DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital prothrombin deficiency — 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 moduleCongenital prothrombin deficiency 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 congenital prothrombin deficiency 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
coagulation factor II, thrombin (F2) — F2 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8RTN · 2.51 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Congenital prothrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of about 1:2,000,000. Two main phenotypes exist: hypoprothrombinemia (type I), with low activity and antigen levels, and dysprothrombinemia (type II), with normal synthesis of a dysfunctional protein. No living patient with undetectable plasma prothrombin has been reported. Forty different mutations have been identified in the prothrombin gene, many around the catalytic site or in the anion binding exosite I. Most hypoprothrombinemia-associated mutations are missense, but nonsense mutations and a single nucleotide deletion also occur.
The 2019 abstract on antithrombin deficiency is about a different disorder — congenital antithrombin deficiency, a thrombophilic state — and does not address prothrombin deficiency. The 2021 abstract describes a phase III study (ATN-106, NCT04918173) of a human antithrombin III concentrate (Atenativ) in congenital antithrombin deficiency, not prothrombin deficiency. That study plans to enrol 34 patients with documented antithrombin deficiency (plasma antithrombin ≤60%) and a personal or family history of thrombotic events. It is a single-group, open-label design, with a primary outcome of composite thrombotic and thromboembolic events. Enrollment was estimated to start in Q3 2021 and end in Q3 2024.
No abstract in this set reports any clinical trial, treatment outcome, or survival data for congenital prothrombin deficiency. The 2009 review states that clinical manifestations and therapy are presented and discussed, but gives no concrete numbers on response rates or survival. What is missing for prothrombin deficiency is any prospective trial data, any evidence for a specific replacement therapy, and any patient stratification beyond mutation type. The field lacks funding for a dedicated trial and a clear design for measuring efficacy in a disorder this rare.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Seminars in Thrombosis and Hemostasis · 2009 · 74 citations
Congenital Prothrombin Deficiency
AbstractProthrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of approximately 1:2,000,000. Two main phenotypes can be distinguished: (1) hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a gene of approximately 21 kb located on chromosome 11 and containing 14 exons. Forty different mutations have been identified and characterized in prothrombin deficiency. Many of them surround the catalytic site, whereas another "hot spot" is localized in the recognition domain called anion binding exosite I, also called fibrinogen recognition site. Recently, mutations were identified also in the Na (+)-binding loop and in the light A-chain of thrombin. Most hypoprothrombinemia-associated mutations are missense, but there are also nonsense mutations leading to stop codons and one single nucleotide deletion. Finally, the main aspects of clinical manifestations and therapy of congenital prothrombin deficiency are presented and discussed.
Management of antithrombin deficiency: an update for clinicians
AbstractIntroduction. Antithrombin is a serpin that inhibits multiple procoagulant serine proteases and acts as an endogenous anticoagulant. Thus, congenital antithrombin deficiency constitutes a major thrombophilic state, the most severe so far.Areas covered. In the present work, we globally review the biology, genetics, diagnosis, and management of congenital antithrombin deficiency, and also discuss puzzling questions and future perspectives regarding this severe inherited thrombophilia.Expert opinion. Although this disorder exerts high clinical heterogeneity, many carriers will need careful and long-term anticoagulation and/or thromboprophylaxis, especially in high-risk situations, such as surgery and pregnancy. Notably, antithrombin concentrates constitute a considerable arsenal for both treatment and prevention of acute venous thrombosis in subjects with antithrombin deficiency. Current evidences are based almost exclusively on retrospective case series, so an integrated functional, biochemical and molecular characterization will be of clinical relevance and guide hematologists’ personalized decisions.
A Study of Three Cases of Familial Congenital Hypoprothrombinaemia (Factor II Deficiency)
AbstractSummary Three cases of true congenital hypoprothrombinaemia are presented. Studies were made to prove the deficiency of prothrombin in the patient’s plasma and to rule out deficiency of other clotting factors or the presence of abnormal anti-thrombin substances. All the patients were of group B. The results obtained confirm that the patients have a real prothrombin deficiency as the cause of a severe haemorrhagic disease.
