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Dysregulated innate immunity participates in the pathomechanisms of disseminated intravascular coagulation (DIC) in trauma-induced coagulopathy. Accidental and regulated cell deaths and neutrophil extracellular traps release damage-associated molecular patterns (DAMPs), such as histones, nuclear and mitochondrial DNA, and high-mobility group box 1, into circulation immediately after trauma. DAMP-induced inflammation activation releases tissue factor-bearing procoagulant extracellular vesicles through gasdermin D-mediated pore formation and plasma membrane rupture by regulated cell death. DAMPs also evoke systemic inflammation, platelet, coagulation activation, and impaired fibrinolysis associated with endothelial injury, leading to the dysfunction of anticoagulation systems, which are the main pathophysiological mechanisms of DIC. All these processes induce systemic thrombin generation in vivo, not restricted to the injury sites immediately after trauma. Thrombin generation at the site of injury stops bleeding and maintains homeostasis. However, DIC associated with endothelial injury generates massive thrombin, enhancing protease-activated, receptor-mediated bidirectional interplays between inflammation and coagulation, aggravating the diverse actions of thrombin and disturbing homeostasis. Insufficiently regulated thrombin causes disseminated microvascular thrombosis, resulting in tissue hypoxia due to reduced oxygen delivery, and mitochondrial dysfunction due to DAMPs causes tissue dysoxia. In addition, DAMP-induced calcium influx and overload, as well as neutrophil activation, play a role in endothelial cell injury. Tissue hypoxia and cytotoxicity result in multiple organ dysfunction in DIC after trauma. Controls against dysregulated innate immunity evoking systemic inflammation, thrombin generation, and cytotoxicity are key issues in improving the prognosis of DIC in trauma-induced coagulopathy., Competing Interests: Declaration of competing interest There are no competing interests to be disclosed., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Heat-related illness is becoming more problematic due to ongoing global warming. Heat-related injury causes systemic inflammation and coagulopathy, due to leukocyte, platelet, and vascular endothelial cell activation and injury. Hyperthermia directly modulates platelet function and can induce cellular damage. Meanwhile, heat also affects platelet function via activated coagulation, excess inflammation, production of cytokines, and heat shock proteins. Aberrant hyperthermia-induced interactions between leukocytes and endothelial cells are also involved in platelet regulation. Heat-induced coagulopathy commonly progresses to disseminated intravascular coagulation (DIC), leading to multiple organ failure and in some cases enhanced bleeding. Consequently, platelet count, prothrombin time, and DIC score are useful for evaluating the severity of heat-related illness in addition to other organ damage markers such as Glasgow Coma Scale, creatinine, and bilirubin. Despite the increasing risk, therapeutic modalities targeting platelets are limited and no established therapy exists. In this review, we summarize the current knowledge about the role of platelets in the pathogenesis, diagnosis, and management of heat-related illness., Competing Interests: Declaration of competing interest TI has received a research grant from Japan Blood Products Organization and JIMRO. JH has received grants from Diagnostica Stago, Pfizer PFE France and Sanofi Aventis France. ML has received grants and has participated in advisory boards of NovoNordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. JHL serves on the Steering Committees for Instrumentation Laboratories, Merck, and Octapharma., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying disease. Based on the dominant clinical phenotype, the current review differentiates between hemorrhagic coagulopathies, characterized by a hypocoagulable and hyperfibrinolysis state, and thrombotic coagulopathies with a systemic prothrombotic and antifibrinolytic phenotype. We discuss the differences in pathogenesis and treatment of the common coagulopathies., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Disseminated intravascular coagulation (DIC) is not a disease criterion but a pathomechanistic process that accompanies various underlying diseases. According to the International Society on Thrombosis and Haemostasis definition, endothelial injury is an essential component in addition to systemic coagulation activation. Despite this definition, current diagnostic criteria for DIC do not include biomarkers for vascular endothelial injury. Endothelial cells are critical for hemostatic regulation because they produce various antithrombotic substances and express anticoagulant factors at the same time as facilitating coagulation, inflammatory reactions, platelet aggregation, and fibrinolysis with acute injury. Endothelial cells also exhibit various receptors, adhesion molecules, and the critical role of glycocalyx that regulates cellular interactions in thromboinflammation. For clinicians, biomarkers suitable for assessing endothelial injury are not readily available. Although we still do not have ideal biomarkers, antithrombin activity and von Willebrand factor can be candidates for the endothelium-related markers because those reflect the severity and are available in most clinical settings. Further, the dysfunction of endothelial cell in DIC arising from various underlying diseases is likely highly variable. For example, the involvement of endothelial dysfunction is significant in sepsis-induced coagulopathy, while moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. Because of the complexity of disease status associated with DIC, further research searching clinically available endothelium-related biomarkers is expected to establish individualized diagnostic criteria and potential therapeutic approaches., Competing Interests: Declaration of competing interest statement T.I. participated on advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. J.H.L. serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. S.S. serves on the Steering or Advisory Committees for Sobi, Roche, CSL Behring, NovoNordisk, Takeda, LFB, and BioMarin. M.L. has received grants and has participated in advisory boards of NovoNordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. The other author has no conflict of interest., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Disseminated intravascular coagulation (DIC) is a life-threatening complication in sepsis and other critical conditions. The International Society on Thrombosis and Haemostasis (ISTH) released the diagnostic criteria for overt DIC in 2001. Since then, ISTH overt DIC has been used as the global standard criterion for a decompensated stage of DIC. Because detecting an earlier stage of DIC would be useful for therapeutic considerations, the scientific standardization committees of the ISTH introduced the sepsis-induced coagulopathy (SIC) scoring system in 2019. The SIC scoring system is specifically designed to detect the compensated phase of DIC in sepsis, which can lead to overt DIC with disease progression. Studies examining the performance of the SIC scoring system have reported its usefulness over the past 5 years. The reported incidence of SIC was approximately 60% in patients with sepsis, which was twice as much as that of overt DIC. Almost all patients with overt DIC were diagnosed with SIC earlier. The reported mortality of SIC was ≥30% and, thus, can be used for patient selection for anticoagulant therapy. Despite the limited data, some continue to suggest the potential efficacy of anticoagulant therapy in patients with SIC. Although heparin, antithrombin, and thrombomodulin are the candidates for anticoagulation, none of them have proven to be effective with robust evidence, and future trials are warranted., Competing Interests: Declaration of competing interest T. Iba participated on the advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. M. Levi has received grants and has participated on the advisory boards of Novo Nordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. J. Helms has received honoraria from Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, MSD, Shionogi, and Inotrem. J. H. Levy serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. E. Scarlatescu has received speaker fees from CSL Behring. J. Thachil has no competing interests to disclose., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC., Competing Interests: T.I. participated in advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. J.H.L. serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. The other authors have no conflict of interest., (Thieme. All rights reserved.)

