Natural anticoagulants deficiency and the risk of venous thromboembolism: A meta-analysis of observational studies

Matteo Nicola Dario Di Minno, Pasquale Ambrosino, Walter Ageno, Frits Rosendaal, Giovanni Di Minno, Francesco Dentali

Research output: Contribution to journalArticlepeer-review


Introduction 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. Materials and 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. Conclusion The VTE risk is increased in patients with natural anticoagulants deficiency, but additional studies are warranted to better assess the risk of VTE recurrence.

Original languageEnglish
Pages (from-to)923-932
Number of pages10
JournalThrombosis Research
Issue number5
Publication statusPublished - May 1 2015


  • Antithrombin
  • Protein C
  • Protein S
  • Venous thromboembolism

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)


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