What Is Dic How to Treat and Prevent
J Intensive Care. 2014; 2(1): xv.
Diagnosis and treatment of disseminated intravascular coagulation (DIC) co-ordinate to four DIC guidelines
Hideo Wada
Department of Molecular and Laboratory Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 Nippon
Takeshi Matsumoto
Department of Blood Transfusion, Mie University Schoolhouse of Medicine, ii-174 Edobashi, Tsu, Mie, 514-8507 Japan
Yoshiki Yamashita
Department of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507 Japan
Received 2013 Dec xviii; Accepted 2014 Feb ten.
Abstruse
Disseminated intravascular coagulation (DIC) is categorized into bleeding, organ failure, massive haemorrhage, and not-symptomatic types according to the sum of vectors for hypercoagulation and hyperfibrinolysis. The British Committee for Standards in Haematology, Japanese Guild of Thrombosis and Hemostasis, and the Italian Society for Thrombosis and Haemostasis published separate guidelines for DIC; all the same, there are several differences betwixt these iii sets of guidelines. Therefore, the International Gild of Thrombosis and Haemostasis (ISTH) recently harmonized these differences and published the guidance of diagnosis and treatment for DIC. There are three dissimilar diagnostic criteria according to the Japanese Ministry building Health, Labour and Welfare, ISTH, and Japanese Association of Acute Medicine. The first and second criteria tin can be used to diagnose the haemorrhage or massive bleeding types of DIC, while the third criteria encompass organ failure and the massive bleeding type of DIC. Handling of underlying conditions is recommended in 3 types of DIC, with the exception of massive haemorrhage. Claret transfusions are recommended in patients with the bleeding and massive bleeding types of DIC. Meanwhile, handling with heparin is recommended in those with the non-symptomatic type of DIC. The administration of constructed protease inhibitors and antifibrinolytic therapy is recommended in patients with the bleeding and massive bleeding types of DIC. Furthermore, the administration of natural protease inhibitors is recommended in patients with the organ failure type of DIC, while antifibrinolytic treatment is non. The diagnosis and treatment of DIC should be carried out in accordance with the type of DIC.
Keywords: Disseminated intravascular coagulation (DIC), Bleeding type, Organ failure type, Massive bleeding blazon, Non-symptomatic type, Guidelines
Introduction
Disseminated intravascular coagulation (DIC) is a syndrome characterized by the systemic activation of blood coagulation, which generates intravascular thrombin and fibrin, resulting in the thrombosis of small- to medium-sized vessels and ultimately organ dysfunction and severe haemorrhage [1, 2]. DIC may result as a complexity of infection, solid cancers, hematological malignancies, obstetric diseases, trauma, aneurysms, and liver diseases, etc., each of which presents feature features related to the underlying disorder. The diagnosis and treatment of DIC must therefore consider these underlying etiological features. The type of DIC is related to the underlying disorder. Three guidelines for diagnosis and treatment of DIC [3–5] accept been published in the literature past the British Committee for Standards in Haematology (BCSH), Japanese Society of Thrombosis and Hemostasis (JSTH), and Italian Society for Thrombosis and Haemostasis (SISET). Although these three guidelines are broadly like, at that place are variations in several recommendations regarding DIC treatment. Therefore, the subcommittee for DIC of the Scientific and Standardization Committee (SSC)/International Society of Thrombosis and Haemostasis (ISTH) harmonized these 3 guidelines in a report entitled, Guidance for the diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines[6] (Table1). The present review describes several recommendations for the diagnosis and handling of DIC related to the type of DIC.
Table 1
Differences in recommendations among three guidelines from BCSH, JSTH, and SISET and harmonized ISTH/SSC guidance
| BCSH | JSTH | SISET | ISTH/SSC | |
|---|---|---|---|---|
| Scoring system for DIC | R; grade C | Ra | R; class C | R; high quality |
| Single test analysis for DIC | NR | NRa | NR; form D | R high quality |
| Treatment of underlying illness | R; form C | R; consensus | R; cornerstone | R; moderate quality |
| Platelet concentration | R; class C | R; consensus | R; class D | R; low quality |
| FFP | R; grade C | R; consensus | R; grade D | R; depression quality |
| Fibrinogen, cryoprecipitate | R; form C | Disregard | R; class D | R; low quality |
| FVIIa | Disregard | Condone | NR; form D | NM |
| UFH (treatment) | R; grade C | R; level C | NR; grade D | R; low quality |
| UFH (prophylaxis for VTE) | R; grade A | Condone | R | R; high quality |
| LMWH | Disregard | R; level B2 | R; grade D | Preferred to UFH |
| Heparin sulfate | Condone | R; level C | NM | |
| Synthetic protease | Disregard | R; level B2 | NR; grade D | NM |
| rhAPC | R; grade A | Disregard | R; form D | Need for further Ed from RCT |
| AT | NR; grade A | R; B1 | NR; form D | Need for further Ed from RCT |
| rhTM | Disregard | Condone | NR; grade B | Need for further Ed from RCT |
| Antifibrinolytic agents | R; grade C | NR; level D | R; depression quality | |
| Plasma exchange | Disregard | Disregard | NR; grade D | NM |
R, recommendation; NR, not recommendation; Ra, suggestive recommendation; NM, not mention; Ed, evidence; FFP, fresh frozen plasma; PCC, FVIIa, activated coagulation factor Vii; UFH, unfractionated heparin; LMWH, low molecular weight heparin; rh, recombinant human; APC, activated protein C; AT, antithrombin; TM, thrombomodulin; RCT, randomized control trial.
