title: Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies.
abstract: BACKGROUND
  Natural anticoagulants deficiency (antithrombin [AT], protein C [PC], protein S [PS]) is a rare, but potent risk factor for venous thromboembolism (VTE). We performed a meta-analysis of observational studies evaluating the impact of inherited natural anticoagulants deficiency on VTE risk.
  
  
  METHODS
  Case-control and cohort studies evaluating the association of these abnormalities with VTE were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases.
  
  
  RESULTS
  Twenty-one studies were included in the analysis. Thirteen studies (3,452 cases and 11,562 controls) showed an increased risk of first VTE in AT deficient subjects compared to controls (OR: 16.26, 95%CI:9.90-26.70; P<0.00001). An increased risk of first VTE was also found in PC (11 studies, 2,554 cases and 9,355 controls; OR: 7.51, 95%CI:3.21-17.52; P<0.00001) and PS deficient patients (14 studies, 4,955 cases and 9,267 controls; OR: 5.37; 95%CI:2.70-10.67; P<0.00001) compared to controls. Evaluating the risk of VTE recurrence, we found a significant association with AT (4 studies, 142 cases and 1,927 controls; OR: 3.61; 95%CI:1.46-8.95; P=0.006) and with PC (2 studies, 80 cases and 546 controls; OR: 2.94; 95%CI:1.43-6.04; P=0.03), but not with PS deficiency (2 studies, 57 cases and 589 controls; OR: 2.52; 95%CI:0.89-7.16; P=0.08). Sensitivity and subgroup analyses confirmed these results. The association among natural anticoagulants deficiency and VTE was maximal for patients with unprovoked events.
  
  
  CONCLUSIONS
  The VTE risk is increased in patients with natural anticoagulants deficiency, but additional studies are warranted to better assess the risk of VTE recurrence.
authors.affiliation: Department of Clinical Medicine and Surgery, Reference Centre for Coagulation Disorders, Federico II University, Naples, Italy; Unit of cell and molecular biology in cardiovascular diseases, Centro Cardiologico Monzino, IRCCS, Milan, Italy. Electronic address: dario.diminno@hotmail.it.
authors.forename: Matteo Nicola Dario
authors.initials: MN
authors.lastname: Di Minno
authors.affiliation: Department of Clinical Medicine and Surgery, Reference Centre for Coagulation Disorders, Federico II University, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ambrosino
authors.affiliation: Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Ageno
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University, Leiden, The Netherlands.
authors.forename: Frits
authors.initials: F
authors.lastname: Rosendaal
authors.affiliation: Department of Clinical Medicine and Surgery, Reference Centre for Coagulation Disorders, Federico II University, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Minno
authors.affiliation: Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dentali
mesh_terms: D000990:Antithrombin III / Q000032:analysis; D020152:Antithrombin III Deficiency / Q000097:blood / Q000150:complications*; D006801:Humans; D011486:Protein C / Q000032:analysis; D020151:Protein C Deficiency / Q000097:blood / Q000150:complications*; D017293:Protein S / Q000032:analysis; D018455:Protein S Deficiency / Q000097:blood / Q000150:complications*; D012306:Risk; D054556:Venous Thromboembolism / Q000097:blood / Q000209:etiology*
chemical_list: D011486:Protein C; D017293:Protein S; D000990:Antithrombin III
keywords: Antithrombin; Protein C; Protein S; Venous thromboembolism