Intestinal Damage in COVID-19: SARS-CoV-2 Infection and Intestinal Thrombosis

Authors: Xiaoming Wu1Haijiao Jing1Chengyue Wang1Yufeng Wang1Nan Zuo1Tao Jiang2*Valerie A. Novakovic3 and Jialan Shi1,3,4* Front. Microbiol., 22 March 2022 | https://doi.org/10.3389/fmicb.2022.860931

The intestinal tract, with high expression of angiotensin-converting enzyme 2 (ACE2), is a major site of extrapulmonary infection in COVID-19. During pulmonary infection, the virus enters the bloodstream forming viremia, which infects and damages extrapulmonary organs. Uncontrolled viral infection induces cytokine storm and promotes a hypercoagulable state, leading to systemic microthrombi. Both viral infection and microthrombi can damage the gut–blood barrier, resulting in malabsorption, malnutrition, and intestinal flora entering the blood, ultimately increasing disease severity and mortality. Early prophylactic antithrombotic therapy can prevent these damages, thereby reducing mortality. In this review, we discuss the effects of SARS-CoV-2 infection and intestinal thrombosis on intestinal injury and disease severity, as well as corresponding treatment strategies.

Introduction

COVID-19 has become a worldwide pandemic causing widespread illness and mortality. SARS-CoV-2 mainly infects the respiratory tract through attachment to angiotensin-converting enzyme 2 (ACE2) receptors (Lan et al., 2020). ACE2 is also highly expressed on intestinal epithelial cells, allowing SARS-CoV-2 to infect the intestinal tract (Xiao et al., 2020a). Recent meta-analyses show that 48%–54% of fecal samples from COVID-19 patients have tested positive for viral RNA, and 15%–17% of patients have gastrointestinal (GI) symptoms (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). Additionally, live virus can be isolated from fecal samples of COVID-19 patients (Wang et al., 2020). Some studies have proposed fecal–oral transmission as the cause of intestinal infection (Guo et al., 2021). However, direct evidence for fecal–oral transmission is still lacking. Meanwhile, the virus has been detected in the blood of both symptomatic and asymptomatic patients (Chang et al., 2020), and disseminated virus could infect extrapulmonary organs (Jacobs and Mellors, 2020). Thus, the potential that intestinal infection occurs via blood transmission should be carefully considered.

Pulmonary infection triggers cytokine storm and induces a prothrombotic state (McFadyen et al., 2020Moore and June, 2020). Venous and arterial thrombosis are common in COVID-19 (Moore and June, 2020). Systematic reviews estimate that 14%–31% of in-hospital patients develop a clinically apparent thrombotic event (Suh et al., 2021Tan et al., 2021), while autopsy reports show a high prevalence of microthrombi in multiple organs, including lung, heart, liver, kidney, and gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). A cohort study showed that COVID-19 patients with intestinal ischemia had markedly elevated D-dimer levels and poor outcomes (Norsa et al., 2020). Additionally, recent studies have shown that mesenteric thrombosis often results in intestinal resection and significantly increases mortality (Bhayana et al., 2020El Moheb et al., 2020). Therefore, it is essential to outline the mechanisms of intestinal thrombosis and its contribution to intestinal damage and disease progression.

In this review, we discuss blood transmission as a potential route for intestinal infection. We then summarize the characteristics and mechanism of intestinal thrombosis formation in COVID-19. Next, we focus on the effects of intestinal infection and thrombosis on intestinal damage and disease severity. Finally, we discuss therapeutic strategies to prevent intestinal damage.

Gastrointestinal Symptoms and SARS-CoV-2 Infection

Multiple studies have reported GI symptoms in COVID-19 patients, including diarrhea, nausea, vomiting, anorexia, and abdominal pain (Cheung et al., 2020Mao et al., 2020Sultan et al., 2020). According to a meta-analysis comprising 10,890 COVID-19 patients, the pooled prevalence estimates of GI symptoms were: diarrhea (7.7%), nausea or vomiting (7.8%), and abdominal pain (2.7%; Sultan et al., 2020) with 10% of these patients reporting GI symptoms as being their initial symptoms (Cheung et al., 2020). These data indicate potential gastrointestinal infection by SARS-CoV-2, which is reported to infect and replicate in epithelial cells of human small intestinal organoids (Zang et al., 2020). Both viral nucleocapsid proteins and viral particles have been detected in infected patient intestinal biopsies (Livanos et al., 2021). Additionally, SARS-CoV-2 RNA and live virus can be found in the stool of patients (Wang et al., 2020). More importantly, SARS-CoV-2 subgenomic mRNA is transcribed in actively replicating cells and has been detected in fecal samples (Wölfel et al., 2020). Further, rectal viral shedding persists for longer than that of the respiratory system (Zhao et al., 2020). All these data demonstrate that SARS-CoV-2 directly infects and replicates in intestinal epithelial cells of patients.

Intestinal Infection and Transmission Routes

With the deepening understanding of COVID-19, GI symptoms have been recognized as early signs of the disease. The high expression of ACE2 in the GI tract, isolation of live virus from fecal samples, and a subset of patients presenting with only GI symptoms seem to suggest fecal–oral transmission. However, problems with the feasibility of this mode of transmission remain. First, studies have shown that SARS-CoV-2 loses infectivity in simulated gastric acid within 10 min (Chan et al., 2020Zang et al., 2020Zhong et al., 2020). Secondly, SARS-CoV-2, as an enveloped virus, is largely unable to withstand the detergent effect of bile salts and the activity of digestive enzymes in the duodenum (Figure 1). Although some studies have suggested that highly viscous mucus in the gastrointestinal tract protects SARS-CoV-2, allowing the virus to retain its infectivity (Guo et al., 2021Zhang H. et al., 2021), there is still a lack of direct evidence. Bushman et al. (2019) had previously investigated the links between the structures of viruses and routes of transmission and found a strong association between fecal–oral transmission and the absence of a lipid envelope. Lastly, although some studies have isolated intact viruses from feces (Wang et al., 2020Zhang Y. et al., 2020Zhou et al., 2020Xiao et al., 2020b), most of them have not further confirmed the infectivity of these viruses (Wang et al., 2020Zhang Y. et al., 2020Xiao et al., 2020b). Zhou et al. (2020) confirmed viral propagation by RT-PCR, but only in a single fecal sample. Previous research has shown that SARS-CoV-2 is completely inactivated in simulated human colonic fluid over the course of 24 h, which may explain the sporadic detection of infection-active SARS-CoV-2 from feces samples.FIGURE 1

Figure 1. Intestinal infection and transmission routes. ① Direct evidence for fecal–oral transmission is still lacking. SARS-CoV-2 may be unable to enter the small intestine from the stomach due to gastric acid, bile and digestive enzymes. ② SARS-CoV-2 released from type II alveolar cells infects alveolar capillary endothelial cells (ECs). The virus replicates in ECs and is released into the blood to form viremia. ③ SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation. ④ Blood transmission after alveolar or nasal infection is a potential route of intestinal infection. Eventually, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract. ⑤ SARS-CoV-2 in the gut can also enter the capillaries and cause viremia, leading to recurrence of disease.

