Protein C

Evidence Level: L5

Predicted Indications: 10

Protein C
Protein C: From Unspecified Original Indication to Glanzmann Thrombasthenia (Top Prediction) — Best-Supported Use: Inherited Thrombophilia

## Pharmacist Assessment Report

Protein C: From Unspecified Original Indication to Glanzmann Thrombasthenia (Top Prediction) — Best-Supported Use: Inherited Thrombophilia

One-Sentence Summary

Protein C is a plasma-derived natural anticoagulant protein. The data compiled for this report do not list an approved indication text for the Singapore licence, but it is used clinically to replace the missing protein in severe congenital Protein C deficiency. The TxGNN model's highest-scoring prediction is Glanzmann thrombasthenia (score 98.6%), but this is biologically implausible: the drug is an anticoagulant and the disease is a bleeding disorder, and no trials or relevant literature support it. The only prediction with real support is inherited thrombophilia (rank 8), backed by 3 relevant clinical studies (1 Phase 2/3, 1 retrospective study and 1 registry) and several review articles. This is essentially the drug's on-label use, not true repurposing.

Quick Overview

Item	Content
Original Indication	Not stated in the licence data (approved indication text is empty)
Predicted New Indication	Glanzmann thrombasthenia (rank 1); best-supported prediction: inherited thrombophilia (rank 8)
TxGNN Prediction Score	98.60% (Glanzmann thrombasthenia); 90.01% (inherited thrombophilia)
Evidence Level	L5 (Glanzmann thrombasthenia); L2 (inherited thrombophilia)
Singapore Market Status	✓ Marketed
Number of Registrations	1
Recommended Decision	Hold (Glanzmann thrombasthenia); Proceed with Guardrails (inherited thrombophilia, restricted to severe Protein C deficiency)

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available from the compiled data. Based on known information, Protein C is a vitamin K-dependent anticoagulant. Its activated form (APC) inactivates coagulation factors Va and VIIIa, which limits clot formation.

Glanzmann thrombasthenia (top-ranked prediction): This is a bleeding disorder caused by a defect in platelet integrin alphaIIb/beta3. Giving an anticoagulant would be expected to worsen bleeding, not relieve it. The high score (0.986) most likely reflects closeness within the haemostasis network of the knowledge graph rather than a real treatment rationale. The same reasoning applies to the other bleeding or platelet disorders in the top 10 (primary release disorder of platelets, pseudo-von Willebrand disease, constitutional thrombocytopenia, collagen receptor defect, Scott syndrome, platelet-type bleeding disorder, fetal and neonatal alloimmune thrombocytopenia). The tenth entry, "flood factor deficiency", appears to be a malformed term that cannot be mapped to a clinical entity.

Inherited thrombophilia (best-supported prediction): Severe congenital Protein C deficiency causes purpura fulminans and venous thromboembolism through loss of the Protein C anticoagulant pathway. Protein C concentrate (Ceprotin) directly replaces the missing protein, so the mechanism is coherent. This is the drug's on-label use, i.e. replacement of the deficient protein rather than repurposing in the strict sense.

Clinical Trial Evidence

No clinical trials are registered for the top-ranked prediction (Glanzmann thrombasthenia). The table below covers the best-supported prediction, inherited thrombophilia. Only trials directly involving Protein C concentrate are included.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00157118	Phase 2/3	Completed	18	Efficacy and safety of Protein C concentrate in severe congenital Protein C deficiency (acute episodes, short-term and long-term prophylaxis)
NCT00161720	N/A	Completed	11	Retrospective dosing and outcome data for patients treated under an emergency use IND; supports clinical use but is not a controlled trial
NCT01127529	N/A	Completed	43	Ceprotin treatment registry; real-world safety and effectiveness data
NCT06590974	N/A	Recruiting	7	Post-marketing surveillance of Ceprotin 1000 IU in Japan; no results available yet
NCT04180657	N/A	Unknown	60	Observational study of ghrelin levels in Protein C deficiency; not an intervention study with Protein C

Literature Evidence

No relevant literature supports Protein C for Glanzmann thrombasthenia. The two retrieved papers (a veterinary review of equine haemostatic disorders and a review of platelet coagulation) are only general background. The table below covers inherited thrombophilia; all are reviews or guidelines, and none is an RCT.

PMID	Year	Type	Journal	Key Findings
39233011	2024	Review (ISTH communication)	J Thromb Haemost	Use of direct oral anticoagulants in severe thrombophilia; evidence limited to cohort and single-centre studies
38733983	2024	Review	Semin Thromb Hemost	Thrombophilia screening should be selective; thrombophilia does not always predict recurrence
24739277	2014	Review	J Pharm Pract	Inherited thrombophilias, including rare natural anticoagulant deficiencies (antithrombin, Protein C, Protein S)
23986205	2013	Review	Adv Clin Exp Med	Practical diagnostic issues in Protein C and Protein S deficiency
29518638	2018	Review	Thromb Res	Thrombophilia testing in children, including Protein C deficiency
37334488	2023	Guideline	BJOG	Recurrent miscarriage guideline; testing for acquired thrombophilia
24365371	2014	Review	Handb Clin Neurol	Thrombophilic states and cerebral venous sinus thrombosis
32204642	2022	Review	J Matern Fetal Neonatal Med	Neonatal thrombosis and its risk factors

Singapore Market Information

Authorization Number	Product Name	Dosage Form	Approved Indication
SIN14933P	OCTAPLEX Powder and Solvent for Solution for Injection 500 IU	Injection, powder, for solution	Not stated in the licence data

Safety Considerations

Drug Interactions: 32 interactions were identified in total. The only one rated Major is caplacizumab. The others are mostly rated Moderate and involve other anticoagulants and thrombolytics, such as warfarin, apixaban, edoxaban, enoxaparin, dalteparin, fondaparinux, argatroban, bivalirudin, alteplase, antithrombin III human and drotrecogin alfa, as well as celecoxib. Concurrent use with these agents needs close monitoring for bleeding.
Mechanism-related concern: For the bleeding and platelet disorders predicted by the model, an anticoagulant would be expected to worsen bleeding.

Please refer to the package insert for further safety information, including warnings and contraindications.

Conclusion and Next Steps

Decision: Hold (Glanzmann thrombasthenia and the other bleeding or platelet disorders); Proceed with Guardrails (inherited thrombophilia, limited to severe congenital Protein C deficiency)

Rationale:

The top-ranked prediction, Glanzmann thrombasthenia, has no trials, no relevant literature and an unfavourable mechanism (an anticoagulant for a bleeding disorder). It should be treated as a graph-proximity artefact.
For inherited thrombophilia, a completed Phase 2/3 study (n=18), a retrospective study and a registry support Protein C replacement in severe congenital deficiency. Evidence is limited to small rare-disease studies and there is no controlled Phase 3 RCT, so the level is L2 rather than L1.

To proceed, the following is needed:

Package insert warnings and contraindications from the HSA (currently missing and blocking for safety screening)
Approved indication text for the Singapore licence
Detailed mechanism of action data
Clarification of whether the Singapore product (a product listed under the Octaplex name) matches the Protein C concentrate used in the trials
Restriction to documented severe Protein C deficiency (not general thrombophilia), with monitoring of Protein C activity and bleeding; the broader thrombophilia literature does not support Protein C supplementation in non-deficient patients
Verification of the term "flood factor deficiency" before any further assessment
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.