Leukocytes and the Natural History of Deep Vein Thrombosis Current Concepts and Future Directions

Observational studies have shown that inflammatory cells accumulate within the thrombus and surrounding vein wall during the natural history of venous thrombosis. More recent studies have begun to unravel the mechanisms that regulate this interaction and have confirmed that thrombosis and inflammation are intimately linked. This review outlines our current knowledge of the complex relationship between inflammatory cell activity and venous thrombosis and highlights new areas of research in this field. A better understanding of this relationship could lead to the development of novel therapeutic targets that inhibit thrombus formation or promote its resolution.</jats:p

Hematopoietic Progenitor Cells and Restenosis After Carotid Endarterectomy

Background and Purpose— Hematopoietic progenitor cells (HPCs) may attenuate the response to vascular injury by maintaining endothelial integrity and function. Our aim was to determine whether circulating HPC number and function correlate with restenosis after carotid endarterectomy. Methods— HPC number (CD34 + /CD133 + cells), early colony-forming units, migratory capacity, and senescence were analyzed in blood collected preoperatively, 1 day, and 6 weeks postoperatively. Mobilizing cytokine levels were also measured. Stenosis was assessed by duplex scanning. Results— HPC numbers ( P &lt;0.001) and early colony-forming unit count ( P =0.001) fell rapidly 24 hours postoperatively. Restenosis at 6 months correlated negatively with the magnitude of postoperative falls in HPC numbers ( R =−0.38, P =0.013) and early colony-forming unit counts ( R =−0.42, P =0.008). The migratory capacity of preoperative HPCs correlated negatively with restenosis ( R =−0.48, P =0.007). Preoperative SDF1 levels correlated with falls in HPC number ( R =0.42, P =0.044) and early colony-forming unit counts ( R =0.56, P =0.004). Conclusions— HPC function appears to be linked to the development of carotid artery restenosis after endarterectomy. These data support the concept that HPCs have a role in regulating remodeling of the injured arterial wall. </jats:sec

Hypoxia and Upregulation of Hypoxia-Inducible Factor 1α Stimulate Venous Thrombus Recanalization

Objective— Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization. Methods and Results— Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS]=−0.77, P &lt;0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R]=0.85, P &lt;0.0005), during resolution in a murine model. HIF1α ( P &lt;0.005), VEGF ( P &lt;0.005), and VEGF receptor 1 (VEGFR1) ( P &lt;0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor l -mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight ( P &lt;0.001) and volume ( P &lt;0.05) were reduced by a third in l -mimosine–treated mice compared with controls, whereas vein recanalization ( P &lt;0.005) and thrombus neovascularization ( P &lt;0.001) were 2-fold greater, and this was associated with increased inflammatory cell content. Conclusion— Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome. </jats:p

Encapsulation of angiogenic monocytes using bio-spraying technology

Therapeutic neovascularisation using angiogenic cells has been hampered by the loss of cells from the target tissue. Encapsulation of these cells within a semi-permeable membrane could improve their retention within the ischaemic tissue without affecting the excretion of the angiogenic growth factors produced. Bio-spraying is a novel cell-handling technique that does not adversely affect cell viability. We used this technique to encapsulate human peripheral blood monocytes and found that cell viability, cell phenotype and functional downstream angiogenic signalling were preserved. Encapsulation of monocytes with macrophage-colony stimulating factor resulted in increased vascular-endothelial growth factor production and enhanced angiogenic function. Bio-spraying/encapsulation has the potential to enhance the efficacy of current angiogenic cell therapy strategies and merits further investigation

A program to respond to otitis media in remote Australian Aboriginal communities: a qualitative investigation of parent perspectives

Abstract Background Indigenous infants and children in Australia, especially in remote communities, experience early and chronic otitis media (OM) which is difficult to treat and has lifelong impacts in health and education. The LiTTLe Program (Learning to Talk, Talking to Learn) aimed to increase infants’ access to spoken language input, teach parents to manage health and hearing problems, and support children’s school readiness. This paper aimed to explore caregivers’ views about this inclusive, parent-implemented early childhood program for 0–3 years in an Aboriginal community health context. Methods Data from in-depth, semi-structured interviews with 9 caregivers of 12 children who had participated in the program from one remote Aboriginal community in the Northern Territory are presented. Data were analysed thematically. Caregivers provided overall views on the program. In addition, three key areas of focus in the program are also presented here: speech and language, hearing health, and school readiness. Results Caregivers were positive about the interactive speech and language strategies in the program, except for some strategies which some parents found alien or difficult: such as talking slowly, following along with the child’s topic, using parallel talk, or baby talk. Children’s hearing was considered by caregivers to be important for understanding people, enjoying music, and detecting environmental sounds including signs of danger. Caregivers provided perspectives on the utility of sign language and its benefits for communicating with infants and young children with hearing loss, and the difficulty of getting young community children to wear a conventional hearing aid. Caregivers were strongly of the opinion that the program had helped prepare children for school through familiarising their child with early literacy activities and resources, as well as school routines. But caregivers differed as to whether they thought the program should have been located at the school itself. Conclusions The caregivers generally reported positive views about the LiTTLe Program, and also drew attention to areas for improvement. The perspectives gathered may serve to guide other cross-sector collaborations across health and education to respond to OM among children at risk for OM-related disability in speech and language development

Upregulation of hypoxia-inducible factor 1 alpha in local vein wall is associated with enhanced venous thrombus resolution

Introduction: Venous thrombus resolution may be regulated by an angiogenic process that involves the surrounding vein wall. The aims of this study were to determine whether: (i) thrombosis stimulates activation of the angiogenic transcription factor, hypoxia-inducible factor (HIF) 1 alpha, and downstream expression of growth factors in vein wall; and (ii) upregulation of HIF1 alpha in vein wall leads to increased growth factor expression and enhanced thrombus resolution. Materials and methods: HIF1 alpha, vascular endothelial growth factor (VEGF), and placental growth factor (PLGF) were quantified in mouse inferior vena cava (IVC) at days 1, 3, 7, and 14 after thrombus formation (n= 10-13 per group). An additional group of thrombosed mice were treated with the prolyl-hydroxylase domain (PHD) inhibitor, L-mimosine (L-mim) or vehicle control. HIF1 alpha, VEGF, and PLGF in IVC were measured at days 1 and 7; and vein recanalisation and thrombus resolution were measured at days 7 and 10 (n= 6-7 per group). Results: HIF1 alpha was expressed in thrombosed IVC and its levels remained relatively constant throughout natural resolution. The levels of VEGF in thrombosed IVC were elevated at days 1 (P &lt;0.0001) and 3 (P &lt;0.05); and PLGF at days 1 (P &lt;0.0001), 3 (P &lt;0.0001), and 7 (P &lt;0.0001). Treatment with L-mim led to: increased HIF1 alpha (P &lt;0.05), VEGF (P &lt;0.005), and PLGF (P &lt;0.001) levels in the IVC; decreased thrombus size (P &lt;0.01); and increased vein recanalisation (P &lt;0.001). Conclusions: HIF1 alpha levels in vein wall are not affected by thrombosis and it appears that the angiogenic drive in the vein surrounding resolving thrombus is regulated independently of HIF1 alpha. Stimulating HIF1 alpha levels in the vein wall leads to an increased angiogenic drive and promotes vein recanalisation and thrombus resolution. (C) 2011 Elsevier Ltd. All rights reserved