Abstract
Severe acute respiratory syndrome coronavirus 2 infection (COVID-19) is known to induce severe inflammation and activation of the coagulation system, resulting in a prothrombotic state. Although inflammatory conditions and organ-specific diseases have been shown to be strong determinants of morbidity and mortality in patients with COVID-19, it is unclear whether preexisting differences in coagulation impact the severity of COVID-19. African Americans have higher rates of COVID-19 infection and disease-related morbidity and mortality. Moreover, African Americans are known to be at a higher risk for thrombotic events due to both biological and socioeconomic factors. In this review, we explore whether differences in baseline coagulation status and medical management of coagulation play an important role in COVID-19 disease severity and contribute to racial disparity trends within COVID-19.
Keywords COVID-19, SARS-CoV-2, race, ethnicity, coagulation, anticoagulation, thrombosis
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) induces a prothrombotic state, resulting in the development of pathologic arterial and venous blood clots.1–4 Severe systemic inflammation often results in disturbances of hemostasis and coagulation. The systemic inflammation and dysregulated cytokine activity (often termed “cytokine storm”) associated with COVID-19 disease is likely a critical event in the development of COVID-19 coagulopathy.1,5 Patients with severe manifestations of COVID-19 often have elevated levels of D-dimer, fibrin-degradation products (FDPs) and fibrinogen, as well as low levels of antithrombin (AT). Many patients also have elevated concentrations of Factor VIII (FVIII) and von Willebrand factor (vWF).1,4 These findings are not unexpected, as many coagulation factors, including the ones listed above, are acute-phase proteins associated with the level of inflammation.6 As COVID-19 continues to spread throughout the United States, the African American community has been disproportionately affected.7 Coagulation status and predisposition to the development of coagulopathies varies between race and ethnicity, with African Americans trending toward a more prothrombotic state.8 Baseline differences in coagulation factors in conjunction with activation of the immune system and platelets likely contribute to the disproportionate impact of COVID-19 disease in African American patients.
The pathology of COVID-19 relies upon the coronavirus (CoV) spike protein (SP) binding to the angiotensin-converting enzyme 2 receptor (ACE2R), where it then undergoes proteolytic cleavage into spike protein 1 and 2 (SP1/SP2), resulting in successful host cell infection.9 Angiotensin-converting enzyme 2 receptors are expressed in a variety of tissues, including the lungs, various parts of the gastrointestinal (GI) tract, the heart, and brain/central nervous system. Accordingly, the primary presentations of COVID-19 in symptomatic patients include respiratory, cardiac, GI, and neurologic signs.10–12 The range of clinical findings in COVID-19 can span the gamut from asymptomatic to severe illness, requiring intensive care unit admission and mechanical ventilation. Additionally, the severity of disease has been linked to the presence of various comorbidities. Given the organ systems for which COVID-19 has tropism (via localization of the host cell receptor expression, ACE2R), patients with preexisting pulmonary and cardiovascular conditions are at increased risk. The risk is further heightened by the fact that many of these conditions, including congestive heart failure and chronic obstructive pulmonary disease (COPD), are associated with increased levels of ACE2R expression.13–16
Although robust basic and clinical studies have yet to be published, various case series reports, clinical observations, and theories have been proposed regarding the pathogenesis of COVID-19-related coagulopathies. Upon exposure to a viral pathogen, such as SARS-CoV-2, there are multiple potential mechanisms that can trigger coagulation pathways, including leukocyte activation, complement activation, systemic inflammation, and pathological changes of infected host cells, such as endotheliitis, which may result in cellular damage and apoptosis, which may then further active inflammation and coagulation.17–20 In addition to the conditions that render specific organ systems at risk, such as COPD and asthma, systemic diseases such as diabetes, obesity, autoimmune disorders, and cancer predispose patients to severe and rapid changes to their inflammatory system and, in many cases, also predispose a patient to being in a prothrombotic state.21–25 Individuals with these preexisting conditions, along with cardiopulmonary disease, appear to be at the highest risk for development of severe COVID-19 as well as higher mortality rate.13–16
Additionally, there is mounting evidence that a major pathological finding in severe COVID-19 is the development of macrothrombi and microthrombi. Multiple recent studies have demonstrated that there is pathological blood clot formation on a systemic level, including deep vein thrombosis (DVT), pulmonary embolisms (PE), pulmonary microthrombi, stroke, and even thrombus formation in the placenta.26–33 Systemic thrombosis has been noted to result in acute bowel ischemia, leading to the need for emergency surgery.34,35
COVID-19 Disease Trends
