Complications of Coagulopathy Caused by COVID-19 Puts Patients With Cancer at Risk

Kashyap Patel, MD, BCMAS

The world facing an unprecedented crisis from the coronavirus disease 2019 (COVID-19), also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially, it was believed to be primarily a respiratory illness causing severe acute respiratory syndrome. Subsequent observations have led to cardiac manifestations, gastrointestinal complications, and hematological manifestations associated with this virus. The most common complications reported during the course of the disease include acute respiratory distress syndrome, disseminated intravascular coagulation (DIC), cardiac injury, and multiple organ dysfunction syndrome.^1-3

A sudden surge in COVID-19 cases and efforts to contain the virus have led to multiple challenges that no country has experienced in the past several decades. The global pandemic poses a unique set of challenges, not only for patients with cancer who need their treatment, but also for caregivers, oncologists, and the overall care team.

Although oncologists recognize the need to continue to treat patients with cancer during the pandemic because of their immunocompromised state caused by the nature of the disease or the type of treatment they are receiving, it is of paramount importance that the oncology care team develop and evolve a systemic approach that prioritizes patients, disease, and types of treatment. A system to determine a priority for treatment of patients with cancer is necessary to create a consistent approach for all providers. So far, the efforts of organizations and individual oncologists are being outpaced rapidly by the exponential and logarithmic growth of patients with COVID-19. It is likely that this will be a dynamic situation that will vary from day to day.

Because of complications of coagulopathy, including higher mortality in hospitalized patients with COVID-19, the American Society of Hematology has recommended the use of either low molecular–weight heparin (LMWH) or fondaparinux for thromboprophylaxis in COVID-19–associated hypercoagulability, except in cases where the risk of bleeding supersedes thrombosis risk.⁴ In those patients with existing contraindications for anti-coagulation, pneumatic compression devices could be initiated instead. The FDA has approved a regimen that may be used for thromboprophylaxis after discharge, such as a first dose of betrixaban (Bevyxxa) 160 mg, followed by 80 mg daily for 35 to 42 days, or rivaroxaban (Xarelto) 10 mg daily for 31 to 39 days.⁴

Therapeutic anticoagulation is initiated in patients with confirmed cases of venous thromboembolism (VTE), with patient comorbidities and coexisting conditions dictating the choice of treatment—either low molecular weight heparin, unfractionated heparin, or direct anti-coagulants. If necessary, reduced antithrombin III levels can be replenished with fresh frozen plasma.⁵

Patients with pulmonary embolism should be treated according to standardized guidelines, with hemodynamically stable patients receiving anticoagulation with close monitoring. For severe cases, clinicians should consider administration of fibrinolytic agents. Heparin should be generally avoided in DIC, but it is recommended in DIC associated with COVID-19.⁶

Patients With Cancer

Patients with cancer and a sepsis syndrome are more likely to have COVID-19–associated coagulopathy than patients with a mild infection. Those who die from COVID-19 are more likely to have DIC compared with survivors. Patients with elevated dimerized plasmin fragment D (D-dimer) at presentation and markedly increasing D-dimer levels (3- to 4-fold) over time are associated with high mortality, likely reflecting coagulopathy from infection/sepsis, cytokine storm, and impending organ failure. Monitoring complete blood counts, platelet count, prothrombin time (PT)/partial thromboplastin time (PTT), D-dimer, and fibrinogen helps deter-mine the appropriate intervention. Progressive rise in D-dimer levels, worsening PT/PTT, and clinical and/or radiological evidence of deep vein thrombosis and/or pulmonary embolism would call for anticoagulation. These patients have higher risk of developing the need for mechanical ventilation support. Worsening of these parameters is indicative of the severity of COVID-19 infection and predicts when more aggressive critical care will be needed.⁷

The role of anti-inflammatory drugs is not established. Low-dose dexamethasone administered as an anti-inflammatory has reduced the risk of death in one-third of patients.

Link to Coagulopathy

Commonly observed hematological abnormalities reported in patients with COVID-19 include leukopenia, thrombocytopenia, lymphopenia and neutrophilia in blood cell lines, and raised markers of inflammation including high sedimentation rate, C-reactive protein, and ferritin.¹ However, these findings are not independent markers of prognosis.

