{"id":50975,"date":"2023-09-30T10:46:52","date_gmt":"2023-09-30T10:46:52","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=50975"},"modified":"2023-10-07T11:19:35","modified_gmt":"2023-10-07T11:19:35","slug":"autologous-platelet-rich-plasma-a-potential-therapy-to-mitigate-severe-covid-19-manifestations","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/autologous-platelet-rich-plasma-a-potential-therapy-to-mitigate-severe-covid-19-manifestations\/","title":{"rendered":"Autologous Platelet-Rich Plasma: A Potential Therapy to Mitigate Severe Covid-19 Manifestations"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

In 31 December 2019, Chinese Department of\nHealth released a press statement regarding the emergence of a string of\npneumonia cases in Wuhan that are connected to a local seafood market.1<\/sup> According to the local health commission,\nsome patients came to the hospital with atypical pneumonia symptoms such as\nheadache, pain, diarrhea, skin lesions, and eye irritation which evolves\novertime as the disease progresses.2,3<\/sup> <\/p>\n\n\n\n

Early studies reported laboratory\nbiomarkers with deviation towards viral infection and inflammation: leukopenia,\nneutrophilia, increased prothrombin time (PT), and hypoalbuminemia.4<\/sup> Coagulation parameters showed an increase\nin fibrin degradation: elevation of fibrin degradation product (FDP) such as\nD-dimer.4,5<\/sup> A drastic increase in pro-inflammatory\ncytokines further causes cytokine release syndrome (CRS) in severe cases.5<\/sup><\/p>\n\n\n\n

Improved understanding about immunologic therapies\nover the last decade has enabled clinicians to conduct researches and trials\nabout the potential usage of immunomodulatory drug, targeting the\npathophysiologic mechanisms of severe clinical manifestation. Take for example\nTocilizumab (TCZ), a monoclonal antibody which specifically blocks IL-6\nreceptor which is an important inflammatory cytokine.6\u20138<\/sup> Although IL-6 may prove itself to be\nbeneficiary in acute response to infections, dysregulated over secretion of\nIL-6 may cause lethal hyperinflammation.6<\/sup> Tocilizumab works by inhibiting the entire\nreceptor complex which prevents signal transduction triggering B and T cells,\nand is proven in clinical trials effective for preventing and mitigating severe\nCOVID-19 symptoms.6\u20139<\/sup><\/p>\n\n\n\n

However, such immunomodulatory modalities\nare costly and not widely available. An alternative modality which utilizes\nactivated autologous platelet-rich plasma (aaPRP) may be the answer to the lack\nof an affordable and widely-available treatment to severe COVID-19.10,11<\/sup> This paper aims to review the detailed\nmechanism of COVID-19 pathophysiology and possible sites of treatment by aaPRP.<\/p>\n\n\n\n

Thrombopathogenesis<\/strong><\/p>\n\n\n\n

After entering the body through the respiratory system, direct viral entry was initiated by adhesion between receptor-binding domain (RBD) and ACE-2 receptor (hACE-2) after cleaving by TMPRSS2, cathepsin L, or furin.12,13<\/sup> Macrophages will recognize S1 and S2 as pathogen-associated molecular patterns (PAMPs) of SARS-CoV-2 via the toll-like receptor 2 (TLR-2) pattern recognition receptors concurrently occurring during viral entry (PRRs).14,15<\/sup> This triggers innate inflammatory response through production of chemokines and pro-inflammatory cytokines.14,16<\/sup> <\/p>\n\n\n\n

Dysregulation of inflammatory mediators due to efficient evasion of IFN-I by various non-structural proteins (NSPS) of SARS-CoV-2 inhibits production of interferon-stimulated genes and its antiviral effects.17<\/sup> This immunopathology allows \u2018free replication\u2019 of the pathogen until a more adaptive immune response kicks in. Massive buildup of mucus within the lungs may create consolidation, dyspnea, up to ARDS.18<\/sup><\/p>\n\n\n\n

Immunopathogenesis due to non-structural proteins of SARS-CoV-2 further triggers both local and systemic immunothrombosis within the patient.<\/p>\n\n\n\n