Competing Interests: None.

Background: Disseminated intravascular coagulation (DIC), a systemic activation of coagulation, presents with multiple clinical and laboratory manifestations. In this International Society on Thrombosis and Haemostasis (ISTH) communication, we examined the importance of identifying the underlying disorder causing DIC to help physicians in the diagnosis and management of this common and severe condition., Methods: Eight DIC experts participated in a three-step consensus process that searched for published guidelines and diagnostic scores on DIC to create a preliminary list of DIC underlying disorders from those reported in the literature Overall, 13 papers were identified, including three guidelines, one harmonization paper by the ISTH, one ISTH recommendation paper on cancer-associated DIC, five general diagnostic scores, two scores specific for pregnancy, and one specific for children. We then assessed the strength of the evidence on the association between the disease and DIC as many postulated DIC-associated disorders are rare., Key Results: Eight main subgroups - 'severe infection', 'solid tumour', 'haematological neoplasia', 'pregnancy complication', 'vascular disease', 'newborn-complication', 'tissue damage due to internal or external insult', and 'chemical and biological agent' - and a detailed list of specific causes of DIC were provided., Conclusions & Inferences: Our results suggest more data are needed to determine the association between DIC and specific diseases such as malignant lymphoma, colorectal cancer, or vasculitis, for which the evidence remains limited. When a patient develops a coagulopathy consistent with DIC, the first step is to immediately search for an underlying disorder, including specific causes that are rarely associated with DIC and to consider that patients may have more than one cause of DIC to identify the principal precipitating disorder to prioritize treatment., (© 2020 International Society on Thrombosis and Haemostasis.)

Competing Interests: Declaration of Competing Interest The author declares that there are no conflicts of interests.

The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain., (© 2020 International Society on Thrombosis and Haemostasis.)

