last visit, spot urine in the morning was collected from all subjects and analyzed for measurement of cotinine by radioimmunoassay. Values were corrected for urine concentration and expressed as nanograms per milliliter of urinary creatinine. The findings suggested that self-reported smoking status did not correlate with cotinine-indicated smoking status. Urinary creatinine-adjusted cotinine values were >500 ng/mL in 17 patients (60.7%), although only five patients admitted that they had restarted smoking. None of the patients underwent major amputation, defined as above-the-knee, below-the-knee, or hand amputation during this time period; however, toe amputation could not be avoided in one patient who continued smoking. Among four patients with Rutherford grade II-III who were excluded from the study because they did not provide informed consent, three underwent a major amputation at 1-year follow-up. The baseline mean VAS pain score was 8.2 ± 1.2. Significant reductions in VAS scores were observed in ABMMNC-implanted limbs at 3 (1.1 ± 1.4 months; P < .0001 vs baseline) and 6 months (0.9 ± 1.7 months; P < .0001 vs baseline), whereas control limbs did not differ with respect to the baseline VAS scores. ABMMNC implantation did not alter blood pressures (mean blood pressure, from 83.4 ± 12 to 81.6 ± 11 mm Hg after 6 months) but improved the ABPI from 0.52 ± 0.09 at baseline to 0.62 ± 0.12 after 3 months (P < .0001) and to 0.67 ± 0.13 after 6 months (P = .001) (Fig 1). A change in the ABPI >0.15 was achieved in eight patients at the 3-month follow-up and in 14 patients at the 6-month follow-up compared with baseline values. Improvement in ABPI was sustained for up to 34 months. No changes in ABPI were detected in contralateral legs injected with saline at 3 (P = .067) and 6 months (P = .055). In review of treadmill testing before ABMMNC implantation and 3 months after, peak walking time and claudication onset time significantly improved (P < .0001), and this improvement was maintained at 6 months (P < .0001) (Fig 2). Three treadmill tests were terminated because of claudication pain in the control leg at 6 months. VascuQol scores also showed significant improvement in QOL after ABMMNC implantation at 3 months (P < .0083), and further improvement was achieved at 6 months (P < .0083). Additional subgroup analyses for activity, pain, other symptoms, emotional, and social items are presented in Fig 3. Ischemic ulcers healed completely in 15 patients (83%) and improved markedly in three (17%). Representative photos are shown in Fig 4. One patient who continued to smoke required toe amputation because of osteomyelitis during follow-up. An ischemic ulcer developed in the control leg of one patient at 11 months after the procedure. Six months after the ABMMNC implantation, angiographic scores of +2 or +3 new collateral vessel formation were noted in 22 (78.6%) of 28 patients (2.64 ± 0.62 in the ABMMNC implanted limbs vs 0.30 ± 0.01 in the contralateral limbs). Representative angiograms are shown in Fig 5. Discussion The results of our study suggest that ABMMNC implantation into ischemic limbs of patients with TAO is associated with improved exercise performance, quality of life, ABPI, pain control, and augmentation of collateral formation at 24 weeks in 78% of patients. The present study confirms that intramuscular injection of ABMMNC is safe and feasible. This study is the first report in a large series consisting only of TAO patients with CLI who underwent ABMMNC implantation and comparing the results with saline-infused control limbs. Inclusion criteria for our study restricted treatment to patients with unilateral CLI to compare multiple injections of placebo to the less ischemic limb. Since multiple injections could also stimulate angiogenesis by a wound-healing response to injury,22 the question of the effect of needle punctures on angiogenesis would be eliminated. In animal models of ischemia, the ability of EPCs isolated from human peripheral blood4 or bone marrow23 to incorporate into sites of neovascularization was shown previously. Culture-expanded EPC transplantation in an animal model of limb ischemia improved neovascularization and blood flow recovery and reduced limb necrosis and autoamputation by 50% compared with controls.24 Several cell types within the bone marrow cavity appear to retain the ability to differentiate into one or more of the cellular components of the vascular bed and thus, in theory, might incorporate directly into the wall of the newly formed or remodeled vessels.25 In addition to incorporation properties, EPCs also secrete multiple angiogenic cytokines, growth factors, and chemokines that could facilitate arteriogenesis and inhibit endothelial and smooth muscle cell apoptosis.25 Therapeutic angiogenesis regimens that have mainly focused on the administration of a single angiogenic agent failed to show significant improvements in the clinical outcome.26, 27 Considering the complexity of the angiogenic process, cellular therapeutic strategies may overcome most of the shortcomings related to single growth factor applications. In fact, Tateishi-Yuyama et al (TACT study)9 recently demonstrated improvement in transcutaneous oxygen pressure, rest pain, and pain-free walking time after ABMMNC intramuscular injections in 25 patients with unilateral CLI. Those results are somewhat similar to the results of the present study, although Tateishi-Yuyama et al recruited patients mostly with atherosclerosis obliterans. Furthermore, they recruited 22 patients with bilateral limb ischemia who were randomly injected with ABMMNC in one leg and APBMNC in the other as control. The TACT study demonstrated that APBMNC injections were less efficient in new collateral vessel formation compared with ABMMNC. Since then, unselected growth factor–induced APBMNC12, 13, 14, 15 or ABMMNC10, 11, 21, 28, 29 have been used in clinical studies for CLI with satisfactory results. Both methods have their own advantages and pitfalls. Potential limitations of APBMNC are the time span necessary for peripheral blood mobilization and collection (approximately 5 days) before implantation, possible side effects of growth factors, and the higher costs compared with bone marrow