An Ounce of Prevention May Prevent Hospitalization

To the Editor: We are writing a letter in response to the article entitled “Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility” in the July issue of Physiological Reviews (13). This review suggests that plasmin is a protease that may cleave the spike proteins of SARS-CoV-2 making it more virulent and increasing its ability to invade cells. Furthermore, patients with chronic illnesses such as diabetes, hypertension, renal insufficiency, and cardiovascular disease have higher levels of plasminogen and plasmin, and it was suggested that this may be one of the reasons these patients have greater morbidity and mortality from SARS-CoV-2. Finally, they bring to light the increase in D-dimer levels in patients with SARS-CoV-2 as hyperactive fibrinolysis and advocate for the targeting of hyperfibrinolysis with anti-plasmin compounds as a potential therapy for COVID-19 patients.

As of April 26, 2020, there are nearly 3 million people diagnosed with COVID-19 worldwide, and more than 200,000 have died as a result of the infection (10). Patients greater than 65 yr old and with chronic cardiovascular and metabolic illnesses are more likely to be hospitalized, admitted to the Intensive Care Unit (ICU), be mechanically ventilated, and succumb to the disease. In an early study out of Wuhan, China, acute respiratory distress syndrome (ARDS) occurs in 41.8% of infected patients. Many of these patients have a “typical” ARDS that includes alveolar flooding, a $\text{P}{\text{a}}_{\text{O}}{}_{{}_2}$/${\text{F}\mathrm{I}}_{{\text{O}}_{\text{2}}}$ ratio <300, need for positive end-expiratory pressure (PEEP), bilateral opacities on chest imaging, and decreased respiratory compliance leading to increased plateau pressures (20). However, an independent study from Italy indicated that a significant proportion of mechanically ventilated patients present with an “atypical” ARDS, requiring high levels of oxygenation support (higher ${\text{F}\mathrm{I}}_{{\text{O}}_{\text{2}}}$ and PEEP) while maintaining normal respiratory compliance (11). It is believed that this phenomenon is due, in part, to a V/Q mismatch secondary to the formation of a large clot burden at the level of the microvascular circulation that prevents systemic oxygenation (16).

The coagulation disorder induced by SARS-CoV-2 is complicated and can cause both bleeding and thrombosis. Critically ill patients have significant thrombocytopenia, increased International Normalized Ratio (INR), and high D-dimer levels, indicating a likely diagnosis of disseminated intravascular coagulopathy (DIC) which can lead to coincident thrombosis and bleeding (9, 13). Interestingly, in the earlier phases of the disease, D-dimer levels are increased, but other coagulation indices remain normal. This may be due to early activation of the coagulation system leading to the formation of neutrophil extracellular traps (12). While the early phase may not alter other parameters of the coagulation system, the continual activation of this system may lead to sepsis-induced coagulopathy and, eventually, DIC. In support of this, a recent publication indicates that some patients with SARS-CoV-2 that are mechanically ventilated for respiratory distress have a solely hypercoagulable state (18). This was measured using thromboelastography that indicated the hypercoagulable state with other measures of coagulopathy (INR, prothrombin time, activated partial thromboplastin time) within normal limits. Additionally, D-dimer was increased along with activated protein C and fibrinogen levels.

Investigators have recently suggested tissue plasminogen activator (tPA) as a therapy to dissolve fibrin clots in patients with ARDS, and two clinical trials have been registered (17; NCT04357730 and NCT04356833). The potential benefits of such therapy would be to rapidly dissolve pulmonary microvascular clots and improve blood flow through the pulmonary circulation to improve systemic oxygenation and provide end-organ support. tPA activates plasminogen and converts it to plasmin with the intent that plasmin will break down fibrin clots, reduce clot burden, and improve pulmonary flow. However, many patients requiring this therapy would be in severe ARDS and may be more likely to have additional coagulopathies. Acute bleeding is a known risk of tPA therapy (2). Additionally, tPA is usually used for clots in larger vessels (e.g., embolic stroke), and its effect may not be able to adequately clear large enough proportions of the microvascular circulation (which has a much larger surface area than the large vessels that feed it) to significantly improve systemic oxygenation (7, 8). Finally, plasmin is a protease that may cleave the spike protein of SARS-CoV-2 and increase its virulence (13). However, given that tPA is indicated as a therapy for severe disease, these risks could likely be worth the reward.

A different therapy that may be of use in patients infected with SARS-CoV-2 is tranexamic acid (TXA). TXA is a synthetic analog of lysine that binds lysine receptor sites on plasminogen and prevents its conversion to plasmin, thereby preventing fibrinolysis. TXA is regularly used to slow bleeding in patients with heavy menstrual bleeding (4). It is also used in traumatic bleeding and is regularly used in surgical cases where heavy blood loss is expected (5). TXA is orally available and is used in patients for up to 8 wk for treatment of melasma with very low incidence of thrombotic events (3). Furthermore, as it prevents the formation of plasmin, it would potentially remove one mechanism by which SARS-CoV-2 becomes more virulent and prevent end-organ dysfunction while leaving adaptive immunity the opportunity to overwhelm the virus. There are current randomized controlled trials registered that are hypothesizing that oral TXA provided to outpatients may prevent hospitalization (NCT04338074), and plans are currently being made for an inpatient trial in which TXA is provided to non-ICU inpatients to prevent ICU admission and mechanical ventilation (NCT04338126). Finally, while TXA is anti-fibrinolytic, and not pro-thrombotic, there is concern that fibrinolysis inhibition will prevent dissolution of existing and/or newly formed clots (19). The coagulation disorder present in SARS-CoV-2 is complicated, and there is clearly a phase in which new clots are formed that cause end-organ dysfunction (6, 15). It has been recommended that prophylactic or therapeutic anticoagulation is warranted to prevent formation of new clots (1, 14). Use of enoxaparin or apixaban could assist in prevention of newly formed clots while allowing TXA to prevent formation of plasmin and slow SARS-CoV-2 virulence. Furthermore, these anticoagulation strategies are currently part of the aforementioned TXA studies.

In conclusion, SARS-CoV-2 is a novel coronavirus causing a global pandemic and a high morbidity and mortality rate. Multiple therapies are being tested to prevent viral infection or the ensuing respiratory distress and coagulation dysfunction leading to death. The aforementioned review article suggests that anti-plasmin therapy may be key to preventing SARS-CoV-2 virulence and its downstream effects. We suggest that TXA would be a useful therapy that is safe and orally available. In our minds, an ounce of prevention while an infected patient remains in the outpatient setting may prevent hospitalization and a pound of morbidity.

DISCLOSURES

A. Barker has no conflicts of interest, financial or otherwise. B. Wagener has an ongoing collaboration with Sadis Matalon (co-author of the primary review) and has published a paper with him within the last 3 yr. Furthermore, B. Wagener is a co-investigator on both the outpatient and inpatient tranexamic acid studies mentioned in the letter.

Editor S. Matalon was not involved in the peer review process of this manuscript.