Several lines of evidence suggest that SARS-CoV-2 may infect the intestinal tract via the bloodstream. Deng et al. (2020) detected SARS-CoV-2 RNA in anal swabs from intratracheally but not intragastrically infected rhesus macaques, suggesting blood transmission. Indeed, SARS-CoV-2 RNA has been detected in blood and urine samples of patients (Wang et al., 2020). The virus can also be detected in multiple organs (including heart, brain, and kidney) and is associated with organ injury, indicating that the virus can reach and infect extrapulmonary organs (Puelles et al., 2020). Another study showed that SARS-CoV-2 viremia was associated with intestinal damage, independent of disease severity (Li Y. et al., 2021). Thus, blood transmission could be the cause of intestinal infection. Specifically, SARS-CoV-2 replicating in alveolar epithelial cells and capillary ECs is released into the bloodstream and infects new vascular ECs. The capillary network is then the main route by which the virus enters and infects extrapulmonary organs. The extensive surface area of intestinal capillaries makes intestinal epithelial cells more susceptible to infection than other extrapulmonary organs. Following infection of intestinal capillaries, SARS-CoV-2 is released into the gut and infects surrounding intestinal epithelial cells along the intestinal tract (Figure 1). Once established in the gut, SARS-CoV-2 can also reenter the capillaries, potentially leading to recurrence of disease. Consistent with this, in patients who experienced recurrence, the phylogenetic analysis of infection samples has shown that recurrent virus evolves from the original parent virus (Hu et al., 2020).

Additionally, SARS-CoV-2 RNA can also be detected in the blood and urine of asymptomatic patients, suggesting a second pathway to viremia through the nasal cavity (Chang et al., 2020Hasanoglu et al., 2021). The abundant blood vessels, thin mucous membrane, and higher levels of ACE2 (Huang et al., 2021) make it possible for the virus to initiate viremia from the nasal cavity. Specifically, SARS-CoV-2 is released from infected ciliary cells of the nasal cavity and breaks through the basement membrane, infecting the vascular ECs and eventually entering circulation (Figure 1). Blood transmission after nasal infection is therefore another potential route of intestinal infection.

Intestinal Damage, Malnutrition, and Poor Outcomes

A recent study has shown that a fecal sample positive for SARS-CoV-2 RNA at any time during hospitalization was associated with higher mortality [HR: 3.4 (1.2–9.9); Das Adhikari et al., 2021]. Similarly, another study showed that small-bowel thickening on CT was strongly associated with ICU admission (Wölfel et al., 2020). This relationship did not hold for colon or rectal thickening. These data indicates that small-bowel damage contributes to poor outcomes. As the main organ for nutrient absorption, damage to the small intestine will result in malabsorption and malnutrition, both of which commonly occur in COVID-19 patients (Di Filippo et al., 2021Lv et al., 2021) and are associated with disease severity (Luo et al., 2020Zhang P. et al., 2021). A fecal metabolome study showed that feces of COVID-19 patients were enriched with important nutrients that should be metabolized or absorbed, consistent with malabsorption (Lv et al., 2021). A prospective study showed that 29% of COVID-19 patients (31% of hospitalization patients and 21% of patients quarantined at home) had lost >5% of body weight [median weight loss, 6.5 (5.0–9.0) kg or 8.1 (6.1–10.9) %; Di Filippo et al., 2021]. Those patients with weight loss had greater systemic inflammation, impaired renal function and longer disease duration. A large, multicenter study (including 3,229 patients with GI symptoms) showed that 23% of patients had malnutrition, of whom 56.4% were unable to gain weight after 6 months follow-up (Rizvi et al., 2021). Studies also showed that malnutrition was associated with higher incidences of acute respiratory distress syndrome, acute myocardial injury, secondary infection, shock, and 28-day ICU mortality (Luo et al., 2020Zhang P. et al., 2021). Overall, malabsorption and malnutrition due to damaged small intestine increased disease severity and mortality.

Nutrient absorption in the small intestine is mainly through ATP-dependent active transport. Intestinal infection, hypoxemia, and intestinal ischemia contribute to malabsorption. SARS-CoV-2 adhesion depletes ACE2 levels on intestinal epithelial cells, which alters the expression of the neutral amino acid transporter B0AT1, reducing the intake of tryptophan and the production of nicotinamide (D’Amico et al., 2020). Meanwhile, uncontrolled viral replication consumes large amounts of ATP and nutrients, resulting in decreased nutrients entering the bloodstream. More importantly, anaerobic glycolysis caused by hypoxemia and intestinal ischemia significantly decreases ATP and active transport, leading to malabsorption. Additionally, hypoxemia and intestinal ischemia can also cause anorexia, nausea, vomiting, and enteral nutrition intolerance, reducing food intake. A prospective multicenter study showed that reduced food intake was associated with higher ICU admission and mortality (Caccialanza et al., 2021).

Intestinal Ischemia and Thrombosis

Intestinal ischemia is a common manifestation in COVID-19 patients. Autopsy results have shown that 31.6% of deceased patients had focal ischemic intestinal changes (Chiu et al., 2020). In a separate imaging study, bowel wall thickening and pneumatosis intestinalis, which indicate intestinal ischemia, were found on 38.1% (16 of 42) of abdominal CT images (Bhayana et al., 2020). Of these, 4 (9.5%) patients with pneumatosis intestinalis developed severe intestinal necrosis and needed resection. In another cohort study, 55.8% (58/104) of ICU patients developed an ileus (Kaafarani et al., 2020). Although mechanical factors cannot be ruled out, insufficient intestinal motility due to intestinal ischemia was more likely to be the cause of ileus in COVID-19 patients. In these patients with ileus, 4 (3.8%) developed severe intestinal ischemia and require emergency surgery. Both studies found microthrombi in these resected intestinal samples, which were the main cause of intestinal ischemia and increased mortality.

Additional intestinal ischemia and necrosis follows the formation of mesenteric thrombosis. However, there is currently relatively little data of mesenteric thrombus in COVID-19. Therefore, we have summarized the characteristics of 40 patients in 39 case reports published on PubMed (Supplementary Table 1). The median age of these patients was 50 (20–82) years, 26 (65%) were male, 38 (95%) developed bowel ischemia or necrosis, 30 (75%) needed bowel resection, 7 (17.5%) required no surgery, at least 3 (7.5%) developed sepsis, and 13 (32.5%) died. Other abdominal thrombotic events (such as celiac aortic thrombosis) leading to mesenteric ischemia can also result in severe intestinal necrosis and require intestinal resection (Zamboni et al., 2021).

