Coronavirus Disease 2019 (COVID-19) and Hypercoagulability

Patients with COVID-19 appear to be at elevated risk for thrombotic complications, including venous thromboembolism (VTE).¹ In addition to traditional risk factors for VTE, indirect effects of the severity of illness as well as direct effects of SARS-CoV2 infection contribute to heightened risk.^1,2 For example, patients with critical illness as a result of COVID-19 are at risk for VTE given prolonged immobility and frequent intravascular access devices promoting venous stasis.¹ In addition, the profound inflammatory response and cytokine storm associated with severe COVID-19 can predispose patients to thromboembolic complications. Viral infection triggers the production of inflammatory cytokines that activate coagulation factors and perpetuate consumptive coagulopathy.³ Patients with severe COVID-19 manifest high levels of inflammatory markers such as C-reactive protein and interleukin-6. In addition, retrospective analyses of patients with severe COVID-19 in a single center have shown that non-survivors demonstrate higher D-dimer levels and fibrin-degradation products (FDP) compared with survivors, with a high prevalence of disseminated intravascular coagulation (DIC) in non-survivors (71.4%).⁴

Direct effects of viral infection also increase risk for VTE. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cell using the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in numerous organs including the vascular endothelium.⁵ As a result, histologic examination has demonstrated evidence of viral inclusions, diffuse inflammation and endothelialitis, which can lead to a procoagulant state in COVID-19 patients.⁶

Thromboembolic Complications of COVID-19

Autopsy studies
VTE has been demonstrated on both microvascular and macrovascular scales in various post-mortem studies in COVID-19. Autopsy studies focused on COVID-19-associated respiratory failure have demonstrated severe endothelial injury in vivo, detailing the high frequency of pulmonary thrombosis, ranging from large vessel thrombosis to small vessel thrombosis, microangiopathy and alveolar capillary microthrombi.^7,8 On a macrovascular level, autopsy studies have demonstrated VTE in the large percentage of patients with COVID-19: in prospective series, deep venous thrombosis (DVT) was found during autopsy in 7 of 12 (58%) of patients and pulmonary embolism (PE) was determined to be the cause of direct cause of death in 4 of 12 (33%) of the cohort.⁹

Epidemiologic studies
There is significant variability in the reported incidence of VTE in COVID-19 across available literature due to dissimilar acuity of illness, study setting (e.g. outpatient, hospital wards, or intensive care unit (ICU)), and practice patterns for screening and diagnostic tests to confirm VTE. Nevertheless, rates of incident VTE appear to be relatively high among patients with COVID-19. In a cohort study of 198 patients hospitalized with COVID-19, 39 patients (20%) were diagnosed with VTE during their hospitalization.¹⁰ Specifically, 13 (6.6%) patients were diagnosed with PE, 14 (7.1%) with proximal DVT, 11 (5.6%) with distal DVT, and 1 (0.5%) with upper extremity DVT. VTE was associated with risk of death in multivariable analysis (HR 2.7, 95% CI 1.3-5.8). VTE was more common among those admitted to the ICU (28%) compared with those hospitalized on the wards (3.3%). High rates of VTE in ICU patients has also been noted in several other cohort studies.^11-13 One such study screened patients with COVID-19 admitted to the ICU in Wuhan, China and detected lower extremity DVT in 41 of 48 (85.7%) of patients.¹⁴

In addition, regardless of the variation in estimated rates, the relative frequency of VTE seems to be higher in patients with COVID-19 compared to other etiologies of acute respiratory distress syndrome (ARDS). One prospective cohort study including 150 patients admitted to the ICU in France showed that compared to those patients with non-COVID-19 ARDS, those with COVID-19 ARDS demonstrated significantly higher unadjusted rates of thromboembolic complications (18.0% vs. 6.0%, p<0.0001),¹² and these findings remained consistent even after propensity score matching for measured potential confounders (11.7% vs. 4.88%, p=0.04).

Although VTE appears to be the predominant thrombotic complication, various other thrombotic events have been reported among patients with COVID-19, including peripheral arterial thrombosis, stroke, myocardial infarction, and placental thrombosis, all of which are indicative of the hypercoagulable state associated with SARS-CoV-2.^15-19

VTE Prophylaxis in COVID-19

Patients hospitalized with moderate-to-severe COVID-19 should undergo careful risk stratification for VTE. Those who are found to be high-risk, including immobile patients and those admitted to the intensive care unit, should receive pharmacologic VTE prophylaxis with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in the absence of contraindications.¹ There is currently insufficient data to recommend the routine use of intermediate-dose or fully-therapeutic doses of heparin-based regimens for VTE prophylaxis in high-risk patients, such as those admitted to the ICU. However, many reports have described breakthrough VTE events despite standard-dose thromboprophylaxis in patients with COVID-19 patients. Therefore, alternative drug and dosing strategies, such as escalated-dose heparin-based regimens, or use of adjunct antithrombotic agents, require further evaluation. Notably, in a recent consensus-based document by the Global COVID-19 Thrombosis Collaborative Group, the majority of the group recommended standard-dose prophylaxis, nearly a third (31.7%) supported the use of intermediate-dose heparin-based regimens for VTE prophylaxis for patients with moderate-to-severe COVID-19.¹ Some centers have implemented a dosing strategy of enoxaparin 0.5 mg/kg twice per day in ICU patients or patients otherwise considered to be at increased risk.³ The relative merits and harms of these dose escalations require additional investigation and is an active subject of investigation in several ongoing randomized trials (COVID-HEP, CORIMMUNO-COAG, IMPROVE, COVI-DOSE, A Randomized Trial of Anticoagulation Strategies in COVID-19,  Safety and Efficacy of Therapeutic Anticoagulation on Clinical Outcomes in Hospitalized Patients With COVID-19, Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care).

