Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

Abstract

Background: Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Methods: Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Results: Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Conclusion: Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.

Decreased antioxidant capacity with serum native thiol and total thiol levels in children with hemophilia A: a prospective case-control study

“…6 Moreover, it has been shown that the joint and bone destruction in hemarthrosis, a typical hallmark of Hemophilia A, is caused by the inability of macrophages to adequately eliminate the oxidative stress created by the proteins (but not recombinant products) in the plasma-derived Factor VIII concentrates. 7 However, the exact cellular mechanisms by which oxidative stress contributes to Hemophilia A pathogenesis has not yet been clarified. 8 Dynamic thiol-disulfide exchange has become a common indicator in recent studies focusing on the role of oxidant stress in the pathophysiology of many diseases.…”

An overview on the investigation of nanomaterials' effect on plasma components: immunoglobulins and coagulation factor VIII, 2010–2020 review

“…Fresh frozen plasma (FFP) is the best and most accessible resource of FVIII. The temperature susceptibility of FVIII storage could restrict getting access to the high amount of FFP resource in a difficult situation (19)(20)(21)(22). Therefore, improving the half-life of the FVIII factor, while trying to maintain its activity and efficacy has a crucial impact on life-threatening disorders such as hemophilia (23).…”