COVID-19-associated coagulopathy and thrombosis in cancer

During the 11th ICTHIC, Marcel M Levi talked about COVID-19 thrombotic implications in patients with cancer. Here, we summarize the highlights of his speech.

Background

From the beginning of the pandemic, in January 2020, a paper reported that many patients with COVID-19, particularly those with severe COVID-19, had very high D-dimer levels, much higher than usual seen in the context of pneumonia or sepsis [1].

It is known that an increase in D-dimer level is associated with a fourfold increase in mortality and a twofold increased risk of developing severe disease. And this is partly related to thromboembolic disease [2].

We now much better understand the coagulopathy associated with severe COVID-19, although it is still an evolving story. One of the most important mechanisms is the cytokine-induced upregulation of mononuclear cells expressing tissue factor, which profoundly impacts platelet–vascular interaction locally and systemically. In addition, SARS-CoV-2 infection causes distinct endothelial cell responses with an interesting role of neutrophil extracellular traps [3].

Clinically, this translates into a very specific coagulopathy that is different from what is usually seen. It has some features similar to disseminated intravascular coagulation and thrombotic microangiopathy; there is a reminiscence of the cytokine storm syndromes and an undetermined role of antiphospholipid antibodies. COVID-19 coagulopathy is a clinical syndrome in itself, and it is different from what can be seen in any other clinical setting [4].

The hypercoagulability and the systemic coagulation defect induced by COVID-19 lead to large vessel thrombosis and major thromboembolic complications, especially pulmonary embolism.

Initially, it was debated if the thromboembolic complications with COVID-19 were more than what is usually seen in an intensive care population [5]. We can now say this is the case, especially in the initial stages of the pandemic. A meta-analysis highlighted that severe COVID-19 is associated with a 30% incidence of venous thromboembolism (VTE), particularly pulmonary embolism [6].

Is cancer a risk factor for COVID-19?

A study showed that patients with cancer with different tumor types have separate susceptibility to SARS-CoV-2 and unique COVID-19 disease phenotypes [7]. In addition, patients with hematological malignancies were at a greater risk of having a more severe COVID-19 clinical phenotype, requiring more intensive supportive interventions, and suffering an increased risk of death than patients with non-hematological malignancies [7].

In addition, patients with cancer presenting COVID-19 had very high case-fatality rates, dependent on their age [7].

A multicenter study of 890 cancer patients with confirmed COVID-19 corroborated a worsening mortality gradient for certain cancer types (such as hematological malignancy). Also, it showed that male gender, older age, and several co-morbidities could lead to worse mortality rates from COVID-19 [8].

Fortunately, a recent study shows that the time-dependent COVID-19 mortality is rapidly declining in cancer patients. This reduction may be associated with earlier diagnosis, improved management, and changes in community transmission over time [9].

Do people with cancer and COVID-19 have an added risk of thrombosis?

People with cancer have an increased risk of thrombosis, and, as said, severe COVID-19 leads to a prothrombotic state. So, if these two conditions happen simultaneously, people with cancer and severe COVID-19 might have a particularly high risk of thrombosis.

A retrospective cohort analysis evaluated the cumulative incidences of thrombotic and hemorrhagic events in hospitalized COVID‐19 patients with and without active cancer at 28 days. Patients without cancer and active cancer were comparable for age, sex, antibiotics administered, length of hospitalization, and critical care [10].

The cumulative incidence of thrombosis was 18.2% in the non‐cancer and 14.2% in the cancer cohorts, while the cumulative incidence of major bleeding was 20.8% in the non‐cancer and 19.5% in the cancer cohort. Overall, a similarly high incidence of thrombosis and bleeding among patients admitted with COVID‐19 with or without active cancer was observed [10].

Although, it seems to be a higher risk of pulmonary embolism in COVID-19 patients with active cancer compared to COVID-19 patients without cancer (60% vs 12.9%), even though the number of patients with active cancer is very low [10].

