The Function of extravascular coagulation factor IX in haemostasis
Bibliographic record
Abstract
Abstract Introduction The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis. Aim We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half‐life FIX, Alprolix®, to extravascular type IV collagen (Col4). Methods Three mouse models of haemophilia were used: the FIX knockout as the CRM− model and two knock‐in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q) or a mutation that binds poorly to Col4 (FIXK5A). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX. Results CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL‐FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20–40 nM) and show dose‐dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574 nM) was greater than for BeneFIX® (405 nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor. Conclusion Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".