Recently, studies have reported that COVID-19 is linked to coagulopathy independent of any other primary risk factors.⁷ Additionally, COVID-19–related coagulopathy has emerged as one of the most important markers of negative prognosis and adverse outcomes. These abnormalities include an elevated D-dimer and prolonged PT and PTT. A significant difference in the levels of PT, PTT, fibrinogen/fibrin degradation products (FDP), and FDP D-dimers has been reported among survivors and nonsurvivors of COVID-19.⁸

Coagulopathy observed on a regular basis indicates that COVID-19 itself can cause thrombophilia, manifesting as both venous and arterial thrombosis that frequently results in the disseminated intravascular coagulation. Helms et al6 have reported the presence of lupus anticoagulant and antiphospholipid antibodies in 90% of severe cases, further supporting the presence of a hypercoagulable state in severe cases of COVID-19. Among patients with COVID-19 who were admitted to the emergency department in critical condition, the cumulative incidence of thrombotic complications was reported to be 31%.⁹

Clinical manifestations of the coagulopathy of COVID-19 include deep vein thrombosis, pulmonary embolism, catheter-associated thrombosis, myocardial infarction, limb ischemia, and cerebrovascular thrombosis.^10,11 In summary, the effect of COVID-19 on the hematologic system is quite diverse and includes cytopenia, raised markers of inflammation, and coagulopathy, all contributing to rising mortality.

COVID-19 Affects Multiple Organ Systems

Though originally thought to affect predominantly the lungs, COVID-19 has proven to be a systemic disease with the potential to affect numerous organ systems, including causing systemic inflammation, cytokine storm, and thrombophilia. For patients with cancer this is particularly relevant because cancer itself is a thrombophilia, so the addition of another insult with systemic inflammation and prothrombotic insult makes patients with cancer more vulnerable to complications, including death. The role of laboratory parameters is increasingly being utilized for diagnosis, prediction of adverse clinical outcomes, and prognosis in hospitalized COVID-19 patients.⁷

It is prudent and important to be extra cautious to monitor prognostic value of hematologic abnormalities. Meticulously monitoring these values in all patients can help in providing urgent intensive-care referral for those at greater risk. COVID-19–associated coagulopathy is an important predictor of mortality, particularly in patients with cancer. Both conditions can trigger thrombophilia that can lead to VTE, arterial thromboembolism, myocardial infarction, cerebral infarction, and DIC.

Monitor platelet count, PT and PTT, D-dimer, and fibrinogen. Worsening of D-dimer, in particular, indicates progressive severity of COVID-19 infection and suggests that more aggressive critical care will be needed. Experimental therapies for COVID-19 infection might be considered in this setting. Improvement in these parameters and stable or improving clinical conditions provide confidence that stepping down of aggressive treatment may be appropriate.¹²

As with all coagulopathies, treatment of the underlying condition is paramount. Although COVID-19 infection leads to abnormal coagulopathy, it does not generally lead to bleeding. Blood product transfusion should be individualized and determined on a case-by-case basis.

In patients who do not have evidence of direct or occult blood loss, transfusion support may be used based on clinical abnormalities, rather than blood test abnormalities alone. Platelets may be infused in a patient experiencing clinically relevant bleeding (especially if the platelet count is less than 50 × 10⁹/L). Plasma may be given if the international normalized ratio is above 1.8. If the fibrinogen level is less than 1.5 g/L, fibrinogen concentrate (4 grams) or cryoprecipitate (10 units) may be ordered. For patients with severe coagulopathy and bleeding, consider a 4-factor prothrombin complex concentrate instead of plasma, as volume status appears to be a significant factor associated with respiratory compromise.

Therapeutic anticoagulation is only required if an indication for therapeutic anticoagulation is documented (eg, VTE, atrial fibrillation, or mechanical heart valve). The efficacy of intermediate or full therapeutic anticoagulation for critically ill COVID-19 patients without documented VTE is undergoing further investigations. In patients already taking anticoagulation for VTE or atrial fibrillation, therapeutic doses of anticoagulation should continue. Individual patient assessment is required to balance risks of thrombosis and bleeding.