Review
Pathophysiology of DIC
Abnormalities of the hemostatic system in patients with DIC result from the sum of vectors for hypercoagulation and hyperfibrinolysis (Effigy1). When the vector for hyperfibrinolysis is remarkable and dominant, haemorrhage is the master symptom; this blazon is called the bleeding blazon or hyperfibrinolysis predominance type of DIC. This course of DIC is often seen in patients with leukemia, such equally acute promyelocytic leukemia (APL), obstetric diseases, or aortic aneurysms [2, seven]. On the other hand, when the vector for hypercoagulation is remarkable and ascendant, organ failure is the main symptom; this type of DIC is called the organ failure blazon, hypercoagulation predominance type or hypofibrinolysis type of DIC. This course of DIC is oftentimes observed in patients with infection, particularly sepsis. An increase in the level of plasminogen activator inhibitor I (PAI-I) induced by markedly increased levels of cytokines [8, 9] and lipopolysaccharide (LPS) [2, seven] in the blood has been reported to a cause of hypofibrinolysis. Moreover, neutrophil extracellular traps (NETs) [x], which release Dna with histone, neutrophil elastase, and cathepsin G in order to trap and kill pathogens, are present in patients with sepsis. Histones promote the apoptosis of vascular endothelial cells and platelet aggregation [11], while neutrophil elastase and cathepsin G decompose tissue factor pathway inhibitor (TFPI) in lodge to promote thrombus formation [12]. Moreover, high mobility group box i (HMGB-1) [13] is emitted from injured and dead cells in lodge to enhance the inflammatory reaction.
Bleeding, organ failubre, massive bleeding, and non-symptomatic types of DIC.
When both vectors for hypercoagulation and hyperfibrinolysis are remarkable and strong, major bleeding occurs, followed past death, if a sufficient amount of claret is not transfused; this type of DIC is called the massive bleeding or consumptive blazon of DIC. This form of DIC is observed in patients who exhibit major haemorrhage subsequently major surgery or in those with obstetric diseases.
When both vectors are weak, there are almost no clinical symptoms, although abnormalities in clinical laboratory tests are observed; this type of DIC is called the non-symptomatic type of DIC or pre-DIC [14, 15]. In a retrospective study [15], the treatment of pre-DIC was reported to be constructive. The diagnosis and handling of the four types of DIC differ [3]. Furthermore, the diagnosis and treatment of DIC is complicated by the fact that the types of DIC may shift or modify. Patients with DIC acquired by sepsis (organ failure type), hematological malignancy, or obstetrics (haemorrhage type) can be successfully treated for DIC, whereas DIC associated with solid cancers may not respond to standard treatments [16]. Equally DIC associated with solid cancers differs from the higher up four types of DIC, it should exist analyzed separately.
Diagnosis of DIC
Scoring system
Various underlying clinical conditions tin can take an effect on the laboratory parameters that are normally obtained to diagnose DIC, such equally global coagulation tests, the platelet count, prothrombin fourth dimension (PT), and the fibrinogen, fibrinogen, and fibrin deposition products (FDPs). In order to facilitate the diagnostic process for detecting DIC, the use of a scoring system is recommended by each of the 4 different guidelines [3–6]. Three dissimilar diagnostic criteria incorporating similar global coagulation tests have been established by the ISTH/SSC [1], Japanese Ministry Wellness, Labour and Welfare (JMHLW) [17], and Japanese Association of Astute Medicine (JAAM) [18]. The JMHLW score is well correlated with the severity of DIC and can be used to predict the issue of the illness [14]. The ISTH overt DIC score is useful and specific for diagnosing DIC due to infective and not-infective etiologies [xiii, 19]. The JAAM score is sensitive for detecting septic DIC and is correlated with the ISTH and JMHLW scores and disease event [thirteen, 18]. A prospective report in Japan reported no significant differences in the odds ratio for predicting DIC outcomes among these three diagnostic criteria [20], suggesting that the identification of molecular hemostatic markers and changes of global coagulation tests is required in addition to the application of scoring systems. The use of a combination of tests repeated over time in patients with suspected DIC can be used to diagnose the disorder with reasonable certainty in most cases [21–23]. A template for a non-overt-DIC scoring organization, including global coagulation tests, changes in global coagulation tests also as hemostatic molecular markers, has been proposed [1, 24, 25].
The haemorrhage blazon of DIC tin can exist easily diagnosed using the ISTH overt-DIC [1] and JMHLW [17] criteria, while the organ failure type of DIC is diagnosed according to the JAAM diagnostic criteria [18]. The massive haemorrhage (consumptive) type of DIC can be diagnosed using whatsoever of the three diagnostic criteria [1, 17, 18]; notwithstanding, it is difficult to diagnose the non-symptomatic blazon of DIC using these criteria. The utilise of hemostatic molecular markers is required to diagnose the non-symptomatic blazon of DIC.