Mild intestinal ischemia can lead to reduced diet and malabsorption. Severe intestinal ischemia or necrosis leads to the dissemination of gut bacteria, endotoxins, and microbial metabolites into the blood (Figure 2 bottom), aggravating hyperinflammation and the hypercoagulability state. Such patients need emergency excision of the necrotic bowel, which significantly increases mortality.FIGURE 2

Figure 2. Intestinal thrombosis leads to intestinal mucosal necrosis and dissemination of gut bacteria, endotoxins, and microbial metabolites in blood. (Top) Mesenteric vascular endotheliitis (initiated by viremia and accelerated by cytokines), hyperactivated platelets and high levels of phosphatidylserine (PS) promote a high rate of mesenteric thrombus in COVID-19 patients (mesenteric vein is shown in Supplementary Figure 1). (Bottom) Intestinal microthrombi and hypoxemia rapidly lead to intestinal mucosal ischemia and necrosis. The damaged gut–blood barrier leads to dissemination of gut bacteria, endotoxins, and microbial metabolites in blood.

Long-Term Gastrointestinal Sequelae

Long-term GI complications are common in recovering COVID-19 patients. In one systematic review of post-acute COVID-19 manifestations, diarrhea was among the top 10 most common complaints, with a prevalence of 6%. Other long-term GI symptoms include nausea, vomiting, abdominal pain, loss of appetite, and weight loss (Aiyegbusi et al., 2021Huang et al., 2021). The exact mechanisms of the GI sequelae remain unclear. Recently, persistent endotheliopathy, higher levels of thrombin (Fogarty et al., 2021), and residual SARS-CoV-2 viral antigens in the GI tract (Cheung et al., 2022) were described in convalescent COVID-19 patients. These data suggest that prolonged intestinal infection, persistent endothelial injury (abnormal intestinal–blood barrier), and microthrombi could be causes of the persistent GI symptoms.

The Mechanisms of Intestinal Thrombosis

Damaged Endothelial Cells

Resected bowel samples from COVID-19 patients routinely exhibit thrombi and endotheliitis, indicating the important role of EC injury in mesenteric thrombosis (Bhayana et al., 2020Chiu et al., 2020Kaafarani et al., 2020). SARS-CoV-2 infection (Varga et al., 2020) and elevated inflammatory cytokines (He et al., 2016) damage mesenteric vascular ECs. In response, EC cell margins retract, extending phosphatidylserine (PS) positive filopods and releasing endothelial microparticles (MPs; Figure 3BHe et al., 2016). The PS+ filopods and MPs can be co-stained by Xa and Va and support fibrin formation (Figures 3BD). The exposed PS then activates tissue factor on ECs, triggering the extrinsic coagulation pathway (Versteeg et al., 2013). Next, higher levels of FVIII and vWF released from damaged EC contribute to the hypercoagulable state and platelet aggregation, respectively (Goshua et al., 2020). Thrombomodulin is then released from ECs in its soluble form, which has an attenuated capacity to activate Protein C due to a lack of other cofactors on ECs, such as endothelial protein C receptor (Versteeg et al., 2013). Finally, upregulation of endothelial cell adhesion molecules recruits neutrophils and platelets and further contributes to thrombosis (Tong et al., 2020Li L. et al., 2021).FIGURE 3

Figure 3. Phosphatidylserine exposure on activated/apoptotic cells and microparticles (MPs) promotes fibrin formation. (A) Phosphatidylserine is usually confined to the inner leaflet of the cell membrane. This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of non-PS by floppases (left). Upon stimulation, calcium transients will inhibit ATP-dependent transport and stimulate the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure (right). (B–D) Human umbilical vein ECs were treated with healthy human plasma and TNF-ɑ (our previous study; He et al., 2016). (B) ECs retracts the cell margins, extends PS positive filopods and releases endothelial-MPs. (C) The PS+ filopods and MPs can be co-stained by Xa and Va. (D) ECs (green) were incubated with MPs-depleted plasma (MDP) in the presence of calcium for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Considerable fibrin stands among cultured ECs along with filopodia. (E) Confocal images showed PS expression on platelets of patients stained with Alexa 488 lactadherin (our previous study; Ma et al., 2017). MPs from the activated platelet (*) had formed at the margin area located between the distinct outlines. (F) MPs from plasma were co-stained by Xa and Va (or lactadherin and annexin V; our previous study; Gao et al., 2015). (G) MPs that were incubated with recalcified MDP for 30 min and stained with Alexa Fluro 647-anti-fibrin for 30 min. Converted fibrin networks were detected around MPs. The inset bars represent 5 μm in (B–D,G) and 2 μm in (E,F).

Hyperactivated Platelets and Phosphatidylserine Storm

Although COVID-19 patients exhibit mild thrombocytopenia, the remaining platelets are hyperactivated (Manne et al., 2020Taus et al., 2020Zaid et al., 2020). Studies have shown that platelets from COVID-19 patients have increased P-selectin and αIIbβ3 expression. P-selectin on activated platelets interacts with integrin αIIb3 on monocytes to form platelet-monocyte complexes, which induce monocyte tissue factor expression (Hottz et al., 2020). The activated platelets can also induce neutrophils to release neutrophil extracellular traps (NETs; Middleton et al., 2020). Furthermore, platelets from COVID-19 patients aggregate and adhere more efficiently to collagen-coated surfaces under flow conditions (Manne et al., 2020Zaid et al., 2020). Meanwhile, activated platelets release α- and dense-granule contents including FV, FXI, fibrinogen and vWF (Zaid et al., 2020). In addition, activated platelets also produce inflammatory cytokines, fueling cytokine storm (Taus et al., 2020Zaid et al., 2020). Most importantly, activated platelets expose higher levels of PS and release higher numbers of PS+ MPs (Figures 3EGZaid et al., 2020Althaus et al., 2021).

Phosphatidylserine is the most abundant negatively charged phospholipid in mammalian cells and is usually confined to the inner leaflet of the cell membrane (Versteeg et al., 2013). This asymmetry is maintained through ATP-dependent inward transport of PS by flippases and outward transport of other phospholipids by floppases (Figure 3A left). Upon stimulation, transiently increased calcium inhibits ATP-dependent transport and stimulates the nonselective lipid transporter scramblase (ATP-independent), resulting in PS exposure on the outer membrane (Figure 3A right). During this process, microvesicles derived from the budding of cellular membranes will be released. These MPs are typically <1 μm and express PS (Burnier et al., 2009). The exposure of PS on the surface of cells and MPs provides a catalytic surface for factor Xa and thrombin formation in vivo (Versteeg et al., 2013). We have previously demonstrated that PS mediates 90% of Xa and thrombin formation and significantly increases thrombosis in vivo (Shi and Gilbert, 2003).

