key: cord-0313266-e88bk5em authors: Laubscher, G. J.; Lourens, P. J.; Venter, C.; Grobbelaar, L. M.; Kell, D. B.; Pretorius, E. title: A decision-tree approach to treat platelet hyperactivity and anomalous blood clotting in acute COVID-19 patients date: 2021-07-07 journal: nan DOI: 10.1101/2021.07.05.21260012 sha: 89eeba4e073927c61922bfea37783776ac809c07 doc_id: 313266 cord_uid: e88bk5em The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden and substantial increase in hospitalizations for pneumonia with multiorgan problems. An important issue is also that there is still no unified standard for the diagnosis and treatment of COVID-19. Substantial vascular events are significant accompaniments to lung complications in COVID-19 patients. Various papers have now also shown the significance of thromboelastrography (TEG) as point-of-care technology to determine the levels of coagulopathy (both clotting and bleeding) in COVID-19, in managing COVID-19 patients. Here we present two treatment protocols that may used to treat thrombotic and bleeding or thrombocytopenia pathologies. We also present a case study, where the thrombotic pathology was successfully treated with the thrombotic protocol. Both the protocols use clinical parameters like D-dimer and CRP, as well as the TEG, to closely follow the daily clotting propensity of COVID-19 patients. We conclude by suggesting that the treatment of COVID-19 patients, should be based on a combination of blood biomarkers, and results from point-of-care analyses like the TEG. Such a combination approach closely follow the physiological responses of the immune system, the haematological, as well as the coagulation system, in real-time. The coronavirus disease 2019 (COVID-19) (SARS-Cov-2) has caused a worldwide, sudden and substantial increase in hospitalizations for pneumonia with multiorgan problems (Docherty, et al 2020 , Wiersinga, et al 2020 , Wynants, et al 2020 . Severe cases of COVID-19 are almost inevitably accompanied by respiratory failure and hypoxia, and treatment includes best practices for supportive management of acute hypoxic respiratory failure (Wiersinga, et al 2020) . Approximately 5% of patients with significant COVID-19 symptoms, experience severe symptoms necessitating intensive care (Wiersinga, et al 2020) , where as many individuals are probably never diagnosed because of a very mild version of the disease. Depending on the clinical protocol followed by the specific hospital, among patients in the intensive care unit (ICU) with COVID-19, between 29% to 91% require invasive mechanical ventilation (Docherty, et al 2020 , Grasselli, et al 2020 . Some COVID-19 patients deteriorate rapidly and seemingly without warning (Ottestad, et al 2020) . This can also be the case for relatively young patients who were previously healthy, or who had only minor underlying conditions (Ottestad, et al 2020) . We have recently shown that in COVID-19, the clotting protein, fibrin(ogen), change to an amyloid form, that platelets are hyperactivated and that they form complexes with erythrocytes . In addition iron and p-selectin levels are also significantly dysregulated. It is also now accepted that coagulation pathology is central in the disease (Giannis, et al 2020 , Kollias, et al 2020 , Levi, et al 2020 , Middeldorp, et al 2020 , Miesbach and Makris 2020 . Despite the worsening trends of COVID-19 deaths, currently no drugs have been validated to have significant efficacy in large-scale studies (Jean, et al 2020) . An important issue is also that there is still no unified standard for the diagnosis and treatment of COVID-19 (Oldenburg and Doan 2020) . However, various antiviral agents, some antibiotics and anti-inflammatory agents have been explored and their efficacy debated (see Table 1 for such a list of medications). Table 1 : Various antiviral agents, antibiotics and anti-inflammatory agents suggested to be useful in the treatment of Use and comments References (general references and those investigating use in COVID-19) Inhibition of the RNA-dependent RNA polymerase (antivirals) Remdesivir Anti-viral therapeutic. Results vary: No statistically significant clinical benefits for severe or improvement time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. (Holshue, et al 2020 , Jean, et al 2020 , Wiersinga, et al 2020 Favipiravir Known to be active in vitro against oseltamivirresistant influenza A, B, and C viruses. Favipiravir was approved for treatment of novel influenza on February 15, 2020 in China. A 2020 study showed significantly better treatment outcomes is COVID-19 , Wang, et al 2019 Protease inhibitors Lopinavir/ritonavir Inhibition of papain-like protease and 3C-like protease, but in hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment An inhibitory effect on transcription-as well as replication-competent virus-like particles in the low micromolar range. (Jean, et al 2020 , Wang, et al 2016 Other therapies of interest Monoclonal or polyclonal antibodies Prophylactic and therapeutic tools against some viral infections, such as influenza. Large gaps exist in our understanding of the risk of immunopathology in COVID-19, the epidemiological risk factors, the mechanism and immune mediators of pathology during CoV infections. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. (Beigel, et al 2019 , de Alwis, et al 2020 , Wiersinga, et al 2020 Convalescent plasma A rapid method to derive antiviral treatment for Covid-19 is the use of convalescent plasma derived hyperimmune globulin. No clear evidence of benefit yet and a randomized trial found that it did not shorten time to recovery. (Bloch, et al 2020 , Brown and McCullough 2020 , de Alwis, et al 2020 , Wiersinga, et al 2020 Dexamethazone Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care. (Wiersinga, et al 2020) L-ergothioneine Potent antioxidant (Borodina, et al 2020, Cheah and Halliwell 2020) Lactoferrin Iron chelator and interferes with viral attachment to membrane receptors Niclosamide Niclosamide has been identified as a potent inhibitor of SARS-Cov-2 by Institut Pasteur Korea, with potency >40 x higher than remdesivir https://news.cision.com/uniontherapeutics/r/union-receives-approvalfrom-danish-medicines-agency-toinitiate-clinical-study-with-niclosamidefor,c3145312 Presently, it is suggested that best practices for supportive management of acute hypoxic respiratory failure and acute respiratory distress syndrome (ARDS) should be followed (Alhazzani, et al 2020 , Wiersinga, et al 2020 China is 80% . In general, the mortality rate of patients with ARDS is proportionate to the severity of the disease, with 27%, 32%, and 45% for mild, moderate, and severe disease, respectively (Diamond 2020) . It was also noted that the pooled mortality rate for all ARDS from 1994 to 2006 in the studies that were evaluated was 43% (Diamond 2020) . The question that now comes to mind is whether there might there be a pathophysiology link that is not considered in the current best-practice protocols. We have presented evidence that COVID-19 can be seen as a two-phase 'rollercoaster' of events, characterized by (i) thrombotic and (ii) bleeding or thrombocytopenia pathologies (Grobler, et al 2020) . These substantial vascular events are significant accompaniments to ARDS and lung complications and both vascular events are seen in COVID-19 patients. (Al-Samkari, et al 2020 , Bikdeli, et al 2020 , Boccia, et al 2020 , Connors and Levy 2020 .0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 2020a, Wright, et al 2020 . Clearly these coagulopathies might be seen as polar opposites, and it might be seen as odd if both are said to accompany COVID-19 pathology; the resolution of the apparent paradox is that these coagulopathies can be differentiated in time (Figure 1 ). During the progression of COVID-19, the circulating biomarkers P-selectin, von Willebrand Factor (VWF), fibrin(ogen) and D-dimer may either be within healthy levels, upregulated or eventually depleted . In COVID-19 patients, dysregulation, has been noted in each of them and this may lead to the extensive endotheliopathy noted in COVID-19 patients (Ackermann, et al 2020 , Goshua, et al 2020b (see Table 2 ). Figure 1 for levels during COVID-19. Circulating biomarker Selected references P-selectin (Goshua, et al 2020a , Neri, et al 2020 ) Fibrinogen and D-dimer (Al-Samkari, et al 2020 , Favaloro and Thachil 2020 , Garcia-Olivé, et al 2020 , Spiezia, et al 2020 Von Willebrand Factor (Escher, et al 2020 , Zachariah, et al 2020 . Figure 1 shows the fine balance during COVID-19, between these biomarkers and the development of an initial hyperclotting and thrombosis that can be followed by thrombocytopenia and bleeding; the latter is followed by the cytokine storm (at the end stage of the disease) (Grobler, et al 2020) . Depending on the direction (i.e, increases or decreases), dysregulation of fibrin(ogen), D-dimer, VWF and P-selectin may result in either hypercoagulation or excessive bleeding and thrombocytopenia (hypocoagulation). We suggested that patients need to be treated early in the disease progression, when hypercoagulation is clinically diagnosed (discussed later in the treatment protocol). Early in the hypercoagulation phase of the disease, high levels of VWF, P-selectin and fibrinogen are present, but there are still normal or slightly increased levels of D-dimer. If the disease is left to progress until the patient presents with VWF and fibrinogen depletion, and with high Ddimer levels (and even higher P-selectin levels), it will be indicative of a poor prognosis, an imminent cytokine storm, and ultimately death. This rollercoaster disease progression is a continuum and the progression of disease has no specific tipping point (Figure 1 ). In a recent JAMA editorial, the question was also asked whether the cytokine storm should be seen as significantly relevant in COVID-19, and it was referred to as "tempest in a teapot" (Sinha, et al 2020) . The basis for this conclusion was that the presence of elevated circulating mediators in the claimed cytokine storm are likely to reflect endothelial dysfunction and systemic inflammation leading to fever, tachycardia, tachypnea, and hypotension (Sinha, et al 2020) , rather than the more immediately lethal ARDS. The JAMA editorial concluded by suggesting . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint that incorporating the cytokine storm may only further increase uncertainty about how best to manage this heterogeneous population of patients (Sinha, et al 2020) . Our rollercoaster diagram ( Figure 1 ) also notes that increased levels of inflammatory cytokines will already start early in the disease (Grobler, et al 2020) . -19) [adapted from (Grobler, et al 2020) ]. We focus on fibrin(ogen), D-Dimer, P-selectin and von Willebrand Factor dysregulation, resulting in endothelial, erythrocyte and platelet dysfunction. A) Early on in the disease dysregulation in clotting proteins and circulating biomarkers may occur and is suggestive of hypercoagulation. B) The disease may progress to bleeding and thrombocytopenia. C) We suggest that each patient should be treated using a personalized medicine approach in the early stages of the disease. Image created with BioRender (https://biorender.com/). Compelling emerging clinical evidence (consistent with our rollercoaster hypothesis) shows that COVID-19 can be complicated by disseminated intravascular coagulation (DIC), which has a strongly prothrombotic character with a high risk of venous thromboembolism (Kollias, et al 2020) . Coagulopathy is now known to occur in the majority of patients who die from . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint COVID-19 (Tang, et al 2020b) . A report from Wuhan, China, indicated that 71% of 183 individuals who died of COVID-19 met criteria for DIC (Tang, et al 2020b , Wiersinga, et al 2020 . Heparin has also been found in some circumstances to be a helpful treatment for COVID-19 (Ayerbe, et al 2020 , Menezes-Rodrigues, et al 2020 . Patients treated with anticoagulants (such as heparin) had a higher survival rate and a much more favourable outcome was seen in ventilated patients were 62,7% of patients without anticoagulants died. This outcome will of course be if the patients are treated when they are still in the early stages of the disease (when hypercoagulation is present). In contrast, only 1% of patients treated with anticoagulants and who were ventilated died (Tang, et al 2020a) . Heparin interferes with von Willebrand factor (VWF), platelet activation, and assists in the prevention of thrombotic events. It was also recently shown, in a study, of 449 patients with severe COVID-19, that anticoagulant therapy, mainly with low molecular weight heparin, appeared to be associated with lower mortality in the subpopulation meeting sepsis-induced coagulopathy criteria or with markedly elevated D-dimer (Kollias, et al 2020 , Tang, et al 2020a . In this study 99 of the patients received heparin (mainly with low molecular weight heparin) for 7 days or longer (such treatment was only given in the initial stages of the disease when the patient is hypercoagulable and not during the bleeding or thrombocytopenia phase of the disease). It should be noted that the timeline of the rollercoaster disease progression can be hours and it is a continuum rather than a clear event or "flip" between hypercoagulation and bleeding. If the disease is left unabated, VWF and fibrinogen depletion, and significantly increased levels of D-dimer and P-selectin will progress on a continuum (Grobler, et al 2020) . Several autopsy results have also confirmed microthrombi throughout the lung and associated with right ventricular dilation of the heart. Recently, Ackermann and co-workers reported that histologic analysis of pulmonary vessels in patients with COVID-19 shows widespread thrombosis with microangiopathy (Ackermann, et al 2020) . Furthermore, they found that alveolar capillary microthrombi were 9 times as prevalent in patients with COVID-19 as in patients with influenza (p<0.001). In autopsy samples of lungs from patients with COVID-19, the amount of new vessel growth -predominantly through a mechanism of intussusceptive angiogenesis (i.e. splitting of an existing vessel where the capillary wall extends into the lumen of an existing vessel) -was 2.7 times as high as that in the lungs from patients with influenza (p<0.001) (Ackermann, et al 2020) . Middleton and co-workers showed the presence of neutrophil extracellular traps (NETs) in lung autopsy results, and suggested that these may be the cause of immune-thrombosis and may, in part, explain the prothrombotic clinical presentations in COVID-19 (Middleton, et al 2020) . Menter and co-workers also showed autopsy findings from 21 COVID-19 patients, and reported that the primary cause of death was respiratory failure, with exudative diffuse alveolar damage and massive capillary . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint congestion, often accompanied by microthrombi despite anticoagulation therapy (Menter, et al 2020) . A possible reason might be because the extent of systemic hypercoagulation was too significant for the medication to have a substantial enough effect. Similarly, Spiezia and co-workers argued in most COVID-19 patients high D-dimer levels are associated with a worse prognosis (Spiezia, et al 2020) . The authors also suggest that COVID-19 patients with acute respiratory failure represent the consequence of severe hypercoagulability, that when left untreated results in consumptive coagulopathy (end-stage DIC) and that excessive fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome (Spiezia, et al 2020) . Consumptive coagulopathy is characterized by abnormally increased activation of procoagulant pathways. This results in intravascular fibrin deposition and decreased levels of hemostatic components, including platelets, fibrinogen, and other clotting factors. Acute DIC results in bleeding and intravascular thrombus formation that can lead to tissue hypoxia, multiorgan dysfunction, and death (Costello and Nehring 2020) . It is therefore worth to note that DIC is a thrombotic coagulopathy that eventually leads to bleeding. Thromboelastometry (TEM), also known as rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelastic method for haemostasis testing. It is a modification of traditional thromboelastography ® (TEG ® ). These techniques are crucial point-of-care techniques that we suggest that should be used in treatment of COVID-19 patients. Spiezia and colleagues also noted that COVID-19 patients with acute respiratory failure present with severe hypercoagulability due to hyperfibrinogenemia, resulting in increased fibrin formation and polymerization that may predispose the patient to thrombosis. Spiezia and co-workers also concluded that thromboelastometry is an important point-of-care test in COVID-19, as it has the advantage of providing a global assessment of whole blood's ability to clot. On the other hand, it is not able to evaluate the contribution to clot formation of each element (including endothelium, platelets, and clotting factors). In 2020, Wright and co-workers also discussed the use of clot lysis at 30 minutes (LY30) on the TEG ® as point-of-care analysis method (Wright, et al 2020) . The LY30 parameter (measured in %) is recorded at 30 minutes, measured from the point where the maximum amplitude (MA) of the clot is reached (see Figure 2 ). LY30 of 3% or greater defines clinically relevant hyperfibrinolysis (Chapman, et al 2013) . The TEG ® results, particularly an increased maximum amplitude (MA) and G-score (that both measures maximal clot strength) and is used to predict thromboembolic events and a poor outcome in critically ill patients with COVID-19 (Wright, et al 2020) . MA is of great significance as it represents clot size (see Figure 2 ), as determined by platelet number and function, as well as fibrin crosslinking to form a stable clot. