Two Japanese families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A: a case report.

Background: Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling.

A Japanese Family Meeting the Clinical Diagnostic Criteria for MEN1 with a MEN1 Variant of Uncertain Significance.

Multiple gastroenteric, pancreatic, and pituitary neuroendocrine neoplasms (NENs) were diagnosed in a 74-year-old man with a history of primary hyperparathyroidism (PHPT). Germline testing demonstrated a variant of MEN1 (c.1694T>A, p.

Sepsis-Associated DIC with Decreased Levels of Antithrombin and Fibrinogen is the Target for Combination Therapy with Thrombomodulin Alfa and Antithrombin.

 Disseminated intravascular coagulation (DIC) is not a homogeneous condition, but rather includes heterogeneous conditions, and its pathophysiology and outcome vary considerably depending on the background. Although anticoagulant therapy is expected to be of benefit in the treatment of DIC, previous studies have suggested that the benefits are limited only to a specific subtype.  The purpose of this study was to identify the group that would benefit from combination therapy using thrombomodulin/antithrombin.

A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis.

Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis.

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.

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.

An evaluation of the Japanese Society on Thrombosis and Hemostasis criteria for disseminated intravascular coagulation as a predictor of prognosis in patients with infection.

Introduction: A criterion for disseminated intravascular coagulation (DIC) that reflects the status of controlled coagulopathy would be useful for determining when to stop treatment. Use of the DIC criteria of the Japanese Society on Thrombosis and Hemostasis (JSTH) for predicting the outcome during recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) treatment was evaluated.

Methods: A retrospective, multicenter survey was conducted in 798 medical facilities in Japan.

Specific detection of high mobility group box 1 degradation product with a novel ELISA.

Background: During sepsis or sterile tissue injury, the nuclear protein high mobility group box 1 (HMGB1) can be released to the extracellular space and ultimately into systemic circulation, where it mediates systemic inflammation and remote organ failure. The proinflammatory effects of HMGB1 can be suppressed by recombinant thrombomodulin (rTM), in part through a mechanism involving thrombin-rTM-mediated degradation of HMGB1. Given that HMGB1 is proinflammatory but the HMGB1 degradation product (desHMGB1) is not, an analytical method that discriminates between these two molecules may provide a more in-depth understanding of HMGB1-induced pathogenicity as well as rTM-mediated therapeutic efficiency.

Effects of thrombomodulin alfa on hemostatic parameters in disseminated intravascular coagulation: Post hoc analysis of a phase 3 randomized controlled trial.

Background: The efficacy and safety of thrombomodulin alfa (TM-α), a cofactor protein promoting thrombin-mediated protein C activation, have been examined in a phase 3 randomized, double-blinded, parallel-group trial in Japan. We have previously reported that TM-α is noninferior to heparin for the resolution of disseminated intravascular coagulation (DIC).

Objective: To investigate the basis for the efficacy of TM-α in the phase 3 clinical trial in Japan through post hoc analysis of coagulation and fibrinolysis parameters.

Severe Antithrombin Deficiency May be Associated With a High Risk of Pathological Progression of DIC With Suppressed Fibrinolysis.

The frequency of severe antithrombin deficiency (SAD) was examined in the hematopoietic disorder-, infectious-, and basic-types of the disseminated intravascular coagulation (DIC). A posthoc analysis of 3008 DIC patients (infectious-type, 1794; hematological disorder-type, 813; and basic-type, 401) from post-marketing surveillance data of thrombomodulin alfa was performed. The clinical features of patients and outcomes were compared between patients with and without SAD, using an antithrombin cutoff value of 50%.

A case of thrombomodulin mutation causing defective thrombin binding with absence of protein C and TAFI activation.

Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki).

Cytoprotective and pro-angiogenic functions of thrombomodulin are preserved in the C loop of the fifth epidermal growth factor-like domain.

We previously found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) exerts cytoprotective and pro-angiogenic functions G-protein coupled receptor 15 (GPR15). TME5 is comprised of three S-S bonds that divide it into three loops: A (TME5A), B (TME5B), and C (TME5C). Herein we identified the minimum structure of TME5 that produces favorable effects in vascular endothelial cells (ECs).

