Disseminated intravascular coagulation is a severe condition that is characterized by widespread coagulation and bleeding. Explain how the disease is initiated and describe its progression. Activation through the extrinsic pathway occurs with liberation of tissue factors, associated with obstetric complications, trauma, bacterial sepsis, and cancers. Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intravascular coagulation (DIC).
Part of the following topical collections:.AbstractSepsis is frequently complicated by coagulopathy and, in about 35% of severe cases, by disseminated intravascular coagulation (DIC). In Japan, aggressive treatment of septic DIC is encouraged using antithrombin and recombinant thrombomodulin. The macrophages, monocytes, and neutrophils are a source of TF and participate in the direct activation of the coagulation cascade in the early phases of sepsis. And activated factor X (FXa), which is involved in hemostasis, thrombogenesis, inflammation, and cellular immune responses, induces TF expression in human peripheral monocytes and, conversely, that inhibition of FXa activity reduces TF expression. Both inflammation and coagulation play an important role in DIC due to sepsis. In addition to inflammatory cytokines (TNF-α, IL-1 and so on), HMGB1 has recently been shown to mediate the lethal late phase of sepsis and caused coagulopathy. TM not only binds HMGB1 but also aids the proteolytic cleavage of HMGB1 by thrombin.
There have been many reports of the efficacy of recombinant TM and antithrombin for treatment of septic DIC from Japan. Further investigation of the efficacy of recombinant TM and AT in countries other than Japan, as well as the monitoring of medical costs incurred during hospitalization, will help validate the use of TM and AT for treatment of septic DIC. Sepsis is a clinical syndrome defined as a systemic response to infection. It is frequently complicated by coagulopathy and, in about 35% of severe cases, by disseminated intravascular coagulation (DIC) ,. In the European Union and the USA, the 2012 guidelines of the Surviving Sepsis Campaign do not recommend treatment for septic DIC ,.
In contrast, in Japan, aggressive treatment of septic DIC is encouraged ,. It is not an exaggeration to state that Japan is one of the countries that most effectively treats patients with septic DIC. In this article, we review the mechanisms that underlie the interaction between sepsis and DIC and, by highlighting our findings, the effects of sepsis on the coagulation system. Sepsis-induced DICDuring sepsis, inflammation diffusely activates the coagulation system, consuming multiple clotting factors and resulting in DIC ,.
In systemic inflammatory response syndromes caused by infection, both perturbed endothelial cells and activated mononuclear cells produce proinflammatory cytokines that promote coagulation ,. Proteins expressed on these cells initiate coagulation. Thrombin elicits the production of monocyte chemoattractant protein 1 and interleukin (IL)-6 in monocytes, fibroblasts, and mesothelial cells, and the production of IL-6 and IL-8 in vascular endothelial cells by interacting with protease-activated receptors (PARs) 1, 3, and 4.
Via PAR 2, factor Xa, and the tissue factor-VIIa complex also upregulate IL-6 and IL-8 in vascular endothelial cells ,. In addition, the inhibition of physiologic anticoagulant mechanisms and fibrinolysis by endothelial cells causes intravascular fibrin deposition.Initiation of the extrinsic coagulation protease cascade requires tissue factor (TF), a 47-KDa transmembrane glycoprotein. We reported that macrophages, monocytes, and neutrophils are a source of TF in sepsis animal models and participate in the direct activation of the coagulation cascade in the early phases of sepsis ,. We also showed that activated factor X (FXa), which is involved in hemostasis, thrombogenesis, inflammation, and cellular immune responses, induces TF expression in human peripheral monocytes and, conversely, that inhibition of FXa activity reduces TF expression in an experimental model of rat endotoxemia. Our results indicate that FXa directly modulates TF expression and that both inflammation and coagulation play an important role in DIC due to sepsis. Development of a procoagulant state in sepsis, due to aberrant expression of tissue factor (TF) and sharp decrease of its major inhibitor tissue factor pathway inhibitor (TFPI), could lead to microthrombotic organ failure.
TFPI is a major inhibitor of the TF-FVIIa-initiated coagulation in vivo. and Gando S et al. suggested that during early sepsis, the available TFPI might not adequately balance the increased TF-dependent coagulation activation. Moreover Tang et al. Suggested that plasmin might be partly responsible for proteolytic degradation of TFPI in the early stages of sepsis. In addition to inflammatory cytokines, other factors have recently been shown to mediate the lethal late phase of sepsis; these factors include tumor necrosis factor (TNF)-α, IL-1, high-mobility group box-1 (HMGB1) protein, and nuclear architectural chromatin-binding protein.
