Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome― Fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction

Abstract

Introduction

Post-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP).

Materials and Methods

Fifty-two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients.

Results

The levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients.

Conclusions

Thrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase-mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS.

Introduction

The majority of research on cardiac arrest over the past half-century has focused on improving the rate of return of spontaneous circulation (ROSC). Progressive improvements have been made in the management of cardiac arrest, including modern cardiopulmonary resuscitation and emergency cardiovascular care. However, improvements in the rate of ROSC have not been accompanied by improvements in the long-term survival of resuscitated patients. The high mortality rate of patients who initially achieve ROSC after experiencing cardiac arrest can be attributed to the development of post-cardiac arrest syndrome (PCAS), a unique and complex combination of pathophysiological processes [1]. One of the important key components of PCAS is systemic ischemia and reperfusion [1], [2]. Endothelial and leukocyte activation induced by cardiac arrest is a critical step in the process of endothelial injury and organ damage [3]. In addition, whole-body ischemia and reperfusion- induced endothelial injury contributes to thrombotic occlusion of the vessels following activation of coagulation and impairment of fibrinolysis [4], [5], [6], [7]. These changes lead to disseminated intravascular coagulation (DIC) in patients resuscitated from cardiac arrest [5], [6].

DIC is characterized by the widespread activation of tissue-factor-dependent coagulation, insufficient control of coagulation by physiologic anticoagulation pathways and plasminogen activator inhibitor-1-mediated attenuation of fibrinolysis, which results in intravascular fibrin formation and ultimately thrombotic occlusion of vessels, followed by deterioration of the oxygen supply to cells and tissues [8]. These changes cause damage to the microvasculature and can produce multiple organ dysfunction syndrome (MODS) [8], [9], [10].

The pathophysiology of MODS in patients with DIC is thought to involve an imbalance between coagulation and fibrinolysis due to activation of coagulation, inhibition of fibrinolysis (fibrinolytic shutdown) and insufficient activation of fibrinolysis [11], [12], [13], [14]. In addition to plasmin, the degradation of fibrin(ogen) is mediated through the actions of neutrophil elastase. The degradation products produced by neutrophil elastase (fibrin degradation product by neutrophil elastase: EXDP) are different from plasmin digests [15], [16]. Thrombin-activatable fibrinolysis inhibitor (TAFI) has also been described as a potent inhibitor of fibrinolysis. TAFI is present in the plasma as a proenzyme and is activated by the thrombin-thrombomodulin complex [17]. The mechanisms underlying the TAFI-induced inhibition of fibrinolysis involve the removal of carboxy-terminal lysines from partially degraded fibrin, thus preventing the binding of plasminogen and tissue-type plasminogen activator (t-PA) for fibrinolytic assembly and activity [18]. We previously demonstrated that activation of the neutrophil-mediated fibrinolytic pathway is not sufficient to overcome the fibrinolytic shutdown induced by plasminogen activator inhibitor-1 (PAI-1) and contributes to poor outcomes in DIC patients with systemic inflammation [13], [19]. A low level of TAFI activity also promotes organ dysfunction in DIC patients with sepsis [19]. Moreover, both the plasmin- and neutrophil-mediated fibrinolytic pathways are involved in the pathogenesis of DIC associated with trauma, and neutrophil-mediated fibrinolysis may compensate for an insufficient plasmin-mediated fibrinolytic pathway in the early phases of trauma [20]. However, no previous reports have documented data regarding the relationship between these markers and DIC associated with PCAS.

The aim of the present study was to examine serial changes in coagulation and fibrinolytic markers in patients with PCAS and to test the hypothesis that increased levels of TAFI and insufficient activation of fibrinolysis mediated through the actions of plasmin and neutrophil elastase are deeply involved in the development of organ dysfunction.