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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Gastrointestinal perforation secondary to COVID-19

Authors: Case reports and literature review Reem J. Al Argan, MBBS, SB-Med, SF-Endo, FACE, ECNU,Safi G. Alqatari, MBBS, MRCPI, MMedSc, CFP (Rheum), Abir H. Al Said, MBBS, SB-Med, CFP (Pulmo.), Raed M. Alsulaiman, MBBS, SB-Med, Abdulsalam Noor, MBBS, SB-Med, ArBIM, SF-Nephro, Lameyaa A. Al Sheekh, MD, SB-med, and Feda’a H. Al Beladi, MD

Introduction:

Corona virus disease-2019 (COVID-19) presents primarily with respiratory symptoms. However, extra respiratory manifestations are being frequently recognized including gastrointestinal involvement. The most common gastrointestinal symptoms are nausea, vomiting, diarrhea and abdominal pain. Gastrointestinal perforation in association with COVID-19 is rarely reported in the literature.

Patient concerns and diagnosis:

In this series, we are reporting 3 cases with different presentations of gastrointestinal perforation in the setting of COVID-19. Two patients were admitted with critical COVID-19 pneumonia, both required intensive care, intubation and mechanical ventilation. The first one was an elderly gentleman who had difficult weaning from mechanical ventilation and required tracheostomy. During his stay in intensive care unit, he developed Candidemia without clear source. After transfer to the ward, he developed lower gastrointestinal bleeding and found by imaging to have sealed perforated cecal mass with radiological signs of peritonitis. The second one was an obese young gentleman who was found incidentally to have air under diaphragm. Computed tomography showed severe pneumoperitoneum with cecal and gastric wall perforation. The third case was an elderly gentleman who presented with severe COVID-19 pneumonia along with symptoms and signs of acute abdomen who was confirmed by imaging to have sigmoid diverticulitis with perforation and abscess collection.

Interventions:

The first 2 cases were treated conservatively. The third one was treated surgically.

Outcome:

Our cases had a variable hospital course but fortunately all were discharged in a good clinical condition.

Conclusion:

Our aim from this series is to highlight this fatal complication to clinicians in order to enrich our understanding of this pandemic and as a result improve patients’ outcome.

Keywords: acute abdomen, acute diverticulitis, cecal mass, corona virus disease-2019, gastrointestinal perforation. 

Introduction

Corona virus disease-2019 (COVID-19) had been declared pandemic in March 2020.[1] It presents most commonly with fever in more than 80% of cases followed by respiratory symptoms which could progress to adult respiratory distress syndrome in critical cases.[2] However, extra respiratory manifestations are being frequently recognized in association with COVID-19.[3] The gastrointestinal (GI) manifestations have been reported in descriptive studies from China.[2] The most frequently reported GI symptoms are nausea, vomiting, diarrhoea, and abdominal pain.[2,4,5] However, it is rarely reported for COVID-19 to present with GI perforation. To the date of writing this report, there have been only 13 reported of GI perforation in association with COVID-19.

In this series, we are reporting 3 cases who developed GI perforation in association with COVID-19. The first 2 cases developed this fatal complication after presenting with critical COVID-19 pneumonia which required intensive care unit (ICU) admission and mechanical ventilation. The third case presented with severe COVID-19 pneumonia and was diagnosed to have GI perforation at the time of presentation. The first 2 cases were managed conservatively, and the third case was managed surgically. All of the 3 cases recovered and were discharged in good condition. We are reporting this series in order to highlight this rare but fatal complication of COVID-19. This will enhance awareness of clinicians to such complication where early diagnosis and management is crucial in order to improve the patients’ outcome.