A growing body of literature describes the disproportionate effect of COVID-19-related morbidity and mortality in minority populations, particularly African Americans. According to a recent report from the Chicago area, greater than 50% of COVID-19 cases and 70% of COVID-19-related deaths have been observed in African Americans, although they make up only 30% of the study population.7 Similar trends have been noted in Louisiana, Michigan, and New York City.17–18 According to a Johns Hopkins University and America Community Survey, COVID-19 rates were 3 times higher, and the death rate was at least 6 times higher, in 131 predominantly African American counties compared to infection and death rates from 2879 predominantly white counties, 6 predominantly Asian counties, and 124 predominantly Hispanic counties.36,37 Health care disparities and socioeconomic status plays a major role in this increase in morbidity and mortality. However, to assume that these 2 factors explain the totality of the racial disparities in outcomes of COVID-19 runs the risk of missing important therapeutic avenues for reducing burden of illness in these vulnerable populations. Indeed, interrogating differences in comorbid conditions and baseline abnormalities of coagulation may provide critical inroads into mitigating the higher risk of adverse outcomes in minority racial groups such as African Americans. Recent studies have shown severe pulmonary and cardiac pathology, associated with increased thrombosis, is prevalent in African Americans with severe COVID-19.26,38 Although more research into this area is needed to draw any conclusions, researchers and clinicians are beginning to take notice of the possibility of differences in baseline coagulation status, in conjunction with other variations, as potentially playing a potential role in the severity of COVID-19.38,39
Coagulation Differences Related to Race or Ancestry
Variations in coagulation activity can be dichotomized into congenital and acquired. Congenital differences in coagulation status are due to genetic differences between individuals. Limited studies describe genetic variation in coagulopathies, although faster and cheaper sequencing tools have changed our understanding of this topic. There are many genetic causes of both excess bleeding (eg, hemophilia) and excess clotting. Although African Americans have been shown to have an increased risk of thrombosis as compared to Caucasians, most of the inherited mechanisms of thrombosis that have been studied are present primarily in Caucasian populations, such as FV Leiden, resulting in resistance to protein C, and prothrombin G20210A.8,40,41 In general, strong evidence supports a tendency toward a prothrombotic phenotype in African Americans. Although the mechanism is not yet fully understood, this evidence includes a combination of differences in measured coagulation biomarkers as well as observations in increased thrombotic events.42
African Americans exhibit a well-documented trend toward having higher baseline levels of coagulation FVIII, increased levels of vWF, increased thrombin generation, and elevated baseline levels of D-dimer (Figure 1).43–48 Factor VIII plays a role in the intrinsic coagulation pathway and is frequently elevated in patients with severe systemic inflammation, as it is a positive acute-phase protein. An increase in FVIII can create an exaggerated coagulation response upon activation of the cascade and has been suggested to be related to resistance to heparin in critically ill patients.49,50 An increase in FVIII has been observed in patients with severe COVID-19.4 Another biomarker D-dimer is released upon the breakdown of a cross-linked fibrin clot, resultant from endogenous activation of the fibrinolytic pathway. Increase in D-dimer is typically used as a marker of active thrombosis and fibrinolysis, such as for the exclusion of a PE, DVT, or stroke, in conjunction with other clinical tests, such as imaging.51 African American women, in particular, have a higher incidence of thrombosis along with a higher level of D-dimer.46,52 D-dimer has also been reported to be an important biomarker of serious COVID-19 and has been shown to correlate with poor prognosis.1–4 African Americans have at least a 30% higher prevalence of venous thromboembolism (VTE), which is suspected to be at least in part due to variations in thrombomodulin, although there is conflicting evidence on the specific mechanism.53,54 Thrombomodulin modulates thrombin and increases the activation of protein C. Limited studies have also identified decreased levels of circulating protein C and protein S, endogenous anticoagulants, in African Americans.55–57 However, some genetic studies identify potential single-nucleotide polymorphisms (SNPs) that may affect the level of circulating protein C in multiple groups, including increased levels of protein C in African Americans.58 While FV Leiden mutation, which results in activated protein C resistance, is a well-characterized mechanism of thrombosis in Caucasian populations, direct changes in protein C, protein S, and thrombomodulin have been found in some African Americans (as described above). African Americans also have increased levels of lipoprotein (a), which is known to play a role in the development of atherosclerosis and the predisposition to thrombosis due to its similarity to plasminogen, as well as through platelet activation.59,60 These findings support the need for further research in this area to fully understand the variations in baseline coagulation status, as they relate to the development of coagulopathies.