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10. 1101 Recently, various papers have shown the significance of TEG ® and the levels of coagulopathy in COVID-19 (an important measurement value of the TEG ® ) in managing COVID-19 patients is also getting more traction (Chandel, et al 2021 , Görlinger and Levy 2021 , Hranjec, et al 2020 (Smolarz, et al 2021) . Hranjec and co-workers in 2020 also noted that TEG ® with platelet mapping, better characterizes the spectrum of COVID-19 coagulation-related abnormalities and may guide more tailored, patient-specific therapies these patients (Hranjec, et al 2020) . Another important test is the PFA-200 platelet test. This test may be seen as a cross between bleeding time and quick aggregation testing. See Table 3 for the various parameters for the TEG ® and PFA-200. Table 3 , visualized. A) Healthy (normocotgulable) trace; B) Hypercoagulable trace and C) Hypocoagulable trace. Image created with BioRender (https://biorender.com/). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. Time of latency from start of test to initial fibrin formation (amplitude of 2mm); i.e. initiation time. Time taken to achieve a certain level of clot strength (amplitude of 20mm); i.e. amplification. The angle measures the speed at which fibrin build up and cross linking takes place, hence assesses the rate of clot formation, i.e. thrombin burst. Maximum clot size: it reflects the ultimate strength of the fibrin clot, i.e. overall stability of the clot. The larger the MA the more hypercoagulable the clot. The maximum velocity of clot growth observed or maximum rate of thrombus generation using G, where G is the elastic modulus strength of the thrombus in dynes per cm -2 . The time interval observed before the maximum speed of the clot growth. The clot strength: the amount of total resistance (to movement of the cup and pin) generated during clot formation. This is the total area under the velocity curve during clot growth, representing the amount of clot strength generated during clot growth. The LY30 parameter (measured in %) is recorded at 30 minutes, measured from the point where the maximum amplitude (MA) of the clot is reached. G value measured in Dyn.sec G-value is a log-derivation of the MA and is meant to also represent the clot strength Elevated G-value is associated with a hypercoagulable state and therefore increases the risk for venous thromboembolic disease. Citrated whole blood is aspirated at high shear rates through disposable cartridges. These cartridges contain an aperture within a membrane coated agonist. The agonist cartridges are Col/EPI, Col/ADP and P2Y and they report data in closure time. The PFA-200 test induces platelet adhesion, activation and aggregation using the three cartridges. Closure times increase progressively as the platelet counts falls below 100 x 10 9 /L. Agonist cartridges (Favaloro and . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint An important consideration is that TEG ® can be used to study the clotting parameters of both whole blood (WB) and platelet poor plasma (PPP). Whole blood TEG ® gives information on the clotting potential affected by the presence of both platelets and fibrinogen, while PPP TEG ® only presents evidence of the clotting potential of the plasma proteins (Nielsen 2008 , Nielsen 2017 . Reasons for a hypercoagulable TEG ® trace when using PPP, may be indicative of the presence of dysregulated inflammatory biomarkers, including P-selectin, inflammatory cytokines and increased levels of fibrinogen (Bester, et al 2018 , Bester, et al 2015 , Pretorius, et al 2017b , Randeria, et al 2019 . Our research group recently found that during the presence of systemic inflammation, and the increased presence of inflammagens, the biochemistry of the fibrin(ogen) molecule changes its folding characteristics (Figure 3 ). We could visualize these changes using fluorescent markers , Kell and Pretorius 2017 , Page, et al 2019 , Pretorius, et al 2017a . The fluorescent markers we use to show these structural changes in the fibrin(ogen) biochemistry was thioflavin T (ThT) and amytracker. These fluorescent markers are typically used to show amyloid changes to proteins , Kell and Pretorius 2017 , Page, et al 2019 , Pretorius, et al 2017a , suggesting the misfolding seen in fibrin(ogen) during the presence of inflammagens in the blood, could also be described as amyloid. We showed, that when fibrin(ogen) is exposed to increased levels of inflammatory biomarkers and bacterial (viral) inflammagens, either in the laboratory or in patients with increased levels, TEG ® of PPP was significantly hypercoagulable (Kell and Pretorius 2017 , Nunes, et al 2020 , Page, et al 2019 . Figure 3A shows the uncoiling of the fibrin(ogen) molecule where it caused plasma and WB to become hypercoagulable. Figure 3B and C shows scanning electron micrographs of representative examples of a healthy clot and a clot from a Type 2 Diabetes (T2DM) individual [taken from (Randeria, et al 2019) ]. The value of using both the TEG ® and fluorescent markers was again seen in our recent studies on the effects that COVID-19 has on the coagulation system, where an increased clot strength and amyloid formations were previously seen . . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint Figure 3: A) The uncoiling of the fibrin(ogen) protein (in part) resulting in whole blood and plasma hypercoagulability. B and C) are examples of scanning electron microscopy micorgraphs of B) fibrin clot from a healthy individual (created with platelet poor plasma with added thrombin); C) fibrin clot from a diabetes individual (created with platelet poor plasma with added thrombin) [B and C taken from (Randeria, et al 2019) ]. Image created with BioRender (https://biorender.com/). Importantly, endotheliopathy is also prevalent in patients with COVID-19 (Meizlish, et al 2020) (Ackermann, et al 2020 , Goshua, et al 2020a . In general, endothelopathy is also known to be significantly linked to coagulopathies. Endotheliopathy activates microthrombotic pathway and initiates microthrombogenesis, leading to endotheliopathy-associated intravascular microthrombi [for a review see (Chang 2018) ]. In this article, we describe a treatment regime that will address the coagulopathy in COVID-19 patients. We have found that addressing hypercoagulation and platelet hyperactivity during the early stages of the disease plays a significant role in stopping the progression of the disease and thus in lowering the high death rate in COVID-19 patients. We provide a decision-. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint tree treatment protocol for the treatment of COVID-19 patients, where treatment protocols were followed as per the patient's symptoms (therefore, following a personalized patientorientated approach), and based on oxygen saturation, TEG ® and PFA-200 analysis (See Table 3 ). The decision-tree treatment protocol was developed by qualified clinicians, working in private practice, based on standard clinical treatment practices. All pharmaceutical intervention suggested is within therapeutic levels and used within prescribed standard clinical protocols. All drugs suggested in the decision-tree protocol must be used as originally indicated/designed and no "off-label" treatment should done. Co-authors (EP, LMG, DBK, CV) are not medically qualified did not participate in either the development or use of the protocol. Two clinical protocols are suggested, based on clinical features of the patient: • A prognostic indicator scoring system was developed, based on a points system, to predict which patient is most likely to develop severe disease. A female patient (age range 55 -60) was diagnosed with COVID-19 (Day 1). A treatment regime was embarked upon based on the decision-tree protocol 1, as the patient showed a worsening of effort tolerance, as well as low oxygen percentage (89.4%). Ethical approval for blood analysis of patients with COVID-19, was given by the Health Research Ethics Committee (HREC) of Stellenbosch University (reference number: 6983). This laboratory study was carried out in strict adherence to the International Declaration of Helsinki, South African Guidelines for Good Clinical Practice and the South African Medical Research Council (SAMRC), Ethical Guidelines for research. Oral consent was obtained from the participant prior to any sample collection, followed by written consent after recovery. In the current analysis, we show the results from a single patient directly after she tested positive for COVID-19, as well as tracking her progression through the disease and various treatment regimes, until she tested negative with a full recovery. The timeline treatment regime from day of . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint admission onwards, was compiled from pathology data.The TEG ® 5000 Hemostasis Analyzer (Haemoscope Crop., Niles, IL, USA) was used to measure the viscoelastic properties of WB. 340μL of the WB was placed in a TEG ® cup, together with 20μL of Kaolin activator and the TEG ® allowed to run to LY30 (Lysis at 30 minutes). A prognostic indicator score system was developed to determine risk of developing severe disease (see Table 4 ). This score indicator system allows the clinician to allocate points for various parameters, including age, effort intolerance, Hypoxemia, O2 saturation, chest Z-ray and/or CT scan carotid intima-media thickness, and other co-morbidities. In addition, a scoring based on parameters from the point-of-care TEG is also suggested. Proposed treatment decision-tree protocol Figure 1A ]: Figure 4A shows the decision-tree protocol that was developed by the clinical team, when a patient is admitted to the hospital with one or more possible clinical features after a positive COVID-19 nasal swab diagnosis. Low risk patients should be treated according to symptoms . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint (Figure 4(1) ). Here it is suggested that high-risk patients should be treated with a regime where anticoagulation is involved. High-risk patients for hospitilization (Figure 4 (2))). are identified based on: • Activity-related worsening effort intolerance from your baseline (short-of breath/ dyspnoea) • Oxygen saturation that is ≤ 95% room air temperature (measured with pulse oximeter to constantly monitor the patient). • A lung CT scan suggestive of COVID-19, by using the radiology grading system, COVID-19 Reporting and Data System (CO-RADS) probability score (Prokop, et al 2020) . The infection is graded from very low or CO-RADS 1 up to very high or CO-RADS 5 and the severity and stage of the disease is determined with remarks on comorbidity and a differential diagnosis (Prokop, et al 2020) . The British Thoracic Society Severity Score (https://www.brit-thoracic.org.uk/about-us/covid-19-information-for-the-respiratorycommunity/) is another such lung CT scan scoring system used in COVID-19 grading. • Once the patient is admitted to hospital, treatment should commence with loading