Hematologic Consequences of the Coronavirus Crisis—Focus on Relevant Clues and Complications for the Perioperative Cardiothoracic and Vascular Community

THE CORONAVIRUS pandemic is a global crisis and has led to a surge in hospital-based care for severe coronavirus disease 2019 (COVID-19).1, 2, 3, 4, 5 The unique considerations for severe COVID-19 have resulted in agile adaptation in the clinical arena, including graduate medical education, echocardiography, perioperative care, critical care, and extracorporeal membrane oxygenation.6, 7, 8, 9, 10, 11, 12

The purpose of this freestanding editorial is to highlight the hematologic consequences of the COVID-19 pandemic as they provide clues and challenges for the delivery of high-quality patient care. These features can improve the design of best practices to navigate this crisis creatively. The provided references can also assist leaders in their management of the pandemic at their respective institutions.

Consider the Complete Blood Count

The white blood cell response to coronavirus infection is characterized by lymphopenia.^{13 , 14} The development of lymphopenia is nearly universal in clinically significant COVID-19, with an observed incidence range of 80% to 100%.13, 14, 15 The degree of the lymphopenic response may significantly correlate with the severity of clinical infection.^{14 , 15} The extent of the lymphopenia has significantly predicted the risks of admission to the intensive care unit, development of acute respiratory distress syndrome, and mortality.13, 14, 15, 16, 17, 18

There appear to be multiple mechanisms for this lymphopenic phenotype in COVID-19. The first mechanism is that coronavirus can infect and directly destroy lymphocytes because they express the viral-binding protein on their surface membrane, namely angiotensin-converting enzyme 2.^{19 , 20} A second mechanism for lymphopenia may be increased lymphocytic apoptosis due to the cytokine storm that may accompany infection with coronavirus.^{7 , 21} This cytokine storm may also result in atrophy of lymphoid reserves, including the spleen, and impair lymphocyte levels.²² A third mechanism for lymphopenia may be decreased proliferation from significant acidosis associated with severe COVID-19.3, 4, 5 ^{, 23}

Beyond lymphopenia, recent evidence from multiple clinical trials has suggested that thrombocytopenia is not only common but is very often associated with severe COVID-19.²⁴ Although the severity of the thrombocytopenia may at times correlate with the clinical severity of coronavirus infection, there may also be a platelet spike in the setting of a pronounced cytokine storm.²⁴ This relative platelet excess may result in an elevated platelet-to-lymphocyte ratio that appears to be an independent predictor for prolonged hospitalization and adverse clinical outcomes in COVID-19.24, 25, 26 These platelet abnormalities may also have a role in the disordered coagulation that may accompany COVID-19, and that is explored further in the following section.

Consider the Coagulation System

Recent reports have demonstrated that COVID-19 may be complicated by thrombotic events in a variety of vascular beds, accompanied by markedly elevated D-dimer levels.26, 27, 28, 29, 30 This hypercoagulability may precipitate both arterial and venous thrombosis. Ischemic stroke, myocardial infarction, deep venous thrombosis, pulmonary embolism, and line-associated thrombosis have been described.28, 29, 30 A retrospective cohort study of 388 patients in Milan reported a cumulative rate of thromboembolic events of 21% in all hospitalized patients and 27.6% in patients receiving critical care.²⁹ A Dutch study reported an incidence of thromboembolic events in 31% of ICU patients.³⁰ However, the concerns about thrombosis in COVID-19 are not limited to overt thromboembolic events.²⁶ The pattern of preserved pulmonary compliance and profound hypoxemia in severe COVID-19 has led to speculation that pulmonary microvascular thrombosis may be a significant contributor to respiratory failure in this setting.^{31 , 32} If pulmonary thrombotic burden is critical, it could lead to ventilation–perfusion mismatch and significant hypoxemia. Indeed, because thrombotic risk increases with age, thrombotic events could partially explain the age-associated mortality of COVID-19.³³ Given these risks of thrombosis, therapeutic anticoagulation in COVID-19 has been suggested as part of clinical management.32, 33, 34