2. Case reports

2.1. The patients provided informed consent for publication of their cases

2.1.1. First case

A 70-year old male patient known to have type 2 diabetes mellitus (T2DM), presented to our emergency department (ED) on 1st of June 2020 complaining of 3-day history of dry cough and fever. On examination: Vital signs were remarkable for tachypnea with respiratory rate (RR): 28/min and desaturation with oxygen saturation (O2 sat):81% on room air (RA) but maintained >94% on 15 litres of oxygen via a non-rebreather mask. Nasopharyngeal swab tested positive for SARS-CoV-2 polymerase chain reaction (PCR). Chest X-ray (CXR) showed bilateral lower lung fields air apace opacities (Fig. ​(Fig.1A)1A) consistent with COVID-19 pneumonia. Laboratory investigations were remarkable for high Lactate dehydrogenase (LDH), inflammatory markers, D-dimer and markedly elevated Ferritin (Table ​(Table1).1). He was started on Methylprednisolone 40 mg IV BID, Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, and Enoxaparin. After 5 days of hospital admission, he deteriorated and could not maintain saturation on non-rebreather mask, so he was shifted to ICU, intubated and mechanically ventilated. Ceftriaxone was upgraded to Meropenem in addition to same previous therapy. COVID-19 therapy was stopped after completing 10 days, but he was continued on steroids. Figure 1

The chest X-ray (CXR) of the 3 cases at the time of presentation. (A): CXR of the 1st case showing bilateral lower lung fields air apace opacities. (B): CXR of the 2nd case showing bilateral scattered air space consolidative patches throughout the lung fields predominantly over peripheral and basal lungs. (C): CXR of the 3rd case showing bilateral middle and lower zones peripheral ground glass opacities.

Table 1

The laboratory investigations of the 3 cases on presentation.

TestFirst caseSecond caseThird caseNormal range
Complete Blood Count
 White Blood cells6.44.25.7(4.0–11.0) K/uI
 Hemoglobin15.112.113.4(11.6–14.5) g/dL
 Platelets147232283(140–450) K/uI
Renal Profile
 Blood urea nitrogen101411(8.4–21) mg/dL
 Creatinine0.920.820.82(0.6–1.3) mg/dL
Liver Profile
 Total Bilirubin0.50.51.0(0.2–1.2) mg/dL
 Direct Bilirubin0.30.20.3(0.1–0.5) mg/dL
 Alanine Transferase (ALT)265241(7–55) U/L
 Aspartate transferase (AST)425052(5–34) U/L
 Alkaline phosphatase (ALP)745574(40–150) U/L
 Gamma-glutamyl transpeptidase (GGTP)532139(12–64) U/L
 Lactate dehydrogenase (LDH)434442617(81–234) U/L
Inflammatory Markers
 Erythrocyte Sedimentation rate (ESR)63101490–10 mm/h
 C-Reactive Protein (CRP)7.9218.3210.780–5 mg/dL
Others
 Ferritin1114.72565.86654.87(21.81–274.66) ng/mL
 D-Dimer0.60.411.66<=0.5 ug/mL

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Multiple trials of weaning from mechanical ventilation failed. So, tracheostomy was carried out on 20th day of ICU admission and then he was successfully extubated. During his stay in ICU, urine analysis was persistently positive for urinary tract infection secondary to Candida Abican. So, he was started on Caspofungin. At that time, blood culture was negative. After 4 days of Caspofungin, urine analysis and culture became negative. On 32nd day of hospital admission, he was stable clinically, requiring 40% FiO2 through tracheostomy mask, so he was transferred to COVID-19 isolation ward. Meropenem was stopped after 20 days of treatment. Steroid was tapered after transfer to the ward till it was discontinued after 28 days of therapy.

After 14 days of treatment with Caspofungin, follow up C-reactive protein was persistently high. Thus, full septic workup was requested and revealed Candida Albican bacteremia. At that time, urine analysis and culture were negative, Caspofungin was continued for additional 14 days. However, Candidemia persisted, so he was shifted to Anidulafungin for another 14 days. Patient at that time did not have any GI symptoms or signs. For work up of Candidemia, echocardiogram could not be done due to the hospital policy of isolation rooms. Bed side ophthalmology examination was unremarkable.