on DAPT, dexamethasone and Fondaparinux (therapeutic levels) (See Figure 4(3) ). Fondaparinux may be substituted with Low Molecular Weight heparin (LMWH) (therapeutic levels) or unfractionated heparin infusion. However, heparin infusion may be more labour intensive and heparin-induced thrombocytopenia (HIT) may come into play as a complication. • TEG and CRP are used to monitor and guide both outpatient as well as inpatient treatment. The rationale for using adjuvant treatment is as follows (see Figure 4 (7)): • SSRI: platelets uses serotonin to degranulate. Blocking serotonin re-uptake by platelets has antiplatelet effects. • Colchicine: Inhibits both IL-6 and IL-8. • Rupanase: This a potent platelet activating factor inhibitor • Dobutamine: Supporting a failing right ventricle (e.g. pulmonary hypertension). • Heparin inhalation: Known to have potent anti-inflammatory, antiviral and antithrombic effects. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi. org/10.1101 org/10. /2021 The protocol suggests that unfractionated heparin 5000 IU in 3 mL sterile water can be administered as inhalations every 4 to 6 hours, at any time during treatment for worsening hypoxaemia/dyspnoea. Therapeutic (not prophylactic) doses of either Fondaparinux unfractionated heparin or LMWH can be used. Therapeutic doses of Fondaparinux, unfractionated heparin or LMWH is used to control the enzymatic pathway of coagulation. The protocol also discussed the use of the potent platelet inhibitor, glycoprotein (GP) IIβ/IIIα inhibitor. This product blocks the GP IIβ/IIIα receptor on platelets. GP IIβ/IIIα inhibitor should be infused for at least 48 hours or continued for 48 hours after the administration of thrombolytic therapy (if thrombolysis is needed). High priority should be given to placement of central lines, under ultrasound guidance to prevent procedure-associated bleeding. An important clinical consideration is that D-dimer is only significantly elevated later in the disease ( Figure 1) . Therefore, our clinical observations suggest that, D-dimer levels early on (when fibrinogen levels are high), should not guide therapy, as it may falsely suggest tha t there is no hypercoagulation present. Therefore, D-dimer levels at presentation of the patient at the hospital should not be used to guide anticoagulation treatment, as this may only be a later sight of coagulopathy (see our rollercoaster hypothesis Figure 1 ). An excellent understanding and interpretation of TEG ® (and PFA-200) (Table 2 and Figure 2 ) is imperative to applying the protocol, and de-escalation of therapy is guided by TEG ® and clinical status of the patient. If the patient is clinically stable, not oxygen dependent and TEG ® normal; the clinician may consider discharge with dual antiplatelet therapy (DAPT) (e.g. Clopidogrel 75g/d / Aspirin 75g/d). To DAPT therapy a PPI is added (1 month), for gastric protection. A DOAC is added to the regime for at least 14 days. The exact duration and anticoagulation regime used for anticoagulation, post-discharge certainly needs to be carefully investigated further. The initiation of the intravenous thrombolysis protocol should be considered if, despite supplementary oxygen, the saturation remains ≤ 94%. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint Figure 4 : Clinical decision-tree protocol if clinical features point to hypercoagulation. 1) The first step would be to decide on outpatients management or if the patient should be hospitalized. 2A) Low risk patients will require symptomatic treatment regime. 2B) High-risk (outpatient) patients are treated with DAPT, as well as DOAC. 3) Once the patient is admitted to hospital, treatment should commence with loading on DAPT, dexamethasone and Fondaparinux (therapeutic levels). 4) With a hypercoagulable TEG result and all 3 channels of the PFA200 not blocked, use (GP) IIβ/IIIα infusion for at least 48 hours, guided by the TEG results. Once the patient is on a (GP) IIβ/IIIα inhibitor, the PFA200 does not have to be repeated as that class of drug inhibits all thee platelet channels. 5) At any time during hospitalization, the initiation of the intravenous thrombolysis protocol should be considered if, despite supplementary oxygen the saturation remails ≤ 94%. Streptokinase (250 000 IU/200 ml normal saline infused over 30 minutes. Do not use a streptokinase continuously infusion, due to potential bleeding risk. Streptokinase may be replaced with Tenecteplase or Alteplace. 6) DAPT (Clopidogrel 150g/d / Aspirin 150g/d), Fondaparinux (therapeutic dose) and proton pump inhibitor (PPI) should be used continued throughout the hospital stay. 7) Adjuvant treatment may be considered. 8) Post-discharge anticoagulation is important, however, research is still needed to determine the exact duration of the treatment. Abbreviations: BD: Twice daily; DAPT: Discharge with dual antiplatelet therapy; DOAC (e.g. Apixaban): Direct oral anticoagulants; IV: Intravenous; STAT: statin (immediately); TEG ® : Thromboelastography ® . Image created with BioRender (https://biorender.com/). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint Figure 1B) ]. Figure 5 shows the decision-tree when bleeding is diagnosed. Minor bleeds for example from puncture wounds (Central line/Arterial line) are treated by local pressure and TEG ® done to evaluate further treatment if necessary. Major or significant bleeds should be treated according to area of bleeding and guided by TEG ® . Blood transfusion may be deemed necessary. When using TEG in order to treat clinical bleeding the following TEG ® parameters are used as guidelines: • Increased R time/ narrow alpha angle: stop anti-factor agents (heparines); Administer clotting factors (FFP/Cryoprecipitate). • Decreased MA: Check platelet count; stop anti platelet agents; administer platelets, if indicated. • Increased Lysis: Administer tranexamic acid. Our clinical observation is that bleeding only occurs later on in the progression of the disease. 