Cytokines and virus infection can activate blood cells and ECs, resulting in higher levels of PS+ cells and MPs. As COVID-19 progresses, the developing cytokine storm activates more blood cells, leading to PS storm. Platelets are highly sensitive to circulating cytokines, releasing large amounts of cytokines and PS exposed MPs into the plasma (Taus et al., 2020Althaus et al., 2021) and thus are a major contributor to PS storm. Previous studies found an unusual elevation of FVa in severe COVID-19 patients (248 IU/dl, higher than any previous disease; Stefely et al., 2020von Meijenfeldt et al., 2021). The degree of FVa elevation in these patients may be the result of PS storm.

Collectively, SARS-CoV-2 infection is the initiating factor for injury of the intestinal vascular ECs, which is then aggravated by systemic cytokines, leading to endotheliitis. Subsequently, the hyperactivated platelets in circulation rapidly accumulate around the damaged ECs, inducing tissue factor expression, NET release, and activating the intrinsic/extrinsic coagulation pathways. Simultaneously, the high levels of PS expression in circulating cells and MPs further promote thrombin and fibrin formation (Figure 2 top).

Early Antithrombotic Treatment

Vaccines and antithrombotic therapy are effective measures to reduce intestinal damage and fight against the COVID-19 pandemic (Baden et al., 2021Chalmers et al., 2021). Vaccines induce adaptive immunity to clear the virus, reducing intestinal infection and intestinal damage. However, the usefulness of vaccines is limited by incomplete vaccine acceptance and viral mutations (Hacisuleyman et al., 2021Wang et al., 2021). Vaccines are also ineffective for already infected patients. Therefore, more attention should be paid to antithrombotic therapy. Studies had shown that thrombotic events mainly occurred within 7 days of COVID-19 diagnosis (both inpatients and outpatients; Mouhat et al., 2020Ho et al., 2021). Meanwhile, two large randomized controlled trials (RCTs) from the same platform showed that therapeutic anticoagulation reduced mortality in moderate cases but not in severe ones, suggesting that delayed anticoagulant therapy may lead to treatment failure (REMAP-CAP Investigators et al., 2021a,b). More importantly, a recent study reported three asymptomatic COVID-19 patients who developed abdominal (or intestinal) thrombosis leading to intestinal necrosis (Zamboni et al., 2021). All these data suggest that antithrombotic therapy should be initiated once COVID-19 is diagnosed (excluding patients with contraindications). Early prophylactic antithrombotic therapy can reduce the activation of vascular ECs and blood cells, preventing intestinal thrombosis, ensuring sufficient intestinal perfusion, maintaining the normal gut–blood barrier, avoiding malabsorption, malnutrition, and intestinal flora entering the bloodstream. Further, attenuated injury and decreased microthrombi in convalescent patients may lower the risk of long-term GI sequelae. Meanwhile, unobstructed systemic circulation can also accelerate the removal of SARS-CoV-2, inflammatory cytokines and damaged blood cells by the mononuclear phagocyte system.

Anticoagulation

Table 1 summarizes the RCTs of anticoagulant therapy in COVID-19 patients. For outpatients, early anticoagulant therapy reduced hospitalization and supplemental oxygen (Gonzalez-Ochoa). While, delayed treatment had no similar effect (ACTIV-4B and Ananworanich). Thus, oral anticoagulant therapy should be initiated in outpatients once COVID-19 is diagnosed. For non-critically ill patients, therapeutic doses of low molecular weight heparin (LMWH) reduced thrombotic events and mortality, and increased organ support-free days (REMAP-CAP, ACTIV-4a, ATTACC; RAPID; HEP-COVID). However, therapeutic doses of rivaroxaban did not improve clinical outcomes and increased bleeding (ACTION). This is potentially because novel oral anticoagulants do not share the anti-inflammatory and antiviral functions of heparin. Intestinal damage might also result in abnormal absorption of oral anticoagulants. Therefore, therapeutic LMWH should be the first choice for non-critically ill patients. For critically ill patients, RCTs showed that moderate and therapeutic doses were not superior to prophylactic ones. Results from several other studies suggest that the overwhelming thrombosis leads to failure of anticoagulant therapy at therapeutic doses (Leentjens et al., 2021Poor, 2021). Faced with this dilemma, an editorial in N Engl J Med argued that profibrinolytic strategies should be considered (Ten Cate, 2021). More studies are needed to explore optimal antithrombotic therapy in critically ill patients.TABLE 1

Table 1. Randomized clinical trials of anticoagulant therapy in COVID-19 patients.

Inhibition of Platelet Activation

As COVID-19 progresses, cytokine storm activates platelets, which not only participate in primary hemostasis, but also are the major components of PS storm. Autopsy results show a high prevalence of platelet-fibrin-rich microthrombi in lung and extrapulmonary organs, including the gastrointestinal tract (Bradley et al., 2020Polak et al., 2020). Early inhibition of platelet activation can reduce platelet activity and prevent PS storm, thus decreasing thrombosis and mortality. Several observational studies have shown that aspirin decreases mechanical ventilation, ICU admission, and mortality (Chow et al., 2020Santoro et al., 2022). The RCTs testing antiplatelet agents were still preliminary. A recent RCT suggested that aspirin was associated with an increase in survival and reduction in thrombotic events (RECOVERY Collaborative Group, 2022). In addition, anti-inflammatory therapy (e.g., dexamethasone, 6 mg once daily; RECOVERY Collaborative Group et al., 2020) inhibits cytokine storm, as well as platelet activation, reducing mortality. Overall, inhibition of platelet activation is also important to reduce mortality through the prevention of thrombosis and organs damage.

Factors Influencing Antithrombotic Treatment

Thrombotic Risk Factors or Co-morbidities

Studies have shown that obesity, hyperglycemia and diabetes are associated with increased thrombotic events (including intestinal thrombosis), COVID-19 severity, and mortality (Drucker, 2021Stefan et al., 2021). Other thrombotic risk factors include previous venous thromboembolism, active cancer, known thrombophilic condition, recent trauma or surgery, age ≥70 years, respiratory/cardiac/renal failure, and inflammatory bowel disease (Susen et al., 2020). These factors or co-morbidities heighten basal inflammatory levels and endothelial damage, leading to premature cytokine and PS storms, ultimately increasing thrombosis and mortality. Thus, more active antithrombotic therapy strategies should be adopted in these patients. For patients with mild COVID-19 with these factors, the French Working Group on Perioperative Hemostasis and the French Study Group on Thrombosis and Hemostasis recommend higher (intermediate) doses of anticoagulant therapy (Susen et al., 2020). For moderately ill patients, therapeutic doses of anticoagulant therapy should be initiated as soon as possible to prevent excessive microthrombus formation. The need for extended thromboprophylaxis in discharged patients remains controversial. However, a recent RCT showed that rivaroxaban (10 mg/day, 35 days) improved clinical outcomes in discharged COVID-19 patients with higher thrombotic risk factors (Ramacciotti et al., 2022), supporting extended thromboprophylaxis in patients with these risk factors or co-morbidities.

