Offering a closer look at the latest literature on the development of coagulation abnormalities in patients with COVID-19, these authors examine the effect of the disease on microcirculation, review current testing and treatment measures for hospitalized patients, and discuss whether “COVID toes” are a legitimate phenomenon.
While numerous publications have discussed the impact and potentially lasting complications of the novel coronavirus-19 disease, emerging literature is beginning to crystallize the relationship between COVID- 19-induced coagulation abnormalities and thromboembolic events. In the setting of podiatric surgery and limb salvage, these systemic manifestations may carry great consequence in an already medically complicated patient population. Accordingly, let us take a closer look at the current literature regarding the COVID-19 virus and its implications in lower extremity surgery.
Coronaviruses are enveloped, non-segmented, positive-sense RNA viruses of the Nidovirales order of the Coronaviridae family. While the majority of coronavirus infections in humans are relatively mild, two recent epidemics of betacoronavirus (Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012) demonstrated significantly higher mortality rates (10 and 35 percent respectively).1,2 While the current observed fatality rate for COVID-19 pandemic may be lower than prior Coronaviridae epidemics, COVID-19 possesses higher rates of infectivity and has rapidly attained worldwide spread, exposing a much higher global population.1,2
Clinical manifestations of patients with COVID-19 infection are similar to other viral respiratory infections. These patients typically present with fever and cough. To a lesser extent, they may have fatigue, dyspnea, headache, sore throat, nausea, vomiting or diarrhea.3 In a case series of over 44,000 COVID-19-positive patients, greater than 75 percent described mild flu symptoms with 14 percent having severe symptoms, five percent having critical issues and an overall fatality rate of two to 2.5 percent.4 While most severe cases of COVID-19 lead to isolated acute respiratory distress syndrome (ARDS), approximately 20 to 30 percent of severe cases may evolve to multiple organ failure (often fatal).4
COVID-19’s high mortality rate and relationship with thromboembolic disease continues to attract attention. Consecutive autopsy findings discovered deep vein thrombosis in 7/12 (58 percent) patients with COVID-19 and pulmonary emboli in 4/12 patients (33 percent).5 In a review of 184 Dutch patients with COVID-19 admitted to the intensive care unit (ICU), 31 percent of patients had an incidence of thromboembolism despite receiving standard venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH).6
What Kind Of Impact Does COVID-19 Infection Have On Microcirculation?
As a whole, COVID-19 infection appears to induce high levels of inflammation, hypoxia and endothelial tissue damage that predispose to elevated rates of thrombus formation in hospitalized patients.3 Early COVID-19 hospitalizations revealed a pronounced association between elevated D-dimer and fibrinogen degradation products (FDPs) and increased mortality, a trend which has continued throughout the pandemic.3 Elevated D-dimer levels are present in up to 45 percent of COVID-19 cases and cases in which levels exceed 1000 ng/ mL are nearly 20 times more likely to be fatal than those that exhibit lower D-dimer values.7 This should not be surprising as elevated D-dimer levels are common in cases of critical illness and researchers found similar elevations and associated mortalities during the H1N1 and the H5N1 outbreaks.8
Initially, researchers believed COVID- 19-induced coagulopathies were similar to disseminated intravascular coagulation (DIC) in which platelet counts and prothrombin time (PT) prolongation levels typically correlate with sepsis severity and mortality.3 Interestingly, despite 71.4 percent of fatal COVID-19 cases developing some level of disseminated intravascular coagulation, large reviews of laboratory data demonstrated only mildly prolonged prothrombin time with mild thrombocytopenia and normal fibrinogen levels.7 While D-dimer and fibrin degradation product levels consistently correlate with COVID-19 severity, markers traditionally consistent with disseminated intravascular coagulation are not as common in COVID-19 cases, indicating the possible triggering of a unique coagulopathic pathway.3 For a comparison of hematologic laboratory values of COVID-19 to those of other coagulopathic disease states, see “What Do The Lab Values Reveal? Keys To Differentiating Between COVID-19 And Other Disease And Coagulopathic States” above.9
Although data remains scarce, there are increasing reports of arterial thrombotic events and isolated cases of ischemic strokes in patients with COVID-19.10 COVID-19 has a predilection for binding to an angiotensin-converting enzyme (ACE2) on endothelial walls. Elevated levels of ACE2 activation possess protective antithrombotic effects. It is believed that COVID-19 binding to the cell entry receptor ACE2 may downregulate receptor expression and, in turn, induce vascular endothelial dysfunction.11 This likely activates a prothrombotic cascade, which may lead to the increased vascular thrombosis observed in patients with COVID-19.