Laboratory tests
Global coagulation tests provide of import evidence regarding the caste of coagulation factor activation and consumption. Although the PT is prolonged in approximately 50% of patients with DIC at some point during their clinical grade [21], abnormalities are oft observed in patients with liver affliction or vitamin K deficiency. A reduction in the platelet count or clear downwards tendency in subsequent measurements is a sensitive sign of DIC [3], although this pattern is likewise observed in patients with bone marrow disorders. A reduced fibrinogen level is a valuable indicator regarding a diagnosis of DIC due to leukemia or obstetric diseases; however, it is not observed in most septic DIC patients [three]. Elevated fibrin-related markers (FRMs), such as FDP [26], D-dimer [27], or soluble fibrin (SF), reflect fibrin germination. SF [28] assays offering theoretical advantages in detecting DIC, more closely reflecting the effects of thrombin on fibrinogen, although the one-half-life is short. Information technology is important to consider that many conditions, such as trauma, recent surgery, bleeding, or venous thromboembolism (VTE), are associated with elevated FRMs. Reductions in the levels of natural anticoagulants, such as antithrombin (AT) and poly peptide C, are common in patients with DIC. Although measuring the AT action is useful for achieving the full efficacy of heparin [29], this parameter cannot be quickly and easily measured in all hospitals. These activities are correlated with the liver part and/or concentration of albumin. A reduced ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type ane motifs 13) activeness and elevated soluble thrombomodulin (TM), PAI-I, and von Willebrand factor propeptide levels are ofttimes observed in patients with DIC and have been shown to have prognostic significance [30–32]. The biphasic waveform of the activated partial thromboplastin time (APTT) has been shown to be associated with DIC and appears to have a positive predictive value for the disease [33, 34]. Although many attractive markers for DIC have been reported, no single marking can be used to diagnose DIC alone (Table2). Therefore, the above 4 guidelines [3–half dozen] recommend that DIC could not be diagnosed according to the level of a single marker but rather based on the combination of laboratory markers. Among the four types of DIC, PT, fibrinogen, and platelets are of import parameters for diagnosing the massive bleeding type of DIC, while fibrinogen, FDP, and plasmin-plasmin inhibitor complex (PPIC) are important for detecting the bleeding type of DIC. Meanwhile, platelets, PT, and AT are important for diagnosing the organ failure type of DICand hemostatic molecular markers, such as SF and the thrombin-AT complex, are important for diagnosing the not-symptomatic type of DIC.
Table two
Laboratory tests for DIC
| Abnormality in DIC | Other cause for the abnormality | Adequate blazon of DIC | |
|---|---|---|---|
| PT | Prolongation | Liver dysfunction, vitamin K deficiency | OF, BL, MB |
| FDP, D-dimer | Elevation | Venous thromboembolism, operation | BL, NS, OF |
| Fibrinogen | Reduction | Liver dysfunction | BL, MB |
| Platelet count | Reduction | Bone marrow disorders | OF, MB, BL, NS |
| AT/PC | Reduction | Liver dysfunction, capillary leak syndrome | OF |
| SF/TAT | Acme | Venous thromboembolism, operation | OF, NS, BL, MS |
| TM | Acme | Renal dysfunction, organ failure | OF |
| VWFpp, PAI-I | Elevation | Organ failure | OF |
| ADATMTS13 | Reduction | Liver dysfunction, thrombotic microangiopathy | OF |
| APTT | Biphasic waveform | Infection | OF |
| PPIC | Peak | Venous thromboembolism, functioning | BL, MB |
PT, prothrombin time; FDP, fibrinogen and fibrin degradation products; SF, soluble fibrin; AT, antithrombin; PC, protein C; TAT, thrombin AT complex; VWFpp, von Willebrand factor propeptide; PAI-I, plasminogen activator inhibitor-I; APTT, activated fractional thromboplastin fourth dimension; PPIC, plasmin-plasmin inhibitor circuitous; OF, organ failure type of DIC; BL, bleeding type of DIC; MB, massive bleeding type of DIC; NS, non-symptomatic type of DIC.
Treatment of DIC
Handling of the underlying disease
The cornerstone of DIC handling is providing treatment for the underlying disorders, such as the administration of antibiotics or surgical drainage in patients with infectious diseases and anticancer drugs or surgery in patients with cancerous diseases. All four guidelines [3–6] agree on this signal, although there is no high-quality evidence for the efficacy of treating the underlying disorder in DIC patients. DIC spontaneously resolves in many cases when the underlying disorder is properly managed and improved. However, some cases crave additional supportive treatment specifically aimed at abnormalities in the coagulation organization. A randomized controlled trial (RCT) of the use of all-trans retinoic acid (ATRA) compared with conventional chemotherapy in patients with APL showed that the mortality rate was significantly lower in the ATRA grouping [35]. ATRA exerts differential furnishings on APL progression, as well as anticoagulant and antifibrinolytic effects [36]. Similarly, several RCTs of the handling of sepsis [37–42] and DIC [43] have shown parallel improvements in coagulation derangement and DIC, although the information have not always been concordant. Treating the underlying disorder is beginning required in patients with bleeding, organ failure, and non-symptomatic types of DIC, while claret transfusions are needed in patients with the massive bleeding type of DIC (Tabular arraythree).
Table 3
Handling of DIC in iv types of DIC
| Treatment | Non-symptomatic type | Organ failure type | Bleeding blazon | Massive bleeding type |
|---|---|---|---|---|
| Underlying conditions | R | R | R | |
| Claret transfusion | R | R | ||
| Heparin | R | NR | NR | |
| Anti-Xa | NR | NR | ||
| Synthetic protease inhibitor | R | R | ||
| Natural protease inhibitor | R | NR | ||
| Antifibrinolytic treatment | NR | NR | R | R |
R, recommended; NR, not recommended.