Platelet-Rich Plasma (Prp)<\/strong><\/p>\n\n\n\n

Platelet-rich plasma (PRP) is a\ncutting-edge intervention classified under regenerative medicine, which\nincludes other forms of treatment modalities such as gene therapies, cell-based\ntherapies, and tissue engineering.10<\/sup> <\/p>\n\n\n\n

PRP is a platelet concentrate which\nconsists of plasma and platelets. Platelet and plasma were closely involved in\ncell recruitment, multiplication and specializes for healing. aaPRP was\nobtained from the centrifugation of patient\u2019s blood samples. Due to its healing\nnature, aaPRP therapy is usually used to induce faster healing in soft tissue,\nbones, and osteoarthritis.19,20<\/sup> During at the COVID-19 pandemic, aaPRP\ntherapy was developed for additional therapy for COVID-19 patients with immune\ndysregulation. aaPRP therapy may reduce clinical severity in COVID-19 patients,\nthus minimizing ventilation needs, relieve lung fibrosis, and reduce hair loss\noften seen in COVID-19 syndrome.21\u201323<\/sup><\/sup><\/p>\n\n\n\n

aaPRP Therapy in COVID-19<\/strong><\/p>\n\n\n\n

Researches had shown that SARS-CoV-2 may\ncause disruption of normal immune response, triggering an uncontrolled\ninflammatory response. This phenomenon may give rise to an increase of\npro-inflammatory cytokines production, triggering the occurrence of Cytokine\nRelease Syndrome (CRS). The development of lymphocyte activation and\ndysfunction, lymphopenia, an increase in pro-inflammatory cytokine productions,\nand abnormalities in granulocytes and monocytes are all indications of CRS.\nMoreover, cytokine storm would lead to the hyper-activation of NF-B in IL-6\nAMP, which in COVID-19 patients results in deadly symptoms such shock, acute\nrespiratory distress syndrome, organ failure, respiratory failure, and death.\nDue to its ability to create massive disruption within the organ system, it is\nimperative to find ways to  reduce\nsymptoms or all in all prevent COVID-19 patients from experiencing CRS and\ncytokine storm.24<\/sup><\/p>\n\n\n\n

Various treatments have been developed to\nprevent cytokine storms such as mesenchymal stem cells (MSCs) therapy, a\ntherapy involving various kinds of growth factors, trophic factors, and cytokines\nthat has anti-inflammatory and immunomodulating effects. However, MSC therapy\nis considered quite expensive because the production is quite difficult and can\nonly be done in special laboratories licensed by the Ministry of Health. In addition,\nautologous MSC therapy needed patient\u2019s own cells to be cultured for 2-3 weeks\nto increase the amount of MSC so that it may be quantically suitable for  COVID-19 therapy.21<\/sup><\/p>\n\n\n\n

aaPRP therapy has advantages because it is\nproduced in a short time, easy, and at a cheaper cost. In research carried out\nby Karina et al. (2021) using autologous activated PRP (aaPRP) found that the\nuse of aaPRP as additional therapy decrease the occurrence of CRS in severe\nCOVID-19. After administration of aaPRP, a considerable reduction in CRP and\nlymphocyte levels was followed by a marginal rise in neutrophil, neutrophil\nlymphocyte ratio (NLR), and lymphocyte C-reactive protein ratio (LCR) values.\nIn terms of safety, administration of aaPRP does not induce serious side\neffects and is clinically safe to use. aaPRP is known to reduce the need for\ninvasive mechanical ventilation, prevent pulmonary fibrosis, alopecia post\nCOVID-19 infection, pulmonary fibrosis, accelerates the regeneration of damaged\nlung cells, and prevents sepsis.22<\/sup><\/sup><\/p>\n\n\n\n