Additionally, COVID-19 infection causes significant systemic inflammation as evidenced by increased interleukin-6, C-reactive protein, erythrocyte sedimentation and elevated fibrinogen levels.12
This combination of an elevated inflammatory state and endothelial injury could be the source of microangiopathic thrombosis, which may also explain increased rates of cerebrovascular and myocardial ischemias.11
Key Considerations In The Management Of COVID-19 Coagulopathies
The virality of COVID-19 forced a policy shift for many health-care centers from hospital to home-based care. To avoid excessive patient and provider exposure, hospital systems increasingly rely on virtual visits and longer follow-up intervals to reduce viral risk.13 However, many high-risk limb salvage and wound care patients require regular in-office examinations for debridements and/or offloading adjustments to maintain ulcer and infection remission. This change in policy may ultimately result in delays to accessing necessary care or referrals, and may postpone presentation to the hospital in critical situations.14
In addition to routine admission labs, newly hospitalized patients with confirmed COVID-19 infection should have testing including D-dimer, prothrombin time, activated partial thromboplastin time (aPTT) and fibrinogen in addition to inflammatory markers such as CRP and ESR. During hospital admission, there should be frequent and close monitoring for thrombosis and microangiopathy. Autopsy reports in fatal COVID-19 cases consistently demonstrate microvascular thrombosis and marked inflammatory changes in tissue.11 Therefore, aggressive efforts for prophylactic anticoagulation are recommended in confirmed cases.11 All confirmed patients with COVID-19 in the hospital should receive pharmacologic prophylaxis (or mechanical prophylaxis if there is pharmacologic contraindication) per hospital protocol.11
Tang and coworkers found lower 28-day mortality rates (32.8 percent) in patients with COVID-19 who received low molecular-weight heparin as anticoagulation prophylaxis in comparison to those who did not receive anticoagulation (52.4 percent).15 The theory is that low molecular-weight heparin may reduce mortality not only through venous thromboembolism prevention but also by suppressing the inflammatory cytokine storm present in severe cases.11
Increased heparin doses may also contribute to prophylaxis to compensate for the increased procoagulant proteins (fibrinogen, factor VIII and von Willebrand factor) in worsening COVID-19 infections. Paranjpe and colleagues reviewed 2,773 hospitalized patients with COVID-19 and found that administration of full dose anticoagulation treatment was associated with decreased mortality and earlier hospital discharge while controlling for severity of illness.3 Despite ongoing investigation outside the ICU setting, full dose anticoagulation as venous thromboembolism prophylaxis remains controversial. For a suggested pharmacologic approach to inpatients with COVID-19, see “A Suggested Approach To Pharmacologic Anticoagulation For COVID-19 Positive Patients” above.11
There are over 300 active trials of medications for patients diagnosed with COVID-19, many of which aim to dampen inflammation and thrombosis. These medications include cytokine-directed agents, corticosteroids, complement inhibitors, N-acetylcysteine, serine protease inhibitors, DNAse enzymes and antiviral agents. However, upstream targets may ultimately prove more effective. Dipyridamole is one of many early candidates for upstream suppression of neutrophil and T-cell activation, and may also inhibit COVID-19 replication in vitro by inhibiting a critical viral replication complex.17 Ultimately, one will likely only obtain comprehensive pharmacologic treatment either through vaccine prevention or monoclonal antibody control of infection.17
Is Surgery Safe During The COVID-19 Pandemic?
In a July 2020 review published in the Lancet, Nepogodiev and colleagues looked at the mortality of 1,128 COVID-19-positive patients who underwent surgery in the United States.18 Surprisingly, 280 cases were elective while the majority took place under emergency conditions. Overall, 30-day mortality was 23.8 percent and the study authors notied that men, patients greater than 70 years of age and patients with an American Society of Anesthesiologists (ASA) classification of greater than 3 were at the highest risk for mortality.18
Unfortunately, many of these variables overlap in the limb salvage population. Ultimately, the authors concluded that surgeons and facilities must heighten thresholds for conducting surgery during the COVID-19 crisis due to the increased exposure risk to providers and significant mortality risk to patients.18 In this regard, operating on patients with COVID-19 infection is best reserved for emergent situations only.
