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Clinical Features of Disseminated Intravascular Coagulation According to the French-American-British Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment-A Cohort Study Using a Postmarketing Surveillance Database.

ABSTRACT: The aims of this study were to analyze the clinical features of a large number of cases with disseminated intravascular coagulation (DIC) associated with acute leukemia and to assess the safety and efficacy of thrombomodulin alfa (TM-α) using the French-American-British (FAB) classification of hematological malignancies. We retrospectively examined 644 patients with acute leukemia in postmarketing surveillance for TM-α. M3, M2, M4, M1, and M5 subtypes of acute myeloid leukemia (AML) and L2 and L1 subtypes of acute lymphoblastic leukemia (ALL) have been found more frequently among patients with DIC. Bleeding symptoms at baseline were more frequent in M3 and M7 subtypes. Fibrinogen concentrations were lower, and plasmin-plasmin inhibitor complex values were higher in M3 and Philadelphia-positive (Ph+) ALL. Overall DIC resolution rate was 60.2%, higher in L1 and Ph+ ALL, lower in M1, and generally higher in ALL than in AML. Overall survival rate was generally high, at 79.8%, with higher rates in L3, Ph+ ALL, and M3. Regardless of FAB subgroup, TM-α showed improved bleeding symptoms and DIC scores in clinical practice for DIC patients with acute leukemia.

SUBMITTER: Yoshinobu S

PROVIDER: S-EPMC8652184 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti-inflammatory and cytoprotective activities in septic DIC patients.

Project description:IntroductionSince disseminated intravascular coagulation (DIC) was first described, it has been considered a serious disease of the coagulation system and a major challenge to clinicians. Currently, several important knowledge gaps remain. The DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study will aim to answer questions regarding the incidence and mortality of patients with DIC including time trends. The study will also identify prognostic factors that may guide personalised prevention and treatment. Furthermore, the study will describe treatment patterns and the safety and effectiveness of various treatment modalities.Methods and analysisWe will establish the DANDIC Cohort using data collected in daily clinical practice from the Central Denmark Region, which covers approximately 1.3 million residents. The study period will encompass 1 January 2011 through 1 July 2021. Potential DIC cases will be identified from the hospital laboratory database, based on coagulation biomarkers, and diagnoses will be adjudicated by medical experts. The dataset will be enriched with detailed clinical data from electronic medical charts on aetiologies, bleeding, microthrombus formation, organ failure, thrombosis, treatments and comorbidities. The dataset will also take advantage of in-hospital data with longitudinal information on laboratory records, transfusions, microbiology and treatments. It will be possible to merge this dataset with other unique Danish health registries with more than 10 years of virtually complete follow-up. The project will use state-of-the-art epidemiological and biostatistical methods.Ethics and disseminationThe project has been approved by the Danish Patient Safety Authority (31-1521-452), the Central Denmark Region (1-45-70-83-21), the Danish Data Protection Agency (1-16-02-258-21) and all the hospital chairs. Register-based studies require no ethical approval in Denmark. The results will be disseminated in international peer-reviewed journals.

Dataset Information

Clinical Features of Disseminated Intravascular Coagulation According to the French-American-British Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment-A Cohort Study Using a Postmarketing Surveillance Database.

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