Vaccination

Although more than half the world population has received at least one dose of the vaccines, there are relatively little data of antithrombotic therapy in vaccinated patients. Studies of viral dynamics show that the viral loads of vaccinated patients are as high as that of unvaccinated patients, but drop significantly faster (Brown et al., 2021Klompas, 2021). Thus, vaccinated patients have shorter hospital stays, and are less likely to progress to critical illness and death (Tenforde et al., 2021Thompson et al., 2021). Nevertheless, antithrombotic therapy is still beneficial for the vaccinated patients. Firstly, heparin has anti-inflammatory and antiviral functions and can interfere with the binding of SARS-CoV-2 to ACE2 and shorten the duration of virus infection (Kwon et al., 2020Pereyra et al., 2021). Secondly, antithrombotic therapy protects cells from damage, PS exposure, and microthrombi formation, maintains unobstructed blood circulation, and facilitates virus clearance (by vaccine-induced adaptive immunity). Thirdly, thrombosis remains an important factor in disease progression. Antithrombotic therapy further reduces thrombosis and mortality, especially in vaccinated patients with high risk factors or co-morbidities. Lastly, although vaccines reduce the incidence, a subset of vaccinated patients will still develop long-term sequelae or Long Covid (Ledford, 2021Antonelli et al., 2022). Persistent viral infection and microthrombi are the primary causes (Ledford, 2021Xie et al., 2022), and early antithrombotic therapy is still needed to prevent them.

Conclusion and Future Research

During COVID-19 disease progression, SARS-CoV-2 infiltrates the blood stream from the initial respiratory tract infection, causing viremia, hyperactivated platelets and PS storm. The virus settles into the vascular beds of extrapulmonary organs, ultimately causing infection of intestinal epithelial cell. Damaged ECs, combined with hyperactivated platelets and PS storm, promote intestinal thrombosis, resulting in intestinal ischemia or necrosis. The damaged gut–blood barrier leads to malabsorption, malnutrition and intestinal flora entering the bloodstream, which significantly increase disease severity and mortality. Prolonged intestinal infection, persistent endothelial injury and microthrombi contribute to the long-term GI sequelae after discharge. Early prophylactic antithrombotic therapy can prevent microthrombi, ensuring sufficient intestinal perfusion, maintaining the normal intestinal function, and reducing the risk of long-term GI sequelae. More active antithrombotic therapy should be adopted in patients with other thrombotic risk factors or co-morbidities. Even in vaccinated COVID-19 patients, antithrombotic therapy is also important to decrease (intestinal) thrombosis, mortality and the risk of long-term GI sequelae.

With the Omicron pandemic, patients requiring hospitalization and ICU treatment decline rapidly. However, people are increasingly concerned about Long Covid. In terms of long-term GI sequelae, the detailed mechanisms of prolonged intestinal infection and persistent microthrombi remain unclear. And whether anticoagulant therapy can decrease GI symptoms in patients with long-term GI sequelae deserves further study. Finally, the impact of vaccines on long-term GI sequelae remains unclear in previously infected and breakthrough infected patients.

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COVID-19-associated coagulopathy: An exploration of mechanisms

Authors: Meaghan E Colling 1Yogendra Kanthi 2 PMID: 32558620

PMCID: PMC7306998 OI: 10.1177/1358863X20932640

Abstract

An ongoing global pandemic of viral pneumonia (coronavirus disease [COVID-19]), due to the virus SARS-CoV-2, has infected millions of people and remains a threat to many more. Most critically ill patients have respiratory failure and there is an international effort to understand mechanisms and predictors of disease severity. Coagulopathy, characterized by elevations in D-dimer and fibrin(ogen) degradation products (FDPs), is associated with critical illness and mortality in patients with COVID-19. Furthermore, increasing reports of microvascular and macrovascular thrombi suggest that hemostatic imbalances may contribute to the pathophysiology of SARS-CoV-2 infection. We review the laboratory and clinical findings of patients with COVID–19-associated coagulopathy, and prior studies of hemostasis in other viral infections and acute respiratory distress syndrome. We hypothesize that an imbalance between coagulation and inflammation may result in a hypercoagulable state. Although thrombosis initiated by the innate immune system is hypothesized to limit SARS-CoV-2 dissemination, aberrant activation of this system can cause endothelial injury resulting in loss of thromboprotective mechanisms, excess thrombin generation, and dysregulation of fibrinolysis and thrombosis. The role various components including neutrophils, neutrophil extracellular traps, activated platelets, microparticles, clotting factors, inflammatory cytokines, and complement play in this process remains an area of active investigation and ongoing clinical trials target these different pathways in COVID-19.Keywords anticoagulationantiplateletCOVID-19inflammationneutrophilsthrombosisvascular endotheliumvenous thromboembolism (VTE)

Introduction

In December 2019, a new betacoronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), thought to originate in Wuhan, China, emerged as a novel human pathogen for viral pneumonia (coronavirus disease [COVID-19]), resulting in an ongoing pandemic.1,2 The number of cases worldwide now exceeds five million, with more than 350,000 associated deaths, triggering a global effort to understand the predictors of disease severity for rapid triage, and the pathology of disease for rational therapeutic development and clinical trials. A consistent finding in early case series in China and New York City is an association between elevations in D-dimer and fibrin(ogen) degradation products (FDPs) and increasing COVID-19 severity and mortality.37 We aim to review the available data on the coagulopathy observed in COVID-19 and draw from studies of prior viral epidemics to explore possible mechanisms and therapies.

Coronaviruses are enveloped, non-segmented, positive-sense RNA viruses of the Nidovirales order within the Coronaviridae family. Different strains are infectious to a broad range of animals including humans, bats, cats, racoon dogs, rabbits, pigs, and cattle.8 In general, coronavirus infections in humans are mild; however, two recent epidemics of betacoronaviruses – SARS in 2003911 and Middle East Respiratory Syndrome (MERS) in 201212,13 – were associated with significant mortality with death rates around 10% and 35%, respectively.14,15 While the observed case fatality rate for the COVID-19 pandemic is lower,16,17 the population at risk is much higher due to the global spread of the disease and the infectivity of the virus,18 and worldwide fatalities already exceed those in the prior epidemics.

