The role of neovascularisation in the resolution of venous thrombus

Deep vein thrombosis (DVT) can give rise to chronic debilitating complications, which are expensive to treat. Anticoagulation, the standard therapy for DVT, prevents propagation, but does not remove the existing thrombus, which undergoes slow natural resolution. Alternative forms of treatment that accelerate resolution may arise from a better understanding of the cellular and molecular pathways that regulate the natural resolution of thrombi. This review will outline our current understanding of the mechanisms of thrombus resolution and the role of neovascularisation in this process. Novel experimental treatments that may one day find clinical use are also discussed. The process of thrombus resolution resembles wound healing. The mainly monocytic inflammatory infiltrate, which develops, is associated with the appearance of vascular channels. These cells may drive resolution by encouraging angiogenesis, which contributes to restoration of the vein lumen. Significant numbers of bone marrow-derived progenitor cells have also been found in naturally resolving thrombi, but their precise phenotype and their role in thrombus recanalisation is unclear. Enhanced thrombus neovascularisation and rapid vein recanalisation have been achieved in experimental models with proangiogenic agents. Recent reports of the role of bone marrow-derived progenitor cells in the revascularisation of ischaemic tissues suggest that it may be possible to obtain the same effect by delivering pluripotent or lineage specific stem cells into thrombus. These cells could contribute to thrombus recanalisation by expressing a variety of proangiogenic cytokines or by lining the new vessels that appear within the thrombus.

[1]  E. Huberman,et al.  A human peripheral blood monocyte-derived subset acts as pluripotent stem cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Rafii,et al.  Vascular Endothelial Growth Factor and Angiopoietin-1 Stimulate Postnatal Hematopoiesis by Recruitment of Vasculogenic and Hematopoietic Stem Cells , 2001, The Journal of experimental medicine.

[3]  T. Wakefield,et al.  Deep vein thrombosis resolution is not accelerated with increased neovascularization. , 2004, Journal of vascular surgery.

[4]  Christoph Dehio,et al.  Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1 , 2003, Nature Medicine.

[5]  J. Isner,et al.  Assessment of risks associated with cardiovascular gene therapy in human subjects. , 2001, Circulation research.

[6]  S. Rafii,et al.  Contribution of marrow-derived progenitors to vascular and cardiac regeneration. , 2002, Seminars in cell & developmental biology.

[7]  J. Millet,et al.  Experimental venous thrombosis induced by homologous serum in the rat. , 1996, Thrombosis research.

[8]  B. Lindblad,et al.  A prospective study of the incidence of deep‐vein thrombosis within a defined urban population , 1992, Journal of internal medicine.

[9]  P. Quax,et al.  Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix. , 2003, Blood.

[10]  C. Frelin,et al.  Coexpression of endothelial markers and CD14 by cytokine mobilized CD34+ cells under angiogenic stimulation. , 2003, Cardiovascular research.

[11]  C. Metz.  Fibrocytes: a unique cell population implicated in wound healing , 2003, Cellular and Molecular Life Sciences CMLS.

[12]  Cox Js.  The maturation and canalization of thrombi. , 1963 .

[13]  L. Orci,et al.  Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migration and morphogenesis. , 1996, Enzyme & protein.

[14]  J. Isner,et al.  Improvement in chronic ischemic neuropathy after intramuscular phVEGF165 gene transfer in patients with critical limb ischemia. , 2001, Archives of neurology.

[15]  L. Happerfield,et al.  TISSUE PLASMINOGEN ACTIVATOR PRODUCTION BY MONOCYTES IN VENOUS THROMBOLYSIS , 1996, The Journal of pathology.

[16]  S. Shapiro,et al.  Contribution of Monocytes/Macrophages to Compensatory Neovascularization: The Drilling of Metalloelastase-Positive Tunnels in Ischemic Myocardium , 2000, Circulation research.

[17]  Christie M. Orschell,et al.  Peripheral Blood “Endothelial Progenitor Cells” Are Derived From Monocyte/Macrophages and Secrete Angiogenic Growth Factors , 2003, Circulation.

