DeCure for Thrombophilia due to protein C deficiency, autosomal recessive
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for thrombophilia due to protein C deficiency, autosomal recessive — 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 recessive 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 recessive 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
Homozygous protein C deficiency can present as massive venous thrombosis in the newborn period, with one 1984 study reporting undetectable protein C antigen by immunologic assay in a deceased infant whose first-cousin parents both had partial deficiency. Among 25 family members, 12 had reduced protein C levels but none aged 4 to 70 years had thrombotic episodes, supporting an autosomal recessive pattern where the homozygous state may be fatal in neonates.
In a 1983 study of 225 patients with a history of venous thrombosis, two females with protein C deficiency were found, and family screening identified seven more deficient members. In eight patients not on anticoagulants, protein C ranged from 36 to 62% (median 45%). Five of the nine deficient patients had severe thrombotic tendency including recurrent deep venous thrombosis (n=4), pulmonary embolism (n=1), probable mesenteric vein thrombosis (n=1), and superficial thrombophlebitis (n=2). All deficient patients without thrombosis were under 17 years old.
A 1988 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 analysis showed a missing protein C allele from the father, and DNA sequencing identified a mutation in the other allele.
A 2024 case report describes a 23-year-old woman with severe homozygous protein C type 1 deficiency diagnosed in early infancy, with a history of misdiagnosed cellulitis, recurrent thrombosis, and permanent vision loss in one eye. Management required fresh frozen plasma, protein C concentrate, warfarin, and heparin, but was complicated by recurrent thrombosis and anaphylaxis to fresh frozen plasma. The authors state that current treatments provide only partial control. What remains missing are safer and more effective therapies, as no controlled trials have established optimal long-term regimens, and patient stratification by genotype or residual protein C activity is not yet standardised.
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.
Archives of Pathology & Laboratory Medicine · 2002 · 86 citations
Laboratory Issues in Diagnosing Abnormalities of Protein C, Thrombomodulin, and Endothelial Cell Protein C Receptor
AbstractAbstract Objective. —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.
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.
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 . . .
Vascular Health and Risk Management · 2020 · 13 citations · open access
<p>Prevalence and Outcomes of Thrombophilia in Patients with Acute Pulmonary Embolism</p>
AbstractBackground: We aimed to study the prevalence and outcomes of thrombophilia in acute pulmonary embolism. Methods: A retrospective observational study was conducted to include patients with a radiologically confirmed diagnosis of PE screened for thrombophilia from May 2011 to February 2015. Data included patients’ demographics; clinical presentation, risk factors, laboratory investigations, management, and outcome were analyzed and compared in patients with and without thrombophilia. Results: A total of 227 cases of PE were included in the study, of which 108 (47.6%) had thrombophilia. The most frequent coagulopathic abnormality included deficiency of protein S, protein C, and antithrombin III and hyperhomocysteinemia. Only seven out of 79 patients were found to have factor V Leiden. PE patients diagnosed with thrombophilia were 10 years younger in age and peaked in the age range 30– 39 years. Prior history of DVT ( p =0.001) and PE ( p =0.001) were the main significant risk factors in the thrombophilia group. The frequency of different risk categories of clinical probability scores did not differ significantly among those with and without thrombophilia. Pulmonary hypertension was a common complication in the thrombophilia group ( P =0.009). Medications used included warfarin (74.7%), enoxaparin (73.9%), and heparin (55.4%). The overall mortality rate was 8.4%, and was non-significantly higher in the non-thrombophilia group. Conclusion: Deficiencies of protein S, protein C, and antithrombin III are the leading causes of thrombophilic defects. Patients with hereditary thrombophilia are at increased risk of acute PE, particularly among young individuals. Therefore, early detection of thrombophilic defects together with other unprovoked risk factors could reduce the risk of recurrent VTE. Keywords: pulmonary embolism, thrombophilia, risk factors, thromboembolism, outcome
Severe protein C deficiency in a newborn caused by a homozygous pathogenic variant in the PROC gene: a case report
AbstractBACKGROUND: Severe protein C deficiency is a rare and inherited cause of thrombophilia in neonates. Protein C acts as an anticoagulant, and its deficiency results in vascular thrombosis. Herein, we report a case of protein C deficiency with a homozygous pathogenic variant in a term neonate, with good outcomes after proper treatment. CASE PRESENTATION: A four-day-old male newborn was transferred to the Seoul National University Hospital on account of dark red to black skin lesions. He was born full-term with an average birth weight without perinatal problems. There were no abnormal findings in the prenatal tests, including intrauterine sonography. The first skin lesion was observed on his right toes and rapidly progressed to proximal areas, such as the lower legs, left arm, and buttock. Under the impression of thromboembolism or vasculitis, we performed a coagulopathy workup, which revealed a high D-dimer level of 23.05 μg/ml. A skin biopsy showed fibrin clots in most capillaries, and his protein C activity level was below 10%, from which we diagnosed protein C deficiency. On postnatal day 6, he experienced an apnea event with desaturation and an abnormal right pupillary light reflex. Brain computed tomography showed multifocal patchy intracranial hemorrhage and intraventricular hemorrhage with an old ischemic lesion. Ophthalmic examination revealed bilateral retinal traction detachments with retinal folds. Protein C concentrate replacement therapy was added to previous treatments including steroids, prostaglandin E1, and anticoagulation. After replacement therapy, there were no new skin lesions, and the previous lesions recovered with scarring. Although there were no new brain hemorrhagic infarctions, there was ongoing ischemic tissue loss, which required further rehabilitation. Ophthalmic surgical interventions were performed to treat the bilateral retinal traction detachments with retinal folds. Molecular analysis revealed a homozygous pathogenic variant in the PROC gene. CONCLUSION: Severe protein C deficiency can manifest as a fatal coagulopathy in any organ. Early diagnosis and proper treatment, including protein C concentrate replacement, may improve outcomes without serious sequelae.
Challenges in managing severe homozygous protein c deficiency: a case report
AbstractProtein C deficiency is a rare autosomal recessive disorder associated with a high risk of thromboembolic complications. This case report describes the challenges in managing a 23-year-old woman with severe homozygous protein C type 1 deficiency diagnosed since early infancy. Her medical history included misdiagnosed cellulitis, recurrent thrombosis, and permanent vision loss in one eye. The laboratory workup confirmed a diagnosis of severe protein C deficiency. Management involved a combination of fresh frozen plasma (FFP), protein C concentrate, warfarin, and heparin, with ongoing challenges due to recurrent thrombosis and anaphylaxis to FFP. This case highlights the challenges in the diagnosis and management of severe protein C deficiency. Although current treatment options provide partial control, further research is crucial to develop safer and more effective therapies to improve long-term outcomes for affected patients.
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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