“Life is short, art long, opportunity fleeting, experience treacherous, judgment difficult.”

―Hippocrates

The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that occasionally quizzes readers on issues in hematology. In this installment, Drs. Abutalib and Connors consider coagulation abnormalities associated with SARS-CoV-2, or COVID-19, which has been spreading worldwide since late 2019, with many continuing to succumb to this deadly disease. For each quiz question that follows, select the one best answer. The correct answers and accompanying discussions follow.

GUEST EDITORS

Syed Ali Abutalib, MD

Jean M. Connors, MD

Dr. Abutalib is Associate Director of the Hematology and Cellular Therapy Program and Director of the Clinical Apheresis Program at Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at the Roseland Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Connors is Associate Professor in the Hematology Division at Harvard Medical School and Medical Director of Anticoagulation Services and Stewardship Programs at Brigham and Women’s Hospital/Dana Farber Cancer Institute in Boston.

The interplay between inflammation and coagulation—thromboinflammation—has been established.^1-15 COVID-19 infection is associated with coagulation abnormalities characterized by increases in procoagulant factor levels, including fibrinogen, and increases in D-dimers that have been associated with higher mortality.^1-12 Both sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC, thought to be part of a continuum of SIC) have been documented with severe disease, especially in those who do not survive COVID-19. However, a hypofibrinolytic consumptive DIC with a bleeding diathesis has not been reported.

As clinicians trained in using an evidence-based medicine approach, we find ourselves forced to practice without data based on real-world experience demonstrating increased thrombosis rates and increased mortality in critically ill patients with COVID-19. Herein, we try to briefly review and highlight currently available major data points—keeping in mind the “on-the-ground” challenges and controversies faced daily by health-care providers—in the management of the hypercoagulability associated with critically ill patients with COVID-19.

Disclaimer: We are not endorsing any changes in practice. All information in this manuscript is for informational purposes and should not be used for the diagnosis or treatment of any disease or medical condition.

Question 1

Recent studies^1-12 suggest there is an increased incidence of venous thromboembolic events (VTE) in critically ill patients with COVID-19. Which of the following statements about anticoagulation in this disease is correct?

A. Immediate prophylactic anticoagulation should be initiated in the absence of absolute contraindication.

B. Based on current published evidence, an empiric increase in prophylactic anticoagulation is justified in patients with high D-dimer and fibrinogen levels.

C. A French guidance document recommends full-therapeutic-dose anticoagulation for patients with increased fibrinogen > 8 g/L or D-dimer > 3.0 μg/mL.

D. A and C

Question 2

Standard thromboprophylaxis is more likely to fail in intensive care unit (ICU) patients.¹⁰ What is the failure rate of prophylactic anticoagulation using low–molecular-weight heparin or unfractionated heparin in ICU patients?

A. 16%–20%

B. 11%–15%

C. 5%–10%

D. 1%–4%

Question 3

COVID-19 may predispose patients to thrombotic disease, in both the venous and arterial circulations, due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. Which of the following statements is correct?

A. COVID-19 has a number of important cardiovascular implications.

B. Individuals without a history of cardiovascular disease are at risk for incident cardiovascular complications.

C. An increase in D-dimer levels in hospitalized COVID-19 patients is associated with a higher mortality rate.

D. All of the above

Question 4

A prospective cohort study conducted by the French CRICS-TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis)⁷ compared the occurrence of any thrombotic event in patients with COVID-19–related acute respiratory distress syndrome (ARDS) vs patients with non–COVID-19 ARDS. Which of the following statements is correct?

A. The patients were not on anticoagulation therapy.

B. About 96% receiving continuous renal replacement therapy experienced circuit clotting.

C. There were no circuit clotting events with the use of extracorporeal membrane oxygenation (ECMO) in patients with COVID-19 ARDS.

D. Coagulation parameters did not differ between the two groups.

Answers to Hematology Expert Review Questions

Question 1

Recent studies^1-12 suggest there is an increased incidence of VTE in critically ill COVID-19 patients. Which of the following statements about anticoagulation in this disease is correct?

Correct answer: D. A and C.

Expert Perspective

It is imperative to start prophylactic anticoagulation in the absence of an absolute contraindication (active bleeding and platelet count less than 25 × 10⁹/L). Monitoring is advised in cases of severe renal impairment, but abnormal partial thromboplastin (PT) or activated partial thromboplastin time (aPTT) is not a contraindication.^1,2

Bleeding is rare in the setting of COVID-19.¹ In critically ill COVID-19 patients, a risk-adapted approach to escalating the dose of anticoagulation despite minimal supporting data should be carefully considered after assessing the bleeding risk for each patient.³ Fibrinogen, D-dimer, PT, aPTT, and renal function should be monitored.^1-5

According to some experts, therapeutic anticoagulation might play a role by preventing the contribution of microvascular thrombosis to the progression of respiratory failure.^2,3,6,7 This also allows time to treat the cytokine storm with anti-inflammatory agents, which can decrease damage and allow innate immunity to clear the virus.

