Rediscovering coagulation factor VIII clearance in health and disease: from bleeding diathesis to thrombotic complications

Coagulation factor VIII (FVIII) plays a prominent role in the amplification and propagation phases of the coagulation, as well as in the delicate balance between health and disease in humans. FVIII is involved in different pathological conditions, from the historically recognized bleeding diseases, like hemophilia A (HA) and von Willebrand disease (VWD), to coronary artery disease (CAD) and cancer. Up to now the modulation of FVIII levels and the consequent functional effects has been mainly linked to a few molecular mechanisms, like severe disruption in F8 gene (like in HA) or the lack of FVIII chaperon in plasma (like in VWD) leading to FVIII deficiency, or inflammatory status (like in CAD or cancer) promoting the FVIII synthesis as acute phase protein. However, clinical and scientific evidences suggest that the pathways regulating FVIII plasma levels include the mechanisms of receptor-mediated clearance, which may be differentially modulated in several clinical settings. Here in this project we hypothesized that the genetic determinants of FVIII clearance and the related molecular mechanisms may not only have a substantial influence on FVIII plasma levels, but also play a role in the physiopathology of different diseases, from HA to CAD and cancer.Therefore, within 4 specific clinical settings (HA, CAD, CAD undergoing rehabilitation program, and cancer) several issues will be investigated, by integrating information about FVIII main interactors such as vWF, ABO gene, activated FIX, and acute phase proteins, with the effects of genetic variants in FVIII/vWF receptors (5 selected genes: LDLR, ASGR2, CLEC4M, TCN2, STAB2) potentially influencing FVIII plasma clearance. Furthermore, taking into account that the activity of most FVIII receptors could be modulated by glycomic modification of FVIII and vWF, we hypothesize that a biologically plausible interaction with ABO blood group would be crucial for a correct comprehension of FVIII clearance. If our working-hypothesis would be validated, our results could not only shed light on the molecular mechanisms of the clearance regulating in vivo FVIII plasma levels, but also suggest innovative treatment strategies and identify novel molecular targets in various clinical conditions: i)In subjects with HA more thorough knowledge of FVIII pharmacokinetics may allow a patient-tailored management with customized doses of FVIII concentrates, optimizing the efficacy and reducing the potential side effects; ii)In subjects with CAD understanding the roles of FVIII and its clearance pathways in atherothrombosis may pave the way for new treatment approaches, also by means of physical rehabilitation, for reducing the residual cardiovascular risk; iii)In subjects with cancer a more detailed comprehension of the mechanisms of coagulation balance/imbalance may allow the identification and the definition of both new biomarkers for diathesis/diagnosis/prognosis and molecular targets for therapy of oncologic diseases.