HMGB1 is secreted by activated monocytes and macrophages and released from necrotic or damaged cells. Extracellular HMGB1 mediates cell-to-cell signaling and activates proinflammatory pathways. When released into the extracellular space, it elicits the production of inflammatory cytokines , which further augment the release of HMGB1 into the extracellular space. The recent published findings by Lu et al. demonstrate that hyperacetylated HMGB1 is a novel biomarker for pyroptosis, though necrosis-induced HMGB1 release is not acetylated.
Moreover, tissue damage induces the release of HMGB1 with all-cysteines reduced, whereas this form of HMGB1 does not stimulate cytokine release; it recruits leukocytes to the site of injury. And during infection or later stage of injury, HMGB1 released is acetylated or disulfide-bonded, and it stimulates cytokine release. The various functions of HMGB1 are shown in Fig.
1The various functions of HMGB1 in sepsis. HMGB1 is actively secreted from macrophages and monocytes, which are activated by inflammatory cytokines, and it is also passively released from necrotic cells.
HMGB1 may then cause activation of phagocytic cells, resulting in production of pro-inflammatory mediators and chemokines. HMGB1 binds to RAGE on endothelial cells. And endothelial cells express RAGE, adhesion molecules, TNF-α, chemokines, PAI-1, and promote down regulation of TM.
RAGE receptor for advanced glycation end-products, IL interleukin, TNF tumor necrosis factor, PAI-1 plasminogen activator inhibitor-1, DIC disseminated intravascular. Coagulation, SIRS systemic inflammatory response syndrome, MAP mitogen-activated protein. Recently, PAMPs and DAMPs in early phase of sepsis trigger tissue factor expression on monocytes and neutrophil extracellular trap (NET) release by neutrophils, promoting immunothrombosis. Although immunothrombosis plays a role in early host defense against bacterial dissemination, uncontrolled immunothrombosis may also lead to DIC. Besides, recent studies have identified histones, the most abundant proteins in the nucleus, as a new class of DAMPs ,.
Extracellular histones promote neutrophil migration, platelet aggregation, and endothelial cell death ,. Histones have been detected in the plasma of mice, baboons, and human patients with sepsis and trauma, and the total concentration of histones can reach 70, with that of histone H3 reaching 15 μg/ml ,. Nakahara et al. Suggested that extracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC and that rTM binds to histones and neutralizes the prothrombotic action of histones. A mechanism of DIC and MOF due to sepsis are shown in Fig.
2A mechanism of DIC and MOF due to sepsis. When the pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and damage-associated molecular patterns (DAMPs) act on monocytes via TLR and on neutrophils, a reactivated monocyte produce TF, various inflammatory cytokines, and HMGB1, and moreover, detection of PAMPs and DAMPs trigger neutrophil extracellular traps (NETs) release by neutrophils, promoting immunothrombosis. The uncontrolled immunothrombosis may lead to disseminated intravascular coagulation. And HMGB1 acts on EC and promotes upregulation of TF and downregulation of TM from EC, resulting endothelial cell injury, and microcirculation disorder develops DIC and MOF. TF tissue factor, TM thrombomodulin, TLR Toll-like receptor, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, EC endothelial cell, HMGB1 high-mobility group box protein 1, PAI plasminogen activator inhibitor, MOF multiple organ failure, NETs neutrophil extracellular traps.
3Effect of surgical stress for coagulopathy (DIC) due to infection. If the severity of the infectious disease is the same, coagulopathy of infectious disease in surgically patients is increased by addition of the coagulation disorder due to surgical stress. We investigated the effects of soluble recombinant human TM on the production of inflammatory cytokines and the plasma level of HMGB1 in an experimental endotoxemia model.
Endotoxemia was induced in rats via a bolus intravenous injection of 4 mg/kg lipopolysaccharide (LPS). Recombinant TM (1 mg/kg) was administered as a bolus injection 30 min before or 4 h after LPS. LPS increased the plasma levels of TNF-α and IL-1β, which peaked at 1 and 3 h, respectively, and over time, the plasma levels of HMGB1. Even when its administration was delayed, recombinant TM markedly inhibited the LPS-induced increase in plasma levels of HMGB1 (Fig. ) and the thrombin-AT complex, as well as the increase in liver dysfunction and mortality.
The use of recombinant TM may therefore be beneficial for treatment of septic patients. 4Effect of rTM on the plasma levels of HMGB1. Temporal changes in plasma HMGB1 concentrations after injection of lipopolysaccharide (LPS). Rats were given saline plus LPS ( closed squares); pretreatment of recombinant human soluble thrombomodulin ( rTM), LPS plus saline ( closed circles); or saline, LPS plus delayed treatment of rTM ( closed triangles).