1) Tranexamic acid may be repeated 6 -8 hourly. 2) TEG and full blood count will help make decision on using fresh frozen plasma, cryoprecipitate or platelet transfusion. 3) Use TEG to decide on restarting anticoagulation. Abbreviations: GP IIβ/IIIα: Glycoprotein IIβ/IIIα; TEG ® : Thromboelastography ® . Image created with BioRender (https://biorender.com/). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10. 1101 Longitudinal case study of a COVID-19 positive patient who presented with hypercoagulation Protocol 1 was followed for the patient, as all clinical features pointed to hypercoagulation, with a worsening effort intolerance (short-of breath/ dyspnoea), and oxygen saturation that was 89.4% room air temperature (measured with pulse oximeter to constantly monitor the patient). A lung computerized tomography (CT) scan was suggestive of severe COVID-19 disease. Table 5 shows pathology data, including blood biomarkers and TEG ® WB analysis. Figure 6 depicts a timeline of the medical intervention used to treat the patient. Table 5 : Pathology data, including blood biomarkers and TEG ® whole blood (WB) analysis. TEG ® was done with freshly drawn citrated blood, using kaolin as activator, while TEG ® of platelet poor plasms (PPP) was done with freshly drawn citrate blood but without kaolin activator. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 mg STAT, Fondaparinux (therapeutic dose), cortisone, and a proton pump inhibitor. On day one the patient required a 60% rebreathing facial mask at 10 L/min of flow. Despite supplemental O2 therapy, saturation remained below 92% and thrombolysis was initiated with streptokinase (250 000 IU/200 ml normal saline infused over 30 minutes) (day 1: 13/01). The daily dose consisting of Clopidogrel 75 mg 2x per day (BD), Aspirin 150mg x 1 per day, Fondaparinux (therapeutic dose) and cortisone was administered from day two onwards. On day two the patient experienced noteworthy nose bleeds and Cyklokapron was administered, whilst all anticoagulants were omitted from the daily dose for that day. The Creactive protein levels slightly decreased to 234.3 mg/L and the serum ferritin was considered high at 1014 ug/L. Clotting parameters such as the α angle, MA, and G-value were low, whereas the R-time was considered high at 12.6 minutes, values typically seen postthrombolysis. On day six, two units of blood were transfused and on day seven the 60% oxygen face mask was replaced with continuous airway pressure (CPAP), due to worsening hypoxia. The C-reactive protein levels peaked on day seven at 426.7 mg/L. Post thrombolysis the patient initially showed hypocoagulable state on the TEG, but over the following 24 hours, developed a hypercoagulable state again. As a last resort, plasmapheresis was administered from day eight to day ten. There has been various papers that noted it that extracorporeal blood purification (or plasmapheresis) in COVID-19 patients could be beneficial, because the procedure can eliminate inflammatory cytokines (Al Shareef and Bakouri 2021 , Asgharpour, et al 2020 , Ramírez-Guerrero, et al 2020 , Yiğenoğlu, et al 2020 . After plasmapheresis, the C-reactive protein level decreased from 416.2 mg/L (day eight) to 140.2 mg/L (day 10). All the clotting parameters that were heightened prior to plasmapheresis recovered after the therapy was concluded. The d-dimer levels also markedly decreased after plasmapheresis. Hypoxemia worsened despite CPAP therapy and the patient had to be intubated on day 10. Mechanical ventilation occurred from day 10, until day 16 when the patient underwent extubation. A 60% oxygen facial mask was re-administered from day 16 up until day 19, followed by CPAP for a second time up until day 23. On day 23 the daily dose concluded, the patient received oxygen nasal cannula (3L/min), and the patient was discharged from hospital. On discharge, the patient received a 30 day course of dual antiplatelet therapy and pantoprazole, together with a 14 day course of apixaban. On day 28 the patient underwent a . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 SARS-CoV-2 PCR test which came back negative, and the C-reactive protein level was 51.9 mg/L. Our longitudinal case study showed that when hypercoagulation is present in the early stages of the condition, TEG ® parameters were crucial in managing the patient. Other markers like CRP, D-dimer and fibrinogen may indicate a probability of a worse prognosis. The hypercoagulable state remains post discharge and patients should be appropriately treated to prevent recurrent thrombo-embolic events. This treatment regime should be monitored closely and the duration of treatment should be clinically investigated further to determine optimal dose and duration of treatment. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10. 