The exponentially increasing numbers of infected patients and the rapid pace of the disease do not leave time for most practitioners to participate in well conducted trials.² The French guidance document⁸ recommends full-therapeutic-dose anticoagulation for patients with increased fibrinogen > 8 g/L or D-dimer > 3.0 μg/mL. The Dutch centers changed practice after a month of experience treating COVID-19 patients.⁷ Like Rannuci and colleagues,⁹ one Dutch center increased doses of nadroparin (which is not U.S. Food and Drug Administration–approved) to 5,700 IU daily regardless of weight, and at another center, the dose was increased to 5,700 IU twice a day.

It is believed that increased doses are required to overcome the dramatic elevation in levels of procoagulant factors such as fibrinogen, factor VIII, and others; abnormalities that are not present in the standard postarthroplasty or hospitalized critically ill non–COVID-19 patients. At this moment, while practitioners use a variety of prophylactic, intermediate, or therapeutic doses of anticoagulants in patients, the optimal dosing in patients with severe COVID-19 remains unknown and warrants further prospective investigation.

In a recent consensus paper,² the majority of panel members considered prophylactic anticoagulation, although a minority considered an intermediate dose or full (therapeutic) dose to be a reasonable option (See reference 2 for endorsement statement by the International Society on Thrombosis and Haemostasis [ISTH], the North American Thrombosis Forum [NATF], the European Society of Vascular Medicine [ESVM], and the International Union of Angiology [IUA]).

Question 2

Standard thromboprophylaxis is more likely to fail in ICU patients.¹⁰ What is the failure rate of prophylactic anticoagulation using low–molecular-weight heparin or unfractionated heparin in ICU patients?

Correct answer: C. 5%–10%

Expert Perspective

The failure rate for standard venous thromboembolism prophylaxis in an ICU setting is 7.7% (n = 289 of 3,746) especially in patients with an elevated body mass index (hazard ratio [HR]  = 1.18 per 10-point increase, 95% confidence interval [CI] = 1.04–1.35; P = .01), those with a personal or family history of venous thromboembolism (HR = 1.64, 95% CI = 1.03–2.59; P = .04), and those on vasopressors (HR = 1.84, 95% CI = 1.01–3.35; P = .046).¹⁰

Alternative management or incremental risk-reduction strategies may be needed in a selected group of patients based on reliable variables. ICU status alone, elevated procoagulant proteins, or elevated D-dimers have been used by many to tailor anticoagulation dose. There are no data to support one approach over another. Institutional guidance developed by experts in coagulation or individual patient assessment for risks and benefits is required.

Question 3

COVID-19 may predispose patients to thrombotic disease, both in the venous and arterial circulations, due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. Which of the following statements is correct?

Correct answer: D. All of the above.

Expert Perspective

The existing evidence, including data on thrombotic complications, is derived primarily from mainly small and retrospective analyses.^1-12 COVID-19 has a number of important cardiovascular implications.³ The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia and increased D-dimer levels, which are associated with a higher risk of requiring mechanical ventilation, ICU admission, or death.^1,3,4

In a retrospective study by Cui and colleagues,¹¹ if 1.5 μg/mL was used as the D-dimer cutoff value to predict venous thromboembolism, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%. With regard to mortality, Zang and colleagues¹² showed that a D-dimer value on admission greater than 2.0 μg/mL (fourfold increase) could effectively predict in-hospital mortality in patients with COVID-19, indicating that D-dimer could be an early and helpful marker to approach the management of COVID-19 patients.

Reports of sudden cardiac death in young patients without preexisting heart disease have made the lay press news. Unlike the lungs, the heart is not the primary site of infection; however, there are reports confirming changes in cardiac imaging of viral myocarditis.13 A recently published case report described the clinical course of an otherwise healthy 53-year-old woman, infected with COVID-19 and acute myopericarditis.13 Such cases have been previously described with influenza or other viral illnesses and have been attributed to a combination of systemic inflammatory response syndrome (SIRS) and localized vascular/plaque inflammation.2 Additionally, there have been ample reports of arterial thrombosis in critically ill patients with COVID-19.1^-14

Question 4

A prospective cohort study conducted by the French CRICS-TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis)⁷ compared the occurrence of any thrombotic event in patients with COVID-19–related acute respiratory distress syndrome (ARDS) vs patients with non–COVID-19 ARDS. Which of the following statements is correct?

Correct answer: B. About 96% receiving continuous renal replacement therapy experienced circuit clotting.