All data represent the mean and SEM ( n = 6 per group). AcknowledgementsThis study was supported in part by research grants from the Japanese Ministry of Health, Labour and Welfare and the Japanese Ministry of Education, Science, Sports and Culture. Competing interestsNone of the authors disclose any financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. Authors’ contributionsKO mainly contributed to write this paper. TT and YS mainly contributed to review references.
All of authors discussed for this review. All authors read and approved the final manuscript.
Disseminated intravascular coagulationOther namesDisseminated intravascular coagulopathy, consumptive coagulopathy, defibrination syndromeshowing acute due to DIC in a. A is present in the of the (center of image).Symptoms, leg pain, problems speaking, problems moving part of the body, bleedingTypesAcute, chronicCauses,TreatmentDirected at the underlying conditionMedication,Prognosis20–50% risk of deathFrequency1% of people admitted to hospitalDisseminated intravascular coagulation ( DIC) is a condition in which form throughout the body, blocking. Symptoms may include, leg pain, problems speaking, or problems moving parts of the body. As and are used up, may occur. This may include, or bleeding into the skin. Complications may include.Relatively common causes include,.
Less common causes include,. There are two main types: acute (rapid onset) and chronic (slow onset).
Diagnosis is typically based on. Findings may include, low, high, or high.Treatment is mainly directed towards the underlying condition.
Other measures may include giving,. Evidence to support these treatments, however, is poor. May be useful in the slowly developing form.
About 1% of people admitted to hospital are affected by the condition. In those with sepsis rates are between 20% and 50%. The risk of death among those affected varies from 20 to 50%. Contents.Signs and symptoms In DIC, the underlying cause usually leads to symptoms and signs, and DIC is discovered on laboratory testing. The onset of DIC can be sudden, as in endotoxic shock or, or it may be insidious and chronic, as in cancer. DIC can lead to multiorgan failure and widespread bleeding.
Causes DIC can occur in the following conditions:. Solid tumors and (particularly ). complications:, or, retained intrauterine fetal demise, post partum haemorrhage.
Massive tissue injury: severe, burns, extensive surgery. or severe infection of any kind (infections by nearly all microorganisms can cause DIC, though bacterial infections are the most common): bacterial ( and sepsis), or. Transfusion reactions (i.e., ). Severe allergic or toxic reactions (i.e. Snake venom). Giant.
LargeLiver disease, /, and may mimic DIC but do not occur via the same pathways. Pathophysiology.
The coagulation cascade of secondary haemostasis.Under homeostatic conditions, the body is maintained in a finely tuned balance of coagulation. The activation of the coagulation cascade yields that converts to; the stable fibrin clot being the final product of. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called (FDPs) or fibrin split products (FSPs). In a state of homeostasis, the presence of plasmin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis. In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding.
Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein called (TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly ),. This plays a major role in the development of DIC in septic conditions.
TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon exposure to blood and platelets, TF binds with activated factor VIIa (normally present in trace amounts in the blood), forming the extrinsic tenase complex. This complex further activates factor IX and X to IXa and Xa, respectively, leading to the common coagulation pathway and the subsequent formation of thrombin and fibrin.The release of endotoxin is the mechanism by which provokes DIC. In, treatment causes the destruction of leukemic granulocyte precursors, resulting in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may enhance the expression of various oncogenes that result in the release of TF and (PAI-1), which prevents fibrinolysis.Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation.
These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.
Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a loop develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs and this has been attributed to the entrapment and consumption of platelets.
![And And](/uploads/1/2/5/3/125383107/190782943.png)
Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC. Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in an excess of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock, hypotension, and increased vascular permeability.
The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high mortality rate. There has been a recent challenge however to the basic assumptions and interpretations of the pathophysiology of DIC. A study of sepsis and DIC in animal models has shown that a highly expressed receptor on the surface of hepatocytes, termed the Ashwell-Morell receptor, is responsible for thrombocytopenia in bacteremia and sepsis due to Streptococcus pneumoniae (SPN) and possibly other pathogens. The observed in SPN sepsis was not due to increased consumption of coagulation factors such as platelets, but instead was the result of this receptor's activity enabling hepatocytes to ingest and rapidly clear platelets from circulation. By removing pro-thrombotic components before they participate in the coagulopathy of DIC, the Ashwell-Morell receptor lessens the severity of DIC, reducing thrombosis and tissue necrosis, and promoting survival. The hemorrhage observed in DIC and among some tissues lacking this receptor may thereby be secondary to increased thrombosis with loss of the mechanical vascular barrier.