On 44th day of hospital admission, he developed fresh bleeding per rectum. Hemodynamics were stable. The bleeding resulted in acute drop of 2 g/dL of hemoglobin over 24 hours. He denied abdominal pain, abdominal examination was negative for signs of peritonitis and per rectum examination was unremarkable. Therefore, computed tomography (CT) scan of the abdomen with contrast was carried out. It showed a well-defined mass within the posterior wall of the cecum measuring 3.1 × 3.2 cm associated with discontinuous enhancement and extra-luminal air foci suggestive of complicated perforated sealed cecal mass. This is in addition to radiological findings of peritonitis (Fig. ​(Fig.22A).Figure 2

The contrast enhanced computed tomography (CT) of the abdomen of the 3 cases. (A): CT scan abdomen of the 1st case (Coronal image) showing a well-defined rounded heterogeneous enhanced soft tissue mass lesion within the posterior wall of the cecum measuring (3.1 × 3.2 cm) in anteroposterior and transverse diameter associated with discontinuous enhancement of posterior cecum wall and extra-luminal air foci suggestive of complicated perforated sealed cecum mass. This is in addition to adjacent fat stranding with free fluid as well as enhancement of peritoneal reflection suggestive of peritonitis. (B &C): CT scan abdomen of the 2nd case (Axial & Coronal images). (2B): Axial image showing moderate to severe pneumoperitoneum with air seen more tracking along the ascending colon suggestive of a wall defect in the anterior aspect of the cecum. (2C): Coronal image showing a second defect in the stomach wall. (D): CT scan abdomen of the 3rd case (Coronal image) showing severe sigmoid diverticulosis with circumferential bowel wall thickening compatible with acute diverticulitis, small amount of free air compatible with bowel perforation likely arising from the sigmoid colon and a well-defined 3.3 × 1.5 cm abscess collection adjacent to the sigmoid colon.

In consideration of his stable clinical status, absent signs of peritonitis clinically and being a sealed perforation, he was managed conservatively. So, Meropenem was resumed and Clindamycin was started. 2 days later, bleeding stopped, and he stayed stable clinically without clinical signs of peritonitis. Feeding through nasogastric tube was introduced gradually as tolerated. Antibiotics were continued for a total of 8 days. Trial of weaning from oxygen was attempted gradually which he tolerated till he was maintained on RA. After closure of tracheostomy, on 70th day of hospital admission, the patient was discharged in a good condition with a plan of follow up of cecal mass progression. However, the patient did not follow up in outpatient clinics after discharge.

2.1.2. Second case

A 37-year old male patient, morbidly obese, negative past history, presented to our ED on 11th June 2020. He reported 3-day history of shortness of breath. Vital signs were remarkable for Temperature (Temp.): 38.5 C, pulse rate (PR): 111/min, RR: 30/min and O2 sat: 80% on RA. Laboratory investigations showed high LDH, inflammatory markers and Ferritin (Table ​(Table1).1). He had positive SARS-CoV-2 PCR and CXR showed bilateral air space consolidative patches scattered throughout the lung predominantly over peripheral and basal lungs (Fig. ​(Fig.1B).1B). He was admitted to COVID-19 isolation ward as a case of COVID-19 pneumonia and started on: Triple therapy in the form of: Interferon B1, Lopinavir/Ritonavir and Ribavirin, in addition to Hydroxychloroquine, Ceftriaxone, Azithromycin, Oseltamivir, Dexamethasone 6 mg IV OD and Enoxaparin.

On the 3rd day of admission, his condition deteriorated so, he was shifted to ICU and intubated because of respiratory failure. He was maintained on same treatment for COVID-19. On 2nd day postintubation, clinically he was vitally stable without active clinical GI signs but a routine follow-up CXR showed air under the diaphragm. Therefore, abdomen CT scan with contrast was carried out and showed moderate to severe pneumoperitoneum with air tracking along the ascending colon suggestive of wall defect at the cecum, in addition to another defect noted in the stomach wall (Fig. ​(Fig.2B2B & 2C). Ceftriaxone was upgraded to Piperacillin-Tazobactam and Caspofungin was added to cover for possibility of peritonitis. Again, the patient was managed conservatively, since he was asymptomatic. He remained vitally stable without signs of peritonitis. Enteral feeding was started gradually 3 days later and on the 10th day of hospital admission, he was extubated and shifted to COVID-19 isolation ward. COVID-19 therapy was continued for 12 days.

He tolerated feeding very well. Gradual weaning of oxygen supplementation was carried out till it was discontinued. After 14 days of antibiotics, a follow up CT scan of abdomen showed interval resolution of previously seen pneumoperitoneum. He was discharged on 30th day of hospitalization in a good condition.