Blood transfusion
Markedly depression levels of platelets and coagulation factors, particularly fibrinogen, may increase the gamble of bleeding. The above four guidelines [3–half-dozen] recommended the administration of platelet concentrate (PC) and fresh frozen plasma (FFP) in DIC patients with active bleeding or those at high take chances of bleeding requiring invasive procedures, without high-quality evidence. The threshold for transfusing platelets depends on the clinical state of the DIC patient. In general, PC is administered in DIC patients with agile bleeding and a platelet count of ≦fifty × ten9/l. A much lower threshold of 10 to xx × 109/l is adopted in non-bleeding patients who develop DIC after undergoing chemotherapy. PC may exist administered at higher levels in patients perceived to exist at high risk of haemorrhage based on other clinical or laboratory features [44]. The transfusion of PC or FFP is usually performed in patients with the massive bleeding or bleeding types of DIC. It is necessary to use large volumes of plasma in order to correct coagulation defects associated with a prolonged APTT or PT (greater than 1.5 times the normal value) or decreased fibrinogen level (less than i.5 1000/dl). An initial dose of 15 ml/kg of FFP is clinically recommended and ordinarily administered. As the consequences of volume overload must be considered in this context, smaller volumes of prothrombin circuitous concentrate may be useful in this setting. Every bit specific deficiencies in fibrinogen associated with the massive bleeding type of DIC can exist corrected with the assistants of purified fibrinogen concentrates or cryoprecipitate, three of the guidelines recommended these treatments (Table3). The response to claret component therapy should be monitored both clinically and with repeated assessments of the platelet count and coagulation parameters following the assistants of these components. The efficacy and safety of recombinant factor VIIa in DIC patients with life-threatening haemorrhage are unknown, and this treatment should be used with caution or as part of a clinical trial.
Heparin
Although the administration of anticoagulant handling is a rational approach based on the notion that DIC is characterized by extensive activation of coagulation, there are several differences in the recommendations for the use of heparin in DIC patients between the four guidelines (Tablei) [3–half-dozen]. Therapeutic doses of heparin should exist considered in cases of DIC in which thrombosis predominates. A small RCT showed that depression molecular weight heparin (LMWH) is superior to unfractionated heparin (UFH) for treating DIC [45], suggesting that the use of LMWH is preferred to that of UFH in these cases. The level of inhibition achieved with LMWH is higher for activated coagulation factor Xa (Xa) than for thrombin. Patients with DIC are at high risk of VTE events, and the administration of VTE prophylaxis using UFH, LMWH, and/or mechanical methods has go the standard of care in patients with DIC [46, 47]. Although experimental studies accept shown that heparin can at least partly inhibit the activation of coagulation in the setting of DIC [48], there are no RCTs demonstrating that the apply of heparin in patients with DIC results in improvements in clinically relevant outcomes. A recent large trial of patients with severe sepsis showed a non-significant benefit of low-dose heparin on the 28-day bloodshed and underscored the importance of not discontinuing heparin treatment in patients with DIC and aberrant coagulation parameters [29]. Meanwhile, the 28-solar day bloodshed is lower in placebo groups treated with heparin than in placebo groups without heparin co-ordinate to subclass analyses [49] of RCT of severe sepsis [37, 38, 42]. Although it is not easy to quickly measure the AT level in all hospitals in club to determine whether to administer urgent heparin handling, measuring this parameter is useful for achieving the full efficacy of heparin. The administration of heparin is not recommended in patients with bleeding or massive bleeding type of DIC due to the increased gamble of bleeding, although it is recommended in those with the non-symptomatic type of DIC in order to prevent the onset of deep vein thrombosis (DVT) (Table3).
Anti-Xa agents
Both Fondaparinux® and Danaparoid sodium® activate AT specifically to inhibit Xa. Handling with Fondaparinux® is recommended for the prophylaxis of DVT after orthopedic surgery; all the same, there is lilliputian prove to support its employ in critically sick patients and those with other type of DIC. Danaparoid sodium® is used to care for DIC in Japan, although no RCTs have shown whatever reductions in bloodshed or the rate of resolution of DIC. There is significant evidence for the use of these drugs as prophylaxis for DVT [l, 51]; notwithstanding, at that place is fiddling evidence for the apply of these agents in patients with DIC, and they are not recommended in those with the bleeding or massive bleeding type of DIC (Tableiii). These drugs are also not recommended in patients with renal failure.
Synthetic protease inhibitors
Constructed protease inhibitors, such as Gabexate mesilate® and nafamostat®, exhibit multiple-functions, including antagonistic effects on the kinin/kallikrein system, fibrinolysis, complement organization, and coagulation system. Gabexate mesilate® and nafamostat® have been frequently used and evaluated in Japan [13, 52, 53]; however, there are no RCTs showing any reductions in mortality or improvements in the rate of resolution of DIC. As these drugs have mild anticoagulant and antifibrinolytic furnishings, they are often used in patients with the bleeding, massive bleeding, and non-symptomatic types of DIC (Tableiii).
Natural protease inhibitor
The utilize of agents capable of restoring dysfunctional anticoagulant pathways in patients with DIC has been studied extensively. Although there are many RCTs of clinically ill patients, almost all RCTs have been carried out in patients with sepsis, with few RCTs of patients with DIC, suggesting that BCSH and SISET determined their recommendations for DIC treatment based on studies of sepsis, not DIC.
AT and the heparin/heparinoid circuitous primarily inhibits Xa and thrombin, while the APC/TM system inhibits thrombin, FVa, and FVIIIa (Effigy2). Each of the four guidelines [3–vi] provides unlike recommendations regarding the use of anticoagulant factor concentrates (Table1). A large-calibration multicenter RCT directly assessing the effects of AT concentrate on mortality in patients with astringent sepsis showed no significant reductions in those treated with AT concentrate [37]. Interestingly, the subgroup of patients with DIC and who did non receive heparin showed a remarkable survival benefit [54]; however, this finding requires prospective validation. In one prospective multicenter survey, the efficacy of AT was college in the 3,000 units/day group than in the 1,500 units/day group [55].
Regulation of the coagulation arrangement.
