Characterising the interaction of coagulation and innate immunity in people being treated for bleeding disorder haemophilia A
Application deadline: 23 November 2018
Start date: October 2019
Research theme: Infection, Immunity & Repair
A novel treatment for bleeding disorder haemophilia A is a bi-specific antibody which binds to coagulation factors IX and X. The antibody works well to prevent bleeding but has been associated with thrombotic microangiopathy (TMA), a potentially life-threatening complication.
TMA has not been observed as a complication of haemophilia treatment previously and appears to be specific to this combined treatment. The TMAs have features suggestive of atypical haemolytic uraemic syndrome (aHUS) which is a severe renal disorder associated with dysfunctional complement proteins relevant to blood immunity and associated with microvascular thrombi in the kidneys. We hypothesise that combined treatment with bi-specific antibody and activated prothrombin complex concentrate (aPCC) affects complement immunity and leads to an atypical HUS-like disorder.
Heurich & Collins have collaborated on the cross-talk of coagulation and complement immunity > 6 years. Heurich developed assays that allow the analysis of interactions between coagulation and complement proteins. Collins’ specialises in the treatment of patients with factor VIII inhibitors and has led on a number of national guidelines in the field. His research includes clinical and laboratory studies into bleeding disorders and blood clot formation. Mumford specialises in research in the causes of bleeding disorders and basic mechanisms of blood coagulation and platelet function, he has expertise in developing specialised assays for monitoring coagulation and assessing their clinical applicability.
Project aims and method
This study aims to generate new understanding of the mechanisms of TMAs in haemophilia A patients caused by the combined treatment of this bi-specific antibody with prothrombin complex concentrate (PCC, a concentrated form of factor II, VII, IX and X).
We plan to:
- Characterise the composition of activated prothrombin concentrate complex with regards to coagulation enzymes and zymogens and complement proteins.
- Investigate whether the bi-specific antibody in complex with coagulation factors can activate complement proteins more readily and whether this can be blocked by inhibitors.
- Determine whether the activation of complement is influenced by the presence of phospholipid surfaces provided by liposomes, endothelial cells, red blood cells or platelets.
- Develop assays based on global tests of coagulation to investigate the coagulant effect of the bi-specific antibody alone and in association with other haemostatic agents.
- Investigate patients receiving the bi-specific antibody to assess for complement activation.
Methods used will include coagulation and complement activity assays, ELISA, SDS-PAGE, Western Blotting and Mass Spectrometry to assess complement and coagulation proteins. In vitro assessment of complement activation using cleavage assays. Global assays of haemostasis such as thrombin generation and whole blood viscoelastometry.
Prof Andrew Mumford, University of Bristol.