Cancer often leads to the activation of coagulation, manifesting as disseminated intravascular coagulation (DIC) in its most extreme form. DIC is characterized by systemic intravascular coagulation activation (leading to deposition of intravascular platelets and fibrin) and simultaneous consumption of coagulation proteins and thrombocytes (which may cause bleeding complications). The clinical course of DIC in patients with malignancies is typically less intense compared with DIC complicating alternative clinical settings, including systemic inflammatory responses following infection or traumatic injury. A more slowly proceeding, less fulminant, and widespread hemostatic derangement can remain asymptomatic. Eventually, the ongoing consumption may result in low levels of platelets and coagulation factors, and bleeding complications (frequently localized at the site of the tumor or distant metastases) may be the first clinical manifestation of DIC. An alternative clinical scenario is dominated by thrombotic complications, ranging from clinically manifest vascular thrombosis to microvascular platelet plugs. The main principle of DIC management is adequate treatment of the precipitating disorder; however, there are clinical presentations that may require additional supportive strategies specifically aimed at the amelioration of the coagulopathy., Competing Interests: The author has no conflicts of interest concerning the contents to report., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Sepsis may be associated with activation of the coagulation system and, in its most severe form, may result in disseminated intravascular coagulation (DIC). Initially, there is thrombosis primarily affecting small and medium sized vessels and contributing to organ dysfunction, but continued activation results in consumption of coagulation factors. This results in prolongation of global coagulation parameters. Often thrombocytopenia is the initial feature in sepsis, which may be followed by prolongation of global coagulation assays, and in severe cases, associated with hypofibrinogenaemia, with overactivation of the fibrinolytic path. The end result is a bleeding phenotype. Scoring systems can be used to help identify patients at risk of DIC and aid in confirming a diagnosis of DIC utilising routine laboratory parameters. Discussion includes medical and blood product support of haemostasis, from thrombotic to bleeding states, in relation to sepsis trigger., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

The delicate biochemistry of coagulation and anticoagulation is greatly affected by deviations from the optimal temperature required for the interactions between various coagulation enzymes, cellular receptors, and intracellular mechanisms. Hyperthermia will lead to a prothrombotic state and, if sufficiently severe such as in heatstroke, a consumption coagulopathy, which will clinically manifest with the simultaneous appearance of intravascular thrombotic obstruction and an increased bleeding tendency. Hypothermia slows down the coagulation process, but as this seems to be adequately balanced by impairment of anticoagulant and fibrinolytic processes, its clinical effects are modest; however, hypothermia may be modestly linked to a somewhat higher risk of localized thrombosis. Restoration of a normal body temperature in patients affected by hyper- or hypothermia is the cornerstone for the management of associated coagulation derangements., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Activation of the hemostatic system can occur in many clinical conditions. However, a systemic and strong activation of coagulation complicating clinical settings such as sepsis, trauma or malignant disease may result in the occurrence disseminated intravascular coagulation (DIC). Areas covered: This article reviews the clinical manifestation and relevance of DIC, the various conditions that may precipitate DIC and the pathogenetic pathways underlying the derangement of the hemostatic system, based on clinical and experimental studies. In addition, the (differential) diagnostic approach to DIC is discussed. Expert commentary: In recent years a lot of precise insights in the pathophysiology of DIC have been uncovered, leading to a better understanding of pathways leading to the hemostatic derangement and providing points of impact for better adjunctive treatment strategies. In addition, simple diagnostic algorithms have been developed and validated to establish a diagnosis of DIC in clinical practice.

Malignant disease can be complicated by disseminated intravascular coagulation (DIC). DIC is defined as systemic intravascular triggering of coagulation (resulting in intravascular fibrin clot formation) and concurrent depletion of clotting factors and platelets (increasing the risk of hemorrhage). The clinical presentation of DIC in patients with cancer has usually a less fulminant presentation than DIC that may accompany other underlying disorders, such as sepsis and trauma. A more insidious, but also more protracted, diffuse activation of coagulation can proceed without any symptom. Ultimately this may lead to deficiency of platelets and clotting factors and hemorrhage (often at the site of the tumor or metastases) may be the first clinical symptom indicating the presence of DIC. An alternative presentation may be thrombosis, ranging from overt venous thrombo-embolism to microvascular disease and thrombotic microangiopathy. The therapeutic foundation of DIC is management of the underlying condition but in some cases supportive interventions, specifically targeting the hemostatic system may be needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Disseminated intravascular coagulation (DIC) is a condition characterized by systemic activation of coagulation, potentially leading to thrombotic obstruction of small and midsize vessels, thereby contributing to organ dysfunction. At the same time, ongoing consumption of platelets and coagulation proteins results in thrombocytopenia and low concentrations of clotting factors, which may cause profuse hemorrhagic complications. DIC is always secondary to an underlying condition, such as severe infections, solid or hematologic malignancies, trauma, or obstetric calamities. A reliable diagnosis of DIC can be made through simple scoring algorithms based on readily available routine hemostatic parameters. The cornerstone of supportive treatment of this coagulopathy is management of the underlying condition. Additionally, administration of heparin may be useful, and restoration of physiological anticoagulants has been suggested, but has not been proven successful in improving clinically relevant outcomes so far. In patients with major bleeding or at risk for hemorrhagic complications, administration of platelet concentrates, plasma, or coagulation factor concentrates should be considered., (© 2018 by The American Society of Hematology.)

