Regular articleFactor XIII in severe sepsis and septic shock
Introduction
Sepsis is the leading cause of mortality in non-cardiologic intensive care units [1]. This is generally considered to result from excessive activation of host's inflammatory defense mechanisms. The development of multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis and associated with poor outcome. Though the pathogenesis of MODS is not well understood, coagulation activation is suggested to be critically involved [2], [3].
It is generally accepted that coagulation activation in sepsis occurs via tissue factor (TF)–factor VII (FVII) pathway [3]. After binding to TF, exposed on activated monocytes and on endothelial cells, FVII is activated and initiates the coagulation cascade finally leading to the formation of thrombin. Fibrinopeptides A and B are cleaved off from fibrinogen (Fbg) by thrombin leading to the exposure of cryptic polymerization sites enabling fibrin monomers (FM) to polymerize [3], [4], [5]. Thrombin also activates FXIII, which then covalently cross-links polymerized FM to form a stable clot [5]. Since anticoagulant pathways, such as antithrombin or activated protein C, are depressed during sepsis, thrombin generation and activity are not properly controlled resulting in enhanced fibrin formation. Likewise, fibrinolysis is abrogated due to inhibition of tissue type plasminogen activator (t-PA) by plasminogen activator inhibitor type 1 (PAI-1). The imbalance between coagulation activation and inhibition of fibrinolysis cumulates in abundant fibrin deposition leading to thrombosis of the microvasculature, which may cause organ failure and death [3], [4].
As evidenced by bleeding complications commonly observed in patients with severe FXIII deficiency, FXIII is considered to play a crucial role in both vascular and extravascular fibrin stabilization in vivo [6]. FXIII, a proenzyme of a transglutaminase, is a heterotetramer consisting of two identical proenzyme subunits (A2) and two identical carrier protein subunits (B2).
Whereas subunit A harbors the catalytic as well as the calcium binding site, subunit B acts as a carrier protein that stabilizes subunit A and may dampen FXIII activation. In contrast, platelet FXIII only consists of an A2 homodimer [5]. FXIII is activated by thrombin hydrolyzing the peptide bond between Arg37 and Gly38 in the A subunit [5]. Activated FXIII (FXIIIa) stabilizes the fibrin clot by cross-linking a lysine of one γ-chain in the fibrin polymer with a glutamine of another γ chain and by cross-linking α-chains by transamidation [5]. Moreover, FXIIIa incorporates α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) into fibrin, thereby enhancing the resistance of the fibrin clot against fibrinolytic enzymes [7], [8].
Since prior Fbg depletion of mice by ancrod, a snake venom specifically degrading Fbg, protected the animals against tissue damage during the classical local Shwartzman reaction, fibrin clot formation and probably clot stabilization seem to play a critical role in vascular thrombosis during inflammation [9]. This hypothesis is supported by the finding in animals that the stability of fibrin clots subcutaneously implanted depended on the degree of fibrin cross-linking [10]. Recently, depletion of FXIII was reported to prevent coagulation-induced organ damage due to generalized Shwartzman reaction in rabbits [11].
Previous studies in patients with sepsis or septic shock have shown reduction of both the catalytic FXIII subunit A and the carrier subunit B suggesting consumption due to activated coagulation and direct proteolysis by neutrophil elastase [12], [13], [14]. Low levels of FXIII cross-linking activity and subunit A and B antigen were also reported in patients with complicated Plasmodium falciparum malaria and FXIII levels were inversely correlated with clinical severity [15]. However, in these previous studies, different methods for FXIII determination have been used. In addition, there are no data available on FXIII levels in relation to the severity of sepsis.
Therefore, we investigated FXIII antigen levels, using a sensitive ELISA method, and FXIII cross-linking activity, using a commercially available incorporation assay, in 40 patients suffering from severe sepsis and septic shock. FXIII results were correlated with coagulation and inflammatory parameters and related to standard clinical scores and survival.
Section snippets
Patients
The protocol was approved by the local ethical committee. Informed consent was obtained from all patients. In case of impaired consciousness, informed consent was obtained from a family member or the closest relative or partner of the patient, according to the national legal guidelines.
Patients of the medical and surgical Intensive Care Units (ICU) were eligible if they met the inclusion criteria for severe sepsis or septic shock. The diagnosis of severe sepsis and septic shock was established
Acknowledgement
We thank Irmela Sulzer for her excellent technical support.
Hans Peter Kohler is supported by a grant from the Swiss National Foundation for Scientific Research (3200-055313).
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