Common clinical manifestations of patients with COVID-19 include fever and cough, and less commonly fatigue, dyspnea, headache, sore throat, anosmia, nausea, vomiting, or diarrhea.6 In the largest case series to date of over 44,000 patients with COVID-19, > 75% of cases were mild, 14% were severe, and 5% were critical, with an overall case fatality rate of 2–2.5%. All deaths occurred in patients with critical disease (in which the case fatality rate was almost 50%).19 While the majority of critically ill patients with COVID-19 have isolated respiratory failure, often acute respiratory distress syndrome (ARDS), multiple organ dysfunction occurs in 20–30% of patients with critical illness and more often in fatal cases.16 Hematologic findings, such as mild to moderate thrombocytopenia and lymphopenia, are associated with COVID-19;20,21 however, the most significant and concerning vascular aspect of this disease is coagulopathy. We have attempted to summarize the data on the pathogenesis, epidemiology and outcomes related to COVID-19-coagulopathy and thrombotic disease using PubMed as well as the pre-print server https://medrxiv.org (date of last search April 23, 2020).

Coagulopathy of SARS-CoV-2 and other infections

There is particular interest in the coagulopathy in patients with COVID-19 as abnormal coagulation parameters, most consistently elevations in D-dimer and FDPs, are associated with disease severity.22,23 An elevated D-dimer, the most common coagulation abnormality in COVID-19 (found in up to 45% of patients), is an independent risk factor for death,6,22,24,25 and patients with D-dimer greater than 1000 ng/mL are almost 20 times more likely to die from their infection than patients with lower D-dimer values.25 In contrast, most patients with COVID-19 have a normal or mildly prolonged prothrombin time (PT) and a normal or shortened activated partial thromboplastin time (aPTT) on presentation and these labs are not reliably associated with disease severity.5,17,22,24,25 Both initial and longitudinal monitoring of coagulation parameters can predict disease severity, as elevated D-dimer and FDP levels on admission and decreased levels of fibrinogen and antithrombin III during the admission are associated with death.23 Although changes in plasminogen activator inhibitor-1 (PAI-1) levels and activity have not been studied, an increase in the PAI-1/tissue plasminogen activator (t-PA) ratio would not be unexpected. These findings may be due to uncontrolled activation of coagulation with ongoing consumption and widespread microvascular thrombosis.

While early descriptions of the coagulopathy identified it as disseminated intravascular coagulation (DIC), in DIC, unlike in severe COVID-19, platelet count and PT prolongation correlate with sepsis severity and mortality, while fibrinogen and FDPs levels do not.26,27 And while the majority of patients who die from COVID-19 develop some laboratory evidence of DIC during their admission, elevations in D-dimer and prolonged PT with mild thrombocytopenia and normal fibrinogen are commonly seen.23 Thromboelastography in patients with COVID-19 in the ICU shows a hypercoagulable state.28 These observations suggest the underlying pathophysiology in at least a subset of critically ill patients with COVID-19 is distinct from traditional systemic DIC and may be due to a unique coagulopathy.

Elevations in D-dimer are common in critical illness and are associated with disease severity and mortality in many severe infections.2931 Patients with influenza, SARS, HIV, hantavirus, Ebola virus, and dengue have elevations in D-dimer, prothrombin fragments, thrombin–antithrombin complexes, and/or plasmin-α2-antiplasmin complexes.32 Similar to patients with SARS-CoV-2 infections, there is an association between elevated D-dimer and mortality in patients with H1N1 and H5N1, which is not seen in SARS.3335

Additionally, in the H1N1 pandemic, patients with severe disease had high rates of venous thromboembolism (VTE) and many patients with thromboembolism did not have evidence of systemic DIC.3639 Patients with ARDS from H1N1 infection had a greater than 20-fold increase in risk of pulmonary embolism compared to patients with ARDS unrelated to H1N1.39 Empiric therapeutic anticoagulation in patients with ARDS was associated with decreased rates of VTE in patients with ARDS from H1N1, but had no effect on VTE rates in patients with ARDS unrelated to H1N1 infection. There are reports of VTE in patients with COVID-19, despite concerns regarding underdiagnosis given baseline elevations in D-dimer, as well as pragmatic challenges in diagnostic imaging while in isolation, including use of personal protective equipment and longer duration of exposure of health care workers.40,41 Although data remain scarce, there are increasing reports of arterial thrombotic events including ischemic strokes in patients with COVID-19.4143 Myocardial injury, defined by elevations in cardiac troponin levels, is common in patients hospitalized with COVID-19 and is associated with severe disease and high risk of mortality.44,45 Myocardial injury may result from systemic inflammatory response syndrome (SIRS) and inflammation as well as due to acute thrombotic events.46,47 Similar observations of myocardial injury have been found in patients with other viral infections.48,49

Pathologic findings in SARS-CoV-2 infection

Although there are only a few published pathologic reports of patients with COVID-19, histopathology of lung specimens from patients with early disease shows characteristic findings of ARDS and evidence of small vessel occlusion.50,51 There are several mechanisms by which SARS-CoV-2 infection may result in microvascular and macrovascular thrombosis, including cytokine storm with activation of leukocytes, endothelium and platelets resulting in upregulation of tissue factor, activation of coagulation, thrombin generation and fibrin formation,52 deranged coagulation with imbalances in PAI-1, tissue factor pathway inhibitor, and activated protein C that promotes fibrin generation and limits fibrinolysis,53,54 hypoxic vaso-occlusion, and direct viral effects with cell activation (Figure 1). It remains an active area of investigation whether these are specific to SARS-CoV-2 infection or a final common pathway in the thromboinflammatory response to viral infections and a marker of disease severity. Early COVID-19 autopsy reports have also identified a possible role for neutrophils as microvascular thrombi contained numerous neutrophils, which in some cases were partially degenerated, consistent with neutrophil extracellular traps (NETs).55,56 NETs are tangles of DNA released from neutrophils, and are decorated with antimicrobial and nuclear proteins that propagate intravascular thrombosis.57,58 NETs initiate both the extrinsic and contact pathways by augmenting presentation of tissue factor, activation of factor XII (FXII), as well as trapping and activating platelets.5962 Consistent with these observations, patients with severe COVID-19 have elevated serum markers of neutrophil activation and NET formation.63 In one study, neutrophil activation measured in serum correlated with, and sometimes preceded, VTE in patients with COVID-19.64

Figure 1. Immune activation and mechanisms of coagulopathy in patients with coronavirus disease 2019 (COVID-19).

