DeCure for Thrombophilia due to protein C deficiency, autosomal dominant
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for thrombophilia due to protein C deficiency, autosomal dominant — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleThrombophilia due to protein C deficiency, autosomal dominant maps to a 2-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 thrombophilia due to protein c deficiency, autosomal dominant 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
pyruvate carboxylase (PC) — PC 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 btndrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8XL9 · 2.61 Å · ligand BIOTIN (BTN). Experimental structure, not a prediction.
What the evidence adds up to
In a family where two infants died of massive venous thrombosis shortly after birth, one infant had undetectable protein C antigen by immunologic assay. The parents, who were first cousins, both had partial protein C deficiency, and reduced protein C levels were found in 12 of 25 additional family members. None of those partially deficient family members, aged 4 to 70 years, had thrombotic episodes. The authors concluded that homozygous protein C deficiency can present as virtual absence of plasma protein C and fatal neonatal thrombosis.
Among 225 patients with a history of venous thrombosis, two females with protein C deficiency were detected by Laurell rocket immunoelectrophoresis. Family studies revealed seven further deficient members. In eight patients not on anticoagulants, protein C ranged from 36 to 62% (median 45%). One patient on oral anticoagulants had protein C antigen below 10%, with factor II and factor X at 65% and 50%. Five of the nine deficient patients had severe thrombotic tendency: recurrent deep venous thrombosis in four, pulmonary embolism in one, probable mesenteric vein thrombosis in one, and superficial thrombophlebitis in two. All deficient patients without thrombosis were under 17 years old. Inheritance was consistent with autosomal dominant transmission.
A 2002 review stated that protein C deficiency is an uncommon genetic abnormality that may contribute to thrombophilia, often together with other genetic or acquired risk factors. The authors recommended a functional amidolytic protein C assay for initial testing, that diagnosis be established only after excluding acquired causes, and that a low level be confirmed on a new specimen. Antigenic assays may help subclassify the type of deficiency. The role of thrombomodulin and endothelial cell protein C receptor in thrombosis was not clearly established, and diagnostic testing for them was not recommended.
One report described a woman with thrombophilia who was heterozygous for both a deficiency and an abnormality of protein C, inherited from her father and mother respectively. Southern blot showed the protein C gene was missing in an allele from her father. In the Vermont II kindred, affected by a clinically dominant type I protein C deficiency, linkage analysis of 34 candidate genes for haemostasis or inflammation — including factor V, prothrombin, protein S, antithrombin III, thrombomodulin, and many others — provided no evidence for a second inherited factor that promotes thrombophilia in that family. A 2018 case report discussed therapeutic alternatives in oral rehabilitation for patients with thrombophilia due to protein C deficiency, but provided no new data on prevalence, natural history, or treatment outcomes. What remains missing is a prospective trial that stratifies patients by protein C level and genotype, and that tests whether anticoagulant prophylaxis reduces thrombosis in asymptomatic carriers, especially children. The cost of such a trial and the rarity of the condition are the main obstacles.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 1984 · 440 citations
Homozygous Protein C Deficiency Manifested by Massive Venous Thrombosis in the Newborn
AbstractWe studied a family in which two infants had died with massive venous thrombosis shortly after birth. Protein C antigen was undetectable by immunologic assays of plasma available from one infant. (Protein C is a potent naturally occurring anticoagulant that inactivates activated coagulation factors V and VIII). The parents, who were first cousins, both had partial protein C deficiency. Reduced protein C levels were also observed in 12 of 25 additional family members. None of the partially deficient family members (age range 4 to 70 years) had thrombotic episodes. Our data support the view that hereditary protein C deficiency is an autosomal disorder in which the homozygous state may be manifested by the virtual absence of plasma protein C and by fatal thrombosis in the neonatal period.