The clinical efficacy of recombinant human activated protein C (rhAPC) in patients with severe sepsis was demonstrated in a large RCT [38], although a prospective trial of septic patients with relatively low illness severity did non testify any benefits of rhAPC therapy [39]. The withdrawal of rhAPC from sepsis treatment regimens was proposed after an RCT of septic shock failed to show whatsoever benefits [40]. Meanwhile, treatment with plasma-derived APC improved outcomes in a pocket-size RCT [56] in Nihon; however, the drug is not approved for the handling of DIC. In that location are no useful RCTs of the administration of protein C concentrate to treat sepsis or DIC.
One RCT comparing handling with rhTM with that of UFH [43] showed that rhTM therapy significantly increased the rate of resolution of DIC, although mortality was non significantly decreased. In another study of DIC, treatment with rhTM relatively reduced bloodshed and significantly reduced the severity of organ failure compared to a placebo [57]. Some other RCT of severe sepsis showed that the administration of rhTM tended to improve mortality [41].
The administration of AT, rhTM, or APC may be considered in DIC patients. Further prospective evidence from RCTs confirming a benefit is required [6]. Handling with AT and rhTM is recommended in patients with the organ failure blazon of DIC (Tabular array3).
Antifibrinolytic handling
Antifibrinolytic agents are effective in treating haemorrhage, although the utilise of these drugs in patients with the organ failure or non-symptomatic type of DIC is by and large non recommended [58]. An exception may be made in those with the bleeding or major bleeding type of DIC. The four guidelines [three–6] showroom some differences in these recommendations (Table1). One study of APL demonstrated a beneficial result of antifibrinolytic agents in this situation [59]; even so, cases complicated with severe thrombosis due to the combined apply of ATRA and tranexamic acid accept been documented [60]. A contempo RCT [61] showed that treatment with tranexamic acrid significantly reduces the mortality of patients with trauma. The administration of antifibrinolytic agents in these cases must occur in the early menstruation of direction earlier the levels of PAI-1 and other endogenous antifibrinolytics become elevated.
Conclusions
In conclusion, DIC is categorized into haemorrhage, organ failure, massive bleeding, and non-symptomatic types. The diagnosis and handling of DIC should be carried out in accord with the type of DIC based on the iv guidelines on DIC.
Acknowledgements
This study was supported in part past enquiry grants from the Japanese Ministry of Health, Labour and Welfare and the Japanese Ministry of Teaching, Scientific discipline, Sports and Culture.
Abbreviations
Footnotes
Competing interests
None 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' contributions
HW mainly contributed to write this paper. TM and YY mainly contributed to review references. All of authors discussed for this review. All authors read and approved the final manuscript.
Contributor Information
Hideo Wada, E-mail: pj.ca.u-eim.cidem.nilc@edihadaw.
Takeshi Matsumoto, Email: moc.ytfin@OTOMUSTAM.eihsekaT.
Yoshiki Yamashita, Electronic mail: pj.oc.oohay@9894nafamayamay.
References
ane. Taylor FB, Toh CH, Hoots WK, Wada H, Levi K. Towards definition, clinical and laboratory criteria, and a scoring organization for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–1330. [PubMed] [Google Scholar]
2. Wada H. Disseminated intravascular coagulation. Clin Chim Acta. 2004;344:xiii–21. doi: ten.1016/j.cccn.2004.02.015. [PubMed] [CrossRef] [Google Scholar]
3. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Commission for Standards in Haematology. Br J Haematol. 2009;145:24–33. doi: 10.1111/j.1365-2141.2009.07600.x. [PubMed] [CrossRef] [Google Scholar]
4. Wada H, Asakura H, Okamoto G, Iba T, Uchiyama T, Kawasugi Grand, Koga S, Mayumi T, Koike K, Gando Southward, Kushimoto S, Seki Y, Madoiwa S, Maruyama I, Yoshioka A, Japanese Society of Thrombosis Hemostasis/DIC subcommittee Skillful consensus for the treatment of disseminated intravascular coagulation in Nippon. Thromb Res. 2010;125:6–11. doi: ten.1016/j.thromres.2009.08.017. [PubMed] [CrossRef] [Google Scholar]
v. Di Nisio Thou, Baudo F, Cosmi B, D'Angelo A, De Gasperi A, Malato A, Schiavoni Thousand, Squizzato A, Italian Social club for Thrombosis and Haemostasis Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian lodge for haemostasis and thrombosis (SISET) Thromb Res. 2012;129:e177–e184. doi: 10.1016/j.thromres.2011.08.028. [PubMed] [CrossRef] [Google Scholar]
half-dozen. Wada H, Thachil J, Di Nisio K, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi 1000, Toh CH, The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from iii guidelines. J Thromb Haemost. 2013;11:761–767. doi: x.1111/jth.12155. [PubMed] [CrossRef] [Google Scholar]
7. Wada H, Matsumoto T, Hatada T. Diagnostic criteria and laboratory tests for disseminated intravascular coagulation. Skillful Rev Hematol. 2012;5:643–652. doi: 10.1586/ehm.12.57. [PubMed] [CrossRef] [Google Scholar]