2.1.3. Third case

A 74-year old male patient known case of T2DM presented to our ED on 17th July 2020. He gave 3-day history of dry cough, shortness of breath and generalized colicky abdominal pain. No other pulmonary or GI symptoms. He had negative past surgical history. Vital signs were remarkable for Temp: 38.4 C, PR: 105/min, RR: 22/min and O2 sat: 90% on RA, required 3 L/min O2 through nasal cannula. Chest examination was remarkable for reduced breath sound intensity bilaterally without added sounds. Abdomen was distended with generalized tenderness and guarding. Blood tests were remarkable for high LDH, inflammatory markers, Ferritin and D-dimer (Table ​(Table1).1). PCR for SARS-COV-2 was positive and CXR showed bilateral peripheral ground glass opacities at middle and lower lung lobes (Fig. ​(Fig.1C).1C). Due to the presence of abdominal pain along with signs of acute abdomen on examination, a CT scan of the abdomen was done. It showed severe sigmoid diverticulosis with radiological findings of acute diverticulitis, free air compatible with bowel perforation likely at the sigmoid colon with 3.3 cm adjacent abscess collection (Fig. ​(Fig.22D).

Therefore, the patient was started on Piperacillin-Tazobactam, Metronidazole in addition to COVID-19 therapy. He underwent emergency exploratory laparotomy. Intra-operatively, pus and fecal peritonitis along with perforation of 0.5 cm at the distal sigmoid colon were found. So, a Hartmann’s procedure was performed. Pathology result of resected sigmoid colon revealed diverticular disease with surrounding fibrosis, moderate mucosal inflammation with mixed acute and chronic inflammatory cells, negative for malignancy.

He had smooth postoperative course. Enteral feeding was started on 3rd day postoperation and he improved clinically. After a total of 10 days of hospitalization, supplemental oxygen and antibiotics were discontinued. He was discharged on 11th day of hospitalization in a good condition.

3. Discussion

The GI manifestations are the most frequently reported extra-pulmonary manifestations of COVID-19[2] with a prevalence of 10% to 50%.[4,5] The most commonly reported GI symptoms are nausea, vomiting, diarrhoea and abdominal pain.[2,4,5] However, there have been case reports of COVID-19 cases presenting with other GI manifestations. Those include acute surgical abdomen,[6] lower GI bleeding[7] and nonbiliary pancreatitis.[8] In fact, the GI manifestations could be the presenting symptoms of COVID-19 as was reported in a case report by Siegel et al where the patient presented with abdominal pain and upon abdominal imaging, the patient was found to have pulmonary manifestations of COVID-19 in the CT scan of the lung bases.[9]

GI perforation is a surgical emergency, carries a significant mortality rate that could reach up to 90% due to peritonitis especially if complicated by multiple organ failure.[10] It can be caused by many reasons. Those include foreign body perforation, extrinsic bowel obstruction like in cases of GI tumors, intrinsic bowel obstruction like in cases of diverticulitis/appendicitis, loss of GI wall integrity such as peptic ulcer and inflammatory bowel disease in addition to GI ischemia and infections.[11] Several infections have been reported to result in GI perforation like Clostridium difficile, Mycobacterium tuberculosis, Cytomegalovirus and others.[1214] COVID-19 have been rarely reported to result in GI perforation. Till the date of writing this report only 13 cases[1523] have been reported in the literature (Table ​(Table2).2). In addition, Meini et al reported a case of pneumatosis intestinalis in association with COVID-19 but without perforation.[25]

Table 2

Summary of the previously published cases of gastrointestinal perforation in association with COVID-19.

