Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin

Abstract

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhagerelated death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

Analysis of the association between resolution of disseminated intravascular coagulation (DIC) and treatment outcomes in post-marketing surveillance of thrombomodulin alpha for DIC with infectious disease and with hematological malignancy by organ failure

“…Keywords: DIC, Infectious disease, Hematological malignancy, SOFA, Bilirubin, Creatinine Background Disseminated intravascular coagulation (DIC) is a lifethreatening clinical condition with high mortality due to the severe underlying disease, such as sepsis, hematological malignancy, and solid tumors, that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure [1][2][3][4][5]. Although the mechanism of DIC differs depending on the underlying disease, there is a common process across all cases, characterized by excessive production of thrombi that cause fibrin generation and deposition.…”

“…Although the mechanism of DIC differs depending on the underlying disease, there is a common process across all cases, characterized by excessive production of thrombi that cause fibrin generation and deposition. Furthermore, fibrinolytic activation and overconsumption of anticoagulation factors can lead to systemic hemorrhage [1][2][3][4][5].…”

Educational Case: Acute Promyelocytic Leukemia With PML-RARA

“…At the same time, APL cells have increased cell surface expression of annexin II and proteases leading to plasmin generation and hyperfibrionolysis. 4 …”

Disseminated intravascular coagulation in non-Hodgkin lymphoma

“…All of them, who were admitted to our institute since Sep. 2008 to May. 2014, had overt DIC at the time of diagnosis and received recombinant thrombomodulin to treat the coagulopathy [4]. Statistical comparison of the laboratory data is based on the Mann-Whitney U test and adjusting the Kaplan-Meier survival curves follows Cox proportional hazard model.…”