Our lab is focused on investigating how clotting factors VIII, IX, fibrinogen and VWF function and are regulated in the blood, with a focus on hemophilia A and B. Our research program seeks to improve our knowledge of the cellular and biochemical factors that regulate hemostasis and generate data to develop novel approaches for hemostasis and thrombosis disorders. We investigate new strategies to optimize replacement therapy for hemophilia and delve into the complexities of inhibitor development, studying adaptive immunity and immunotolerance mechanisms to FVIII. In addition, we investigate the effects of gene silencing on various coagulation proteins to better understand potential therapeutic interventions for bleeding and thrombotic disorders. Our lab employs animal models to evaluate hemostasis in vivo and investigate new therapies for treating bleeding and thrombotic disorders.
From left to right: Melak Ifrim, Dalia Zubashev, Davide Matino, Jaimie Lai, Ghazaleh Dadashi, Bonnie Chu, Hasam Madarati, Helen Atkinson.
Missing from photo: Taylor Lieber, Nikola Svazic, Manmeet Kaur.
Project
Hemophilia A
FVIII replacement therapy in hemophilia A can be ineffective due to the development of anti-FVIII antibodies. Our objective is to understand and characterize the regulatory mechanism behind the immune response to FVIII in hemophilia A patients. We’re currently investigating the role of immune complexes and inhibitory surface receptors in the activation and modulation of FVIII-specific B cells and anti-FVIII antibody production. We are exploring the potential of various tolerization approaches to avoid inhibitors development and develop immune tolerance to exogenous FVIII.
Hemophilia B
Hemophilia B (HB) is a bleeding disorder caused by a deficiency in coagulation factor IX (FIX). Patients with severe HB (FIX less than one per cent of normal) are prone to spontaneous bleeds into the joints and muscles and life-threatening intracranial bleeding can also occur. Prophylaxis with recombinant FIX (rFIX) to maintain the plasma FIX level above one per cent of normal is the mainstay of HB treatment. Previous studies have shown that there is a large reservoir of extravascular FIX, which may contribute to hemostasis in vivo. The relative importance of extravascular and intravascular FIX in hemostasis is not completely understood, its relevance for HB treatment is still controversial and further research on its potential to reduce bleeding is needed. To explore whether tissue distribution and the ability of FIX to bind collagen IV impacts hemostasis, we are using mouse models of HB to evaluate the protection from muscle and joint bleeding. Our study involves analyzing the pharmacokinetic properties of recombinant wild-type FIX (rFIX), numerous FIX mutants and extended half-life molecules and examining their localization in peripheral tissue, particularly its co-localization within the sub endothelial matrix.
Key components of our research method include pharmacokinetic studies, confocal imaging and hemostasis challenges in vivo in hemophilic mice followed by bleeding evaluation.
