Thrombin activatable fibrinolysis inhibitor is associated with severity and outcome of severe meningococcal infection in children

Abstract

To cite this article: Emonts M, de Bruijne ELE, Guimarã es AHC, Declerck PJ, Leebeek FWG, de Maat MPM, Rijken DC, Hazelzet JA, Gils A.Thrombin activatable fibrinolysis inhibitor is associated with severity and outcome of severe meningococcal infection in children. J Thromb Haemost 2008; 6: 268-76.Summary. Background and objectives: In pediatric meningococcal sepsis, an imbalance between coagulation and fibrinolysis and proinflammatory action play major roles. We hypothesized that thrombin activatable fibrinolysis inhibitor (TAFI) and/or TAFI activation markers are involved in the pathogenesis of meningococcal sepsis. Patients and methods: Children with severe meningococcal sepsis (n = 112) previously included in Rotterdam-based trials participated in this study. Clinical and laboratory parameters and severity scores were assessed. TAFI and TAFI activation markers were determined: TAFI activation peptide (TAFI-AP) and (in)activated TAFI [TAFIa(i)]. The -438G/A, Ala147Thr, and Thr325Ile polymorphisms were genotyped. Results: TAFI levels were significantly decreased in patients with meningococcal disease at admission compared to the convalescence state. TAFI was decreased in patients with septic shock vs. those with no shock. TAFI-AP levels were increased in patients with disseminated intravascular coagulation (DIC) vs. patients without DIC. TAFI-AP and TAFIa(i) were significantly increased in non-survivors vs. survivors. TAFI-AP levels and the TAFI-AP/TAFI ratio were also strongly correlated to severity scores and laboratory parameters. The TAFI 325Ile/Ile genotype was overrepresented in patients with DIC. Conclusions: Activation markers of TAFI were associated with the occurrence of DIC and mortality in meningococcal sepsis patients. A determination of TAFI, TAFI-AP, and TAFIa(i) is required to enable coherent interpretation of the role of TAFI in disease.

Assessment of thrombin-activatable fibrinolysis inhibitor (TAFI) activation in acquired hemostatic dysfunction: a diagnostic challenge

“…Although only a few septic patients (n=25) were enrolled in the study, the activation status of TAFI could clearly differentiate septic patients from healthy controls. This result is in agreement with the results of a recent study [10] that reported a significant elevation of TAFI activation in meningococcal infection. Since decreases in total TAFI level are associated with increases of TAFI activation level, simultaneous determination of total TAFI and TAFI activation marker is required to interpret the role of TAFI in acquired hemostatic dysfunctions including sepsis.…”

A toll‐like receptor 4 variant is associated with fatal outcome in children with invasive meningococcal disease

“…Given that LPS hyporesponsiveness has also been reported in MyD88 (30), TRIF (5), TIRAP (5,8) and MD‐2 knockout mice (30), genetic variations in these or related genes might modulate disease susceptibility and/or clinical phenotype as well. In addition, it has been demonstrated that genetic variants in other components of the host immune and coagulation system such as TNF‐α (12), plasminogen activator inhibitor‐1 (PAI‐1) (22,31), thrombin activatable fibrinolysis inhibitor (TAFI) (32,33) or variants of the protein C (PC) promoter (34) can also modulate disease severity and/or outcome in meningococcal disease (also reviewed in (35)).…”

Sepsis-Associated Disseminated Intravascular Coagulation and Thromboembolic Disease

“…It was unclear whether activation or consumption or both were the cause of this decrease. In a comprehensive study evaluating TAFI activation markers on a rather large series of patients with severe meningococcal infection, Emonts et al128 demonstrated that TAFI levels were significantly decreased at admission compared to the convalescence state and were lower in patients with septic shock. More important, the levels of TAFI activation peptide (TAFI-AP) were augmented in patients with DIC as compared with those without.…”