To What Extent Are the Terminal Stages of Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome Actually Driven by a Prion/Amyloid Form of Fibrin?

Abstract

A well-established development of increasing disease severity leads from sepsis through systemic inflammatory response syndrome, septic shock, multiple organ dysfunction syndrome, and cellular and organismal death. Less commonly discussed are the equally well-established coagulopathies that accompany this. We argue that a lipopolysaccharide-initiated (often disseminated intravascular) coagulation is accompanied by a proteolysis of fibrinogen such that formed fibrin is both inflammatory and resistant to fibrinolysis. In particular, we argue that the form of fibrin generated is amyloid in nature because much of its normal α-helical content is transformed to β-sheets, as occurs with other proteins in established amyloidogenic and prion diseases. We hypothesize that these processes of amyloidogenic clotting and the attendant coagulopathies play a role in the passage along the aforementioned pathways to organismal death, and that their inhibition would be of significant therapeutic value, a claim for which there is considerable emerging evidence.

Fig. 1

A standard cascade illustrating the progression of infection through sepsis, systemic inflammatory response syndrome, and death.

Fig. 2

The classical coagulation pathways, where assembly of fibrin fibers proceeds in a stepwise fashion (redrawn from Kell and Pretorius under an open access CC-BY license).

Fig. 3

The results of thrombin-mediated blood clotting. (A–C) Micrographs taken with a Zeiss LSM 800 superresolution Airyscan confocal microscopy using the α Plan-Apochromat 63x/1.46 Oil DIC M27 Elyra objective. (D) Micrograph taken with a Zeiss LSM 510 META confocal microscope with a Plan-Apochromat 63x/1.4 Oil DIC objective. ( A ) Healthy platelet poor plasma (PPP) with added thioflavin T (ThT) (5-μM exposure concentration) and thrombin. ( B ) The same PPP, with added lipopolysaccharide (LPS) (0.2 ng/L exposure concentration), followed by addition ThT and thrombin. ( C ) The same PPP, with added LPS followed by LPS-binding protein (2 ng/L final exposure concentration) followed by addition ThT and thrombin. ( D ) PPP, with added LPS (0.2 ng/L exposure concentration), followed by addition ThT and thrombin.

Fig. 4

A systems biology model of the development of coagulopathies during sepsis, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. An elementary systems biology model of how iron dysregulation can stimulate dormant bacterial growth that can, in turn, lead to antigen production (e.g., of lipopolysaccharide [LPS]) that can then trigger inflammation leading to cell death and a variety of diseases. While it is recognized that this simple diagram is very far from capturing the richness of these phenomena, there is abundant evidence for each of these steps, starting with ( 0 ) an infection/gut dysbiosis and the creation of a (dormant) blood and tissue microbiome. This is typically accompanied by ( 1 ) iron dysregulation, which is known to be present in many diseases, as both cause and result ( 5 ) and as an important cause of inflammation ( 6 ) and even organism death ( 10 ). Iron, in turn, feeds bacterial growth ( 2 ), leading to production of, for example, LPS with an accompanying upregulated inflammatory cytokine profile ( 3 ), leading to disease ( 4 ). In inflammation both apoptotic death ( 8 ) and coagulopathies ( 7 ) are well-known phenomena. In turn, apoptotic death can lead to organism death ( 9 ).

Fig. 5

A schematic representation outlining our hypothesis based on current knowledge (A) , experimental evidence for our hypothesis (B) , hypothetical evidence ( C ), and finally our thoughts on (new) treatment regime approaches and early disease diagnosis ( D ).