Severe sepsis is almost invariably associated with systemic activation of coagulation. There is ample evidence that demonstrates a wide-ranging cross-talk between hemostasis and inflammation, which is probably implicated in the pathogenesis of organ dysfunction in patients with sepsis. Inflammation not only leads to initiation and propagation of coagulation activity, but coagulation also markedly influences inflammation. Molecular mechanisms that play a role in inflammation-induced effects on coagulation have been recognized in much detail. Pro-inflammatory cells and cyto- and chemokines can activate the coagulation system and downregulate crucial physiological anticoagulant mechanisms. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and endothelial cells and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Increased fibrin generation and impaired break down lead to deposition of (micro)vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. The foundation of the management of coagulation in sepsis is the explicit and thorough treatment of the underlying disorder by antibiotic treatment and source control measures. Adjunctive strategies focused at the impairment of coagulation, including anticoagulants and restoration of physiological anticoagulant mechanisms, may supposedly be indicated and have been found advantageous in experimental and initial clinical trials., (Copyright © 2016. Published by Elsevier Ltd.)

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation that can be caused by infectious insults (such as sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient control of anticoagulant pathways and plasminogen activator inhibitor 1-mediated suppression of fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent observations have pointed to an important role for extracellular DNA and DNA-binding proteins, such as histones, in the pathogenesis of DIC. The International Society on Thrombosis and Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test parameters. This scoring system has now been well validated in diverse clinical settings. The theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH guidance for the treatment of DIC recommends treatment strategies that are based on current evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and management of DIC and discuss the future directions of basic and clinical research in this field.

The cornerstone of the management of disseminated intravascular coagulation (DIC) is the treatment of the underlying condition triggering the coagulopathy. However, a number of uncertainties remain over the optimal supportive treatment. The aim of this study was to provide evidence and expert-based recommendations on the optimal supportive haemostatic and antithrombotic treatment strategies for patients with DIC. A working group defined five relevant clinical scenarios. Published studies were systematically searched in the MEDLINE and EMBASE databases (up to May 2014). Seven internationally recognised experts were asked to independently provide clinical advice. A two-phase blinded data collection technique was used to reach consensus. Only three randomised controlled trials (RCTs) on the supportive management of DIC were identified. The RCTs (overall less than 100 patients) investigated the use of fresh frozen plasma and platelet transfusion and found no differences in survival between the intervention and control groups. The experts' approach was heterogeneous, although there was consensus that supportive management should vary according to the underlying cause, clinical manifestations and severity of blood test abnormalities. Platelet transfusion should be given to maintain platelet count > 50×10⁹/l in case of bleeding while a lower threshold of 20 to 30×10⁹/l may be used in DIC without bleeding. Thromboprophylaxis with low-molecular-weight heparin is advised until bleeding ensues or platelet count drops below 30×10⁹/l. In conclusion, in the absence of solid evidence from RCTs, an individualised supportive management of DIC is advisable based on the type of underlying disease, presence of bleeding or thrombotic complications and laboratory tests results.