aspiration. The optimal route of delivery has not been established in the setting of CLI, either. Direct intramuscular injections have been performed by several groups9, 10, 12, 13 and by us.21, 29 The risk of amputation in patients with TAO was questioned previously.30 During the mean follow-up of 91.6 months, 27% of 112 patients with TAO required one or more of the amputations. The same study demonstrated that only 5% of the patients had amputations after smoking cessation, but 42% had amputations while continuing to smoke (P < .0001). Recently, Cooper et al reported that the risk of any amputation was 25% at 5 years, 38% at 10 years, and 46% at 20 years among 111 patients with TAO based on the information gathered from the Mayo Clinic registry.31 Ohta et al32 also clearly demonstrated a strong correlation between continued smoking and limb amputation in one of the largest series of TAO evaluating the social problems and impaired quality of life.31 It is important to remember that 60% of the subjects in our series continued smoking after cellular therapy. Minor amputation was only required in one patient (3.6%) during the mean follow-up of 16.6 ± 7.8 months. Furthermore, striking improvement in ischemic rest pain and ABPI after implantation of ABMMNC was gratifying and maintained after 3 months. The clinical improvement was independent from smoking status and patterns of smoking. Induction of angiogenic diseases, such as proliferative retinopathy, accelerated arteriosclerosis via proinflammatory growth factors, enhanced restenosis, arrhythmias, teratoma formation, and ectopic calcification are possible deleterious effects of cellular therapy. Because of the proinflammatory potential of ABMMNC implantation via growth factors and cytokines, we closely monitored serum inflammatory markers in our patient population; however, our data on C-reactive protein, white blood cell count, fibrinogen at baseline and at follow-up at 3 and 6 months did not show any difference. Furthermore, repeat digital subtraction angiography at 6 months confirmed no progression of the disease or new stenotic lesions in both treated and control limbs. A number of medications such as captopril, furosemide, spironolactone, and cyclooxygenase-2 inhibitors have been shown to potentially interfere with the angiogenic process. However, there is an increasing experimental and clinical evidence to support that pleiotropic effects of statins involve improving or restoring endothelial function and decreasing oxidative stress and vascular inflammation.33 Although patients with atherosclerosis obliterans were strictly excluded in this series, we targeted total cholesterol concentrations <150 mg/dL, and 78% of patients were discharged home on statin therapy and L-arginine aiming to balance the orchestrating factors that play a crucial role in the fundamental steps of stem-cell mediated angiogenesis. Major limitations of this study are the small number of patients enrolled and the lack of long-term follow-up, which limit conclusion about efficacy. Second, contralateral “control” limbs are not ideal matches for comparison with the treated limbs. However, our intention for choosing contralateral leg as control was to investigate the possible angiogenic effects of mechanical punctures caused by simple needle injections. Furthermore, we are aware of the limitations of currently available diagnostic contrast angiographic studies to demonstrate angiogenesis or arteriogenesis especially for the vessels measuring <200 μm in diameter.34 We also acknowledge that flow hemodynamics, including cardiac output, blood pressure, and heart rate can effect distal perfusion and vessel imaging so the acquisition of the digital subtraction arteriography images are prone to error. However, if confirmed with advanced imaging techniques such as gadolinium-enhanced magnetic resonance angiography or 64-row multidetector computed tomography angiography, our results may suggest that ABMMNC implantation has a positive effect on therapeutic angiogenesis in patients with TAO and CLI. Finally, no safety issues associated with ABMMNC implantation were identified throughout the 16.6 months of mean follow-up. Author contributions
Conception and design: SD, ARA, MA, TS, UO
Analysis and interpretation: SD, ARA, MA, TS
Data collection: SD, ARA, MA
Writing the article: SD, ARA, MA, TS
Critical revision of the article: MA, NTE, UO
Final approval of the article: SD, ARA, TS, NTE, UO
Statistical analysis: ARA, SD, MA
Obtained funding: ARA, NTE, UO
Overall responsibility: ARA
Drs Durdu and Akar contributed equally to this work.
We would sincerely like to thank all the participants and colleagues who were involved in this study, including Osman Ilhan, Onder Arslan, Ender Akcaglayan Soydan, Erol Ayyildiz and the other members of hemapheresis team for their outstanding technical assistance and continuing support of this research program; Tumer Corapcıoglu, Bulent Kaya, Sadık Eryilmaz for thoughtful discussions, comments on the manuscript, and supporting the study; Cagdas Baran for collecting data of exceptional quality and his efforts for patients’ care; Leyla Yigit, PhD, for her statistical review, and Arzu Akar for proofreading of the manuscript. References 1.
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MEDLINE a Department of Cardiovascular Surgery, Heart Center, Ankara University School of Medicine, Ankara, Turkey b Department of Haematology, Cebeci Campus, University School of Medicine, Ankara, Turkey c Department of Radiology, Ibni Sina Hospital, Ankara University School of Medicine, Ankara, Turkey.  Reprint requests: Ruchan Akar, MD, FRCS CTh, Department of Cardiovascular Surgery, Heart Center, Ankara University School of Medicine, Dikimevi, Ankara 06340 Turkey.
This work was supported by the Biotechnology Institute Research Fund and Ankara University School of Medicine Research Council, Turkey. Dr Arat has been supported by the Turkish Academy of Sciences, in the framework of the Young Scientist Award Program (EA-TUBA-GEBIP/2004-1-1). Competition of interest: none. PII: S0741-5214(06)01142-6 doi:10.1016/j.jvs.2006.06.023 © 2006 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. | |
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