viii. Wada H, Tamaki S, Tanigawa One thousand, Takagi M, Deguchi A, Mori Y, Katayama Due north, Yamamoto T, Deguchi K, Shirakawa S. Plasma level of IL-1β in disseminated intravascular coagulation. Thromb Haemost. 1991;65:364–368. [PubMed] [Google Scholar]
9. Wada H, Ohiwa M, Kaneko T, Tamaki Southward, Tanigawa M, Takagi Grand, Mori Yard, Shirakawa M. Plasma level of tumor necrosis factor in disseminated intravascular coagulation. Am J Hematol. 1991;37:147–151. doi: 10.1002/ajh.2830370302. [PubMed] [CrossRef] [Google Scholar]
10. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Scientific discipline. 2004;303:1532–1535. doi: x.1126/science.1092385. [PubMed] [CrossRef] [Google Scholar]
11. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–15885. doi: ten.1073/pnas.1005743107. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
12. Massberg Southward, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann Five, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht East, Reges Chiliad, Holdenrieder Due south, Braun Due south, Reinhardt C, Spannagl Yard, Preissner KT, Engelmann B. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;xvi:887–896. doi: x.1038/nm.2184. [PubMed] [CrossRef] [Google Scholar]
13. Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama One thousand, Abe Y, Uemoto S, Yamada S, Maruyama I. Plasma concentrations and importance of high mobility grouping box poly peptide in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost. 2005;94:975–979. [PubMed] [Google Scholar]
14. Wada H, Wakita Y, Nakase T, Shimura M, Hiyoyama Grand, Nagaya S, Mori Y, Shiku H. Result of disseminated intravascular coagulation in relation to the score when treatment was begun. Thromb Haemost. 1995;74:848–852. [PubMed] [Google Scholar]
15. Wada H, Minamikawa K, Wakita Y, Nakase T, Kaneko T, Ohiwa M, Tamaki S, Deguchi A, Mori Y, Deguchi Thou, Shirakawa S. Hemostatic study before onset of disseminated intravascular coagulation. Am J Hematol. 1993;43:190–194. doi: 10.1002/ajh.2830430306. [PubMed] [CrossRef] [Google Scholar]
16. Kawasugi K, Wada H, Hatada T, Okamoto K, Uchiyama T, Kushimoto S, Seki Y, Okamura T, Nobori T, Japanese Society of Thrombosis Hemostasis/DIC subcommittee Prospective evaluation of hemostatic abnormalities in overt DIC due to various underlying diseases. Thromb Res. 2011;128:186–190. doi: 10.1016/j.thromres.2011.02.015. [PubMed] [CrossRef] [Google Scholar]
17. Kobayashi N, Maegawa T, Takada Grand, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the assay of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Nippon. Bibl Haemotol. 1983;49:265–275. [PubMed] [Google Scholar]
18. Gando Southward, Iba T, Eguchi Y, Ohtomo Y, Okamoto Thousand, Koseki K, Mayumi T, Murata A, Ikeda T, Ishikura H, Ueyama G, Ogura H, Kushimoto S, Saitoh D, Endo S, Shimazaki Due south, Japanese Association for Astute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Written report Group A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparison current criteria. Crit Intendance Med. 2006;34:625–631. [PubMed] [Google Scholar]
19. Gando S, Wada H, Asakura H, Iba T, Eguchi Y, Okamoto Yard, Ohtomo Y, Kawasugi K, Koga S, Koseki Chiliad, Tsuji H, Mayumi T, Murata A, Nakagawa M, Endo Southward. Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients. Clin Appl Thromb Hemost. 2005;11:71–76. doi: 10.1177/107602960501100108. [PubMed] [CrossRef] [Google Scholar]
20. Takemitsu T, Wada H, Hatada T, Ohmori Y, Ishikura K, Takeda T, Sugiyama T, Yamada N, Maruyama M, Katayama N, Isaji South, Shimpo H, Kusunoki M, Nobori T. Prospective evaluation of three unlike diagnostic criteria for disseminated intravascular coagulation. Thromb Haemost. 2011;105:40–44. doi: 10.1160/TH10-05-0293. [PubMed] [CrossRef] [Google Scholar]
21. Bick R. Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemost. 1996;22:69–88. doi: 10.1055/due south-2007-998993. [PubMed] [CrossRef] [Google Scholar]
22. Levi M, Ten Cate H. Disseminated intravascular coagulation. Northward Engl J Med. 1999;341:586–592. doi: 10.1056/NEJM199908193410807. [PubMed] [CrossRef] [Google Scholar]
23. Toh CH, Dennis Thousand. Disseminated intravascular coagulation, old disease, new hope. BMJ. 2003;327:974–977. doi: 10.1136/bmj.327.7421.974. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
24. Toh CH, Hoots WK. The scoring arrangement of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost. 2007;v:604–606. doi: 10.1111/j.1538-7836.2007.02313.ten. [PubMed] [CrossRef] [Google Scholar]
25. Wada H, Hatada T, Okamoto K, Uchiyama T, Kawasugi K, Mayumi T, Gando S, Kushimoto S, Seki Y, Madoiwa S, Okamura T, Toh CH, Japanese Society of Thrombosis Hemostasis/DIC subcommittee Modified non-overt DIC diagnostic criteria predict the early phase of overt-DIC. Am J Hematol. 2010;85:691–699. doi: 10.1002/ajh.21783. [PubMed] [CrossRef] [Google Scholar]
26. Prisco D, Paniccia R, Bonechi F, Francalanci I, Abbate R, Gensini GF. Evaluation of new methods for the selective measurement of fibrin and fibrinogen degradation products. Thromb Res. 1989;56:547–551. doi: 10.1016/0049-3848(89)90239-nine. [PubMed] [CrossRef] [Google Scholar]
27. Shorr AF, Trotta RF, Alkins SA, Hanzel GS, Diehl LF. D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease. Intens Intendance Med. 1999;25:207–210. doi: 10.1007/s001340050817. [PubMed] [CrossRef] [Google Scholar]
