Bertling Anne, Brodde Martin F, Visser Mayken, Treffon Janina, Fennen Michelle, Fender Anke C, Kelsch Reinhard, Kehrel Beate E
Department of Anesthesiology, Intensive Care and Pain Medicine, Experimental and Clinical Hemostasis, University of Münster, Münster, Germany.
OxProtect GmbH, Münster, Germany.
Transfus Med Hemother. 2017 Sep;44(5):351-357. doi: 10.1159/000472157. Epub 2017 Aug 11.
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.
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.
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.
Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.
关节积血，即血液渗入关节，是血友病的一个标志。血红素引发氧化应激、炎症以及软骨和骨骼的破坏。触珠蛋白 - CD163 - 血红素加氧酶 - 1（HO - 1）途径通过血红素的酶促降解和抗氧化基因的转录来规避血红素毒性。血浆源性凝血因子浓缩物包含许多可能影响关节、血液和血管中细胞途径的蛋白质。
通过纤维蛋白原结合和CD62P表达的流式细胞术分析评估健康志愿者血小板的活化情况。用酶联免疫吸附测定法测量血小板CXCL4释放量。在人外周血单核细胞分化为巨噬细胞的过程中，将其暴露于CXCL4或血小板上清液（未处理或用凝血因子VIII（FVIII）产品预刺激）中，并分析CD163表达情况。一些巨噬细胞培养物还与自体血红蛋白一起孵育18小时，以分析HO - 1表达情况。
所有8种测试的血浆源性FVIII产品均增加了血小板CXCL4释放，但3种重组产品未增加。暴露于用某些血浆源性FVIII产品处理过的血小板上清液的巨噬细胞下调了CD163表面表达，并且在接触血红蛋白时未能上调对动脉粥样硬化和关节有保护作用的酶HO - 1。
血浆源性FVIII产品可能通过产生无法抵抗氧化还原应激的巨噬细胞来促进出血诱导的关节损伤。