First Author [Reference]Age/ SexCo-morbid ConditionsPresenting symptomsSeverity of COVID-19 pneumoniaCOVID-19 TherapySymptoms prompted investigations for GI perforationSite of PerforationTiming of Perforation post admissionManagement of PerforationOutcome
1Gonzalvez Guardiola et al [15]66 Y/ MMetabolic syndromeNot mentionedCriticalMethylprednisoloneTocilizumab Hydroxychloroquine AzithromycinLopinavir/RitonavirAbdominal painIncreased WBC and CRP.CecumNot mentionedRight colectomyNot mentioned
2De Nardi et al [16]53 Y/MHypertension Supra-ventricular tachycardiaFeverCoughDyspneaCriticalAnakinra Lopinavir/Ritonavir Hydroxychloroquine + AntibioticsAbdominal pain Abdominal distentionSigns of PeritonitisCecum11th day of admissionRight colectomy & ileo-transverse anastomosisDischarged Home
3Kangas-Dick et al [17]74 Y/MNegativeFeverDyspneaDry coughCriticalHydroxychloroquine +AntibioticsIncreased Oxygen requirementMarkedly distended abdomenNot specified (CT scan: Not done)5th day of admissionConservativeDied
4Galvez et al [18]59 Y/MStatus post laparoscopic Roux-en-Y gastric bypass surgeryFeverDry coughMyalgiaHeadacheDyspneaModerateMethylprednisolone + COVID-19 protocol (Not specified)Acute abdominal painWorsening dyspneaGastro-jejunal anastomosis5th day of admissionLaparoscopy& Graham Patch RepairDischarged Home
5Poggiali et al [19]54 Y/ F§HypertensionFeverDry coughGERD symptomsSevereCOVID-19 therapy (Not specified) +AntibioticsAcute chest pain Painful abdomenDiaphragm StomachAt presentationSurgical RepairNot mentioned
6Corrêa Neto et al [20]80 Y/FHypertensionCoronary artery diseaseDry coughFeverDyspneaCriticalCOVID-19 therapy(Not specified) +AntibioticsDiffuse abdominal pain & stiffnessSigmoidAt PresentationLaparotomy with recto-sigmoidectomy & terminal colostomyDied
7Rojo et al [21]54 Y/FHypertensionObesityDyslipidemiaEpilepsyCough,MyalgiaCostal painCriticalHydroxychloroquine Lopinavir/Ritonavir MethylprednisoloneTocilizumabFeverHemodynamic instabilityAnemiaCecum15th day of admissionLaparotomy with right colectomy and ileostomyDied
8Kühn et al [22]59 Y/MNot mentionedFeverNauseaAbdominal pain Fatigue, HeadacheNot specifiedNot mentionedAbdominal painJejunal diverticulumAt presentationOpen small bowel segmental resection & anastomosisDischarged Home
9Seeliger et al [23]31Y/MNot mentionedDyspneaSevereNot mentionedNot mentionedLeft colonAt presentationLeft HemicolectomyDischarged Home
1082 Y/FDyspnea, DiarrhoeaCriticalSigmoidAt presentationOpen drainage of peritonitisDied
1171 Y/FFeverSevereGangrenous appendixAt presentationLaparoscopic appendectomyDischarged Home
1280Y/MNot mentionedSevereSigmoiditisAt presentationHartmann procedureDischarged Home
1377 Y/MDyspneaCriticalDuodenal ulcer23rd day of admissionOpen duodenal exclusion, omega gastro-enteric anastomosisDied
14This Report70Y/MT2DMFeverCoughCriticalMethylprednisolone HydroxychloroquineOseltamivir Enoxaparin+AntibioticsBleeding per rectumHemoglobin DropCecal mass44th day of admissionConservativeDischarged Home
1537Y/MMorbid obesityDyspneaCriticalInterferon B1Lopinavir/RitonavirRibavirinHydroxychloroquineOseltamivirDexamethasone+AntibioticsAir under diaphragm was found incidentally in a follow up CXRCecum4th day of admissionConservativeDischarged Home
1674Y/MT2DMCoughDyspnea Abdominal pain.SevereLopinavir/RitonavirRibavirinMethylprednisolone+AntibioticsAbdominal painSigns of peritonitisSigmoid diverticulosis/diverticulitisAt presentationExploratory laparotomy with Hartmann’s procedureDischarged Home

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Severity of COVID-19 pneumonia is based on classification of severity by Ministry of Health-Saudi Arabia.[24]†Y = Year.M = Male.§F = Female.

