As is the case for so many aspects of the COVID-19 pandemic, information on clinical complications caused by this virus continues to emerge and evolve in real time. The majority of patients who have tested positive for COVID-19 present with symptoms of an acute respiratory illness including fever, body aches, lethargy, dry cough and breathing difficulties. However, it appears that the novel coronavirus may impact more than just the lungs, especially in severe cases.
Clinicians from around the globe report kidney damage, liver dysfunction, heart problems and, most recently, issues with blood clots such as deep vein thrombosis (DVT). These systemic complications appear to increase patient morbidity and mortality. In recent days, this issue was thrust into the media spotlight with coverage surrounding the April 12 leg amputation of Tony award-winning Broadway star Nick Cordero, who developed a DVT during his intensive care unit (ICU) hospitalization for COVID-19.
Deep vein thrombosis occurs when a blood clot forms in a large vein, usually in the calf. Swelling, pain and serious complications, such as pulmonary embolism (PE) or a sudden blockage in the lung, can occur and make DVTs a potentially fatal condition. Thus, rapid treatment is imperative. The use of venous duplex ultrasound enables clinicians to screen patients for whom there is a high clinical suspicion of thrombosis.
What We Know About DVTs
Patients admitted to the ICU are at an increased risk for thrombolytic events due to multiple comorbidities, invasive tests and treatments, and prolonged immobilization. Physicians often attribute the elevated probability of DVT formation to Virchow’s triad, which consists of three major risk factors: venous stasis, vessel injury and hypercoagulability. The incidence of DVT during an ICU stay reportedly ranges between five and 15 percent.1 The COVID-19 virus induces a hyper-inflammatory state. Sources suggest that systemic inflammation induces endothelial injury. This will activate the coagulation cascade and impair fibrinolysis with disruption of the endothelial barrier and loss of physiologic antithrombotic factors.2 This may significantly elevate the risk for DVTs.
What Is The Latest Data On Thrombotic Events And COVID-19?
In my clinical experience, and in that of my hospital colleagues, in some severe cases, patients with COVID-19 crash hard and fast from cardiac episodes. This leads some clinicians to believe that these sudden arrests may stem from thrombolytic events, such as DVT, that they had not considered looking for. There is the hypothesis that critically-ill patients with COVID-19 patients may develop a pro-thrombotic form of disseminated intravascular coagulation (DIC) that is putting them at increased risk for thrombotic events. This concern is growing so much that the American Society of Hematology has identified this as a new pattern of clotting, which is referred to as COVID-19-associated coagulopathy or CAC.3
In a recent observational study of 184 patients, Klok and colleagues determined that the cumulative incidence of venous thrombotic complications was as high as 31 percent during ICU admissions for patients with COVID-19.4 That equates to at least a twofold increase over the median DVT occurrence rate in patients admitted to the ICU.1 The authors concluded that the study findings reinforce the addition of pharmacological thrombosis prophylaxis to treatment algorithms of all patients with COVID-19 admitted to the ICU.4
In a recent single-center retrospective analysis involving 81 COVID-19-positive patients in China who required ICU admission, Cui and coworkers evaluated patients for lower extremity DVT.5 The group found that the rate of DVT in patients with severe COVID was substantial with elevated D-dimer levels emerging as the best single predictor of clot development. In this patient cohort, a D-dimer greater than 1,500 ng/ml had an 85 percent sensitivity and 89 percent specificity for predicting which patients would develop DVT.
The American Society of Hematology recommends monitoring platelet count, partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), D-dimer and fibrinogen in all patients with COVID-19.3 Worsening of these parameters may indicate increasing severity of infection that needs more aggressive critical care. The society recommends prophylactic dosing of low-molecular weight heparin (LMWH) for all hospitalized patients with COVID-19 despite abnormal coagulation tests in the absence of active bleeding and holding off dosing only if platelet counts fall below 25x109 L, or if fibrinogen is less than 0.5 g/L.3 Thromboprophylaxis via mechanical means is applicable when pharmacological prophylaxis is contraindicated.3
Although hematology experts recommend the use of low molecular weight heparin to decrease the risk of disseminated intravascular coagulation in severe cases of coronavirus, the efficacy is not yet validated. In a retrospective study conducted at Tongji Hospital in Wuhan, China, Tang and colleagues analyzed 449 patients with severe COVID-19 and 99 of these patients received low molecular weight heparin for seven days or longer.6 The 28-day mortality rate was lower in the heparin group versus the non-users in patients with a sepsis-induced coagulopathy (SIC) score of greater than four or a D-dimer greater than sixfold of the upper limit of normal. The authors concluded that anticoagulant therapy with low molecular weight heparin appears to be associated with better prognosis in patients with severe COVID-19 who meet sepsis-induced coagulopathy (SIC) criteria or have a markedly elevated D-dimer level.6 The use of anticoagulant therapy did not seem to influence mortality rate in patients without evidence of sepsis-induced coagulopathy or an elevated D-dimer level. Additional longitudinal randomized trials are necessary to validate these findings.