Many humoral and cellular components participate in bidirectional communication between the coagulation and inflammation pathways. Natural anticoagulant proteins, including antithrombin (AT), tissue factor pathway inhibitor, and protein C, suppress proinflammatory mediators. Conversely, inflammation blunts anticoagulant activity and, when uncontrolled, promotes systemic inflammation-induced coagulation, such as those that occur in disseminated intravascular coagulation and severe sepsis. This review discusses the mechanisms of action and clinical use of AT concentrate in critically ill patients and in the settings of perioperative anticoagulation management for surgery and obstetrics. AT is a serine protease inhibitor with broad anticoagulant activity and potent anti-inflammatory properties. In clinical conditions associated with hereditary or acquired AT deficiency, administration of AT concentrate has been shown to restore proper haemostasis and attenuate inflammation. Of note, AT modulates inflammatory responses not only by inhibiting thrombin and other clotting factors that induce cytokine activity and leukocyte-endothelial cell interaction, but also by coagulation-independent effects, including direct interaction with cellular mediators of inflammation. An increasing body of evidence suggests that AT concentrate may be a potential therapeutic agent in certain clinical settings associated with inflammation. In addition to the well-known anticoagulation properties of AT for the treatment of hereditary AT deficiency, AT also possesses noteworthy anti-inflammatory properties that could be valuable in treating acquired AT deficiency, which often result in thrombotic states associated with an inflammatory component.

Cancer may be complicated by the occurrence of disseminated intravascular coagulation (DIC). DIC is characterized by a widespread and intravascular activation of coagulation (leading to intravascular fibrin deposition) and simultaneous consumption of coagulation factors and platelets (potentially resulting in bleeding). Clinically, DIC in cancer has in general a less fulminant presentation than the types of DIC complicating sepsis and trauma. A more gradual, but also more chronic, systemic activation of coagulation can proceed subclinically. Eventually this process may lead to exhaustion of platelets and coagulation factors and bleeding (for example at the site of the tumor) may be the first clinical symptom indicating the presence of DIC. In some cases, the clinical presentation of DIC in cancer may be reminiscent of thrombotic microangiopathies, which is understandable in view of the role of endothelium in both conditions. The therapeutic cornerstone of DIC is treatment of the underlying disorder but supportive treatment, specifically aimed at the hemostatic system may be required., (© 2016 Elsevier Ltd. All rights reserved.)

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to a widespread deposition of fibrin in the circulation. There is ample experimental and pathological evidence that the fibrin deposition contributes to multiple organ failure. The massive and ongoing activation of coagulation may result in depletion of platelets and coagulation factors, which may cause bleeding (consumption coagulopathy). The syndrome of DIC is well known in the medical literature for centuries, although a more precise description of the underlying mechanisms had to await the 20th century. Initial ideas on a role of the contact activation system as the primary trigger for the systemic activation of coagulation as well as a presumed hyperfibrinolytic response in DIC have been found to be misconceptions. Experimental and clinical evidence now indicate that the initiation of coagulation in DIC is caused by tissue factor expression, which in combination with downregulated physiological anticoagulant pathways and impaired fibrinolysis leads to widespread fibrin deposition. In addition, an extensive bidirectional interaction between coagulation and inflammation may further contribute to the pathogenesis of DIC., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation., Design: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial., Setting: Two hundred and thirty-three ICUs in 17 countries., Patients: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score., Interventions: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity., Measurements and Main Results: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline., Conclusions: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

The diagnosis of disseminated intravascular coagulation (DIC) based on composite scoring systems using routinely available coagulation tests has been greatly facilitated. Such scoring instruments not only adequately assess the presence of DIC but also have strong prognostic power for morbidity and mortality. In this issue of Critical Care, Gando and colleagues report on the prospective validation of the Japanese Association of Acute Medicine score for DIC in patients with severe sepsis.

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to widespread deposition of fibrin in the circulation. Recent knowledge on important pathogenetic mechanisms that may lead to DIC has resulted in novel preventive and therapeutic approaches to patients with DIC. The diagnosis of DIC can be made by sensitive laboratory tests; however, most of these tests are not readily available in a clinical setting. A reliable diagnosis can also be made on the basis of a small series of laboratory tests that can be combined in a scoring algorithm. The cornerstone of the management of DIC is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways.