28. Wada H, Sakuragawa N. Are fibrin-related markers useful for the diagnosis of thrombosis? Semin Thromb Hemost. 2008;34:33–38. doi: 10.1055/s-2008-1066021. [PubMed] [CrossRef] [Google Scholar]
29. Levi M, Levy M, Williams Doctor, Douglas I, Artigas A, Antonelli 1000, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL. Safe heparin in patients with astringent sepsis treated with drotrecogin alfa (activated) Am J Respir Crit Care Med. 2007;176:483–490. [PubMed] [Google Scholar]
30. Wada H, Mori Y, Shimura M, Hiyoyama Thousand, Nakasaki T, Ioka M, Nakano Chiliad, Nishikawa K, Kumeda K, Nakamura S, Shiku H. Poor upshot in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with astringent vascular endothelial prison cell injuries. Am J Hematol. 1998;58:189–194. doi: 10.1002/(SICI)1096-8652(199807)58:three<189::AID-AJH5>three.0.CO;2-Due north. [PubMed] [CrossRef] [Google Scholar]
31. Faust SN, Levin M, Harrison OB, Goldin RD, Lockhart MS, Kondaveeti S, Laszik Z, Esmon CT, Heyderman RS. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med. 2001;345:408–416. doi: x.1056/NEJM200108093450603. [PubMed] [CrossRef] [Google Scholar]
32. Habe M, Wada H, Ito-Habe N, Hatada T, Matsumoto T, Ohishi K, Maruyama K, Imai H, Mizutani H, Nobori T. Plasma ADAMTS13, von Willebrand factor (VWF) and VWF propeptide profiles in patients with DIC and related diseases. Thromb Res. 2012;129:598–602. doi: ten.1016/j.thromres.2011.10.011. [PubMed] [CrossRef] [Google Scholar]
33. Downey C, Kazmi R, Toh CH. Early identification and prognostic implications in disseminated intravascular coagulation through transmittance waveform analysis. Thromb Haemost. 1998;80:65–69. [PubMed] [Google Scholar]
34. Toh CH, Samis J, Downey C, Walker J, Becker L, Brufatto North, Tejidor L, Jones G, Houdijk West, Giles A, Koschinsky M, Ticknor LO, Paton R, Wenstone R, Nesheim Yard. Biphasic transmittance waveform in the APTT coagulation analysis is due to the germination of a Ca(++)- dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel mark of impending disseminated intravascular coagulation. Claret. 2002;100:2522–2529. doi: 10.1182/blood.V100.7.2522. [PubMed] [CrossRef] [Google Scholar]
35. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd Fifty, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in astute promyelocytic leukemia: long-term outcome and prognostic cistron analysis from the North American intergroup protocol. Claret. 2002;100:4298–4302. doi: x.1182/blood-2002-02-0632. [PubMed] [CrossRef] [Google Scholar]
36. Tallman MS, Lefèbvre P, Baine RM, Shoji M, Cohen I, Green D, Kwaan HC, Paietta Eastward, Rickles FR. Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia. J Thromb Haemost. 2004;2:1341–1350. doi: 10.1111/j.1538-7836.2004.00787.x. [PubMed] [CrossRef] [Google Scholar]
37. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. Caring for the critically ill patient. High-dose antithrombin Iii in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–1878. doi: ten.1001/jama.286.15.1869. [PubMed] [CrossRef] [Google Scholar]
38. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJJ. Efficacy and prophylactic of recombinant homo activated protein C for severe sepsis. North Engl J Med. 2001;344:699–709. doi: 10.1056/NEJM200103083441001. [PubMed] [CrossRef] [Google Scholar]
39. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332–1341. doi: 10.1056/NEJMoa050935. [PubMed] [CrossRef] [Google Scholar]
40. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer South, Gårdlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi Hr, Thompson V, Janes J, Macias WL, Vangerow B, Williams Dr., PROWESS-SHOCK Study Grouping Drotrecogin alfa (activated) in adults with septic daze. Due north Engl J Med. 2012;366:2055–2064. doi: 10.1056/NEJMoa1202290. [PubMed] [CrossRef] [Google Scholar]
41. Vincent JL, Ramesh MK, Ernest D, Larosa SP, Pachl J, Aikawa Northward, Hoste Eastward, Levy H, Hirman J, Levi K, Daga K, Kutsogiannis DJ, Crowther M, Bernard GR, Devriendt J, Puigserver JV, Blanzaco DU, Esmon CT, Parrillo JE, Guzzi L, Henderson SJ, Pothirat C, Mehta P, Fareed J, Talwar D, Tsuruta K, Gorelick KJ, Osawa Y, Kaul I. A randomized, double-bullheaded, placebo-controlled, stage 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, Fine art-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Intendance Med. 2013;41:2069–2079. doi: ten.1097/CCM.0b013e31828e9b03. [PubMed] [CrossRef] [Google Scholar]
42. Abraham E, Reinhart G, Svoboda P, Seibert A, Olthoff D, Dal Nogare A, Postier R, Hempelmann Thou, Butler T, Martin Due east, Zwingelstein C, Percell Southward, Shu Five, Leighton A, Creasey AA. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med. 2001;29:2081–2089. doi: x.1097/00003246-200111000-00007. [PubMed] [CrossRef] [Google Scholar]
43. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa Northward, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima Grand, Aoki N. Efficacy and prophylactic of recombinant human soluble thrombomodulin (Art-123) in disseminated intravascular coagulation: results of a stage 3, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41. doi: ten.1111/j.1538-7836.2006.02267.x. [PubMed] [CrossRef] [Google Scholar]