VTE Treatment in COVID-19

Considerations for VTE prophylaxis and treatment in COVID-19 are provided in Figure 1. In the absence of contraindications, anticoagulation should be continued in patients with COVID-19 with pre-existing indications for therapeutic anticoagulation. Patients with unstable renal function, high-risk for bleeding, or other complications of COVID-19 that may affect the safety of certain anticoagulants (i.e. direct oral anticoagulants) may require switch to UFH in this setting. Additionally, the numerous potential drug-drug interactions between anticoagulants and drug therapies for COVID-19 should be taken into account.^1,2,20

Figure 1: Considerations for VTE prophylaxis and treatment in COVID-19

In patients with new suspected or confirmed VTE, initiation of therapeutic anticoagulation is recommended unless otherwise contraindicated (e.g. active bleeding). Choice of anticoagulant agent should be guided by patient comorbidities and COVID-19-related sequelae, including impaired renal function, hepatic injury, and coagulopathy resulting in bleeding risk. In patients with high-risk VTE with hemodynamic compromise, the severity of the VTE event and COVID-19 must be weighed when considering advanced therapies including systemic fibrinolysis as well as catheter-directed and surgical approaches to treatment.¹ Decisions regarding management of VTE should be made with consideration for risk for viral spread among patients and healthcare workers.

Future Directions

Higher-quality data are needed to understand the hypercoagulable state associated with COVID-19 as well as the most effective VTE prophylaxis and treatment regimens in this high-risk disease. Given the number of antithrombotic agents with potential for efficacy for VTE prophylaxis and treatment in COVID-19, further high-quality investigations into optimal agents and treatment strategies are needed.²⁰ Specifically, the role of empiric uses of intermediate-dose or fully therapeutic anticoagulation with heparin-based regimens in high-risk patients with COVID-19 warrants additional assessment in randomized studies and findings from ongoing trials will be informative.

In conclusion, the high incidence of COVID-19-associated VTE likely has significant implications with regards to morbidity and mortality in affected patients. Further study and advances in the area of thromboprophylaxis and treatment of VTE will be crucial in improving outcomes in these at-risk patients.

References

1. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020;Apr 15:[Epub ahead of print].
2. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020;75:2352-71.
3. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020;135:2033-40.
4. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.
5. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-10.
6. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8.
7. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;May 21:[Epub ahead of print].
8. Fox SE, Akmatbekov A, Harber JL, Li G, Brown JQ Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Resp Med 2020;May 27:[Epub ahead of print].
9. Wichmann D, Sperhake JP, Lutgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med 2020;May 6:[Epub ahead of print].
10. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020;May 5:[Epub ahead of print].
11. Klok FA, Kruip MJHA, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020;191:148-50.
12. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020;May 4:[Epub ahead of print].
13. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res 2020;191:9-14.
14. Ren B, Yan F, Deng Z, et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 Patients with severe COVID-19 in Wuhan. Circulation 2020;May 15:[Epub ahead of print].
15. Bellosta R, Luzzani L, Natalini G, et al. Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc Surg 2020;Apr 29:[Epub ahead of print].
16. Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med 2020;382:e60.
17. Stefanini GG, Montorfano M, Trabattoni D, et al. ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. Circulation 2020;Apr 30:[Epub ahead of print].
18. Bangalore S, Sharma A, Slotwiner A, et al. ST-segment elevation in patients with Covid-19 - a case series. N Engl J Med 2020;Apr 17:[Epub ahead of print].
19. Mulvey JJ, Magro CM, Ma LX, Nuovo GJ, Baergen RN. A mechanistic analysis placental intravascular thrombus formation in COVID-19 patients. Ann Diagn Pathol 2020;46:151529.
20. Bikdeli B, Madhavan M, Gupta A, et al. Pharmacological agents targeting thrombo-inflammation in COVID-19: review and implications for future research. Thromb Haemost 2020;May 30:[Epub ahead of print].

Clinical Topics: Anticoagulation Management, COVID-19 Hub, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism

Keywords: Aneurysm, Coronavirus, Coronavirus Infections, COVID-19, Heparin, Low-Molecular-Weight, Anticoagulants, Heparin, Fibrinolytic Agents, Enoxaparin, Peptidyl-Dipeptidase A, Venous Thromboembolism, Fibrin Fibrinogen Degradation Products, C-Reactive Protein, C-Reactive Protein, Interleukin-6, Respiratory Distress Syndrome, Prospective Studies, severe acute respiratory syndrome coronavirus 2

< Back to Listings