Non-plasma antithrombotic effects of oral anticoagulants and synergy with hydroxychloroquine
Lead Research Organisation:
Imperial College London
Department Name: Immunology and Inflammation
Abstract
Stroke is the second most common cause of death and morbidity worldwide affecting over 100,000 people each year causing 38,000 deaths and considerable disability, with an estimated annual cost to UK society of £26 billion. One of the major causes of stroke as well as other thromboses (blood clots) is antiphospholipid syndrome (APS); an autoimmune disease characterised by the constant presence of autoantibodies called antiphospholipid antibodies in the blood. Approximately 13.5% of thromboses causing stroke (up to 1/3 in patients <50 years2) and 11% of heart attacks, are attributable to APS. APS affects both sexes and all ethnic groups.
In health, the lining of blood vessels (endothelium) helps to prevent blood clots and to break down those that do begin to form. We know that antiphospholipid antibodies can bind to the endothelium and cause inflammation which tends to reverse its protective effect against thrombosis. Current drugs to prevent blood clots (anticoagulants) are targeted at proteins and cells in the blood which create blood clots but not the endothelium.
New anticoagulants (DOACs) target the blood enzymes factor Xa or thrombin and have proven equally successful as the traditional anticoagulant warfarin in some forms of thrombosis but are much less effective in patients with APS4,5. Although warfarin is therefore the oral anticoagulant of choice for APS, the risk of recurrent thrombosis in APS is still unacceptably high at 30% in 10 years. Therefore, identifying alternative ways that drugs can prevent recurrent stroke, without excess bleeding, is a vital and urgent need. Understanding how the differences in efficacy between different anticoagulants arise from their different mechanisms of action is an important step towards to this goal.
In my current CARP award, I hypothesised that the difference in efficacy between warfarin and DOACs, arise from differences in their effects on the endothelium and the on endothelium's response to inflammation. My work so far confirms that they do indeed have significant but different effects on endothelium but also suggests that this is not the complete explanation. I now propose to explore these initial findings further and to extend the study to investigate the effects of anticoagulants on platelets (blood cell fragments essential for clotting). Finally I will study whether combining anticoagulants with the immunomodulatory drug hydroxychloroquine (HCQ) will have additional beneficial effects on endothelium. In summary I will:
1) Determine the effects of oral anticoagulants on platelet function. This is plausible because platelets are sensitive to thrombin and a to protein called Gas6 which is reduced by warfarin.
2) Determine the effects of warfarin and DOACs on the ability of endothelium to capture and activate blood cells (neutrophils) and platelets.
3) Determine the effects of anticoagulants on the ability of endothelium to break down blood clots (fibrinolysis). Fibrinolysis is known to be impaired in APS.
4). Determine the effects of combining anticoagulants and HCQ in reducing the endothelial prothrombotic response to aPL and inflammation.
This work will provide better understanding of the differences between the current anticoagulants and the importance of the endothelium as a treatment target to prevent thrombosis. Using the immunomodulatory agent HCQ in combination with anticoagulants will begin to translate this understanding into new therapeutic approaches for patients with stroke and APS without increasing risk of bleeding.
In health, the lining of blood vessels (endothelium) helps to prevent blood clots and to break down those that do begin to form. We know that antiphospholipid antibodies can bind to the endothelium and cause inflammation which tends to reverse its protective effect against thrombosis. Current drugs to prevent blood clots (anticoagulants) are targeted at proteins and cells in the blood which create blood clots but not the endothelium.
New anticoagulants (DOACs) target the blood enzymes factor Xa or thrombin and have proven equally successful as the traditional anticoagulant warfarin in some forms of thrombosis but are much less effective in patients with APS4,5. Although warfarin is therefore the oral anticoagulant of choice for APS, the risk of recurrent thrombosis in APS is still unacceptably high at 30% in 10 years. Therefore, identifying alternative ways that drugs can prevent recurrent stroke, without excess bleeding, is a vital and urgent need. Understanding how the differences in efficacy between different anticoagulants arise from their different mechanisms of action is an important step towards to this goal.
In my current CARP award, I hypothesised that the difference in efficacy between warfarin and DOACs, arise from differences in their effects on the endothelium and the on endothelium's response to inflammation. My work so far confirms that they do indeed have significant but different effects on endothelium but also suggests that this is not the complete explanation. I now propose to explore these initial findings further and to extend the study to investigate the effects of anticoagulants on platelets (blood cell fragments essential for clotting). Finally I will study whether combining anticoagulants with the immunomodulatory drug hydroxychloroquine (HCQ) will have additional beneficial effects on endothelium. In summary I will:
1) Determine the effects of oral anticoagulants on platelet function. This is plausible because platelets are sensitive to thrombin and a to protein called Gas6 which is reduced by warfarin.
2) Determine the effects of warfarin and DOACs on the ability of endothelium to capture and activate blood cells (neutrophils) and platelets.
3) Determine the effects of anticoagulants on the ability of endothelium to break down blood clots (fibrinolysis). Fibrinolysis is known to be impaired in APS.
4). Determine the effects of combining anticoagulants and HCQ in reducing the endothelial prothrombotic response to aPL and inflammation.
This work will provide better understanding of the differences between the current anticoagulants and the importance of the endothelium as a treatment target to prevent thrombosis. Using the immunomodulatory agent HCQ in combination with anticoagulants will begin to translate this understanding into new therapeutic approaches for patients with stroke and APS without increasing risk of bleeding.