Acute coagulopathic peripartum calamities are relatively rare but contribute importantly to maternal morbidity and mortality in the Western world. Abruptio placenta, amniotic fluid embolism, and retained fetal or placental material may lead to fulminant intravascular activation of coagulation which results in thromboembolic complications and consumption coagulopathy causing severe hemorrhage. The central underlying pathophysiological pathway in the coagulopathy associated with these syndromes is the occurrence of tissue factor, released from the placenta and amniotic fluid, in the circulation, in combination with low levels of physiological anticoagulant factors during pregnancy. The diagnosis of DIC may be made trough conventional composite scoring systems employing routine coagulation tests, whereas for the diagnosis of amniotic fluid embolism measurement of insulin like growth factor binding protein-1 seems promising. Therapy is aimed at removing the precipitating factor combined with supportive adjunctive treatment options., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In patients with disseminated intravascular coagulation (DIC) a variety of altered coagulation parameters may be detectable, such as thrombocytopenia, prolonged global coagulation times, reduced levels of coagulation inhibitors, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. There is not a single test, however, that is sufficiently accurate to establish or reject a diagnosis of DIC. Nevertheless, a combination of widely available tests may be helpful in making the diagnosis of DIC and can also be helpful to guide in the selection of DIC patients that require specific, often expensive, interventions in the coagulation system. More recently developed dynamic algorithms, assessing changes in coagulation parameters over sequential days, could further increase the diagnostic accuracy for DIC and may be helpful to detect early stages of coagulopathy potentially evolving into DIC., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. Systemic inflammation as a result of severe infection leads to activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the results of the treatment of severe systemic infection with modulators of coagulation and inflammation., (Copyright Thieme Medical Publishers.)

Disseminated intravascular coagulation (DIC) is a syndrome that may complicate a variety of diseases, including malignant disease. DIC is characterized by widespread, intravascular activation of coagulation (leading to intravascular fibrin deposition) and simultaneous consumption of coagulation factors and platelets (potentially resulting in bleeding). Clinically, DIC in cancer has, in general, a less fulminant presentation than the types of DIC complicating sepsis and trauma. A more gradual, but also more chronic, systemic activation of coagulation can proceed subclinically. Eventually, this process may lead to exhaustion of platelets and coagulation factors, and bleeding (e.g. at the site of the tumour) may be the first clinical symptom indicating the presence of DIC. In some cases, the clinical presentation of DIC in cancer may be reminiscent of thrombotic microangiopathies, which is understandable in view of the role of the endothelium in both conditions. The therapeutic cornerstone of DIC is treatment of the underlying disorder, but supportive treatment specifically aimed at the haemostatic system may be required.

Sepsis is often associated with systemic intravascular activation of coagulation, potentially leading to widespread microvascular deposits of fibrin, and thereby contributing to multiple organ dysfunction. A complex interaction exists between activation of inflammatory systems and the initiating and regulating pathways of coagulation. A diagnosis of sepsis-associated disseminated intravascular coagulation can be made by a combination of routinely available laboratory tests, for which simple diagnostic algorithms have become available. Strategies to inhibit coagulation activation may theoretically be justified and are being evaluated in clinical studies.

Critically ill patients often have systemic activation of both inflammatory systems and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut off by proinflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa, and thrombin, can bind to protease-activated receptors on various cells, and the ensuing intracellular signaling leads to increased production of proinflammatory cytokines and chemokines. Activated protein C can bind to the protein C receptor on endothelial cells and mononuclear cells, thereby affecting NF-kappaB nuclear translocation and subsequently influencing inflammatory gene expression and inhibition of tissue factor expression on mononuclear cells. Observations in experimental models of targeted disruption of the protein C gene and restoration of the downregulated protein C pathway by administration of recombinant activated protein C support this notion.

Background: Coagulopathy is present at admission in 25% of trauma patients, is associated with shock and a 5-fold increase in mortality. The coagulopathy has recently been associated with systemic activation of the protein C pathway. This study was designed to characterize the thrombotic, coagulant and fibrinolytic derangements of trauma-induced shock., Methods: This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of partial thromboplastin and prothrombin times, prothrombin fragments 1 + 2 (PF1 + 2), fibrinogen, factor VII, thrombomodulin, protein C, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator (tPA), and D-dimers. Base deficit was used as a measure of tissue hypoperfusion., Results: Two hundred eight patients were studied. Systemic hypoperfusion was associated with anticoagulation and hyperfibrinolysis. Coagulation was activated and thrombin generation was related to injury severity, but acidosis did not affect Factor VII or PF1 + 2 levels. Hypoperfusion-induced increase in soluble thrombomodulin levels was associated with reduced fibrinogen utilization, reduction in protein C and an increase in TAFI. Hypoperfusion also resulted in hyperfibrinolysis, with raised tPA and D-Dimers, associated with the observed reduction in PAI-1 and not alterations in TAFI., Conclusions: Acute coagulopathy of trauma is associated with systemic hypoperfusion and is characterized by anticoagulation and hyperfibrinolysis. There was no evidence of coagulation factor loss or dysfunction at this time point. Soluble thrombomodulin levels correlate with thrombomodulin activity. Thrombin binding to thrombomodulin contributes to hyperfibrinolysis via activated protein C consumption of PAI-1.