[18]  B. Ghelman,et al.  Deep-vein thrombosis following total knee replacement. An analysis of six hundred and thirty-eight arthroplasties. , 1984, The Journal of bone and joint surgery. American volume.

[19]  J. Isner,et al.  Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration , 2002, Circulation.

[20]  M. Goodell,et al.  Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. , 2003, The Journal of clinical investigation.

[21]  T. Wakefield.  Treatment options for venous thrombosis. , 2000, Journal of vascular surgery.

[22]  A. Reynolds,et al.  Integrins in angiogenesis: multitalented molecules in a balancing act , 2003, Cell and Tissue Research.

[23]  T. Wakefield,et al.  Deep Vein Thrombosis Resolution Is Modulated by Monocyte CXCR2-Mediated Activity in a Mouse Model , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[24]  James T. Willerson,et al.  Transdifferentiation of Human Peripheral Blood CD34+-Enriched Cell Population Into Cardiomyocytes, Endothelial Cells, and Smooth Muscle Cells In Vivo , 2003, Circulation.

[25]  Vishva Dixit,et al.  Vascular Endothelial Growth Factor Regulates Endothelial Cell Survival through the Phosphatidylinositol 3′-Kinase/Akt Signal Transduction Pathway , 1998, The Journal of Biological Chemistry.

[26]  Y. Yoon,et al.  Intramyocardial Transplantation of Autologous Endothelial Progenitor Cells for Therapeutic Neovascularization of Myocardial Ischemia , 2003, Circulation.

[27]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[28]  J. Isner,et al.  Left Ventricular Electromechanical Mapping to Assess Efficacy of phVEGF165 Gene Transfer for Therapeutic Angiogenesis in Chronic Myocardial Ischemia , 2000, Circulation.

[29]  S. Schellong,et al.  Ultrasound screening for distal vein thrombosis is not beneficial after major orthopedic surgery. , 2003, Thrombosis and Haemostasis.

[30]  K. Burnand,et al.  A model of in vivo human venous thrombosis that confirms changes in the release of specific soluble cell adhesion molecules in experimental venous thrombogenesis. , 1999, Journal of vascular surgery.

[31]  D. Knighton,et al.  Macrophage-derived growth factors in wound healing: regulation of growth factor production by the oxygen microenvironment. , 1989, The American review of respiratory disease.

[32]  J. Isner,et al.  Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. , 1998, Circulation.

[33]  M. Waltham,et al.  Vascular endothelial growth factor and basic fibroblast growth factor are found in resolving venous thrombi. , 2000, Journal of vascular surgery.

[34]  M. Burdick,et al.  Neovascularization during venous thrombosis organization: a preliminary study. , 1999, Journal of vascular surgery.

[35]  R. Benza,et al.  Therapeutic angiogenesis: review of current concepts and future directions. , 2003, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[36]  D. Goeddel,et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. , 1989, Science.

[37]  D. Strandness,et al.  Long-term sequelae of acute venous thrombosis. , 1983, JAMA.

[38]  M. Takigawa,et al.  Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: a possible mechanism of pathological neovascularization in arthritis. , 1996, Endocrinology.

[39]  K. Tanaka,et al.  Rate of endothelialization in venous thrombi: an experimental study. , 1982, Archives of surgery.

[40]  P. Shamamian,et al.  Hematopoietic stem cells and endothelial cell precursors express Tie-2, CD31 and CD45. , 2004, Blood cells, molecules & diseases.

[41]  P. Polverini,et al.  Role of the Macrophage in the Regulation of Physiological and Pathological Angiogenesis , 1992 .

[42]  R. Strieter,et al.  Detection of perivenous inflammation in a rat model of venous thrombosis using MRV. , 1999, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[43]  M. Mewissen.  Catheter-directed thrombolysis for lower extremity deep vein thrombosis. , 2001, Techniques in vascular and interventional radiology.

[44]  F. Fowkes,et al.  Incidence of diagnosed deep vein thrombosis in the general population: systematic review. , 2003, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[45]  M. Entman,et al.  Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. , 2001, The Journal of clinical investigation.

