A functional single-nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) associated with risk and outcome of meningococcal disease (MD)

Abstract number: OC086

Kremer Hovinga^* J., Franco† R. F., Zago† M. A., Ten Cate^* H., Westendorp‡ R. G., Reitsma^* P. H.

‡Deptartment of General Internal Medicine, LUMC, Netherlands ^*Laboratory for Experimental Internal Medicine, AMC, Netherlands; †University of Sao Paolo, Brazil;

Background  

Intravascular coagulation with deposition of fibrin and formation of microthrombi is a hallmark of meningococcal sepsis. Activation of the extrinsic pathway of coagulation is associated with the consumption of the natural coagulation inhibitors leading to an imbalance between pro- and anticoagulant systems. The counteraction of the fibrinolytic system is often insufficient due to (highly) increased levels of PAI-1 and TAFI. The resulting effects is a procoagulant state. TAFI, a plasma carboxypeptidase zymogen, is activated by thrombin, the thrombin/thrombomodulin complex or by plasmin. TAFIa attenuates clot lysis by removing lysine residues from the fibrin clot. Conformational instability rather than proteolysis causes inactivation of TAFIa. A common variation (SNP) in TAFI at position 325, Ile instead of Thr, doubles TAFIa half-life and increases anti-fibrinolytic activity by 60%. We postulated that patients with the TAFI Ile/Ile variant would develop a more severe coagulopathy and have a greater risk of death during MD. Therefore, we studied this SNP in 179 first-degree relatives of 80 patients with MD, 50/64 surviving patients and 272 controls from the same geographical region.

Results  

The TAFI 325 Ile/Ile variant was more common among parents of patients with MD than in controls (11% vs. 4.8%, P = 0.03). This difference was even more pronounced among the subgroup of parents of nonsurviving patients (18%, P = 0.01). Based on these gene frequencies patients whose parents were carriers of the TAFI 325 Ile/Ile genotype had a 2.4 (95% CI 1.1–5.6) fold increased risk to contract MD and 2.7 (95% CI 0.8–9.7) fold increased risk of fatal outcome once MD had been contracted compared to all other genotypes. Survivors had a genotype frequency that was not different from that of the general population.

Conclusions  

The common, functional variation 325 Thr/Ile in TAFI affects the susceptibility for and influences the outcome of MD. Therefore, specific inhibition of TAFI could be a new therapeutic target in severe MD with DIC.