Prospective, Phase III Study of the Efficacy, Safety, and Pharmacokinetics of a Human Antithrombin III Concentrate in Congenital Antithrombin Deficiency during Surgery or Childbirth
AbstractAbstract Introduction: Congenital antithrombin deficiency (CAD) is a rare genetic blood disorder commonly associated with spontaneous thrombotic events (TEs) and thromboembolic events (TEEs) that can occur in connection with surgery and childbirth. Although regular prophylactic antithrombin substitution is not necessary, human plasma-derived antithrombin replacement therapy or recombinant antithrombin replacement therapy can be used for the prevention of TEs/TEEs during and after surgery or childbirth. This study will aim to evaluate the efficacy, safety, and pharmacokinetics (PK) of a high-purity, double virus inactivated, lyophilized human antithrombin III concentrate (Atenativ ®) in these settings. Methods: The ATN-106 study (NCT04918173) is a multicenter, prospective, interventional, single-group, open-label, Phase III study in adult (≥18 and ≤80 years) male and female patients with documented CAD (plasma antithrombin ≤60%), and personal or family history of TEs or TEEs. The study will enrol 34 patients with CAD, including >14 non-pregnant patients for the PK phase and ~20 patients who are either a) non-pregnant and scheduled to undergo an elective surgical procedure known to be associated with a high risk for occurrence of TEs or TEEs, or b) pregnant and scheduled for caesarean section or delivery. For PK analysis, patients will receive a single 60 IU/kg intravenous (IV) infusion of antithrombin concentrate. For efficacy and safety analyses, a single IV dose to target an antithrombin level of 120% of normal will be administered to patients prior to surgery/delivery followed by maintenance doses administered every 24 hours for ~2-7 (surgical patients) or ~5 (delivery patients) days to target an antithrombin level of 80-120% of normal. A schematic representation of the ATN-106 study design is presented in Figure 1. The primary outcome measure will be the incidence of the composite of TEs and TEEs; secondary outcome measures will include single-dose PK (area under the curve [AUC norm(0-∞)], maximum plasma concentration [C max], half-life [T 1/2], mean residence time [MRT], clearance [CL], incremental in vivo recovery [IVR], volume of distribution at steady state [V ss]) and coagulation (activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalised ratio [INR], fibrinogen level) parameters, as well as safety and tolerability (number of adverse events [AEs]). Results: Enrollment of participants in the ATN-106 study is estimated to start in Q3 2021 and end in Q3 2024. Conclusions: The results from this pivotal registration study are expected to confirm and strengthen the available evidence indicating that human plasma-derived antithrombin concentrate is effective in preventing thrombotic and thromboembolic events in patients with CAD in surgery and delivery settings and has a favorable safety profile. Figure 1 Figure 1. Disclosures Schwartz: Octapharma: Current Employment. Solomon: Octapharma: Current Employment. Knaub: Octapharma: Current Employment. Kessler: Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Indian Journal of Child Health · 2019 · 0 citations · open access
Isolated congenital factor VII deficiency
AbstractCongenital factor VII (FVII) (proconvertin) is a rare autosomal recessive bleeding disorder. Bleeding manifestations and clinical findings vary widely, ranging from being asymptomatic to life-threatening bleeding. Intracranial bleeding is relatively less common with inherited FVII deficiency than with other coagulation disorders. We report a rare case of congenital FVII deficiency in an 11-year-old male child. The patient had recurrent subdural hemorrhages. The prothrombin time was markedly prolonged with a normal bleeding time, normal partial thromboplastin time and normal platelet count. Treatment consists of replacement therapy with fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII concentrates, and/or recombinant factor VIIa. Clinical heterogeneity is the hallmark of this disorder.
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.
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