Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation

Dhainaut, Jean-François; Yan, S. Betty; Joyce, David E.; Pettilä, Ville; Basson, Bruce R.; Brandt, John; Sundin, David P.; Levi, Marcel

doi:10.1111/j.1538-7836.2004.00955.x

Cited by 392 publications

(263 citation statements)

References 16 publications

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“…However, the post‐hoc subgroup analyses of those RCTs indicated that the anticoagulant therapies resulted in improved mortality rates in patients with sepsis‐induced DIC 8, 9. In Japan, anticoagulant therapy has been approved for use as adjunctive therapy for patients with sepsis‐induced DIC and is now widely applied in clinical settings.…”

Section: Introductionmentioning

confidence: 99%

A summary of the Japan septic disseminated intravascular coagulation study

Hayakawa

Ono

2018

Acute Medicine & Surgery

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Over the past few decades, the large, international, randomized controlled trials of anticoagulant therapies for patients with sepsis have not yielded any improvement in mortality rates. However, in Japan, anticoagulant therapies are administered for sepsis patients with disseminated intravascular coagulation (DIC), but not for sepsis patients without DIC. Furthermore, epidemiological data regarding sepsis in Japan are scarce. Therefore, a nationwide multicenter retrospective observational study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study, was undertaken. The JSEPTIC DIC study enrolled 42 intensive care units and included 3,195 patients with sepsis. The results of the JSEPTIC DIC study indicated the following: (i) anticoagulant therapy may be effective in sepsis‐induced DIC patients at high risk for death, (ii) recombinant human soluble thrombomodulin administration and antithrombin supplementation are associated with survival benefits in patients with sepsis‐induced DIC.

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Section: Introductionmentioning

confidence: 99%

A summary of the Japan septic disseminated intravascular coagulation study

Hayakawa

Ono

2018

Acute Medicine & Surgery

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“…Response to corticotropin test for corticosteroids in septic shock (59) IL-6 level for monoclonal anti-tumor necrosis factor in sepsis ( mortality but also showed a trend toward greater RRR with activated protein C treatment (29 vs. 18%, P = 0.26) (43). An ongoing phase III study of a related therapy-recombinant human thrombomodulin-now requires evidence of disseminated intravascular coagulation for study enrollment (44).…”

Section: Identifying Biomarkers To Use For Predictive Enrichmentmentioning

confidence: 99%

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Prescott

Calfee

Thompson

et al. 2016

Am J Respir Crit Care Med

272

237

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Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.

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“…5 DIC may lead to microvascular thrombosis, causing multiple organ dysfunctions, and it is conceivable that a prothrombotic disposition such as FVL would be associated with an increased rate of fibrin disposition, causing organ dysfunction and death in sepsis.…”

Section: Introductionmentioning

confidence: 99%

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

Elmas

Suvajac

Jilma

et al. 2010

Blood

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Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activatorinduced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogenand fibrin-degradation products. (Blood. 2010;116(5):801-805) IntroductionReplacement of Arg506 with Gln in coagulation factor V (the factor V Leiden [FVL] mutation) 1 results in the loss of an important cleavage site for activated protein C (aPC). Factor Va carrying the FVL mutation is less sensitive to inactivation by aPC. In addition, FVL may display an impaired cofactor function in the degradation of factor VIIIa by aPC. FVL predisposes for the development of venous thrombosis. 2 The high prevalence of FVL in the European population 3 indicates some survival advantage, which might be related to less blood loss on injury or childbirth or to improved wound healing. 4 This may be a consequence of enhanced fibrin formation due to the impaired inactivation of factor Va.Presence of disseminated intravascular coagulation (DIC) in sepsis is associated with an adverse outcome. 5 DIC may lead to microvascular thrombosis, causing multiple organ dysfunctions, and it is conceivable that a prothrombotic disposition such as FVL would be associated with an increased rate of fibrin disposition, causing organ dysfunction and death in sepsis.Astonishingly, data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) and Extended Evaluation of Recombinant Human Activated Protein C in Severe Sepsis (ENHANCE) trials indicate that the FVL mutation might be associated with improved survival in severe sepsis. 6,7 In the PROWESS trial, mortality of patients with severe sepsis with heterozygous FVL was 15.6%, compared with 31.0% in patients without FVL in the patient group not treated with recombinant aPC (Drotrecogin alfa [activated]). In patients treated with Drotrecogin alfa (...

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Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation

Abstract: To cite this article: Dhainaut J-F, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.

Cited by 392 publications

References 16 publications

A summary of the Japan septic disseminated intravascular coagulation study

A summary of the Japan septic disseminated intravascular coagulation study

Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

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