Mechanism of aaPRP Therapy<\/strong><\/p>\n\n\n\n

When COVID-19 is severe, hyperinflammation\nis a symptom that the patient needs intensive care unit (ICU) treatment.25<\/sup> Inflammation begins with the occurrence of\nprimary infection. Inflammatory cytokine production increases dramatically in\nresponse to white blood cell activation. White blood cells will then be\nattracted to the infection location by inflammatory signals.26<\/sup> The inflammatory cytokines IL-2, IL-6,\nmonocyte chemoattractant protein-1 (MCP-1), protein-1a inflammatory macrophage\n(MIP-1A), and tumor necrosis factor-beta (TNF-beta) may be discovered to be elevated\nin severe cases. In this situation, the body will try to decrease the\nanti-inflammatory cytokines.21,27<\/sup><\/p>\n\n\n\n

aaPRP is known to have several substances\nthat exerts anti-inflammatoric effect. epidermal growth factor (EGF), basic\nfibroblast growth factor (BFGF), hepatocyte growth factor (HGF),\nplatelet-derived growth factor (PDGF), transforming growth factor beta (TGF-), vascular\nendothelial growth factor (VEGF), and insulin-like growth factor 1 (IGF-1) are\nthe aaPRP growth factor\u2019s. These growth factors are generated by the platelets\nto inhibit the production of IL-1, IL-6, and TNF by the synoviocytes. TGF-\nfunctions as an immunosuppressant throughout the inflammatory phase, preventing\nthe production of cytokines that promote inflammation. Moreover, aaPRP posses\nanti-inflammatory components such interleukin-1 receptor antagonist (IL-1RA),\nwhich can stop IL-6 from being released.21<\/sup><\/sup><\/p>\n\n\n\n

aaPRP Making Process for COVID-19<\/strong><\/p>\n\n\n\n

Eight BD vacutainer citrate tubes with a\n1.2% sodium citrate buffer and 3 ml of blood each are used to collect blood\nsamples. Next the blood will be centrifuged for 10 minutes with a speed of\n1000rpm (188 x g) to plasma separate in red blood cells. The plasma that is\nseparated is then moved carefully into 2 15ml tubes. After that, plasma is\ncentrifuged for 10 minutes with a speed of 3000rpm (1690 x g). Platelet Poor\nPlasma (PPP) located at the top is removed by aspiration until the remaining 3\nml and is homogenized so that only leaves an aaPRP. Add calcium activator\nsolution next to promote the development of fibrin clots. The removal of formed\nfibrin lumps allows for the isolation of autologous activated PRP.21<\/sup><\/p>\n\n\n\n

aaPRP Administration<\/strong><\/p>\n\n\n\n

A blood transfusion set was used to\nintravenously administer aaPRP after diluting it in 100 mL of 0.9% sodium\nchloride for 10 to 15 minutes. The patient was given an aaPRP therapy 3 times,\nnamely on day 1, 3, and 5 after the patient was transferred to ICU.21<\/sup> Based on the clinical trial phase I\/II\nstudy, it shows that giving aaPRP through intravenously known safely given and\nnot found side effects in COVID-19 patients even in various patients with\npathological conditions.28,29<\/sup><\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Patients treated in the ICU showed the occurrence of leukopenia, neutrophilia, increased prothrombin time, hypoalbuminemia, and increased D-dimer. On the other hand, there is also an increase in fibrin degradation products (FDP) accompanied by a simultaneous increase in D-Dimer and fibrinogen and the increase in pro-inflammatory cytokines which will cause CRS occurrence. Various treatments were developed to overcome these conditions, one of which was aaPRP therapy. In terms of production, aaPRP is cheaper, easier, and may be produced in a short time. aaPRP contains several anti-inflammatory growth factors that can suppress overregulation of pro-inflammatory cytokines, thereby preventing the occurrence of CRS and cytokine storm. In addition, aaPRP therapy has the benefit of preventing pulmonary fibrosis and alopecia. aaPRP therapy was given intravenously and clinical trials had found minimal to no side effects in COVID-19 patients.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

The authors give credit to everyone who helped in the writing of this work.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There was no conflict of interest in the writing of this scientific publication.<\/p>\n\n\n\n

Funding Source<\/strong><\/p>\n\n\n\n

There are no funding sources<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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