Skip to main content

GAS6 in systemic inflammatory diseases: with and without infection


Vitamin K-dependent proteins are not only essential regulators of blood coagulation. A recent paper in Critical Care describes the levels of the vitamin K-dependent GAS6 and the soluble form of its receptor Axl in plasma from patients with sepsis of systemic inflammation. The results confirm that GAS6 is elevated during septicemia, but the fact that inflammatory conditions without infection produce a similar effect suggests it is inflammation that induces the synthesis of GAS6, rather than the interactions with bacteria or other infectious agents. The soluble form of the GAS6 receptor Axl was induced less compared with the effect observed in GAS6. This is important as the two proteins form an inactive complex in plasma, suggesting that a functional GAS6 form could be synthesized under these conditions. GAS6 has been proposed as a broad regulator of the innate immune response. GAS6 synthesis is therefore likely to be a regulatory mechanism during systemic inflammation. Recent advances provide the necessary tools for further research, including genetic screenings of the components of this system.

Since its discovery in 1929 as the 'Koagulations-Vitamin' by Henrik Dam, the main role assigned to vitamin K has been linked to maintaining hemostasis. Vitamin K inhibitors have been used in the clinic as anticoagulants since the 1950 s. Vitamin K is an essential cofactor in the post-transcriptional modification of glutamic residues of a small number of proteins in the human genome. Although the majority of these vitamin K-dependent proteins are part of the coagulation cascade or its regulators, others are involved in different processes. The view of vitamin K function is therefore now broader, and recent research has demonstrated a wide range of functions associated with vitamin K-dependent proteins; for instance, their implication in calcium homeostasis in the bone and other tissues. Furthermore, vitamin K-dependent proteins are present in invertebrates and other species lacking a coagulation cascade.

A later addition to these functions has been produced by studies on GAS6, the subject of the recent report by Ekman and colleagues [1]. GAS6 and the highly similar anticoagulant protein S were discovered to be ligands of a family of formerly orphan receptor protein tyrosine kinases, the TAM family [2, 3]. The function of this family of receptors was soon recognized to be important in mechanisms of defense against injuries, especially through their action as regulators of inflammation, apoptotic cell clearance and platelet-endothelial activation [47].

Owing to the low concentration of GAS6 in plasma and its similarity to protein S, which is 1,000-fold more concentrated, creating a reliable test to detect its concentration under different disease conditions has been a challenge. Despite these difficulties, several groups have reported that GAS6 acts as an acute-phase reactant, increasing its concentration during sepsis [8, 9]. The present study by Ekman and colleagues provides detailed evidence of this increase by comparing at the same time patients with different diagnoses related to septicemia - including severe sepsis, sepsis, systemic inflammatory response syndrome without infection, and verified infection - blood donors, systemic inflammatory response syndrome patients with infections, and patients without systemic inflammatory response syndrome as controls. Furthermore, the study determines the concentration of soluble Axl, a processed form of the receptor that is present in plasma at molar excess compared with GAS6 and that seems to capture most of the GAS6, forming a stable complex [10]. Previous studies have clearly established that GAS6 is increased in septic patients, and its concentration correlates with disease severity [8, 9].

In the present study, the authors show that plasma GAS6 increased in all conditions studied, irrespective of the presence of infection. Other conditions with an important activation of inflammation, such as pancreatitis, also show increased levels of GAS6 [11]. Taken together, these data suggest that GAS6 would be a general marker of inflammatory conditions rather than a specific marker for sepsis. This hypothesis would fit well with the view of the TAM receptor system as a brake for the innate immunity [12]. GAS6 itself shows anti-inflammatory properties in certain cells, reducing cytokine synthesis [13], but could also orchestrate the course of inflammation by favoring platelet and leukocyte interactions with the endothelium [7].

The study of the role of GAS6 and its TAM receptors in human pathology has just begun. Recent developments include assays to test the genetic variability of the GAS6 gene [14] and to test the TAM receptors in the human genome [15]. These assays would allow correlating plasma parameters with the genetic background, leading to a deeper understanding of the possible role of the GAS6-TAM system in sepsis.


  1. 1.

    Ekman C, Linder A, Akesson P, Dahlback B: Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit Care. 2010, 14 (4): R158-

    PubMed Central  Article  PubMed  Google Scholar 

  2. 2.

    Linger RM, Keating AK, Earp HS, Graham DK: TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008, 100: 35-83.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  3. 3.

    Fernandez-Fernandez L, Bellido-Martin L, Garcia de Frutos P: Growth arrest-specific gene 6 (GAS6). An outline of its role in haemostasis and inflammation. Thromb Haemost. 2008, 100: 604-610.

    CAS  PubMed  Google Scholar 

  4. 4.

    Angelillo-Scherrer A, de Frutos P, Aparicio C, Melis E, Savi P, Lupu F Arnout J, Dewerchin M, Hoylaerts M, Herbert J, Collen D, Dahlback B, Carmeliet P: Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001, 7: 215-221.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Lu Q, Lemke G: Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001, 293: 306-311.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL, Earp HS, Matsushima GK: Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature. 2001, 411: 207-211.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Tjwa M, Bellido-Martin L, Lin Y, Lutgens E, Plaisance S, Bono F, Delesque-Touchard N, Herve C, Moura R, Billiau AD, Aparicio C, Levi M, Daemen M, Dewerchin M, Lupu F, Arnout J, Herbert JM, Waer M, Garcia de Frutos P, Dahlback B, Carmeliet P, Hoylaerts MF, Moons L: Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes. Blood. 2008, 111: 4096-4105.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Borgel D, Clauser S, Bornstain C, Bieche I, Bissery A, Remones V, Fagon JY, Aiach M, Diehl JL: Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis. Crit Care Med. 2006, 34: 219-222.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Gibot S, Massin F, Cravoisy A, Dupays R, Barraud D, Nace L, Bollaert PE: Growth arrest-specific protein 6 plasma concentrations during septic shock. Crit Care. 2007, 11: R8-

    PubMed Central  Article  PubMed  Google Scholar 

  10. 10.

    Ekman C, Stenhoff J, Dahlback B: Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood. J Thromb Haemost. 2010, 8: 838-844.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Uehara S, Handa H, Gotoh K, Tomita H, Sennshuu M: Plasma concentrations of growth arrest-specific protein 6 and protein S in patients with acute pancreatitis. J Gastroenterol Hepatol. 2009, 24: 1567-1573.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G: TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007, 131: 1124-1136.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Alciato F, Sainaghi PP, Sola D, Castello L, Avanzi GC: TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages. J Leukoc Biol. 2010, 87: 869-875.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Munoz X, Sumoy L, Ramirez-Lorca R, Villar J, de Frutos PG, Sala N: Human vitamin K-dependent GAS6: gene structure, allelic variation, and association with stroke. Hum Mutat. 2004, 23: 506-512.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hurtado B, Abasolo N, Munoz X, Garcia N, Benavente Y, Rubio F, Garcia de Frutos P, Krupinsky J, Sala N: Association study between polymorphims in GAS6-TAM genes and carotid atherosclerosis. Thromb Haemost. 2010, 104: 592-598.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Pablo García de Frutos.

Additional information

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hurtado, B., de Frutos, P.G. GAS6 in systemic inflammatory diseases: with and without infection. Crit Care 14, 1003 (2010).

Download citation


  • Pancreatitis
  • GAS6 Synthesis
  • Systemic Inflammatory Response Syndrome
  • Coagulation Cascade
  • Orphan Receptor