Wind and clouds,
Expanding storm,
Explode-Implode
In time.
Then silence forms;
Thoughts emerge.
Strength grows
and
Life reforms.
2013

Sepsis, defined as the dissemination of infection throughout the vascular tree and circulating blood is produced by all pathogens from bacteria to viruses, fungi and parasites. In severe septic states there is a high associated mortality up to 25% in bacterial sepsis and higher with viremia. In severe infections where there is shock, there is often an excess outpouring of inflammatory cytokines with excess inflammatory cell activation and invasion followed by a loss or attrition of normal immune responses - the ‘cytokine storm’. With the onset of this cytokine storm there can also be an excessive activation of the coagulation system with microvascular coagulation, occlusion of small vessels which cause ischemia of multiple organs resulting in circulatory collapse, pulmonary distress and renal failure. This excess clotting againdepletes clotting factors, causing subsequent bleeding. This dysregulated clotting and bleeding is called disseminated intravascular coagulation or DIC. With DIC the mortality in septic shock is even higher, up to 40% to 70% in viral sepsis. We are thus proposing here that this clotting and bleeding disorder (DIC) be called the ‘Hemorrhagic Hurricane’, as the clotting disorder partner to the ‘Cytokine Storm’. These inflammatory and coagulation disorders in septic shock are produced by aberrant responses in the arterial vessels and the circulating blood and thus represent a form of vascular disease. Both the cytokine storm and the hemorrhagic hurricane in severe septic states remain an unmet therapeutic need in vascular and hematological diseases and as noted mortality in septic shock remains high.

In a septic shock state there is a loss of vascular competence, termed leaky capillaries with hypotension and end-organ ischemia due to reduced blood flow and oxygen and/ or nutrient supply. With the systemic infectious process there is reported cytokine storm that is the result of a massive outpouring of inflammatory cytokines that increase this loss of vascular integrity, leaky capillaries, extravasation of fluids and tissue edema which impedes normal oxygen exchange. Endothelial cells become dysfunctional and junctions between cells weaken. Dysfunctional endothelial cells allow for exaggerated inflammatory mononuclear cell migration. The accompanying inflammatory cell response can further damage arteries and organs and again reduce blood and oxygen supply. The endothelium is often considered a large organ transiting throughout the arterial tree covering many miles throughout the mammalian body. When the endothelium fails the natural barriers to arterial leak and also protective mechanisms that prevent clotting and arterial occlusion is lost with resultant disseminated clotting.

Many of the cytokines that are up-regulated in the acute inflammatory responses are also reported to activate the clotting (thrombotic) and clot dissolving (thrombolytic) cascades. These serine proteases in the thrombotic and thrombolytic pathways are sequentially activated and are regulated by serine protease inhibitors, termed serpins. Conversely, many of the thrombolytic factors such as the plasminogen activators and the clotting factors X and thrombin are also reported to activate inflammatory responses. While the inflammatory mononuclear cells, neutrophil, macrophage, and T lymphocyte responses increase arterial and organ damage due to invasion and organ damage, the role of the thrombotic and thrombolytic protease cascades in driving excess inflammation is often overlooked.

The thrombolytic plasminogen activators, urokinase- and tissuetype plasminogen activators (uPA and tPA, respectively) activate plasminogen to form plasmin that in turn dissolve fibrin clots. However, whatis less well known is that uPA activates the pro forms of matrix degrading enzymes, matrix metalloproteinase (MMPs), which break down connective tissue collagen and elastin and allows cellular invasion into the arterial wall and organs. uPA and tPA also have intrinsic ability to break down fibrin. The PAs also can break down connective tissues or activate growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFβ), and basic fibroblast growth factor (bFGF) and / or release these growth factors from connective tissue stores further activating inflammatory cell responses and cell proliferation. uPA interacts with the uPA receptor that sits at the leading edge of invading inflammatory cells promoting cell invasion by breaking down connective tissue barriers to cell migration. The clotting factors thrombin and factor X also interact with protease activated receptors (PARs) on the cell surface of endothelial cells and inflammatory mononuclear cells and are reported to increase cytokine expression and thus again further enhance activation of the innate immune response.These serine protease in the coagulation and thrombolytic cascades are generally regulated by serpins that represent up to 2-10% of circulating plasma proteins. These serpin regulators are also consumed in the DIC state causing further dysregulation and again excess bleeding and clotting.

Once a septic state has deteriorated to shock with DIC there is limited effective therapy. Treatment of the underlying infection is the front line of therapy but is less effective for shock and of course antiviral agents are less available except in select viral infections. Prior trials with serpins such as anti-thrombin III, which is activated by heparin, have had reported partial efficacy in sepsis and DIC, but have proven effective only under restricted conditions, e.g. in the absence of heparin. Treatment with clotting factors and thrombolytic is also limited to septic states with ongoing excess bleeding or clotting. Similarly while animal models and even clinical trials have suggested some benefit with steroid and anti-inflammatory cytokines, such as interleukin 10 (IL-10), there is at present no recognized proven beneficial treatment for septic shock and many agents have failed clinical testing. In our research group we have recently detected improved outcomes in viral sepsis in mouse models during treatment with a virus-derived serpin that inhibits both coagulation and also thrombolytic proteases. Whether this will translate to efficacy in clinical trials is of course unknowns but again suggests that the interactions of the coagulation and inflammatory systems in lethal septic states bear further investigation.

In conclusion, septic shock with associated cytokine storm and DIC is,by many criteria, a vascular disease with pathogenic disorders of the arterial endothelium, the circulating mononuclear cells and the coagulation cascade. The role of dysregulated coagulation in driving the septic shock state remains incompletelyunderstood. The interactionsforinflammatory cytokines withthrombotic and thrombolytic cascades isalso defined in part. We would suggest that the ‘hemorrhagic hurricane’, as for the cytokine storm, is associated with increased mortality in septic shock and represents an unmet therapeutic need. The molecular interactions between the coagulation and inflammatory cascades may in fact represent a potential, untapped therapeutic target for treatment of severe septic shock, deserving of further investigation.