Inter Individual Variability in Initiation Pathway Activation and Regulation and Phenotypic Heterogeneity in Patients With Haemophilia A and B

Study Overview
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Brief Summary
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Severe haemophilia A and B (SHA, SHB) are X - linked inherited bleeding disorders, characterised by factor VIII and IX levels of <1 IU/dL respectively. The mainstay of treatment in SHA and SHB is replacement therapy with intravenous infusions of factor VIII and IX. However, there is significant variability in the bleeding phenotype within severe haemophiliacs with some presenting with minimal bleeding episodes even on less intensive treatment regimens. A significant contributor to inter-individual variability in the bleeding phenotype is the coagulation phenotype, but there are no established assays in routine clinical practice that can be used to quantify this. This study aims to study novel assays and characterise the observed phenotypic heterogeneity.

Official Title
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Inter Individual Variability in Initiation Pathway Activation and Regulation and Phenotypic Heterogeneity in Patients With Haemophilia A and B

Conditions
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Haemophilia

Intervention / Treatment
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* Diagnostic Test: Thrombophilia screen
* Diagnostic Test: Initiation pathway analysis


Participation Criteria
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Eligibility Criteria
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Patients Inclusion Criteria: Patients with haemophilia A or B (baseline FVIII/FIX level <30%) Age ≥ 18 years Written informed consent in accordance with local and institutional guidelines. Exclusion Criteria: 1. Patients currently enrolled into a clinical trial of investigational medicinal product for haemophilia. Healthy Volunteers Inclusion Criteria: Currently not receiving any antiplatelet or anticoagulant therapy or other drugs that can affect the coagulation system. Age ≥ 18 years Written informed consent in accordance with local and institutional guidelines.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Haemophilia patients<br>Persons with haemophilia A or B - 240 to be recruited | Diagnostic Test: Thrombophilia screen<br>* Thrombophilia screen (including antithrombin activity (AT:Ac), protein S antigen (PS:free), protein C activity (PC:Ac) , genetic analysis for FV Leiden and Prothrombin 3'UTR mutations and screening for lupus anticoagulant.<br>Diagnostic Test: Initiation pathway analysis<br>* Evaluation of inter-individual variability in regulation of TF.VIIa.Xa.TFPI complex (tissue factor, activated Factor VII, activated factor X, tissue factor pathway inhibitor)<br>|
| Healthy volunteers<br>Healthy volunteers - 10 to be recruited | Diagnostic Test: Thrombophilia screen<br>* Thrombophilia screen (including antithrombin activity (AT:Ac), protein S antigen (PS:free), protein C activity (PC:Ac) , genetic analysis for FV Leiden and Prothrombin 3'UTR mutations and screening for lupus anticoagulant.<br>Diagnostic Test: Initiation pathway analysis<br>* Evaluation of inter-individual variability in regulation of TF.VIIa.Xa.TFPI complex (tissue factor, activated Factor VII, activated factor X, tissue factor pathway inhibitor)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initiation pathway correlation with clinical phenotype | Correlate lab assays that characterise initiation pathway with clinical phenotype. | Within 18 months of consent | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation analysis between FVIII:C/FIX:C levels and whole blood clotting time, thrombin generation in platelet poor plasma. |  | Within 18 months of consent | 
| Evaluation the sensitivity and specificity of global assays for disease severity and clinical phenotype. |  | Within 18 months of consent | 
| Correlation analysis between activation threshold of initiation pathway to thrombin generation and clinical phenotype |  | Within 18 months of consent |