What is factor XI?

Updated: Feb 07, 2020
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP; Chief Editor: Eric B Staros, MD  more...
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The so-called contact factors include factor XI, factor XII, high-molecular-weight kininogen (HK), and prekallikrein (PK). Factor XI is synthesized in the liver and megakaryocytes and is an 80-kd zymogen precursor of a serine protease. It circulates in complex with the nonenzymatic cofactor HK [1] and has a mean plasma half-life of about 52 hours. The gene for factor XI is located on chromosome 4. [3]

There are multiple mechanisms by which factor XI can be activated. It can be activated in vitro by activated factor XII (XIIa). It can be activated by thrombin in the fluid phase and on charged surfaces even without the presence of other contact factors [4, 5] ; it can also be activated by thrombin on the surface of activated platelets, a pathway that is the most likely mechanism of in vivo activation in vivo during hemostasis. [6] In a mouse model, factor XI appears to play a greater role in thrombosis than in hemostasis. [7]

Activation of factor IX by activated factor XI (XIa) is calcium-dependent but requires no other cofactors. Binding of factor XIa to activated platelets localizes it to the site of clot formation and protects it from plasma protease inhibitors. [1] Factor XI enhances generation of thrombin at the platelet surface.

In mice, knockout of the gene for factor XI does not lead to death in utero. [8] In humans, however, factor XI deficiencies can give rise to bleeding tendencies, [9] which, though significant, are not as severe as those seen in hemophilia A or hemophilia B. This finding reflects the important role factor XI plays in hemostasis.

A study by Kyrle et al reported that in patients who had experienced an unprovoked venous thromboembolism (VTE), the 10-year probability of VTE recurrence was 31% in individuals below the 34th percentile for factor XIa, compared with 43% for those between the 34th and 67th percentiles, and 41% for patients in a higher percentile. [10]

A study by Gill et al indicated that greater genetically determined levels of factor XI increase the risk of ischemic stroke arising from cardioembolisms, while not impacting ischemic stroke risk associated with large artery atherosclerosis or small artery occlusion. [11]

On the other hand, a study by Georgi et al indicated that in persons genetically disposed to lower concentrations of factor XI, the risk of venous thrombosis and ischemic stroke are reduced. Employing data related to genetic variants that alter factor XI levels, the investigators found that in these individuals, the odds ratios (ORs) for venous thrombosis and ischemic stroke were 0.1 and 0.47, respectively, with the OR for major bleeding being 0.7. Moreover, the results indicated that among patients with lower factor XI levels, the absolute risk reductions are greater in individuals at high risk for thrombosis, including those with atrial fibrillation or cancer. The authors suggested that the risk of venous thrombosis and ischemic stroke may be significantly reduced by pharmacologic inhibition of factor XI, with no clear evidence demonstrating that this therapy would increase the risk for major bleeding. [12]

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