Are There Alternatives To Low-Molecular Weight Heparin Treatment?
Following several public promotions by President Donald Trump, the use of hydroxychloroquine to treat COVID-19 has increased. Historically, physicians use hydroxychloroquine to treat malaria, rheumatoid arthritis and lupus. Multiple clinical trials are ongoing to determine if this drug does in fact exhibit antiviral properties against the novel coronavirus. This past week media outlets reported on an unpublished analysis of the medical records of patients treated for coronavirus in Veterans Health Administration medical centers nationwide.7 This initial retrospective examination of 368 males estimates that roughly 28 percent of patients receiving hydroxychloroquine plus routine care died versus 11 percent of those receiving standard of care alone. One should note that this was not a controlled randomized clinical trial and the results are not yet vetted by the scientific community. Additional rigorous research is necessary to validate if this drug is or is not an effective therapeutic agent for the treatment of the novel coronavirus.7
Past studies demonstrate that hydroxychloroquine interferes with the immune activation of various cells such as monocytes and macrophages.8 This direct immunomodulatory effect results in inhibition of the production of pro-inflammatory cytokines, which can subsequently protect against cytokine-mediated inflammation.8
Although hydroxychloroquine is not an anticoagulant, it is widely believed to have protective effects including inhibiting the development of thrombotic events such as DVT.8 This protective effect may be the most significant therapeutic benefit in patients with COVID-19. The complete mechanism of action of this drug is unknown and under investigation.
Where Do We Go From Here?
More clinical information is necessary before we can connect the dots linking COVID-19 and DVT. Until additional data is available, initiating full anticoagulation therapy to prevent DVT in these cases remains controversial. There is currently at least one clinical trial listed on clinicaltrials.gov investigating the prevalence and possible risk factors of DVT in 12 intubated and mechanically ventilated patients with COVID-19 admitted to the ICU at a single time point.9 For now, one should weigh both risks and benefits on a case-by-case basis. Going forward, podiatrists will play a vital role in prevention of DVTs in this patient population by ordering screenings for early detection and making proper referrals for patients needing prophylactic therapy. Together, we can help decrease complications and mortality in these patients.
Dr. Cole is the Medical Director of the Wound Care Center at University Hospitals Ahuja Medical Center in Beachwood, Ohio. She is also an Adjunct Professor and Director of Wound Care Research at the Kent State University School of Podiatric Medicine.
1. Boddi M, Peris A. Deep vein thrombosis in intensive care. Adv Exp Med Biol. 2017;906:167–181.
2. Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord. 2015;15:130.
3. American Society of Hematology. COVID-19 and coagulopathy: frequently asked questions. Available at: https://hematology.org/covid-19/covid-19-and-coagulopathy . Updated April 14, 2020. Accessed April 23, 2020.
4. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146714/ . Published April 10, 2020. Accessed April 23, 2020.
5. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020. Available at: https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14830. Published April 9, 2020. Accessed April 23, 2020.
6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020. Available at: https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14817 . Published March 27, 2020. Accessed April 23, 2020.
7. Marchione M. Nationwide study finds malaria drug touted by President Trump leads to more deaths, no benefits in coronavirus patients. Time. Available at: https://time.com/5825398/hydroxychloroquine-study-coronavirus/ . Published April 22, 2020. Accessed April 28, 2020.
8. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155–166.
9. U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/results?cond=COVID-19+AND+%22Embolism+and+Thrombosis%22 . Accessed April 23, 2020.