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inflammatory cell profiles and/or numbers of astrocytes and microglia in the resting state. This suggests that fib- rin(ogen)-driven neurodegeneration can also be inflamma- tion-independent (Figure 3B).105
Association studies have correlated elevated plasma fib- rinogen levels with cognitive decline, independently of inflammatory markers.109,110 Proteomic studies detected higher fibrinogen levels on platelets from subjects with secondary progressive multiple sclerosis.111 This highlights dysfunctional coagulation as a common thread among diverse neurovascular abnormalities. Fibrin(ogen) may,
A
however, be beneficial in acute CNS injuries by delaying regeneration until the extracellular environment is con- ducive to repair.100
Pharmacological agents targeting fibrinogen or fibrino- gen interactions with CNS cells or other players may have potential as therapeutics for neurological diseases. Such drugs could include agents that enhance fibrin(ogen) degradation, protect the BBB to limit fibrin(ogen) entry into the CNS, or selectively inhibit the interactions of fib- rinogen and fibrin with their CNS receptors, αMβ2 or Aβ, while preserving the beneficial functions of fibrinogen.85
B
Figure 3. Schematic repre- sentation of the mecha- nisms linking fibrin(ogen), neurological diseases and cognitive impairment upon blood-brain barrier break- age. (A) The main compo- nents of the pathways that ultimately lead to neuroin- flammation and neurodegen- eration are described in this panel, including the interac- tion with Aβ peptides observed in Alzheimer dis- ease. (B) An alternative mechanism that does not implicate inflammation. Increased fibrin(ogen) accu- mulation results in pericyte and oligodendrocyte loss, without affecting astrocytes or microglia. This will lead to microvascular dysfunction and white matter pathology. This figure has been adapted from Petersen et al.85 and Merlini et al.97 and created with BioRender.com. ACVR1: activin A receptor type 1; Aβ: amyloid-β; OPC: oligodendro- cyte progenitor cell; ROS: reactive oxygen species; TGFR1: transforming growth factor-β receptor type 1; Th1: T helper 1 cells.
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haematologica | 2020; 105(2)