A study assessed the incidence of thrombosis and its risk factors in hospitalized patients with cancer and COVID-19. Hospitalized patients with both active cancer and COVID‐19 have an elevated risk of VTE (7.6%) [11].

Is cancer therapy a risk factor for COVID-19 and thrombotic complications?

Cancer therapies do not seem to be a risk factor for patients with cancer and COVID-19.

A multicenter study showed that providing chemotherapy, targeted therapy, or immunotherapy did not worsen mortality in patients with cancer and COVID-19 [8].

Another study investigated mortality among adults with cancer and COVID-19 undergoing chemotherapy or immunotherapy. No association was found between recent treatment with chemotherapy and COVID-19-specific mortality [12].

Treatment with immunotherapy before COVID-19 diagnosis was associated with a significant reduction in mortality. Immunotherapy, hormonal therapy, targeted therapy, radiotherapy, or surgery within 4 weeks of COVID-19 diagnosis were also not associated with higher mortality [12].

Thromboprophylaxis

A retrospective observational study evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Results found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% CI: 0.49–0.74; E-value = 2.04). This association was particularly evident in patients with higher disease severity or strong coagulation activation [13].

Therefore, standard-dose pharmacologic thromboprophylaxis should be given to cancer patients with COVID-19.

Since critically ill cancer patients with COVID-19 still have a high risk for thrombosis, an open-label, adaptive, multiplatform, randomized clinical trial investigated the effectiveness and safety of therapeutic-dose anticoagulation [14].

Results showed that, in critically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis [14].

The incidence of major bleeding was numerically higher but still low (3.8%) with therapeutic-dose anticoagulation than with usual-care thromboprophylaxis [14].

A randomized clinical trial evaluated the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit. The results showed that intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not improve venous or arterial thrombosis risk or mortality within 30 days [15].

In noncritically ill patients with COVID-19, instead, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis [16].

However, there was a slight increment of major bleeding patients receiving therapeutic-dose anticoagulation compared to those receiving thromboprophylaxis (1.9% vs 0.9%) [16].

Finally, a multicenter randomized clinical trial, including cancer patients, showed that a therapeutic dose of heparin reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 and much elevated D-dimer levels [17].

Importantly, bleeding rates were higher in patients receiving therapeutic dose of heparin (incidence of major bleeding: 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins [RR, 2.88; 95% CI, 0.59–14.02; p=0.17]) [17].

These results indicate that therapeutic-dose heparin might be preferable in certain patients. Still, bleeding risk must be carefully considered, especially in cancer patients.

For more information about thromboprophylaxis in cancer patients with COVID-19, also read “COVID-19 and microvascular thrombosis/inflammation effects.”

Conclusion

Severe COVID-19 infection is associated with a coagulopathy that results in a pro-hemostatic state and increased Incidence of VTE.

Cancer patients have a modestly elevated risk of more severe COVID-19 dependent on tumor type and treatment. However, importantly, initial higher case-fatality rates in cancer patients have been reduced over time.

The risk of venous thromboembolism in cancer patients with COVID-19 is comparable to that of non-cancer patients (based on the most recent studies), but the bleeding might be higher. Therefore, heparin prophylaxis should be given to all of these patients considering the bleeding risk.

References

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12. Várnai C, Palles C, Arnold R, et al. Mortality among adults with cancer undergoing chemotherapy or immunotherapy and infected with COVID-19. JAMA Netw Open. 2022;5(2):e220130. doi:10.1001/jamanetworkopen.2022.0130
13. Di Castelnuovo A, Costanzo S, Antinori A, et al. Heparin in COVID-19 patients is associated with reduced in-hospital mortality: The multicenter Italian CORIST study. Thromb Haemost. 2021;121(8):1054-1065. doi:10.1055/a-1347-6070
14. REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med. 2021;385(9):777-789. doi:10.1056/nejmoa2103417
15. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: The INSPIRATION randomized clinical trial. JAMA. 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152
16. ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802. doi:10.1056/NEJMoa2105911
17. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: The HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620. doi:10.1001/jamainternmed.2021.6203