Surveillance of the safety and efficacy of recombinant human soluble thrombomodulin in patients with obstetrical disseminated intravascular coagulation.

Background: Recombinant human soluble thrombomodulin (TM-α) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study, and has been available for clinical use in Japan since 2008. However, use of TM-α for obstetrical DIC has not yet been established, so efficacy and safety were analyzed in 117 obstetrical DIC patients identified from post-marketing surveillance.

Materials And Methods: From June 2010 to March 2012, the cases of 117 patients with obstetrical DIC treated with TM-α were registered.

Human soluble thrombomodulin-induced blockade of peripheral HMGB1-dependent allodynia in mice requires both the lectin-like and EGF-like domains.

Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMα) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMα sequesters HMGB1 with the lectin-like D1 and promotes its degradation by thrombin binding to the EGF-like D2.

The Fifth Epidermal Growth Factor-like Region of Thrombomodulin Alleviates Murine Graft-versus-Host Disease in a G-Protein Coupled Receptor 15 Dependent Manner.

Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD.

The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15.

Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation.

LFA-1 and Mac-1 integrins bind to the serine/threonine-rich domain of thrombomodulin.

LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins regulate leukocyte trafficking in health and disease by binding primarily to IgSF ligand ICAM-1 and ICAM-2 on endothelial cells. Here we have shown that the anti-coagulant molecule thrombomodulin (TM), found on the surface of endothelial cells, functions as a potentially new ligand for leukocyte integrins. We generated a recombinant extracellular domain of human TM and Fc fusion protein (TM-domains 123-Fc), and showed that pheripheral blood mononuclear cells (PBMCs) bind to TM-domains 123-Fc dependent upon integrin activation.

Thrombomodulin alfa treatment in patients with acute promyelocytic leukemia and disseminated intravascular coagulation: a retrospective analysis of an open-label, multicenter, post-marketing surveillance study cohort.

Introduction: Patients with acute promyelocytic leukemia (APL) can develop disseminated intravascular coagulation (DIC) that results in life-threatening hemorrhagic complications. Studies regarding the safety and efficacy of thrombomodulin alfa (TM-α; recombinant human soluble thrombomodulin) in patients with APL and DIC are limited.

Materials And Methods: A retrospective evaluation was performed on a cohort of 172 patients with APL from an open-label, multicenter, post-marketing surveillance study of TM-α.

Postmarketing Surveillance of Recombinant Human Soluble Thrombomodulin (Thrombomodulin α) in Pediatric Patients With Disseminated Intravascular Coagulation.

Recombinant human soluble thrombomodulin (thrombomodulin α [TM-α]) has been marketed as a novel anticoagulant for disseminated intravascular coagulation (DIC) in Japan since 2008. Postmarketing surveillance (PMS) has been conducted since its approval. As effectiveness and safety were not previously determined in pediatric patients, this study evaluated PMS data and examined the usefulness of TM-α in treating pediatric DIC.

Recombinant soluble human thrombomodulin (thrombomodulin alfa) in the treatment of neonatal disseminated intravascular coagulation.

Unlabelled: Recombinant soluble human thrombomodulin (TM-α) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study and has been available for clinical use in Japan since 2008. However, data on its use for neonatal DIC have not been reported from any clinical studies, so efficacy and safety were analyzed in 60 neonatal DIC patients identified in post-marketing surveillance. The DIC resolution rate as of the day after last administration of TM-α was 47.

Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling.

We found recombinant human soluble thrombomodulin (rTM) induced growth arrest and differentiation of THP-1 cells by activating JNK/c-Jun signaling. Further activation of JNK by 1,25-(OH)(2)D(3) significantly enhanced rTM-mediated growth arrest and differentiation of THP-1 cells. Importantly, forced expression of domains 1, 2 and 3 of TM (TMD123) induced growth arrest and differentiation of leukemia cells freshly isolated from individuals with AMLs of M4/M5-French-American-British classification subtypes, but not those with less advanced AML.