Multiple processes may contribute to COVID-19-associated coagulopathy including direct infection of type II pneumocytes and endothelial cells, leading to barrier dysfunction and increased permeability; inflammatory responses characterized by activation of T cells, neutrophils, monocytes, macrophages, and platelets resulting in exuberant inflammatory cytokine release (including IL-1, IL-6, IL-10, TNF-α), monocyte-derived TF and PAI-1 expression; and culminating in the development of microvascular and macrovascular thrombi composed of fibrin, NETs, and platelets.

IL, interleukin; NETs, neutrophil extracellular traps; PAI-1, plasminogen activator inhibitor-1; TF, tissue factor; TNF-α, tumor necrosis factor-alpha.

Dysregulation of hemostasis and coagulopathy in acute respiratory distress syndrome (ARDS)

Thrombi in the pulmonary micro- and macrovasculature are observed in patients with ARDS with or without overt DIC, and changes consistent with a prothrombotic state have been found both in blood and in alveolar fluid studies of these patients.65,66 Higher levels of FDPs and D-dimer are seen in patients who developed ARDS as compared to patients with similar predisposing conditions that did not develop ARDS.67 Lower levels of protein C and higher levels of soluble thrombomodulin and PAI-1 are also associated with multiple organ failure, disease severity, and mortality in ARDS in some studies.53,6872 Finally, plasma and alveolar levels of tissue factor are higher in patients with ARDS than patients with pulmonary edema.73 Mechanistically, there is increased thrombin generation by tissue factor coupled with an impaired fibrinolytic response due to elevations in PAI-1. Elevations in D-dimer, a breakdown product of crosslinked fibrin, may result from residual t-PA/plasmin activity, as well as from alternative fibrinolytic pathways such as human neutrophil elastase activity.74,75

As patients with COVID-19 frequently have isolated pulmonary findings, the initial hemostatic dysregulation may be localized to the lungs as a consequence of the bidirectional relationship between the innate immune system and thrombosis. Activated platelets through degranulation and coordinated interactions with monocytes, dendritic cells, and neutrophils, as well as activated T cells, NETs, tissue factor-bearing microparticles, and coagulation proteases may facilitate this crosstalk.54,76,77 In this model, immune cells, inflammatory cytokines, and pathogen-associated molecular patterns induce thrombi consisting of fibrin, monocytes, neutrophils, and platelets.57,58,78 These immunothrombi initially serve a protective purpose, promoting pathogen recognition and creating a sterile barrier against further pathogen invasion, but can become maladaptive and injurious to tissue and organ perfusion.57,79,80 During this process, there is abundant intra- and extra-vascular fibrin deposition and impaired fibrinolysis, which has been well described in ARDS.81,82 In postmortem studies, both macro- and microvascular thrombi are common in patients in ARDS (observed in up to 95% of patients).82,83 In COVID-19, the alveolar immunothrombotic response may be an attempt to limit dissemination of SARS-CoV-2 outside the alveoli.

Findings from the SARS epidemic provide possible viral-specific mechanisms for ARDS and uncontrolled coagulation. Autopsy studies of patients who died of SARS pneumonia, identified the SARS-CoV spike (S) protein in cells expressing the receptor angiotensin-converting enzyme 2 (ACE2),8487 the leading candidate receptor for SARS-CoV-2.88,89 Binding of the S protein to ACE2 induces expression of a nuclear factor kappa B (NFκB)-driven inflammatory module, resulting in production of proinflammatory cytokines including monocyte chemoattractant protein 1 (MCP-1), transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6, which have been implicated in thrombogenesis.90 Although inflammatory responses are important in host-defense, hyperinflammatory responses result in tissue damage, disruption of the endothelial barrier, and uncontrolled activation of coagulation.54 Overall, these findings are consistent with a model in which SARS-CoV and SARS-CoV-2 directly infect endothelial and epithelial cells, increasing levels of proinflammatory cytokines, causing immune-mediated damage to the vasculature and surrounding tissue, with exposure of tissue factor and associated thromboinflammatory changes.91 While these changes appear to be predominantly in the lungs, endotheliitis in COVID-19 has been observed in kidneys, liver, heart, and intestine.91

Additional studies in SARS-CoV and influenza found dysregulation of urokinase, coagulation, and fibrinolysis pathways contributed to the severity of lung injury, possibly through altering the hemostatic balance with subsequent coagulation-induced ischemic injury.92 Plasminogen was protective against severe influenza A, H5N1, and H1N1 infections.93 These groups hypothesized that increased fibrinolysis led to a positive feedback loop of vascular permeability, leukocyte recruitment, and fibrin generation. Interestingly, one hypothesis suggests that elevated plasminogen may be a risk factor for SARS-CoV-2 infection because plasmin may cleave the S protein of the virus and increase its infectivity.94 These findings highlight the delicate balance between corralling infection and uncontrolled inflammation and thrombosis.

Therapeutic considerations

Markers of hypercoagulability and higher inflammatory mediators are consistently associated with worse outcomes in patients with ARDS and sepsis. These observations have led to numerous clinical trials targeting various components of inflammatory and coagulation pathways in acute lung injury, ARDS or sepsis. Studies with heparin, steroids, non-steroidal anti-inflammatory drugs, and TNF-α inhibitors have been disappointing.95100

Given the laboratory and clinical findings in patients with severe COVID-19, several repurposed and novel therapies are under investigation in clinical trials to prevent the hyperinflammatory response or mitigate uncontrolled coagulation. As elevations in D-dimer and FDPs likely reflect ongoing lung injury and microvascular thrombi, possible therapeutic targets include inflammatory cytokines, activated platelets, neutrophils, or microparticles that may propagate thrombosis; or anticoagulants and fibrinolytics that could limit thrombosis. Supporting this enthusiasm was a recent retrospective study in China in which VTE prophylaxic dose heparin was associated with a survival benefit in patients with severe COVID-19 and evidence of sepsis-induced coagulopathy.101 The study found no benefit among patients with milder COVID-19 illness; however, the study did not control for other markers of disease severity nor other therapies, such as antivirals. The study raises the possibility that prophylactic or therapeutic anticoagulation may benefit patients with severe infection. Heparin may alter the biology of the disease not only through its anticoagulant properties, but also due to its anti-inflammatory effects that promote a quiescent endothelium.

