In a paper just published on Preprints, REGENHEALTHSOLUTIONS Research Team shows that, in Covid-19 critically ill patients, serine proteases released by recruited neutrophils are responsible for endothelitis, NETosis, platelet activation, ULVWF multimers release, thrombi formation and MOF for viral sepsis.

Based on Chinese CDCP report on COVID-19, 14% of patients presented severe disease and 5% critical conditions. The average case-fatality rate was 2.3%, but mortality was as high as 49% in patients with critical illness.

Serious life threatening thromboembolic complications have been
found in 71·4% of non-survivors and micro/macro angiopathic coagulopathy has been found, also at autopsy, with highly increased neutrophil number, fibrinogen, concentrations of D-dimer and
FDPs and NETs, ATIII decrease and normal number of platelets.

“A cytokine storm and interaction between inflammation and coagulation has been advocated as explanation of hypercoagulability and, based on that, largely used terapies are based and main cytokine inhibition” says Dr. Pier Maria Fornasari, REGENHEALTHSOLUTIONS reseacher and founder.

In this paper, it’s hypothesised that SARS-CoV-2 infection of alveolar cells induces recruitment of innate responder neutrophils, which release proteases and NETs inducing endothelial damage/endotheliopathy and imbalance of the four major proteolytic cascades (coagulation,
complement, fibrinolysis and kallikrein) with prevalence of activators over inhibitors and consequent thrombotic complications.

Platelets adhesion to damaged endothelium and the presence of ULVWF multimers, due to decreased ADAMTS13, contributes to the state of
hypercoagulability.

Neutrophil innate “unfriendly fire” response can be identified as the trigger of a “proteolytic storm”, responsible for subsequent well known prothrombotic condition and “cytokine storm”.
The hypothesis explains also the pathology of recently described systemic “Kawasaki Disease like” vasculitis cases in Covid-19 young ill patients.

“Very recently, Cochrane Database of Systematic Reviews published a rapid review on convalescent plasma or hyperimmune immunoglobulin for people with COVID-1932, including eight anedoctical studies from China and South Corea (uncontrolled studies, 7 case series and 1 prospectively
registered single-arm intervention study) describing 32 critically ill participants.” says Fornasari. “Other 47 ongoing studies (21 randomised) evaluating CP and one ongoing study evaluating hyperimmune immunoglobulin were identified.

For the primary outcomes, the included studies reported that all participants were alive at the end of follow, thus concluding that plasma therapy is safe and improves patient outcome, but there are significant limitations to each of these studies, due to small number of treated patients and absence of a control group. Two studies reported adverse events that were potentially grade 3 and grade 4, of which one was serious.”

“Worldwide there are over 66 clinical trials, as reported by Clinical Trials.gov, actively recruiting COVID-19 patients to study the effect of convalescent plasma.
In many studies plasma from non-infected patients is used as the placebo arm of the trial, to ensure that any benefits identified are indeed specific for SARS-CoV-2 antibodies33″

To better understand the potential role of CP in Covid-19 treatment, Fornasari highlights the following:
1) CP is a “scarce resource” and thus should be reserved to critically ill patients,
2) CP isn’t a “single active principle” product, but contains a multiplicity of active ingredients,
3) Human plasma is the defined first-line therapy in diseases like TTP, presenting with clinical and pathological features similar to Covid-19,
4) Based on the objects of the trials, the timing, the quantity, the frequency, the haematological and clinical parameters monitoring and the side effects need to be evaluated and defined,
5) Human non-convalescent plasma must be used as placebo in the control arm.”

Following this hypothesis, CP doesn’t supply only NAbs, but also supplies:
1) Other antibodies able to mediate/neutralize pathways such as complement activation, antibody-dependent cellular cytotoxicity and/or phagocytosis, limiting immune complexes formation and cytokine release such as IL-1β and TNFα,
2) SERPIN family serine proteases inhibitors of the four interconnected proteolytic cascades (clotting, complement, fibrinolysis and kallikrein),
3) ADAMTS13 metalloprotease, which cleaves ULVWF, reducing hypercoagulability and thrombogenicity,
4) SERPINA1 inhibiting neutrophil elastase deleterious effects, mainly at alveolarcapillary level
5) SERPING1 counteracting platelet activation action on clotting and complement cascade and Pselectin/HGMB1 expression,
,6) Other inhibitors like the generic Alfa2 Macroglobulin and Thrombomodulin,
7) CP NAbs boost a much stronger immune response of newly dendritic cells inf-cDC236
.
“In conclusion, Fornasari tells, CP can be considered a very effective “fire extinguisher” for neutrophils “unfriendlyfire” and its consequences of “proteolytic storm”, hypercoagulability, thrombosis and sepsis with
MOF, but the absence of clinical trials, with human plasma as placebo in control arm, doesn’t allow to exclude that human nonconvalescent plasma can obtain at least part of the same expected clinical outcomes.”