Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum

Abstract

It has been suggested that use of recombinant soluble thrombomodulin (rTM) is superior to conventional drugs in treatment of disseminated intravascular coagulation (DIC) complicating acute leukemia. However, its safety and efficacy have not been fully examined in prospective studies. Here, we performed a multicenter prospective study to examine outcomes of rTM treatment for DIC in patients with acute leukemia. Of 33 patients registered in this study, 13 had acute myeloid leukemia (AML), three had acute lymphoblastic leukemia (ALL), and 17 had acute promyelocytic leukemia (APL). The cumulative rates of DIC resolution at day 7 and day 35 were 56 and 81% in AML/ALL and 53 and 77% in APL, respectively. The median time from the initiation of rTM to DIC resolution was 4 days in AML/ALL and 6 days in APL patients. Adverse events related to hemorrhage occurred in two AML/ALL patients (13%) and three APL patients (18%). Of these, one AML/ALL patient died with intracranial hemorrhage, and two APL patients died with intracranial hemorrhage and pulmonary hemorrhage. These results suggest that rTM may improve the survival of acute leukemia patients with DIC by inhibiting early death related to hemorrhagic events, as reported previously.

Comparison of Danaparoid Sodium and Synthetic Protease Inhibitors for the Treatment of Disseminated Intravascular Coagulation Associated with Hematological Malignancies: A Retrospective Analysis

“…There are some differences in the recommendations regarding the use anticoagulants for DIC, and a consensus has not been reached in the guidelines, which could be attributed to the scarcity of randomized controlled studies and clinical results of observational studies. Table 5 summarizes prior studies on the use of anticoagulants for the treatment of DIC in patients with hematological malignancies [9, 12, 15, 18-25]. DIC resolution rates on day 7 have been reported to be 40–60%, which is consistent with our results.…”

“…DIC resolution rates on day 7 have been reported to be 40–60%, which is consistent with our results. The cumulative incidence of bleeding-related mortality tended to be lower in the SPI group than in the danaparoid group (3.3 vs. 6.6%); however, these incidences were lower than those in previous studies about UFH and LMWH (6.1–12.5%) [15, 22-23, 25]. In addition, most previous studies were retrospective studies in patients with different backgrounds, and therefore prospective studies are needed to evaluate the use of anticoagulants, including danaparoid and SPIs, for the treatment of DIC.…”

Hemostatic function in hyperfibrinolytic disseminated intravascular coagulation

“…This novel agent seems to mediate fewer hemorrhagic side-effects than low-molecularweight heparin and improves overall survival. [20][21][22] Daily rTM from admission, however, failed to prevent severe epistaxis in the present young patient. Combination therapy using nafamostat mesilate or heparin and TXA may be dramatically effective for severe bleeding in patients with DIC and enhanced fibrinolysis.…”

“…Recombinant thrombomodulin is generally recommended in DIC associated with adult AML. This novel agent seems to mediate fewer hemorrhagic side‐effects than low‐molecular‐weight heparin and improves overall survival . Daily rTM from admission, however, failed to prevent severe epistaxis in the present young patient.…”

Disseminated Intravascular Coagulation in Cancer: An Update

“…A large series of retrospective trials, typically from Japan, confirmed a possible benefit of thrombomodulin in the supportive management of cancer coagulopathies. [70][71][72][73] Antifibrinolytic treatment, usually by lysine analogues, such as tranexamic acid, is an effective therapy in patients with severe hemorrhage, in particular in cases with a hyperfibrinolytic pattern (identified by very low α2-antiplasmin and fibrinogen levels). 74 However, as fibrin deposition in cancer-related coagulopathy can partly be caused by an already insufficient endogenous fibrinolytic system, additional inhibition of the fibrinolysis may theoretically be inappropriate and can even contribute to thrombotic complications.…”