Current expert recommendations, including interim guidelines from the International Society on Thrombosis and Haemostasis (ISTH) and the American College of Cardiology (ACC), recommend use of prophylactic dose LMWH or unfractionated heparin in all COVID-19 patients requiring hospital admission; for patients with a contraindication to pharmacologic prophylaxis, mechanical prophylaxis should be used.102,103 While a number of VTE risk stratification tools exist for hospitalized medical patients, these have not been validated in patients with COVID-19. Extended VTE prophylaxis with LMWH or direct oral anticoagulants after hospitalization for acute medical illness reduces the risk of VTE with an associated increased risk of bleeding.104106 There are currently no data regarding extended prophylaxis in patients with COVID-19; however, the ACC expert opinion statement recommends consideration of extended prophylaxis in patients with elevated risk of VTE, such as patients with cancer or prolonged immobility who have low bleeding risk. Given early reports and ongoing concerns of high rates of VTE, randomized trials of empiric therapeutic anticoagulation or antifibrinolytics are ongoing, and there are reports of empiric therapeutic anticoagulation in patients with significantly elevated D-dimer both in Italy and in the US. While heparin offers both anti-inflammatory and anticoagulant effects, the benefit of therapeutic anticoagulation remains uncertain, with a risk of bleeding complications in critically ill patients with respiratory failure.95,107 Clinical trials will help define the role of heparin in the treatment of hospitalized patients with COVID-19. Outside of a trial setting, we advocate universal standard-dose pharmacologic VTE prophylaxis in patients without a contraindication. In patients with a high suspicion of VTE where access to confirmatory or serial imaging is limited, clinicians may consider empiric anticoagulation, although there is a paucity of evidence to provide guidance in this context. There are currently no randomized data to recommend empiric therapeutic or intermediate-dose anticoagulation in patients without documented VTE, or an other indication for anticoagulation, or outside the context of a clinical trial. A recent retrospective, observational study in New York City showed therapeutic anticoagulation was associated with decreased mortality in patients with COVID-19 who required mechanical ventilation, but not in all hospitalized patients with COVID-19. Although these findings are provocative, interpretation is limited by their observational nature.108

There are over 300 trials ongoing for patients with COVID-19, many of which aim to simultaneously reduce inflammation and thrombosis, including cytokine-directed therapies (against IL-1, IL-6, interferon gamma), corticosteroids, Janus kinase inhibitors, TLR ligands, complement inhibitors, N-acetylcysteine, serine protease inhibitors, DNAse enzymes, and anti-viral agents. However, suppressing the cytokine storm or hypercoagulability may be insufficient once initiated, and targeting upstream pathways to prevent activation of this self-amplifying feedback loop may be more effective.

One therapeutic candidate to treat COVID-19 is dipyridamole, an adenosinergic drug indicated for use as an arterial thromboembolic prophylaxis agent in combination with aspirin or warfarin.109 Dipyridamole has recently been shown to suppress human neutrophil and T-cell activation, upstream of cytokine effectors.58,110 Dipyridamole induces a type I interferon response, which is necessary for physiologic anti-viral activity, and inhibits SARS-CoV-2 replication in vitro by inhibiting a critical viral replication complex.111,112 Administered orally, dipyridamole has a favorable safety profile, and a small clinical trial in patients with COVID-19 suggests it may improve D-dimer levels.113 Randomized clinical trials of agents active at the intersection of inflammation and coagulation in COVID-19, such as dipyridamole, t-PA, and heparin are necessary to determine if these therapeutics can restore the balance of inflammation and coagulation without dampening early or late physiologic anti-viral responses. The heterogenous response to the SARS-CoV-2 infection and the various time-dependent pathways driving pathology make universal therapies challenging. The temporal and mechanistic role each pathway plays in severe SARS-CoV-2 infection remains uncertain and requires further exploration for treatment opportunities as efforts to control this pandemic continue.

Conclusions

In conclusion, in patients with COVID-19, the presence of coagulopathy, characterized by elevations in D-dimer and FDPs, is consistently associated with more severe illness and mortality. Laboratory, clinical, and early histopathologic findings suggest this coagulopathy is distinct from sepsis-induced DIC and may reflect dysregulated hemostasis. Similar findings have been associated with several other viral infections, and it remains uncertain if this coagulopathy is specific to SARS-CoV-2 or the end common pathway of the thrombo-inflammatory response to severe viral infections. There are efforts to target numerous components of the thrombo-inflammatory pathway to improve outcomes in patients with severe COVID-19. The optimal management for these patients including strategies to diagnose VTE, appropriate anticoagulation doses and duration, and effectiveness of novel therapies are under active investigation in the current pandemic.

Acknowledgements

The authors would like to thank Charles Bolan, MD and Jason Knight, MD, PhD for guidance and review of the manuscript, and all members of the ‘NETwork to Target Neutrophils in COVID-19’ and the SVM Next Generation Committee for their helpful advice and encouragement. The authors credit Alan Hoofring for the illustration.

Declaration of conflicting interests
Yogen Kanthi has served as a consultant for Surface Oncology and has a pending patent on use of biogases in vascular disease. Meaghan E. Colling has nothing to disclose.

Funding
Meaghan E. Colling is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH). Yogen Kanthi is supported by grant funding from the NIH-NHLBI (K08HL131993, R01HL150392), A. Alfred Taubman Medical Research Institute, Michigan Medicine Frankel COVID-19 Cardiovascular Impact Research Ignitor Program, Falk Medical Research Trust Catalyst Award, American Venous Forum-JOBST Award, University of Michigan BioInterfaces Institute, and Bo Schembechler Heart of A Champion Foundation.

ORCID iD
Yogendra Kanthi  https://orcid.org/0000-0002-5660-5194

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Platelet Gene Expression and Function in COVID-19 Patients

Authors: Bhanu Kanth Manne (University of Utah, United States) Frederik Denorme (Molecular Medicine Program, University of Utah, United States), Elizabeth Middleton (University of Utah, United States), Irina Portier (University of Utah, United States) Jesse Rowley (University of Utah, United, States) Chris Stubben (University of Utah, United States) Aaron Petrey (University of Utah, United States) Neal Tolley (University of Utah, United States) Li Guo (University of Utah, United States) Mark Cody (University of Utah, United States) Andrew Weyrich (University of Utah, United States) Christian Yost (Department of Pediatrics, University of Utah, United States) Matthew Rondina (University of Utah Health Sciences Center, United States) Robert Campbell (University of Utah, United States).

Abstract:

There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in
patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic
abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of
thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2.
RNA sequencing demonstrated distinct changes in the gene expression profile of circulating platelets of COVID-19 patients. Pathway analysis
revealed differential gene expression changes in pathways associated with protein ubiquitination, antigen presentation and mitochondrial
dysfunction. The receptor for SARS-CoV-2 binding, ACE2, was not detected by mRNA or protein in platelets. Surprisingly, mRNA from the SARSCoV-2 N1 gene was detected in platelets from 2/25 COVID-19 patients, suggesting platelets may take-up SARS-COV-2 mRNA independent of
ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, –
monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared to healthy donors. Furthermore, platelets from
COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and
aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that
SARS-CoV-2 infection is associated with platelet hyperreactivity which may contribute to COVID-19 pathophysiology.

For More Information: https://medicine.utah.edu/internalmedicine/generalmedicine/files/campbell-covid-platelet-blood-2020.pdf