Understanding the diverse and opposing thrombin-orchestrated effects is important in judging and refining management approaches when the fine homeostatic balance of normal thrombin generation is lost in DIC. Thrombin is typically associated with procoagulant properties in cleaving fibrinogen into fibrin and also activating platelets, on which tenase (FIXa/VIIIa) and prothrombinase (FXa/Va) complexes assemble to propagate coagulation [5]. Conversely, thrombin also has anticoagulant properties through thrombomodulin (TM)-dependent protein C (PC) activation, and these mechanisms are well reviewed elsewhere [6]. Equally, thrombin is also pivotal in affecting opposing aspects of fibrinolysis, i.e., promoting through stimulating endothelial cell release of tissue plasminogen activator (tPA) [7] to generate plasmin, and conversely, inhibiting through plasminogen activator inhibitor 1 (PAI-1) [8] induction and thrombin-activatable fibrinolysis inhibitor (TAFI) activity [9]. Whilst the DIC process could consume these different pathway components proportionately, the triggering pathology can influence the rate of thrombin generation and direct its function [10]. One example of disease-specific tailoring of DIC is the significantly more intense coagulant response in early trauma. Together with the extensiveness of endothelial cell activation, the excessive surge in thrombin leads to overdrive of tPA-triggered fibrinolysis and indiscriminate fibrin(ogen)olysis, as observed in a baboon model of DIC following blockade of the PC anticoagulant pathway to enhance thrombin generation [11].

Cell surfaces and site-specific vascular endothelial features control the processes consequent to thrombin generation [12]. The microvasculature is particularly affected in DIC because of its higher endothelial-cell surface to blood volume ratios [13]. Receptors of the PC pathway, i.e., the endothelial PC receptor (EPCR) and TM, are among the most relevant as both have direct pleiotropic effects on coagulation and inflammation. Activated protein C (APC) when bound to EPCR can directly cleave and activate protease-activated receptor 1 (PAR1) to generate anti-inflammatory, antiapoptotic, and endothelial-barrier-protective effects [14]. These are directly opposite to those generated by thrombin on PAR1 and exemplify the yin-yang balance between thrombin and APC in harmonizing the coagulation and inflammatory processes at the blood-endothelial interface [6]. The lectinlike domain of TM has been implicated in reducing the proinflammatory effects of high-mobility group box protein 1 (HMGB1) released from the nucleus [15]. Consequently, loss of EPCR and TM through receptor shedding or endothelial down-regulation in microvessels with low constitutive expression could shift the thrombin–PC axis toward site-specific thrombosis and barrier destabilization. This has been reported in cerebral malaria with DIC [16], especially as Plasmodium falciparum-infected erythrocytes bind EPCR to reduce APC generation [1718].

Significant cross-talk between these components with the coagulant response has been increasingly characterized as immunothrombosis [1920]. With cell damage and death common to all the causes of DIC, there is triggering of damage-associated molecular patterns (DAMPs) leading to promotion of thrombin generation [21]. Cross-activation of pathways such as the complement system [22] results in reciprocal escalation causing further cell damage and an increased release of nuclear breakdown products, such as histone-DNA complexes (nucleosomes) and double-stranded DNA [23]. Elevated circulating histone levels occur in patients with DIC [24], and mechanistically, they bind phospholipid surfaces to damage cell membranes [2526]. Functional consequences include platelet aggregation and thrombocytopenia [27], thrombi that are more resistant to lysis [28], and vascular leakage as well as a release of proinflammatory cytokines and extracellular traps from leucocytes, especially neutrophils [25]. Referred to as neutrophil extracellular traps (NETs), these are prothrombotic [29] by providing a scaffold for assembling clot components including tissue factor, degrading tissue factor pathway inhibitor (TFPI), and histone-dependent Factor VII-activating protease activity [30] as well as a platelet polyphosphate release [31]. In addition to suppressing TM-dependent PC activation [32], histone 4 can induce prothrombin autoactivation in vitro [33]. Such a mechanism would generate thrombin independently of activation of the coagulation cascade if present in vivo. The infusion of histones in experimental models leads to DIC with the spectrum of hemorrhage and microvascular thrombosis [2425]. Blocking histones reduces thrombin generation [25] and ameliorates cardiac dysfunction and acute lung injury in murine models of sepsis [34] and trauma [25], respectively.