Most of the previously reported cases presented initially with respiratory symptoms, 4 cases had also GI symptoms at presentation in the form of abdominal pain, stiffness, nausea and diarrhoea[19,20,22,23] [Table ​[Table2].2]. Eleven out of the 13 cases had severe-critical pneumonia that required either high flow oxygen, intubation or mechanical ventilation which is similar to our first 2 cases. This may indicate that GI perforation is more common in severe and critically ill COVID-19 cases. The most common symptoms which prompted investigations for bowel perforation were abdominal pain and distention [Table ​[Table2].2]. Other indications were signs of peritonitis,[16] worsening hemodynamics[17,18,21] and rising inflammatory markers.[15]

Only one of our cases had abdominal pain and tenderness at presentation. Another developed anemia due to active lower GI bleeding which is similar to the case published by Rojo et al[21] where the patient developed anemia and found to have hemoperitoneum with pericecal hematoma. This is probably explained by the site of perforation since both had cecal perforation. Our other case was diagnosed incidentally after demonstration of air under diaphragm in routine CXR. GI perforation was diagnosed from first day up to 23rd day of presentation with COVID-19 [Table ​[Table2].2]. Our patients had similar variable timing of GI perforation in relation to presentation with COVID-19. It ranged from the first day of diagnosis up to 40 days after presentation with COVID-19 pneumonia. This may tell us that GI perforation could happen at any time during the course of the infection. Our report demonstrates different presentation of GI perforation with COVID-19 since in 2 of the 3 cases, the infection predisposed to having perforation of an underlying GI lesions (cecal mass and diverticulosis). Only Kuhn et al reported similar presentation where the patient had perforation of jejunal diverticulum.[22] This may tell us that having COVID-19 predispose patients with underlying GI lesions to perforation. In addition, in our first case, we think that the source of Candidemia was most probably the bowel since it was persistent even after clearance of Candida Albican from the urine, but it was overlooked due to the absence of GI symptoms at the time of developing the Candidemia. In a study of 62 cases with peritonitis secondary to gastric perforation, Candida species was isolated in 23 cases in peritoneal fluid culture.[26] Therefore, in presence of Candidemia especially in absence of clear source, evaluation of the bowel as a potential source should always be kept in mind.

The effect of SARS-COV-2 virus on the GI system can be explained by different mechanisms. First, the virus uses the same access to enter respiratory and GI tract epithelium which are Angiotensin converting enzyme 2 receptors giving the virus the chance to replicate inside GI cells.[27] In addition, faecal-oral transmission has also been postulated, due to the presence of viral RNA in stool samples.[28] Perforation could result from altered colonic motility due to neuronal damage by the virus[29] in addition to local ischemia resulting from hypercoagulable state caused by the virus especially in critically ill patients.[30] Corrêa Neto et al reported finding ischemia of the entire GI tract during exploratory laparotomy for sigmoid perforation with COVID-19.[20] In addition, Rojo et al reported presence of microthrombi and wall necrosis in the pathology examination of his COVID-19 case with bowel perforation.[21] Other possible implicating factors are the use of Tocilizumab and high dose steroids.[21,31] Both are indicated in severe and critically ill COVID-19 cases. Steroids were used in all of our 3 cases since it is indicated in severe COVID-19 pneumonia according Saudi Arabian Ministry of health guidelines[24] but none of our patients received Tocilizumab. Some of these mechanisms could explain the higher risk of GI perforation in severe and critically ill COVID-19 patients.

The diagnosis of GI perforation is based mainly on radiological findings on CT scan. The most specific findings are segmental bowel wall thickening, focal bowel wall defect, or bubbles of extraluminal gas concentrated in close proximity to the bowel wall.[32] Treatment of GI perforation is mainly surgical in order to improve survival.[33] This is in line with the previously published cases where all were managed surgically except the one reported by Kangas-Dick et al due to the patient’s critical condition, so he was managed conservatively but unfortunately, he died.[17] However, in selected cases where there are no active signs of peritonitis, abdominal sepsis or having sealed perforation, conservative treatment is an acceptable management strategy.[34,35] This was the case in 2 of our cases who were managed conservatively. Fortunately, they did very well and had good outcome.

4. Conclusion

GI manifestations are common in patients with COVID-19. However, GI perforation is rarely reported in the literature. Severe and critically ill COVID-19 patients seem to be at a higher risk of this complication. It has a variable presentation in patients with COVID-19 ranging from incidental finding discovered only radiographically to acute abdomen. The presence of underlying GI lesion predisposes patients with COVID-19 to perforation. High index of suspicion is required in order to manage those patients further and thus, improve their outcome.