45. Sakuragawa N, Hasegawa H, Maki Yard, Nakagawa Yard, Nakashima 1000. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC); a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res. 1993;72:475–500. doi: ten.1016/0049-3848(93)90109-2. [PubMed] [CrossRef] [Google Scholar]
46. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger Due north. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients; prophylaxis in medical patients with enoxaparin study group. N Engl J Med. 1999;341:793–800. doi: 10.1056/NEJM199909093411103. [PubMed] [CrossRef] [Google Scholar]
47. Patel R, Cook DJ, Meade MO, Griffith LE, Mehta Grand, Rocker GM, Marshall JC, Hodder R, Martin CM, Heyland DK, Peters S, Muscedere J, Soth Thousand, Campbell North, Guyatt GH. Brunt of illness in venous thromboembolism in critical care: a multicenter observational study. J Crit Care. 2005;20:341–347. doi: 10.1016/j.jcrc.2005.09.014. [PubMed] [CrossRef] [Google Scholar]
48. Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, Eichler HG, Speiser Due west, Jilma B. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999;100:2485–2490. doi: 10.1161/01.CIR.100.25.2485. [PubMed] [CrossRef] [Google Scholar]
49. Polderman KH, Girbes AR. Drug intervention trials in sepsis: divergent results. Lancet. 2004;363:1721–1723. doi: 10.1016/S0140-6736(04)16259-four. [PubMed] [CrossRef] [Google Scholar]
50. Beyer-Westendorf J, Lützner J, Donath L, Radke OC, Kuhlisch Eastward, Hartmann A, Weiss N, Werth S. Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry. J Thromb Haemost. 2012;10:2045–2052. doi: ten.1111/j.1538-7836.2012.04877.ten. [PubMed] [CrossRef] [Google Scholar]
51. Girard P, Demaria J, Lillo-Le Louët A, Caliandro R, Le Guillou JL, Crespin M, de Sanctis A, Stern JB. Transfusions, major haemorrhage, and prevention of venous thromboembolism with enoxaparin or fondaparinux in thoracic surgery. Thromb Haemost. 2011;106:1109–1116. doi: x.1160/TH11-06-0433. [PubMed] [CrossRef] [Google Scholar]
52. Umeki Southward, Adachi Thousand, Watanabe M, Yaji S, Soejima R. Gabexate equally a therapy for disseminated intravascular coagulation. Arch Intern Med. 1988;148:1409–1412. doi: 10.1001/archinte.1988.00380060173030. [PubMed] [CrossRef] [Google Scholar]
53. Nishiyama T, Matsukawa T, Hanaoka G. Is protease inhibitor a choice for the treatment of pre- or mild disseminated intravascular coagulation? Crit Care Med. 2000;28:1419–1422. doi: 10.1097/00003246-200005000-00027. [PubMed] [CrossRef] [Google Scholar]
54. Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, Keinecke HO, Warren BL, Opal SM. Treatment effects of high-dose antithrombin without concomitant heparin in patients with astringent sepsis with or without disseminated intravascular coagulation. J Thromb Haemost. 2006;iv:xc–97. doi: 10.1111/j.1538-7836.2005.01697.x. [PubMed] [CrossRef] [Google Scholar]
55. Iba T, Saito D, Wada H, Asakura H. Efficacy and bleeding gamble of antithrombin supplementation in septic disseminated intravascular coagulation: a prospective multicenter survey. Thromb Res. 2012;130:e129–e133. doi: 10.1016/j.thromres.2012.03.021. [PubMed] [CrossRef] [Google Scholar]
56. Aoki N, Matsuda T, Saito H, Takatsuki K, Okajima K, Takahashi H, Takamatsu J, Asakura H, Ogawa N. CTC-111-IM Clinical Research Grouping. A comparative double-bullheaded randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol. 2002;75:540–547. doi: 10.1007/BF02982120. [PubMed] [CrossRef] [Google Scholar]
57. Yamakawa K, Fujimi S, Mohri T, Matsuda H, Nakamori Y, Hirose T, Tasaki O, Ogura H, Kuwagata Y, Hamasaki T, Shimazu T. Handling effects of recombinant human being soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit Care. 2011;xv:R123. doi: 10.1186/cc10228. [PMC complimentary article] [PubMed] [CrossRef] [Google Scholar]
58. Mannucci PM, Levi One thousand. Prevention and treatment of major blood loss. North Engl J Med. 2007;356:2301–2311. doi: ten.1056/NEJMra067742. [PubMed] [CrossRef] [Google Scholar]
59. de la Serna J, Montesinos P, Vellenga E, Rayon C, Parody R, Leon A, Esteve J, Bergua JM, Milone G, Deben Chiliad, Rivas C, Gonzalez Chiliad, Tormo M, az-Mediavilla J, Gonzalez JD, Negri South, Amutio Eastward, Brunet S, Lowenberg B, Sanz MA. Causes and prognostic factors of remission consecration failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–3402. doi: 10.1182/blood-2007-07-100669. [PubMed] [CrossRef] [Google Scholar]
sixty. Brown JE, Olujohungbe A, Chang J, Ryder WD, Morganstern GR, Chopra R, Scarffe JH. All-trans retinoic acid (ATRA) and tranexamic acid: a potentially fatal combination in acute promyelocytic leukaemia. Br J Haematol. 2000;110:1010–1012. doi: 10.1046/j.1365-2141.2000.02270-8.x. [PubMed] [CrossRef] [Google Scholar]
61. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe Due east, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S, CRASH-2 trial collaborators Effects of tranexamic acrid on death, vascular occlusive events, and blood transfusion in trauma patients with pregnant haemorrhage (CRASH-two): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. doi: x.1016/S0140-6736(ten)61479-i. [PubMed] [CrossRef] [Google Scholar]
Manufactures from Journal of Intensive Intendance are provided here courtesy of BioMed Central
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267589/
0 Response to "What Is Dic How to Treat and Prevent"
Postar um comentário