Inherited Antithrombin Deficiency (v2)

• Research type

  Research Study

• Full title

  Clinical, biochemical and molecular characterisation of patients with inherited antithrombin deficiency, with investigation of the possible interactions between antithrombin and the inflammatory response

• IRAS ID

  284810

• Contact name

  Beverley Hunt

• Contact email

  Beverley.Hunt@gstt.nhs.uk

• Sponsor organisation

  The University of Portsmouth

• Clinicaltrials.gov Identifier

  N/A, N/A

• Duration of Study in the UK

  2 years, 5 months, 27 days

• Research summary

  Research Summary:

  Inherited antithrombin deficiency is associated with a significant risk for developing venous thromboembolism. An accurate diagnosis of antithrombin deficiency is crucial for antithrombotic treatment, screening other family members and the management of clinical situations such as pregnancy.
  This is a cross-sectional study aiming to provide an improved understanding of the condition by further defining the genotypes of the largest cohort in the UK, who are a well-typed patient cohort. Biochemical and genetic results will be correlated with clinical manifestations. This research project will also examine links between antithrombin deficiency and inflammation by determining the levels of markers of inflammation and complement activation.

  Blood samples will be collected from consenting patients with inherited antithrombin deficiency who attend the Thrombosis clinics at Guy’s and St Thomas’ Hospital. The samples will be taken at the same time as routine blood samples are collected.
  The sample collection stage will take approximately 18 months to complete as stable patients are only seen annually and the COVID-19 pandemic means that many appointments are currently virtual. Sample processing and results analysis will take another 18 months.

  Summary of Results:

  Main findings:
  The clinical, biochemical and extended molecular characterisation of the large cohort of ATD provided a vital contribution to the knowledge on this rare condition. This is the first ATD cohort from the UK including several patients with the most severe types of ATD. This project provided a deep insight into the ATD deficiency cohort. We analysed individual genotypes, compared them with healthy controls and between the ATD groups according to the personal history of venous thrombosis. We summarised the clinical manifestations, compared the biochemical results with the healthy controls. The extended molecular analysis revealed the co-existence of a potentially new regulatory gene outside the antithrombin coding gene that may alter the clinical phenotype. The thrombin generation study allowed us to asses the global state of haemostasis as the function of pro- and anticoagulant forces. The results showed that despite no personal history of VTE, patients with ATD had increased thrombin generation potential compared to healthy controls. This might be related to an increased risk of developing VTE, however a follow up studies would be necessary to verify that. In addition, we analysed plasma of those on anticoagulation. Interestingly, despite the use of anticoagulation, some thrombophilia patients still had increased thrombin generation parameters. The lowest thrombin generation values were observed in patients receiving warfarin while for some patients on DOACs the values were still increased compared to healthy controls. This initial pilot study showing a potential to utilise St Genesia to monitor anticoagulant therapy which would enhance a personalised approach to the patient management. In the second part of the project we tested the hypothesis that antithrombin is associated with pro-inflammatory state. We concluded that although some markers of inflammation were increased including the markers of NETosis, we otherwise did not find any evidence that antithrombin deficiency is linked to elevated inflammatory response.
  Benefits:
  We provided a vital contribution to the knowledge on ATD by analysing the clinical, biochemical and extended molecular data. For the first time, the ATD cohort was analysed for markers of inflammation. This is also the first study to test the thrombin generation potential on a large cohort of ATD using the most recently developed platform St Genesia; results of this part of the study are promising and this is a step forward in the direction of implementing the thrombin generation assay in the diagnostic haemostasis for improved personalised patient management. As a result of this work we are discussing setting up the thrombin generation assay as a routine assay in the Haemostasis Laboratory
  

• REC name

  North West - Liverpool Central Research Ethics Committee

• REC reference

  21/NW/0162

• Date of REC Opinion

  14 Jun 2021

• REC opinion

  Further Information Favourable Opinion