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Protein S and Risk for Venous Thrombosis

November 19, 2013

Protein S and Risk for Venous Thrombosis

  1. David Green, MD, PhD

Low levels of free and total protein S do not identify patients at risk for sporadic venous thrombosis.

  1. David Green, MD, PhD

Protein S circulates freely or binds to complement-binding protein; only the free form inhibits coagulation, functioning as the cofactor for both protein C and the tissue-factor pathway inhibitor. Traditionally, thrombophilia testing panels for patients with unprovoked venous thrombosis (VT) have included proteins S and C, factor V Leiden, prothrombin G20210A, and antithrombin.

To determine whether free protein S deficiency is a risk factor for thrombosis, investigators in the Netherlands measured free and bound protein S in more than 2300 patients 3 or more months after a first VT and in age and gender-matched controls. Patients were enrolled in the prior population-based, case-control MEGA study (JAMA 2005; 293:715).

Patients with levels of free protein S and total protein S that were less than levels in the 2.5th percentile of controls were not at increased risk for thrombosis: odds ratios, 0.82 (95% confidence interval, 0.56–1.21) and 0.92 (95% CI, 0.63–1.33), respectively. After excluding patients who were pregnant, postpartum, or estrogen users, the ORs were 1.51 (95% CI, 0.82–2.78) and 1.34 (95% CI, 0.74–2.44). If free protein S was <0.10th percentile, the OR was higher, but not significantly so (OR, 5.4; 95% CI, 0.61–48.8), and even very low levels of total protein S were not associated with VT. Furthermore, ORs were not significantly increased when the analysis was confined to patients with a family history of VT. Gene sequencing in the 48 participants with the lowest free protein S levels disclosed mutations in the protein S gene in five patients but also in five controls without VT, indicating that some mutations in this gene are incidental and not detrimental.

Comment

This elegant investigation shows that low levels of free and total protein S do not identify patients at risk for venous thrombosis. Only patients with very low levels of protein S and complete gene deletions are thrombophilic, but such patients are encountered very rarely in clinical practice. Therefore, assays of free and total protein S should not be included in thrombophilia panels. Protein S should be requested only when there are no other explanations for recurrent VT.

  • Disclosures for David Green, MD, PhD at time of publication Consultant / Advisory board Altor Bioscience Grant / research support NIH

Citation(s):

Reader Comments (1)

Bruce Wallach Physician, Oncology, PRIVATE PRACTICE

will be difficult to translate this finding into clinical practice since multiple "hyper coag" panels include protein s testings3ms

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