This discovery has possible significant clinical implications in devising new approaches to reducing the morbidity and mortality of DIC. There is activation of intrinsic as well as extrinsic coagulation pathway, this results in excess thrombus formation in the blood vessels. Due to extensive coagulation there is consumption of coagulation factors which causes bleeding.Diagnosis The diagnosis of DIC is not made on a single laboratory value, but rather the constellation of laboratory markers and a consistent history of an illness known to cause DIC. Laboratory markers consistent with DIC include:. Characteristic history (this is important because severe liver disease can essentially have the same laboratory findings as DIC). Prolongation of the (PT) and the (aPTT) reflect the underlying consumption and impaired synthesis of the. Fibrinogen level has initially thought to be useful in the diagnosis of DIC but because it is an acute phase reactant, it will be elevated due to the underlying inflammatory condition.
Therefore, a normal (or even elevated) level can occur in over 57% of cases. A low level, however, is more consistent with the consumptive process of DIC. A rapidly declining platelet count. High levels of fibrin degradation products, including, are found owing to the intense fibrinolytic activity stimulated by the presence of fibrin in the circulation. The may show fragmented (known as ) due to shear stress from.
However, this finding is neither sensitive nor specific for DICA diagnostic algorithm has been proposed by the International Society of Thrombosis and Haemostasis. This algorithm appears to be 91% sensitive and 97% specific for the diagnosis of overt DIC. A score of 5 or higher is compatible with DIC and it is recommended that the score is repeated daily, while a score below 5 is suggestive but not affirmative for DIC and it is recommended that it is repeated only occasionally: It has been recommended that a scoring system be used in the diagnosis and management of DIC in terms of improving outcome. Presence of an underlying disorder known to be associated with DIC (no=0, yes=2). Global coagulation results.
Platelet count ( 100k = 03 sec = 16 sec = 2). Fibrinogen level ( 1.0g/L = 0. Retrieved 20 December 2017. ^.
Merck Manuals Professional Edition. September 2016. Retrieved 20 December 2017. ^ Levi, M (2007). 'Disseminated Intravascular Coagulation'. Critical Care Medicine. 35 (9): 2191–2195.
^ Gando, Satoshi; Levi, Marcel; Toh, Cheng-Hock (2 June 2016). 'Disseminated intravascular coagulation'. Nature Reviews Disease Primers. 2: 16037. ^ Robbins, Stanley L.; Cotran, Ramzi S.; Kumar, Vinay; Collins, Tucker (1999). Robbins' Pathologic Basis of Disease (6 ed.). Philadelphia: Saunders.
Davidson's Principles and Practice of Medicine (19 ed.). Churchill Livingstone. 2002. ^ Haematology: Basic Principles and Practice (6 ed.). Elsevier Saunders. 2012. Clark, Michael; Kumar, Parveen J.
Clinical Medicine: A Textbook for Medical Students and Doctors (4 ed.). Philadelphia: W.B. Saunders. Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. Robbins Basic Pathology (8th ed.). Saunders Elsevier. 469-471.
Rak J, Yu JL, Luyendyk J, Mackman N (2006). 66 (22): 10643–6. Grewal, PK; Uchiyama, S; Ditto, D; Varki, N; Le, DT; Nizet, V; Marth, JD (June 2008). Nature Medicine. 14 (6): 648–55. ^ Levi, M; Toh, C-H; et al. 'Guidelines for the diagnosis and management of disseminated intravascular coagulation'.
British Journal of Haematology. 145 (5): 24–33. Taylor, F; Toh, C-h; et al. 'Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation'.
Thrombosis and Haemostasis. 86 (5): 1327–30. Gando, S (2012). 'The Utility of a Diagnostic Scoring System for Disseminated Intravascular Coagulation'.
28 (3): 378–88. 'Guidelines for the diagnosis and management of disseminated intravascular coagulation'. British Journal of Haematology. 145 (1): 24–33.
Franchini, M; Manzato, F; Salvagno GL; et al. 'Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review'. Blood Coagul Fibrinolysis. 18 (7): 589–93.
^ Becker, Joseph U and Charles R Wira. At, 10 September 2009.
Matsuda, T (Jan–Feb 1996). 'Clinical aspects of DIC-disseminated intravascular coagulation'. Pol J Pharmacol.
48 (1): 73–5. Smith, OP (1997). 'Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans'. 350 (9091): 1590–1593. Gando, S (1999). 'Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis'. 229 (1): 121–127.
Sallah, S (2001). 'Disseminated intravascular coagulation in solid tumors: clinical and pathologic study'. 86 (3): 828.External links Classification.