Factor XI Deficiency
Although two factor XI concentrates are available (largely in Europe or in other countries under an investigational new drug application), these products have not been subjected to rigorous clinical trials and therefore need further study. However in light of the reported thrombotic events, the SPC (summary of product characteristics) for the LFB concentrate has been modified and clinicians are more cautious in its use.49 The guidance document can be obtained from email@example.com.
Further research is needed to elucidate contributing factors to the observed variable bleeding tendency in FXI deficiency. A more accurate predictor of bleeding than the FXI level is needed, and studies with thrombin generation tests suggest that this assay may be more useful,18 although other work contradicts this observation.50 Reported differences may relate to the experimental conditions, particularly the TF concentration, as additional evidence from animal studies indicates that the role of FXI becomes more important when TF levels are low.51 This finding is reflected in human studies with the thrombin generation test in FXI deficient patients, as described by Pike and colleagues19
The discovery of the key role of polyphosphates in coagulation provides several new potential avenues for further research.9 Further work is needed to confirm the presence of a pool of FXI in the vasculature and to fully understand its role.
The potential for inhibition of FXI or FXII as targets for antithrombotic strategy is of considerable interest. FXI deficiency protects against stroke52 and venous thrombosis,53 although not against myocardial infarction.54 Several animal experiments using monoclonal antibodies, small molecules and antisense nucleotides show promising results, and suggest that such a strategy is feasible.55-58 Recent work demonstrated that a human IgG1 antibody against activated FXI produced a sustained reduction in FXI with a half-life of 30 days in healthy young men without bleeding complications.59 FXI plays a pivotal role in the balance between hemostasis and thrombosis. A clinical study in patients undergoing knee replacement surgery demonstrated the efficacy of an antisense oligonucleotide (ASO-XI) in both suppressing the FXI level to 25-30% of normal (without bleeding complications) and reducing venous thrombosis (from 30% to 5%, venographically confirmed).60
A genome-wide association study for regulators of plasma FXI levels searched for loci that might be involved in FXI regulation, and several were found.61 The recent rapid development of genome research is likely to lead to additional methods of thrombosis mitigation using these newly-discovered pathways.Next