If a condition is life- or limb-threatening and requires emergent operation in a COVID-19 positive case, one should perform the operation in a designated negative pressure environment. All operating room staff should take full body personal protective equipment (PPE) precautions per hospital protocol and aerosol generating procedures (AGPs) should be limited when possible. Common AGPs include intubation, extubation, endoscopy/laparoscopy and use of high-energy devices. If electrocautery is required, one should use the lowest setting possible to reduce smoke and prioritize smoke evacuation.
In the scenario in which one obtains any specimens, label them as 2019-nCoV and handle them as infectious specimens until they are sent out to the laboratory. Surgeons should don and doff PPE according to hospital policy, and changing hospital scrubs following the procedure is recommended.19
COVID Toes: Phenomenon Or Faux-nomenon?
In late spring 2020, scattered medical reports and collections of case series began to emerge in the literature describing young healthy adults without prior medical history experiencing purplish or erythematous macules to their toes.20 Patients became increasingly concerned about their appearance as social media outlets began to spread the fear of a possible “COVID toes” phenomenon as a possible precursor to COVID-19 infection. Due to the vague flu-like symptomatology of early COVID-19 infection, patients began reporting to dermatologists and podiatric offices with similar complaints.
While descriptions now exist for a multitude of skin manifestations secondary to COVID-19 infection, a chilblain-like presentation was an unexpected consequence. Historically, clinicians described chilblains as an exaggerated skin response to cold in disposed individuals, clinically appearing as pink to violaceous papules on the acral surfaces of hands and feet. Histologically, chilblains is an inflammatory disorder with dermal edema and deep perivascular lymphocytic infiltrate.20
Some authors show positive anti-SARS-CoV-2 immunostaining on skin biopsy specimens of chilblains, which appeared to confirm the presence of the virus in the lesions.21 However, due to lack of specificity in testing, immunostaining alone is likely not a direct confirmation.21 Additionally, other authors hypothesized this chilblains-like phenomenon could be a result of a high cutaneous type I interferon (IFN-1) response. High expression of IFN-1 is associated with early attempts at viral and antibody suppression in mild cases of COVID-19 and other systemic disease states with cutaneous vasculopathy and interstitial lung diseases being typical manifestations.22
Others speculate a more indirect association from lockdown-induced lifestyle changes as a possible causative factor. Specifically, factors may include prolonged sedentary behavior, increased barefoot time while at home and simply an extended period of time to observe one’s feet due to increased working from home.23 Regardless, despite the first reported case of chilblain-like lesions in March 2020, there is no definitive correlation at this time.
The subject of COVID-19-induced coagulation abnormalities and thrombotic complications requires further large-scale clinical studies and biologic studies at the molecular level. For COVID-19 confirmed cases, providers should pay special attention to coagulation dysfunction and prevention for venous thromboembolisms. COVID-19 pathogenicity may exacerbate existing metabolic conditions and place patients at significantly increased risk of thrombus formation. Therefore, all hospitalized patients with COVID-19 should receive pharmacologic venous thromboembolism prophylaxis per hospital protocol. In the complicated limb salvage patient population, knowledge of these increased risks should only empower great multidisciplinary care and medical management in this at-risk population.
Dr. Miller is a current Research Fellow in the Department of Plastic Surgery Limb Salvage Division at Georgetown University Hospital in Washington, D.C.
Dr. Atves is an Associate of the American College of Foot and Ankle Surgeons, an Assitant Professor of Plastic Surgery at Georgetown University Medical Center, and Director of the MedStar Georgetown Foot and Ankle Research Fellowship in Washington, D.C.
Dr. Steinberg is a Fellow and Past President of the American College of Foot and Ankle Surgeons. He is the Co-Director of the Center for Wound Healing at MedStar Georgetown University Hospital and the Director of the Podiatric Residency Program at MedStar Washington Hospital Center in Washington, D.C.
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2. World Health Organization. Middle East Respiratory Syndrome Coronavirus (MERS-CoV). World Health Organization; 2015. Available at: https://www.who.int/news-room/fact-sheets/ detail/middle-east-respiratory-syndrome-coronavirus-(mers-cov) . Published March 11, 2019. Accessed January 20, 2021.
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19. Al-Balas M, Al-Balas HI, Al-Balas H. Surgery during the COVID-19 pandemic: A comprehensive overview and perioperative care. Am J Surg. 2020;219(6):903-906.
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