Objective: To review the current knowledge on the clinical manifestation, pathogenesis, diagnosis, and management of disseminated intravascular coagulation (DIC)., Data Source: Selected articles from the MEDLINE database., Data Synthesis: DIC may complicate a variety of disorders and can cause significant morbidity (in particular related to organ dysfunction and bleeding) and may contribute to mortality. The pathogenesis of DIC is based on tissue factor-mediated initiation of systemic coagulation activation that is insufficiently contained by physiologic anticoagulant pathways and amplified by impaired endogenous fibrinolysis. The diagnosis of DIC can be made using routinely available laboratory tests and scoring algorithms. Supportive treatment of DIC may be aimed at replacement of platelets and coagulation factors, anticoagulant treatment, and restoration of anticoagulant pathways., Conclusions: Insight into the pathogenesis of DIC has resulted in better strategies for clinical management, including straightforward diagnostic criteria and potentially beneficial supportive treatment options.

A variety of clinical conditions can cause systemic activation of coagulation that ranges from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). DIC consists of a widespread systemic activation of coagulation, resulting in diffuse fibrin deposition in small and midsize vessels. There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation can result in depletion of platelets and coagulation factors, which might cause bleeding. Recent insight into important pathogenetic mechanisms that might lead to DIC has resulted in novel preventive and therapeutic approaches to patients with sepsis and derangement of coagulation. Supportive strategies aimed at inhibition of coagulation activation might theoretically be justified and have been found beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways.

Disseminated intravascular coagulation (DIC) is a syndrome characterized by a systemic activation of coagulation leading to the intravascular deposition of fibrin in the (micro) vasculature and the simultaneous consumption of coagulation factors and platelets. The occurrence of microvascular thrombosis as a consequence of DIC is underscored by pathological, experimental and clinical findings, demonstrating a link between DIC and organ dysfunction. Pathogenetic pathways that play a role in the development of DIC include tissue factor-dependent activation of coagulation, defective physiological anticoagulant pathways (such as the antithrombin system and the protein C system), and impaired fibrinolysis, caused by elevated levels of plasminogen activator inhibitor type 1. Novel therapeutic strategies are based on current insights into the pathogenesis of DIC, and include anticoagulant strategies (eg, directed at tissue factor) and strategies to restore physiological anticoagulant pathways (such as activated protein C concentrate).

Objectives: A diagnosis of disseminated intravascular coagulation (DIC) is hampered by the lack of an accurate diagnostic test. Based on the retrospective analysis of studies in patients with DIC, a scoring system (0-8 points) using simple and readily available routine laboratory tests has been proposed. The aim of this study was to prospectively validate this scoring system and assess its feasibility, sensitivity, and specificity in a consecutive series of intensive care patients., Design: Prospective cohort of intensive care patients., Setting: Adult intensive care unit in a tertiary academic center., Patients: Consecutive patients with a clinical suspicion of disseminated intravascular coagulation., Interventions: Patients were followed during their admission to the intensive care unit, and the DIC score was calculated every 48 hrs and compared with a "gold standard" based on expert opinion. In addition, an activated partial thromboplastin time (aPTT) waveform analysis, which has been reported to be a good predictor for the absence or presence of DIC, was performed., Measurements and Main Results: We analyzed 660 samples from 217 consecutive patients. The prevalence of DIC was 34%. There was a strong correlation between an increasing DIC score and 28-day mortality (for each 1-point increment in the DIC score, the odds ratio for mortality was 1.25). The sensitivity of the DIC score was 91% and the specificity 97%. An abnormal aPTT waveform was seen in 32% of patients and correlated well with the presence of DIC (sensitivity 88%, specificity 97%). In 19% of patients, the aPTT waveform-based diagnosis of DIC preceded the diagnosis based on the scoring system., Conclusions: A diagnosis of DIC based on a simple scoring system, using widely available routine coagulation tests, is sufficiently accurate to make or reject a diagnosis of DIC in intensive care patients with a clinical suspicion of this condition. An aPTT waveform analysis is an interesting and promising tool to assist in the diagnostic management of DIC.