Thromboprophylaxis with LMWH is recommended for all hospitalized patients with COVID-19 in the absence of bleeding (and held only if platelet counts are less than 20 × 10⁹/L or fibrinogen is less than 0.5 g/L). Mechanical thromboprophylaxis may be used when pharmacological thromboprophylaxis is contraindicated.

Death From Multiple Organ Dysfunction

Deaths from COVID-19 have been caused by multiple organ dysfunction. This observation might be attributable to the widespread distribution of angiotensin-converting enzyme 2—the functional receptor for SARS-CoV-2—in multiple organs.^13,14 Patients with cancer are more susceptible to infection than individuals without cancer because of their malignancy and anticancer treatments, such as chemotherapy.¹⁵ These patients might be at increased risk of COVID-19 and have a poorer prognosis.

Venous thromboembolism and arterial thromboembolism are common complications for patients with cancer and can be multifactorial. The thrombophilia of malignancy may be due to the capacity of malignant cells to interact with and activate the host hemostatic system. Thrombophilia of cancer also impacts the morbidity and mortality of the underlying disease.¹⁶

_References:

_{1. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720. doi:10.1056/NEJMoa2002032}

_{2. Harapan H, Itoh N, Yufika A, et al. Coronavirus disease 2019 (COVID-19): a literature review. J Infect Public Health. 2020;13(5):667-673. doi:10.1016/j.jiph.2020.03.019}

_{3. Gerges Harb J, Noureldine HA, Chedid G, et al. SARS, MERS and COVID-19: clinical manifestations and organ-system complications: a mini review. Pathog Dis. 2020;78(4):ftaa033. doi:10.1093/femspd/ftaa033}

_{4. COVID-19 and VTE/anticoagulation: frequently asked questions. American Society of Hematology. Updated November 30, 2020. Accessed December 2, 2020. https://bit.ly/37xJhwI}

_{5. Song JC, Wang G, Zhang W, et al; People’s Liberation Army Professional Committee of Critical Care Medicine, Chinese Society on Thrombosis and Haemostasis. Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19. Mil Med Res. 2020;7(1):19. doi:10.1186/s40779-020-00247-7}

_{6. Helms J, Tacquard C, Severac F, et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. doi:10.1007/s00134-020-06062-x}

_{7. Bhattacharyya R, Iyer P, Phua GC, Lee JH. The interplay between coagulation and inflammation pathways in COVID-19-associated respiratory failure: a narrative review. Pulm Ther. 2020;6(2):215-231. doi:10.1007/s41030-020-00126-5}

_{8. 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(4):844-847. doi:10.1111/jth.14768}

_{9. 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;191:145-147. doi:10.1016/j.thromres.2020.04.013}

_{10. Gupta A, Madhavan MV, Sehgal K, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-1032. doi:10.1038/s41591-020-0968-3}

_{11. Shi W, Lv J, Lin L. Coagulopathy in COVID-19: focus on vascular thrombotic events. J Mol Cell Cardiol. 2020;146:32-40. doi:10.1016/j.yjmcc.2020.07.003}

_{12. Kinasewitz GT, Zein JG, Lee GL, Nazir SA, Taylor FB Jr. Prognostic value of a simple evolving disseminated intravascular coagulation score in patients with severe sepsis. Crit Care Med. 2005;33(10):2214-2221. doi:10.1097/01.ccm.0000181296.53204.de}

_{13. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273. doi:10.1038/s41586-020-2012-7}

_{14. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. a first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. doi:10.1002/path.1570}

_{15. Kamboj M, Sepkowitz KA. Nosocomial infections in patients with cancer. Lancet Oncol. 2009;10(6):589-597. doi:10.1016/S1470-2045(09)70069-5}

_{16. Falanga A. Thrombophilia in cancer. Semin Thromb Hemost. 2005;31(1):104-110. doi:10.1055/s-2005-863812}