AbstractProtein C antigen was determined by Laurell rocket immunoelectrophoresis in 225 patients with a history of venous thrombosis. Among these patients two females with protein C deficiency were detected. Additional studies in the families of the protein C deficient patients revealed further 7 family members with protein C deficiency. In 8 not anticoagulated patients with protein C deficiency the protein C ranged from 36 to 62% (median: 45%). In one patient on oral anticoagulant treatment protein C antigen concentration was less than 10%, F II and FX were 65 and 50%, respectively. The pattern of inheritance was consistent with autosomal dominant inheritance. 5 of the 9 protein C deficient patients had severe thrombotic tendency characterized by recurrent deep venous thrombosis (n = 4), pulmonary embolism (n = 1), probable mesenteric vein thrombosis (n = 1) and superficial thrombophlebitis (n = 2). All protein C deficient patients without thrombosis were less than 17 years old.
Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and endothelial cell protein C receptor.
AbstractOBJECTIVE: To review the current understanding of the pathophysiology of protein C deficiency and its role in congenital thrombophilia. Recommendations for diagnostic testing for protein C function and concentration, derived from the medical literature and consensus opinions of recognized experts in the field, are included, specifying whom, how, and when to test. The role of related proteins, such as thrombomodulin and endothelial protein C receptor, is also reviewed. Data Sources.-Review of the published medical literature. DATA EXTRACTION AND SYNTHESIS: A summary of the medical literature and proposed testing recommendations were prepared and presented at the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. After discussion at the conference, consensus recommendations presented in this manuscript were accepted after a two-thirds majority vote by the participants. CONCLUSIONS: Protein C deficiency is an uncommon genetic abnormality that may be a contributing cause of thrombophilia, often in conjunction with other genetic or acquired risk factors. When assay of protein C plasma levels is included in the laboratory evaluation of thrombophilia, a functional amidolytic protein C assay should be used for initial testing. The diagnosis of protein C deficiency should be established only after other acquired causes of protein C deficiency are excluded. A low protein C level should be confirmed with a subsequent assay on a new specimen. Antigenic protein C assays may be of benefit in subclassification of the type of protein C deficiency. The role of thrombomodulin and endothelial cell protein C receptor in thrombosis has yet to be clearly established, and diagnostic testing is not recommended at this time.
New England Journal of Medicine · 1988 · 55 citations
A Thrombotic State Due to an Abnormal Protein C
AbstractPROTEIN C is the zymogen of a serine protease that regulates blood coagulation by inactivating thrombin-activated blood coagulation factors V and VIII.1 2 3 A congenital deficiency of this plasma protein is associated with a high incidence of thromboembolic disease.4 5 6 We report the case of a woman with thrombophilia who was heterozygous for both a deficiency and an abnormality of protein C, conditions inherited from her father and mother, respectively. Southern blot analysis of leukocyte DNA showed that the protein C gene was missing in an allele derived from the patient's father. DNA-sequence analysis of the protein C gene in the mutant . . .
Genetic Screening of Candidate Genes for a Prothrombotic Interaction with Type I Protein C Deficiency in a Large Kindred
AbstractThe incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.
International Journal of Medical and Surgical Sciences · 2018 · 0 citations · open access
Therapeutic Approach in Oral Rehabilitation of Patients Diagnosed with Thrombophilia, Protein C Deficiency
AbstractThrombophilia is defined as any alteration, either congenital or acquired, which promotes and/or facilitates the presentation of a thrombotic phenomenon. Drug treatment of this condition is to prevent (prophylaxis) other thrombotic event by anticoagulant therapy and hemostasis is affected, taking this great implication in the therapeutic approach in oral rehabilitation, leaning realize treatments with prosthetic structures on implants, teeth or tissue-borne. The aim of this case report is to present therapeutic alternatives in patients diagnosed with thrombophilia with protein C deficiency.
Internal Medicine · 2019 · 0 citations · open access
Significance of a Family-based Study of Hereditary Thrombosis: A Single-family Case Series of Protein C Deficiency
AbstractThrombophilia is a serious unpredictable complication caused by gene mutations, resulting in anticoagulant deficiencies. We herein report a single-family case series of protein C (PC) deficiency. Case 1 involved a Japanese man whose PC deficiency resulted in severe systemic thrombosis. The patients in cases 2 and 3 were his daughters who were diagnosed with PC deficiency via carrier screening in 2001 and later both became pregnant. Owing to appropriate treatments during pregnancy, they did not develop thrombosis and safely gave birth to healthy infants. This family case series suggests that appropriate knowledge concerning thrombophilia helps prevent future emergencies.
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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