title: Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia.
abstract: The present study investigated factors associated with therapeutic benefits after autologous bone marrow cell (BMC) therapy in patients with "no-option" critical limb ischemia (CLI).
  
  
  
  Sixty-two patients with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were randomized to treatment with 40 ml of autologous BMCs (SmartPreP2) by local intramuscular (n = 32) or intra-arterial (n = 30) application. The primary endpoint was limb salvage and wound healing at 12 months. Seven patients (11 %) died during the follow-up from reasons unrelated to stem cell therapy. The BMC product of patients with limb salvage and wound healing (33/55) was characterized by a higher CD34(+) cell count (p = 0.001), as well as a higher number of total bone marrow mononuclear cells (BM-MNCs) (p = 0.032), than that of nonresponders (22/55). Patients with limb salvage and wound healing were younger (p = 0.028), had lower C-reactive protein levels (p = 0.038), and had higher transcutaneous oxygen pressure (tcpO2) (p = 0.003) before cell application than nonresponders. All patients with major tissue loss at baseline (Rutherford 6 stage of CLI, n = 5) showed progression of limb ischemia and required major limb amputation. In the multiple binary logistic regression model, the number of applied CD34(+) cells (p = 0.046) and baseline tcpO2 (p = 0.031) were independent predictors of limb salvage and wound healing. The number of administrated BM-MNCs strongly correlated with decreased peripheral leukocyte count after 6 months in surviving patients with limb salvage (p = 0.0008).
  
  
  
  Patients who benefited from autologous BMC therapy for "no-option" CLI were treated with high doses of CD34(+) cells. The absolute number of applied BM-MNCs correlated with the improvement of inflammation. We hypothesize that the therapeutic benefit of cell therapy for peripheral artery disease is the result of synergistic effects mediated by a mixture of active cells with regenerative potential. Patients at the most advanced stage of CLI do not appear to be suitable candidates for cell therapy.
  
  
  
  The study was approved and registered by the ISRCTN registry.
  
  
  
  ISRCTN16096154 . Registered: 26 July 2016.
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia. madaric@nusch.sk.|Slovak Medical University, Bratislava, Slovakia. madaric@nusch.sk.
authors.forename: Juraj
authors.initials: J
authors.lastname: Madaric
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Klepanec
authors.affiliation: Slovak Medical University, Bratislava, Slovakia.
authors.forename: Martina
authors.initials: M
authors.lastname: Valachovicova
authors.affiliation: Clinic of Haematology and Transfusiology, Faculty Hospital, Bratislava, Slovakia.
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.affiliation: Institute of Imunology, Faculty of Medicine Comenius University, Bratislava, Slovakia.
authors.forename: Maria
authors.initials: M
authors.lastname: Bucova
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Olejarova
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia.
authors.forename: Roman
authors.initials: R
authors.lastname: Necpal
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia.
authors.forename: Terezia
authors.initials: T
authors.lastname: Madaricova
authors.affiliation: Institute of Pathophysiology, Faculty of Medicine Comenius University, Bratislava, Slovakia.
authors.forename: Ludovit
authors.initials: L
authors.lastname: Paulis
authors.affiliation: National Institute of Cardiovascular Diseases, Slovak Medical University, Pod Krasnou horkou 1, 833 48, Bratislava, Slovakia.|Slovak Medical University, Bratislava, Slovakia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vulev
mesh_terms: D000368:Aged; D000671:Amputation, Surgical / Q000379:methods; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods; D002097:C-Reactive Protein / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005260:Female; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D007958:Leukocyte Count / Q000379:methods; D023821:Limb Salvage / Q000379:methods; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism; D014182:Transplantation, Autologous / Q000379:methods; D016896:Treatment Outcome; D014945:Wound Healing / Q000502:physiology
chemical_list: D002097:C-Reactive Protein; D010100:Oxygen
keywords: Angiogenesis; Critical limb ischemia; Inflammation; Limb salvage; Stem cells