1101 Our longitudinal case study showed that when hypercoagulation is present in the early stages of the condition, coagulation parameters can be tracked very successfully with the TEG ® . A close monitoring of clinical parameters of clotting, including D-dimer and TEG ® parameters were crucial in managing the patient. A major challenge in early response in a rapidly evolving epidemic caused by a novel pathogen is the lack of traditional randomized placebo-controlled trials (RCTs) on which to make treatment and prevention decisions (Oldenburg and Doan 2020) . The identification and development of new therapeutic candidates or treatment regimes, based on emerging research and clinical evidence, require flexibility and a willingness to embrace treatment protocols that might deviate slightly from the recognized protocols. With this statement we most certainly do not imply that clinicians and researchers should lower the bar for standards of evidence. However, during this pandemic with the rapidly changing environment, traditional RCT rules may not apply (Oldenburg and Doan 2020) . Because the coagulopathy changes over time (and this timeframe can be within hours), therapy should be guided by clinical parameters, including TEG ® parameters, levels of fibrinogen, VWF, as well as D-dimer. Given the high stakes, the imperative for high-quality research is greater than ever. Flexible and reflective treatment protocols will be our only chance to lower the increasing death rates and eventually the outcome of this pandemic. We therefore suggest that COVID-19 is indeed (also) a true vascular disease. We conclude by suggesting that the treatment of COVID-19 patients, should be based on results from pointof-care analyses like the TEG ® , that shows the physiological status of the haematological and coagulation system in real-time. Ethics approval and consent to participate Ethical approval for blood collection and analysis of the patient with acute COVID-19, by the Health Research Ethics Committee (HREC) of Stellenbosch University (reference number: 9521). This laboratory study was carried out in strict adherence to the International Declaration of Helsinki, South African Guidelines for Good Clinical Practice and the South African Medical Research Council (SAMRC), Ethical Guidelines for research. Consent was obtained from the participant. The patient or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. All authors approved submission of the paper. The authors have no competing interests to declare. DBK thanks the Novo Nordisk Foundation for financial support (grant NNF20CC0035580). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint Authors' contributions GJL: Clinician and patient sample identification and writing of clinical workflow protocols; PSL: clinical workflow protocols; CV and LMG: technical assistance; DBK: co-corresponding author; EP: Sample analysis, writing and editing of the paper, co-corresponding author. Table 1 : Various antiviral agents, antibiotics and anti-inflammatory agents suggested to be useful in the treatment of COVID-19. Table 2 : Dysregulation of circulating biomarkers P-selectin, von Willebrand Facto, fibrin(ogen) and D-dimer in COVID-19. See Figure 1 for levels during COVID-19. Table 5 : Pathology data, including blood biomarkers and TEG ® whole blood (WB) analysis. TEG ® was done with freshly drawn citrated blood, using kaolin as activator, while TEG ® of platelet poor plasms (PPP) was done with freshly drawn citrate blood but without kaolin activator. Red values = too high; Blue values = too low. (Grobler, et al 2020) ]. We focus on fibrin(ogen), D-Dimer, Pselectin and von Willebrand Factor dysregulation, resulting in endothelial, erythrocyte and platelet dysfunction. A) Early on in the disease dysregulation in clotting proteins and circulating biomarkers may occur and is suggestive of hypercoagulation. B) The disease may progress to bleeding and thrombocytopenia. C) We suggest that each patient should be treated using a personalized medicine approach in the early stages of the disease. Image created with BioRender (https://biorender.com/). Table 3 , visualized. A) Healthy (normocotgulable) trace; B) Hypercoagulable trace and C) Hypocoagulable trace. Image created with BioRender (https://biorender.com/). 1) The first step would be to decide on outpatients management or if the patient should be hospitalized. 2A) Low risk patients will require symptomatic treatment regime. 2B) High-risk (outpatient) patients are treated with DAPT, as well as DOAC.3) Once the patient is admitted to hospital, treatment should commence with loading on DAPT, dexamethasone and Fondaparinux (therapeutic levels). 4) With a hypercoagulable TEG result and all 3 channels of the PFA200 not blocked, use (GP) IIβ/IIIα infusion for at least 48 hours, guided by the TEG results. Once the patient is on a (GP) IIβ/IIIα inhibitor, the PFA200 does not have to be repeated as that class of drug inhibits all thee platelet channels. 5) At any time during hospitalization, the initiation of the intravenous thrombolysis protocol should be considered if, despite supplementary oxygen the saturation remails ≤ 94%. Streptokinase (250 000 IU/200 ml normal saline infused over 30 minutes. Do not use a streptokinase continuously infusion, . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260012 doi: medRxiv preprint due to potential bleeding risk. Streptokinase may be replaced with Tenecteplase or Alteplace. 6) DAPT (Clopidogrel 150g/d / Aspirin 150g/d), Fondaparinux (therapeutic dose) and proton pump inhibitor (PPI) should be used continued throughout the hospital stay. 7) Adjuvant treatment may be considered. 8) Post-discharge anticoagulation is important, however, research is still needed to determine the exact duration of the treatment. Abbreviations: BD: Twice daily; DAPT: Discharge with dual antiplatelet therapy; DOAC (e.g. Apixaban): Direct oral anticoagulants; IV: Intravenous; STAT: statin (immediately); TEG ® : Thromboelastography ® . Image created with BioRender (https://biorender.com/). Our clinical observation is that bleeding only occurs later on in the progression of the disease. 1) Tranexamic acid may be repeated 6 -8 hourly. 2) TEG and full blood count will help make decision on using fresh frozen plasma, cryoprecipitate or platelet transfusion. 3) Use TEG to decide on restarting anticoagulation. Abbreviations: GP IIβ/IIIα: Glycoprotein IIβ/IIIα; TEG ® : Thromboelastography ® . Image created with BioRender (https://biorender.com/). . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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