Author contributions

Conceptualization: Reem J. Al Argan, Safi G. Alqatari

Data curation: Reem J. Al Argan, Abdulsalam Noor, Lameyaa A. Al Sheekh

Writing – original draft: Reem J. Al Argan, Lameyaa A. Al Sheekh, Feda’a H. Al Beladi

Writing – review & editing: Reem J. Al Argan, Safi G. Alqatari, Abir H. Al Said, Raed M. AlsulaimanGo to:

Footnotes

Abbreviations: COVID-19 = corona virus disease-2019, CT = computed tomography, CXR = chest X-ray, ED = emergency department, GI = gastrointestinal, ICU = intensive care unit, LDH = lactate dehydrogenase, O2 sat = oxygen saturation, PCR = polymerase chain reaction, PR = Pulse rate, RA = room air, RR = respiratory rate, Temp = Temperature, T2DM = Type 2 diabetes mellitus.

How to cite this article: Al Argan RJ, Alqatari SG, Al Said AH, Alsulaiman RM, Noor A, Al Sheekh LA, Al Beladi FH. Gastrointestinal perforation secondary to COVID-19: Case reports and literature review. Medicine. 2021;100:19(e25771).

The authors have no funding and conflicts of interests to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Eyes can be infected by COVID-19: 4 things to know

Authors: Gabrielle Masson – Wednesday, May 19th, 2021 Print 

Cells in the eye can be directly infected by SARS-CoV-2, the virus that causes COVID-19, according to findings published May 17 by ScienceDirect. 

Below are four things to know about COVID-19 infections of the eye:

1. Researchers exposed adult human eyes to SARS-CoV-2 in an in vitro stem cell model and then studied them after 24 hours. The virus is able to infect surface cells of the eye, the researchers found. Ocular surface cells, particularly the limbus, were particularly susceptible to infection, while the central cornea was less vulnerable.

2. Researchers are currently trying to determine if the virus can be spread through the eyes, Timothy Blenkinsop, PhD, study author and assistant professor of cell, developmental and regenerative biology at New York City-based Mount Sinai Health System, told Becker’s. While aerosol transmission is thought to be the primary route of spread, viral particles detected in ocular fluid suggest the eye may be a vulnerable point of viral entry. However, scientists don’t have evidence to back the theory up yet, in part because it is difficult to develop experiments where nasal infections don’t complicate the results. 

3. To prevent the transmission of COVID-19, people in dense areas that aren’t well ventilated would benefit from eye protection. Front-line providers should definitely have eye protection, Dr. Blenkinsop said, which is already fairly standard in the U.S.  

4. Other studies have found a significant number of patients with severe COVID-19 experience abnormal nodules of the eye. Three recent reports showed retinal findings, such as hemorrhages, cotton wool spots, dilated veins or tortuous vessels, are possibly tied to COVID-19.

Late Complications of COVID-19; a Systematic Review of Current Evidence

Authors: SeyedAhmad SeyedAlinaghi,1Amir Masoud Afsahi,2Mehrzad MohsseniPour,1Farzane Behnezhad,3Mohammad Amin Salehi,1Alireza Barzegary,4Pegah Mirzapour,1Esmaeil Mehraeen,5,* and Omid Dadras6

Introduction

Introduction:

COVID-19 is a new rapidly spreading epidemic. The symptoms of this disease could be diverse as the virus can affect any organ in the body of an infected person. This study aimed to investigate the available evidence for long-term complications of COVID-19.

Methods:

This study was a systematic review of current evidence conducted in November 2020 to investigate probable late and long-term complications of COVID-19. We performed a systematic search, using the keywords, in online databases including PubMed, Scopus, Science Direct, Up to Date, and Web of Science, to find papers published from December 2019 to October 2020. Peer-reviewed original papers published in English, which met the eligibility criteria were included in the final report. Addressing non-human studies, unavailability of the full-text document, and duplicated results in databases, were characteristics that led to exclusion of the papers from review.