DIC is a clinical-laboratory diagnosis, and laboratory changes need to be interpreted with knowledge of the patient's underlying disorder [35]. In a relevant clinical scenario, several laboratory parameters are analyzed together as part of a diagnostic algorithm that includes prothrombin time (PT), activated partial thromboplastin time (aPTT), the platelet count, fibrinogen level, and a marker of fibrin degradation, e.g., D-dimer or the soluble fibrin monomer (SFM) [35]. None of these markers are taken in isolation, and a combination of results at different time points is particularly helpful in determining the presence of DIC (Table 1). It must also be emphasized that certain profiles may be more indicative of certain pathological mechanisms, e.g., hyperfibrinolysis is typically characterized by very low fibrinogen levels with very high concentrations of FDPs.

The ISTH scoring system of routine global coagulation tests provides a framework for diagnosing DIC that also standardizes criteria for clinical studies. This is now well validated in different settings, and a cumulative score of 5 or more from increased PT, reduced platelet counts and fibrinogen levels, together with elevated FDPs forming the basis of our approach [36]. There are country-specific refinements [37], which similarly confirm the independent prediction of mortality by the ISTH DIC score and its added prognostic value to the Acute Physiology and Chronic Health Evaluation (APACHE) II system [438]. Specific caveats for the individual parameters are discussed in the sections below, and our practice relies on a high index of suspicion for increasing abnormalities, with particular emphasis on serial monitoring. Conceptually, this is encapsulated as "nonovert DIC" by the ISTH, where subtle hemostatic dysfunction could provide forewarning of an overt DIC process [3]. Indeed, several studies have shown how scoring for abnormal trends in PT, platelets, and/or D-dimer has identified patients deteriorating clinically with new organ failure [394041]. Clinicians and laboratory staff who are caring for critically ill patients with disorders that can potentially trigger DIC (e.g., sepsis, trauma, malignancy, and certain obstetrical conditions) should be vigilant to this aspect of management. The presence of "normal" values for PT, platelets, and/or D-dimers in such patients upon admission should not mean the end of monitoring of these parameters. Awareness of the possibility of DIC should trigger serial monitoring of these parameters, and other measurements may be requested to confirm nonovert DIC (see the section below). This strategy provides a safeguard for the early recognition of DIC in such patients, with a major impact on management and prognosis.

There are certain caveats in interpreting results from the recommended tests:

Significant reductions in these endogenous anticoagulants correlate with DIC severity and adverse outcomes [606162]. However, their sensitivity for early DIC is unclear as DIC is usually obvious from the global coagulation tests when levels are below 50% of normal [61]. Indeed, worsening trends in PT, platelets, and _D-dimer provide sufficient robustness without needing PC or AT levels [39]. Large clinical studies have also shown that it is not PC/AT but PT and D-dimer changes that significantly relate to mortality when analyzed as continuous variables [41].

With automation of theomboelastography (TEG) to provide point-of-care assessment of coagulation, there is a potential for real-time assessment of a more comprehensive picture of the hemostatic condition [63]. In DIC, Sivula et al [64] identified hypocoagulation in patients with overt DIC, while those without DIC showed hypercoagulation. However, both hyper- and hypocoagulability TEG changes have been linked with adverse clinical events in DIC-relevant diseases [65], and a systematic review of TEG in sepsis confirmed this variability [66]. Often, the values fall within normal reference ranges, and the overall superiority of these tests over conventional tests in DIC has not been proven. Only in cardiac surgery is the use of TEG sufficiently cost and clinically effective. As such, we do not routinely use TEG in DIC and await results from large prospective trials.

With the increasing relevance of DAMPs in the cross-talk among coagulation, inflammation, and innate immunity, levels of circulating histones and histone-DNA complexes as well as double-stranded cell-free DNA could have translational relevance in patients with DIC. In 199 patients with suspected DIC, histone–DNA complexes and cell-free DNA levels correlated with the severity of DIC scores [23]. Levels were also significantly higher in nonsurvivors as compared to survivors. As to circulating histones, their direct infusion into mice at high doses induces features of DIC [24]. However, no clinical studies have yet shown their value as diagnostic or prognostic markers in human DIC. Future work is therefore warranted.