Coagulofibrinolytic Changes in Patients with Post-cardiac Arrest Syndrome

Abstract

Whole-body ischemia and reperfusion due to cardiac arrest and subsequent return of spontaneous circulation constitute post-cardiac arrest syndrome (PCAS), which consists of four syndromes including systemic ischemia/reperfusion responses and post-cardiac arrest brain injury. The major pathophysiologies underlying systemic ischemia/reperfusion responses are systemic inflammatory response syndrome and increased coagulation, leading to disseminated intravascular coagulation (DIC), which clinically manifests as obstruction of microcirculation and multiple organ dysfunction. In particular, thrombotic occlusion in the brain due to DIC, referred to as the "no-reflow phenomenon," may be deeply involved in post-cardiac arrest brain injury, which is the leading cause of mortality in patients with PCAS. Coagulofibrinolytic changes in patients with PCAS are characterized by tissue factor-dependent coagulation, which is accelerated by impaired anticoagulant mechanisms, including antithrombin, protein C, thrombomodulin, and tissue factor pathway inhibitor. Damage-associated molecular patterns (DAMPs) accelerate not only tissue factor-dependent coagulation but also the factor XII- and factor XI-dependent activation of coagulation. Inflammatory cytokines are also involved in these changes via the expression of tissue factor on endothelial cells and monocytes, the inhibition of anticoagulant systems, and the release of neutrophil elastase from neutrophils activated by inflammatory cytokines. Hyperfibrinolysis in the early phase of PCAS is followed by inadequate endogenous fibrinolysis and fibrinolytic shutdown by plasminogen activator inhibitor-1. Moreover, cell-free DNA, which is also a DAMP, plays a pivotal role in the inhibition of fibrinolysis. DIC diagnosis criteria or fibrinolysis markers, including d-dimer and fibrin/fibrinogen degradation products, which are commonly tested in patients and easily accessible, can be used to predict the mortality or neurological outcome of PCAS patients with high accuracy. A number of studies have explored therapy for this unique pathophysiology since the first report on "no-reflow phenomenon" was published roughly 50 years ago. However, the optimum therapeutic strategy focusing on the coagulofibrinolytic changes in cardiac arrest or PCAS patients has not yet been established. The elucidation of more precise pathomechanisms of coagulofibrinolytic changes in PCAS may aid in the development of novel therapeutic targets, leading to an improvement in the outcomes of PCAS patients.

Keywords: activation of coagulation; disseminated intravascular coagulation; fibrinolytic shutdown; impaired anticoagulant; no-reflow phenomenon; post-cardiac arrest syndrome; systemic ischemia/reperfusion.

Figure 1

A schematic illustration of the coagulofibrinolytic changes in patients with PCAS. Systemic ischemia/reperfusion leads to the activation of coagulation by the induction of TF on monocytes and endothelial cells, ultimately resulting in thrombin burst. DAMPs, including cfDNA, histones, and HMGB1, play a crucial role in the generation of thrombin via both TF-dependent pathways and XII-dependent pathways. The binding of thrombin to PARs produces several cytokines, which subsequently upregulate the expression of TF on endothelial cells and monocytes. Decreased levels of protein C and AT in circulation and reductions in AT, TM, TFPI, and EPCR on endothelial cells, which are caused by downregulation due to hypoxia and inflammatory cytokines and cleavage from the endothelium, are involved in the impairment of anticoagulant system. NE and the DAMP-mediated inhibition of the anticoagulant pathway also lead to the deterioration of the anticoagulant activity. t-PA is released from endothelial cells in the early phase of PCAS. PAI-1 increases 24 h after the onset of PCAS and keeps increasing in the late phase of PCAS, resulting in “no-reflow,” multiple organ dysfunction, and poor outcome. High concentrations of cfDNA also reduce the rate of fibrinolysis by competing for plasmin with fibrin. TM, thrombomodulin; PC, protein C; APC, activated protein C; EPCR, endothelial protein C receptor; AT, antithrombin; TFPI, tissue factor pathway inhibitor; PARs, protease-activated receptors; TF, tissue factor; HMGB1, high-mobility group box 1 protein; cfDNA, cell-free DNA; NE, neutrophil elastase; NETs, neutrophil extracellular traps; HMWK, high-molecular-weight kininogen; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue-type plasminogen activator; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; IX, factor IX; IXa, activated factor IX; X, factor X; Xa, activated factor X; XI, factor XI; XIa, activated factor XI; XII, factor XII; XIIa, activated factor XII; PCAS, post-cardiac arrest syndrome; DAMP, damage-associated molecular pattern. This figure was created by author.

Figure 2

Chronological changes in the coagulofibrinolytic status of patients with post-cardiac arrest syndrome. The vertical axis shows the increases from the values of control subjects (times). A, thrombin activity; B, plasmin activity; C, tissue-type plasminogen activator activity; D, plasminogen activator inhibitor-1 activity; E, neutrophil elastase-mediated fibrinolytic activity.

Figure 3

Serial changes in soluble fibrin (A) (a marker of thrombin activation) and plasmin-α2 plasmin inhibitor complex (PPIC) (B) (a marker of plasmin activation). Thirteen patients with post-cardiac arrest syndrome (PCAS) caused by cardiogenic cardiac arrest (black bars) and 13 patients with PCAS caused by hypoxia-related cardiac arrest were enrolled. The white bars represent control subjects (healthy adult). All results were expressed as the mean ± SEM. ⁺p < 0.05 vs control subjects, *p < 0.05 cardiogenic group vs hypoxia group.