Expert Perspective

The primary endpoint of this observational (a limitation of the study) prospective investigation was to compare the occurrence of any thrombotic event (ie, deep-vein thrombosis, pulmonary embolism, myocardial infarction, mesenteric ischemia, lower-limb ischemia, cerebral ischemic attack) between patients with COVID-19 ARDS and patients with non–COVID-19 ARDS.⁷ A total of 77 patients with COVID-19 ARDS and 145 with non–COVID-19 ARDS were matched. Secondary endpoints included occurrence of renal replacement therapy filter (RRT) coagulation, the median lifespan of each RRT circuit, and the occurrence of ECMO oxygenator coagulation.⁷

Despite anticoagulation, a high number of patients with COVID-19 ARDS developed life-threatening thrombotic complications. The incidence of pulmonary embolism was much higher in COVID-19 ARDS (9 patients [11.7%] vs 3 patients [2.1%] in non–COVID-19 ARDS, odd ratio = 6.2 [1.6–23.4]; P = .008).⁷ About 28 of 29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. The median lifespan of a renal replacement therapy circuit was 1.5 (1.0–2.0) days, compared to the 3 days recommended by the manufacturer. The total number of renal replacement therapy circuits per dialyzed patient was higher in COVID-19 patients, and their median lifespan was shorter. Twelve patients (8%) were supported by ECMO, with three thrombotic occlusions of the centrifugal pump occurring in two patients.⁷ Coagulation parameters differed between the two groups; prothrombin time, antithrombin, fibrinogen, and platelets were higher in COVID-19 patients compared to non–COVID-19 ARDS patients, whereas aPTT and D-dimers were significantly lower in COVID-19 patients.

The authors concluded that mechanisms leading to coagulopathy most likely differ in COVID-19 patients from those usually described in ICU patients. Early in the course of infection, those with a more severe inflammatory response to the viral infection demonstrate increased procoagulant factor levels, which may increase the risk for thrombosis. Patients who have had prolonged ICU level care, however, are still at risk for typical complications, including secondary infections and DIC. The precise mechanism(s) of higher-risk thrombosis in critically ill COVID-19 patients is unclear and the subject of robust worldwide research.  

DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca. Dr. Connors has received personal fees from Abbott, Bristol-Meyers Squibb, Portola, and Pfizer, and institutional research funding from CSL Behring.

REFERENCES

1. Thachil J, Tang N, Gando S, et al: ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. March 25, 2020 (early release online). Available at https://doi.org/10.1111/jth.14810. Accessed April 22, 2020.

2. Bikdeli BB, 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. April 17, 2020 (early release online). Available at https://doi.org/10.1016/j.jacc.2020.04.031. Accessed April 22, 2020.

3. Connors JM, Levy JH: Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. April 17, 2020 (early release online). Available at https://doi.org/10.1111/jth.14849. Accessed April 22, 2020.

4. Tang N, Li D, Wang X, et al: Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18:844-847, 2020.

5. Tang N, Bai H, Chen X, et al: Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. March 27, 2020 (early release online). Available at https://doi.org/10.1111/jth.14768. Accessed April 22, 2020.

6. Klok FA, Kruip MJHA, van der Meer NJM, et al: Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. April 10, 2020 (early release online). Available at https://doi.org/10.1016/j.thromres.2020.04.013. Accessed April 22, 2020.

7. Helms J, Tacquard C, Severac F, et al, for the CRICS-TRIGGERSEP Group: High risk of thrombosis in patients [with] severe SARS-CoV-2 infection: A multicenter prospective cohort study. Intensive Care Med 2020 (early release online). Available at https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf. Accessed April 22, 2020.

8. Susen S, Tacquard CA, Godon A, et al: Anticoagulant treatment for the prevention of thrombotic risk in a patient hospitalized with COVID-19 and hemostasis monitoring proposals from the GIHP and the GFHT. Available at https://www.fichier-pdf.fr/2020/04/03/covid-19-gihp-gfht-3-avril-final-3/?. Accessed April 22, 2020.

9. Rannuci M, Ballotta A, Di Dedda U, et al: The procoagulant pattern of patients with COVID 19 acute respiratory distress syndrome. J Thromb Haemost. April 17, 2020 (early release online). Available at https://doi.org/10.1111/jth.14854. Accessed April 22, 2020.

10. Lim W, Meade M, Lauzier F, et al: Failure of anticoagulant thromboprophylaxis: Risk factors in medical-surgical critically ill patients. Crit Care Med 43:401-410, 2015.

11. Cui S, Chen S, Li X, et al: Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. April 9, 2020 (early release online). Available at https://doi.org/10.1111/jth.14830. Accessed April 24, 2020.

12. Zang L, Yan X, Fan Q, et al: D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. April 9, 2020 (early release online). Available at https://doi.org/10.1111/jth.14859. Accessed April 22, 2020.

13. Inciardi RM, Lupi L, Zaccone G, et al: Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. March 27, 2020 (early release online). Available at https://doi.org/10.1001/jamacardio.2020.1096. Accessed April 24, 2020.

14. Magro C, Mulvey JJ, Berlin D: Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. April 15, 2020 (early release online). Available at https://doi.org/10.1016/j.trsl.2020.04.007. Accessed April 24, 2020.

15. Risitano AM, Mastellos, DC, Huber-Lang M, et al: Complement as a target in COVID-19? Nat Rev Immunol. April 23, 2020 (early release online). Available at https://doi.org/10.1038/s41577-020-0320-7. Accessed April 24, 2020.