[46]  G. Raskob,et al.  Hemorrhagic complications of anticoagulant treatment. , 1992, Chest.

[47]  J. Hirsh,et al.  How we diagnose and treat deep vein thrombosis. , 2002, Blood.

[48]  F. Spencer,et al.  Risk Factors for Venous Thromboembolism , 2003, Circulation.

[49]  Alberto Smith,et al.  Failure of Thrombus to Resolve in Urokinase-Type Plasminogen Activator Gene-Knockout Mice: Rescue by Normal Bone Marrow-Derived Cells , 2003, Circulation.

[50]  Salman Rahman,et al.  Novel Vascular Endothelial Growth Factor Binding Domains of Fibronectin Enhance Vascular Endothelial Growth Factor Biological Activity , 2002, Circulation research.

[51]  J. Weisel,et al.  Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk , 2003, The Lancet.

[52]  G. Bauer.  VENOUS THROMBOSIS: EARLY DIAGNOSIS WITH THE AID OF PHLEBOGRAPHY AND ABORTIVE TREATMENT WITH HEPARIN , 1941 .

[53]  M. Fussenegger,et al.  Design and in vivo characterization of self-inactivating human and non-human lentiviral expression vectors engineered for streptogramin-adjustable transgene expression. , 2004, Nucleic acids research.

[54]  S. Sevitt,et al.  The mechanisms of canalisation in deep vein thrombosis , 1973, The Journal of pathology.

[55]  A. Luttun,et al.  The Emerging Role of the Bone Marrow-Derived Stem Cells in (Therapeutic) Angiogenesis , 2001, Thrombosis and Haemostasis.

[56]  U. Losert,et al.  Organisation of experimental thrombosis by blood cells , 1985, Virchows Archiv A.

[57]  R. Hull,et al.  5 Heparin and low-molecular-weight heparin in the treatment of venous thromboembolism , 1998 .

[58]  D. Hosmer,et al.  A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. , 1991, Archives of internal medicine.

[59]  H. Fine,et al.  Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors , 2003, Gene Therapy.

[60]  D. E. Strandness,et al.  Deep venous insufficiency: the relationship between lysis and subsequent reflux. , 1993, Journal of vascular surgery.

[61]  M. Bonneau,et al.  In vivo pig models of venous thrombosis mimicking human disease , 2003, Thrombosis and Haemostasis.

[62]  E. Oger.  Incidence of Venous Thromboembolism: A Community-based Study in Western France , 2000, Thrombosis and Haemostasis.

[63]  V. Kähäri,et al.  Expression and activity of matrix metalloproteinase‐2 and ‐9 in experimental granulation tissue , 2000, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[64]  S. Spinler,et al.  Low-molecular-weight heparins for the treatment of deep-vein thrombosis. , 1993, Clinical pharmacy.

[65]  Chad Jacobs,et al.  Epidemiology of acute deep vein thrombosis. , 2004, Techniques in Vascular and Interventional Radiology.

[66]  J. Fowlkes,et al.  Interleukin-8 administration enhances venous thrombosis resolution in a rat model. , 2001, The Journal of surgical research.

[67]  Matthew O'Donnell,et al.  Staging deep venous thrombosis using ultrasound elasticity imaging: animal model. , 2004, Ultrasound in medicine & biology.

[68]  G. Seabrook,et al.  Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. , 1999, Radiology.

[69]  G. Stirling,et al.  Organization of thrombi , 1966, The British journal of surgery.

[70]  A. Forster,et al.  Thrombolysis in Deep Vein Thrombosis: Is there still an Indication? , 2001, Thrombosis and Haemostasis.

[71]  M. Holmström,et al.  A 6-month Venographic Follow-up in 164 Patients with Acute Deep Vein Thrombosis , 1997, Thrombosis and Haemostasis.

[72]  J. Isner,et al.  Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[73]  Xiaodong Feng,et al.  Angiogenesis in wound healing. , 2000, The journal of investigative dermatology. Symposium proceedings.

[74]  K. Alitalo,et al.  Gene transfer as a tool to induce therapeutic vascular growth , 2003, Nature Medicine.