The laboratory findings in COVID-19 include elevated D-dimers, suggesting high fibrinogen turnover.26, 27, 28 Furthermore, D-dimer levels predict not only clinical severity but also mortality.³⁴ These levels may be as high as 10 times the normal levels in severe COVID-19.32, 33, 34 Although these D-dimer levels can be remarkably high, further features of disseminated intravascular coagulation may not be present.35, 36, 37 The fibrinogen levels are elevated, thrombocytopenia is not always present, and the prothrombin and activated partial thromboplastin times are either normal or minimally elevated.³⁸ Although antiphospholipid antibodies have been observed in this setting, this is not a uniform finding.^{38 , 39} Furthermore, although disseminated intravascular coagulation typically presents as a mix of thrombosis and bleeding, the coagulation disturbance in COVID-19 appears to be primarily thrombotic.26, 27, 28, 29

Because of these features, increased testing with thromboelastography has been explored to further characterize the prothrombotic effects of COVID-19.³⁸ The reported coagulation profile in this setting includes shortened clot times, increased maximum amplitude, and delayed clot lysis with a contact pathway initiator.³⁸ In addition to elevated fibrinogen and D-dimer levels, factor VIII and von Willebrand factor levels were also elevated, and antithrombin levels were mildly decreased to about 75% of normal.³⁸

These findings provide further evidence that the microvascular thrombosis in severely ill patients with COVID-19 is often not consistent with disseminated intravascular coagulation that may accompany severe sepsis.39, 40, 41 The clinical and laboratory evidence previously described suggest that the microvascular thrombosis in COVID-19 patients has many distinct differences that may also offer some clues about the mechanism of the disease process. The first observation is that it does not exhaust fibrinogen stores, which suggests that the normal hemostatic regulatory mechanisms can limit “runaway” coagulation activation.³⁸ The thrombosis that occurs in COVID-19 is probably the result of multiple foci of triggered coagulation. The second observation is that thrombocytopenia may not always be present, suggesting alternative drivers for this thrombotic disorder, including viral endothelial damage and marked complement activation.^{20 , 26 ,} 31, 32 ^{, 36}

Mechanisms beyond complement activation must also be considered for the thrombotic disorder in COVID-19. The elevated fibrinogen and factor VIII levels could also lead to thrombosis.³⁸ However, these proteins are both acute phase reactants, and therefore their elevated levels alone are unlikely to explain the differences in thrombosis between COVID-19 and other severe inflammatory states.⁴² The prothrombotic features of COVID-19 may also be triggered by damage-associated molecular patterns such as neutrophil extracellular traps.⁴³ These molecules contribute to disordered coagulation in inflammatory states through monocyte activation to link inflammation and thrombosis.^{41 , 43 , 44} Neutrophil extracellular traps have been observed in COVID-19 plasma and may offer not only an explanation for the thrombotic features of COVID-19 but also a therapeutic targer.45, 46, 47, 48

As the pandemic progresses, patients with COVID-19 may require cardiac surgery.1, 2 Given the importance of hemostasis in cardiac surgery and the disordered coagulation system in COVID-19, there may be important implications for the perioperative management of cardiac surgical patients. An important example of this is perioperative anticoagulation monitoring. Because factor VIII levels may at times be markedly elevated in COVID-19, this may lead to artificially lower clotting times in contact-dependent assays such as the activated clotting time and the partial thromboplastin time.⁴⁹ This resulting over-anticoagulation may precipitate bleeding complications. Adequate anticoagulation must, however, be maintained both for cardiopulmonary bypass and extracorporeal membrane oxygenation, given the risks of hypercoagulability in this setting.2, 3 ^{, 50 , 51} Disordered coagulation in COVID-19 is a key consideration that contributes to large and small vessel thrombosis. These thrombotic complications contribute to mortality and have unique features that require further investigation to advance clinical management.

Consider the Challenges With Blood Product Supply

The COVID-19 pandemic has precipitated an acute shortage of blood products, mostly from reduced blood donation due to social distancing.51, 52, 53 This has prompted a series of public awareness programs to restore blood donation in a safe and appropriately adapted fashion to maintain a national blood supply.51, 52, 53 Further attention to managing demand has also been advocated as an important strategy to navigate this crisis.⁵³ The measures that could ease demand include higher transfusion thresholds and multimodal guideline-driven perioperative blood management.54, 55, 56 These measures have been covered in detail elsewhere in the journal for adult and pediatric cardiothoracic and vascular practice.54, 55, 56 The priority through the pandemic is balance supply with demand in this space.

Conclusions

The hematologic response to COVID-19 significantly guides diagnosis and management in this challenging disease. The prothrombotic vascular milieu is likely multifactorial but should be considered in tailored patient management. A sustained focus on infection control and blood management remains essential.