Results:

The full-texts of 65 articles have been reviewed. We identified 10 potential late complications of COVID-19. A review of studies showed that lung injuries (n=31), venous/arterial thrombosis (n=28), heart injuries (n=26), cardiac/brain stroke (n=23), and neurological injuries (n=20) are the most frequent late complications of COVID-19.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927752/

Thrombocytopenia following Pfizer and Moderna SARS‐CoV‐2 vaccination

Authors: Eun‐Ju Lee, 1 Douglas B. Cines, 2 Terry Gernsheimer, 3 Craig Kessler, 4 Marc Michel, 5 Michael D. Tarantino, 6 John W. Semple, 7 Donald M. Arnold, 8 Bertrand Godeau, 5 Michele P. Lambert, 9 , 10 and James B. Bussel 11

Cases of apparent secondary immune thrombocytopenia (ITP) after SARS‐CoV‐2 vaccination with both the Pfizer and Moderna versions have been reported and reached public attention. Public alarm was heightened following the death of the first identified patient from an intracranial hemorrhage, which was reported on the Internet, then in USA Today 1 and then in The New York Times. 2 Described below, we have collected a series of cases of very low platelet counts occurring within 2 weeks of vaccination in order to enhance our understanding of the possible relationship, if any, between SARS‐CoV‐2 vaccination and development of ITP with implications for surveillance and management.

Twenty case reports of patients with thrombocytopenia following vaccination, 17 without pre‐existing thrombocytopenia and 14 with reported bleeding symptoms prior to hospitalization were identified upon review of data available from the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), agencies of the U.S. Department of Health and Human Services (HHS) Vaccine Adverse Events Reporting System (VAERS), published reports, 3 and via direct communication with patients and treating providers. These cases were investigated as suspicious for new onset, post‐vaccination secondary ITP; we could not exclude exacerbation of clinically undetected ITP. Search terms relating to “decreased platelet count”, “immune thrombocytopenia”, “hemorrhage”, “petechiae”, and “contusion” were utilized to identify cases reported in VAERS.

The reports describing 19 of 20 patients included age (range 22–73 years old; median 41 years) and gender (11 females and 8 males). Nine received the Pfizer vaccine and 11 received the Moderna vaccine. All 20 patients were hospitalized and most patients presented with petechiae, bruising or mucosal bleeding (gingival, vaginal, epistaxis) with onset of symptoms between 1–23 days (median 5 days) post vaccination. Platelet counts at presentation were available for all 20 cases with the majority being at or below 10 × 109/L (range 1–36 × 109/L; median 2 × 109/L).

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014568/

Hypercoagulability in COVID-19: A review of the potential mechanisms underlying clotting disorders

Authors: Walid Alam

Severe acute respiratory syndrome coronavirus-2 has emerged as a new viral pandemic, causing Coronavirus disease 2019 (COVID-19) leading to a wide array of symptoms ranging from asymptomatic to severe respiratory failure. However, coagulation disorders have been found in some patients infected with SARS-CoV-2, leading to either a clotting disorder or hemorrhage. Several mechanisms attempt to explain the mechanism behind the pro-coagulant state seen with COVID-19 patients, including different receptor binding, cytokine storm, and direct viral endothelial damage. SARS-CoV-2 has also been recently found to bind to CLEC4M receptor, a receptor that participates in the clearance of von Willebrand Factor and Factor VIII. The competitive binding of SARS-CoV-2 to CLEC4M could lead to decreased clearance, and therefore a promotion of a pro-coagulative state; however, an experimental study needs to be done to prove such an association.

For More Information: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989108/

Clots, Strokes and Rashes: Is COVID a Disease of the Blood Vessels?

Whether it’s strange rashes on the toes or blood clots in the brain, the widespread ravages of COVID-19 have increasingly led researchers to focus on how the novel coronavirus sabotages blood vessels.

As scientists have come to know the disease better, they have homed in on the vascular system — the body’s network of arteries, veins and capillaries, stretching more than 60,000 miles — to understand this wide-ranging disease and to find treatments that can stymie its most pernicious effects.

Some of the earliest insights into how COVID-19 can act like a vascular disease came from studying the aftermath of the most serious infections. Those reveal that the virus warps a critical piece of our vascular infrastructure: the single layer of cells lining the inside of every blood vessel, known as the endothelial cells or simply the endothelium.

For More Information: https://khn.org/news/clots-strokes-and-rashes-is-covid-a-disease-of-the-blood-vessels/