DeCure for Thrombomodulin-related bleeding disorder
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for thrombomodulin-related bleeding disorder — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleThrombomodulin-related bleeding disorder maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for thrombomodulin-related bleeding disorder is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
thrombomodulin (THBD) — THBD is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 2s,3sdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5TO3 · 2.34 Å · ligand D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide (0G6). Experimental structure, not a prediction.
What the evidence adds up to
A 2015 study of one family with an autosomal dominant bleeding disorder identified the THBD c.1611C>A mutation, which produces a truncated thrombomodulin that is shed from the endothelium. The proband had life-threatening bleeding during routine surgery, normal clotting times, markedly reduced prothrombin consumption, and severely impaired thrombin generation at low triggers. The patient showed decreased endothelium-bound thrombomodulin and extremely elevated soluble thrombomodulin in plasma, which impaired coagulation by rapidly activating protein C and inactivating factors Va and VIIIa. An unrelated British family with strikingly similar features carried the same mutation.
A 2021 study measured soluble thrombomodulin levels and performed THBD gene analysis in 507 patients with mild to moderate bleeding disorders, including patients with bleeding of unknown cause, and compared them to 90 healthy controls. No difference in soluble thrombomodulin levels was found between patients and controls (median 5.0 vs 5.1 ng/ml, p = 0.762). High soluble thrombomodulin levels were not overrepresented in patients, and soluble thrombomodulin levels had no impact on bleeding severity, thrombin generation, or plasma clot formation. No known pathogenic or novel disease-causing THBD variants affecting soluble thrombomodulin levels were identified in this cohort. The authors concluded that thrombomodulin-associated coagulopathy appears to be rare.
A 2013 case report described a 70-year-old man with decompensated liver cirrhosis and chronic disseminated intravascular coagulation who was treated with recombinant human soluble thrombomodulin. The disseminated intravascular coagulation improved rapidly, but purpura and coagulopathy recurred after two months, requiring repeated treatments. The coagulopathy was controlled for two years without bleeding complications. This is a single case, not a controlled trial.
What is still missing is a systematic trial of any intervention for the thrombomodulin-related bleeding disorder, a clear estimate of its prevalence, and any evidence that reducing soluble thrombomodulin levels improves clinical bleeding outcomes. The 2021 study suggests that in a general mild-to-moderate bleeding disorder population, soluble thrombomodulin is not a useful biomarker, and the disorder itself is too rare to be captured in a cohort of 507 patients. No drug has been tested in patients with the THBD mutation.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2015 · 53 citations · open access
Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation
AbstractWe describe a family with an autosomal dominant disorder characterized by severe trauma- and surgery-related bleeding. The proband, who experienced life-threatening bleeding during a routine operation, had normal clotting times, but markedly reduced prothrombin consumption. Plasma levels of all coagulation factors and of the main coagulation inhibitors were normal. Thrombin generation at low triggers was severely impaired and mixing experiments suggested the presence of a coagulation inhibitor. Using whole exome sequencing, the underlying genetic defect was identified as the THBD c.1611C>A mutation (p.Cys537Stop), which predicts a truncated form of thrombomodulin that is shed from the vascular endothelium. The patient had decreased expression of endothelium-bound thrombomodulin, but extremely elevated levels of soluble thrombomodulin in plasma, impairing the propagation phase of coagulation via rapid activation of protein C and consequent inactivation of factors Va and VIIIa. The same thrombomodulin mutation has been recently described in an unrelated British family with strikingly similar features.
Thrombomodulin in patients with mild to moderate bleeding tendency
AbstractINTRODUCTION: A massive increase of soluble thrombomodulin (sTM) due to variants in the thrombomodulin gene (THBD) has recently been identified as a novel bleeding disorder. AIM: To investigate sTM levels and underlying genetic variants as a cause for haemostatic impairment and bleeding in a large number of patients with a mild to moderate bleeding disorder (MBD), including patients with bleeding of unknown cause (BUC). PATIENTS AND METHODS: In 507 MBD patients, sTM levels, thrombin generation and plasma clot formation were measured and compared to 90 age- and sex-matched healthy controls. In patients, genetic analysis of the THBD gene was performed. RESULTS: No difference in sTM levels between patients and controls was found overall (median ([IQR] 5.0 [3.8-6.3] vs. 5.1 [3.7-6.4] ng/ml, p = .762), and according to specific diagnoses of MBD or BUC, and high sTM levels (≥95th percentile of healthy controls) were not overrepresented in patients. Soluble TM levels had no impact on bleeding severity or global tests of haemostasis, including thrombin generation or plasma clot formation. In the THBD gene, no known pathogenic or novel disease-causing variants affecting sTM plasma levels were identified in our patient cohort. CONCLUSION: TM-associated coagulopathy appears to be rare, as it was not identified in our large cohort of patients with MBD. Soluble TM did not arise as a risk factor for bleeding or altered haemostasis in these patients.
Internal Medicine · 2013 · 1 citations · open access
Effective Control of Relapsing Disseminated Intravascular Coagulation in a Patient with Decompensated Liver Cirrhosis by Recombinant Soluble Thrombomodulin
AbstractA 70-year-old Japanese man was hospitalized for expanding purpura and chronic disseminated intravascular coagulation (DIC) caused by decompensated liver cirrhosis. As there are no effective treatments for chronic DIC caused by liver cirrhosis, we decided to administer recombinant human soluble thrombomodulin (rhsTM) after he provided informed consent. The DIC was rapidly improved; however, the purpura and coagulopathy recurred after two months, and repeated rhsTM treatments were required. The rhsTM treatment sufficiently controlled the coagulopathy for two years, without any complications, including bleeding. This is the first report demonstrating that rhsTM can be administered safely and repeatedly to a patient with decompensated liver cirrhosis, and that it appears to be associated with a favorable outcome.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