[75]  M. Bendeck.  Mining the myocardium with macrophage drills: A novel mechanism for revascularization. , 2000, Circulation research.

[76]  D. Berman,et al.  The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003, Circulation.

[77]  A. Kosaki,et al.  Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines , 2001, Circulation.

[78]  C. Kearon,et al.  Natural History of Venous Thromboembolism , 2003, Circulation.

[79]  J. A. George,et al.  Gene therapy progress and prospects: adenoviral vectors , 2003, Gene Therapy.

[80]  J. Hirsh,et al.  Treatment of Venous Thromboembolism , 1995, Thrombosis and Haemostasis.

[81]  Yasuhiko Tabata,et al.  Collagenous matrices as release carriers of exogenous growth factors. , 2004, Biomaterials.

[82]  L. Orci,et al.  Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. , 1991, Biochemical and biophysical research communications.

[83]  D. Connolly,et al.  Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration , 1990, The Journal of experimental medicine.

[84]  M. Waltham,et al.  Monocyte chemotactic protein-1 (MCP-1) accelerates the organization and resolution of venous thrombi. , 1999, Journal of vascular surgery.

[85]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[86]  Alberto Smith,et al.  Vascular endothelial growth factor enhances venous thrombus recanalisation and organisation , 2003, Thrombosis and Haemostasis.

[87]  R. Clark.  Biology of dermal wound repair. , 1993, Dermatologic clinics.

[88]  E. Raines,et al.  Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. , 2000, Circulation research.

[89]  H. Büller,et al.  Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis , 1997, The Lancet.

[90]  J B Fowlkes,et al.  Ultrasound echogenicity in experimental venous thrombosis. , 1998, Ultrasound in medicine & biology.

[91]  V. Nehls,et al.  The configuration of fibrin clots determines capillary morphogenesis and endothelial cell migration. , 1996, Microvascular research.

[92]  M. Dake,et al.  Vascular endothelial growth factor enhances atherosclerotic plaque progression , 2001, Nature Medicine.

[93]  P. Romano,et al.  Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures , 2003, Thrombosis and Haemostasis.

[94]  M. Kutryk,et al.  Endothelial progenitor cells: new hope for a broken heart. , 2003, Circulation.

[95]  G. Majno,et al.  Cells, tissues, and disease : principles of general pathology , 1996 .

[96]  S. Ylä-Herttuala,et al.  Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[97]  Jie Li,et al.  Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix , 2003, Microscopy research and technique.

[98]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[99]  T. Murohara,et al.  Augmentation of Postnatal Neovascularization With Autologous Bone Marrow Transplantation , 2001, Circulation.

[100]  W. Daniel,et al.  Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. , 2001, Cardiovascular research.

[101]  L. Zentilin,et al.  Recombinant AAV vector encoding human VEGF165 enhances wound healing , 2002, Gene Therapy.

[102]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[103]  K. Shimada,et al.  Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial , 2002, The Lancet.

[104]  Takayuki Asahara,et al.  Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb , 1996, The Lancet.

[105]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[106]  Y. Tintut,et al.  Mesenchymal stem cells and the artery wall. , 2004, Circulation research.

[107]  J. Isner,et al.  Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. , 1998, Journal of vascular surgery.

[108]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[109]  R. Coleman,et al.  Therapeutic angiogenesis in chronically ischemic porcine myocardium: comparative effects of bFGF and VEGF. , 2004, The Annals of thoracic surgery.

[110]  A. Forster,et al.  The rationale and evidence for the treatment of lower-extremity deep venous thrombosis with thrombolytic agents. , 2002 .

[111]  M. Waltham,et al.  Recruitment of Labelled Monocytes by Experimental Venous Thrombi , 2001, Thrombosis and Haemostasis.

[112]  R. Crystal,et al.  Adenovirus-mediated transfer of a minigene expressing multiple isoforms of VEGF is more effective at inducing angiogenesis than comparable vectors expressing individual VEGF cDNAs. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[113]  T. Wakefield,et al.  Neutropenia impairs venous thrombosis resolution in the rat. , 2003, Journal of vascular surgery.