The COVID-clot connection

A review of thrombotic complications with COVID-19

by ,

Thrombotic complications, including venous thromboembolism (VTE), myocardial infarction and central catheter or device occlusion, are recognized causes of morbidity and mortality in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Though data collected during this period were extremely variable due to heterogeneity of study methods, including screening methods, ability to obtain confirmatory images and inconsistent use of thromboprophylaxis, studies from the early phases of the COVID-19 pandemic supported that there was an increased rate of thrombosis in patients with COVID-19 illness.

Early data

For example, initial data from the first three months of the recognized outbreak in Wuhan, China, demonstrated a 25% incidence of VTE in patients with COVID-19,1 whereas a retrospective multi-center study of patients hospitalized in the United States through April 2020 demonstrated a VTE rate of 4.8% (95% confidence interval [CI], 2.9–7.3) and a thrombotic complication rate of 9.5% (95% CI, 6.8–12.8%).2

As the pandemic continued, there remained an increased risk of thrombosis in all patients admitted with COVID-19, and it became clear that a large part of this clinical incidence was due to a particularly high rate of VTE in patients with critical illness. Data from Netherlands showed a thrombotic incidence of 49% (95% CI, 41–57%) despite thromboprophylaxis, of which 87% were pulmonary embolism.3 Further, a meta-analysis of 86 studies and over 28,000 patients through August 2020 found VTE rates of 22.7% (95% CI, 18.1–27.6) in patients in the intensive care unit (ICU); patients that were not admitted to the ICU had a VTE rate of 7.9% (95% CI, 5.1-11.2).4 Additionally, historical VTE rates in patients that did not have COVID-19 that were admitted to the ICU was 5–15%.4 Reported VTE rates remained high during the latter part of 2020 despite reduced mortality.5 Furthermore, it became better appreciated that in addition to thrombosis, bleeding incidence was also higher in patients with COVID-19. One study demonstrated bleeding rates of 4.8% (95% CI, 2.9–7.3), including major bleeding rates of 2.3% (95% CI, 1.0–4.2) overall, and 5.6% (95% CI, 2.4–10.7) in patients with critical COVID-19 illness.2

Further studies

Prompted by high rates of thrombosis and bleeding, the concept of COVID-19-associated coagulopathy (CAC) emerged. Studies also sought to determine predictors of complications, and most consistently showed D-dimer as a marker of worsening disease and poor outcomes6 including coagulation-associated complications during hospitalization,2 thrombosis,2, 4 bleeding, critical illness and death.2, 7, 8 While the CAC is multifactorial and complex, two prevailing theories exist on the drivers of CAC. First, thromboinflammation, in which the viral infection initiates inflammation that leads to production of cytokines (including IL-6), neutrophil extracellular traps and polyphosphates that induce a prothrombotic state; further, tissue injury and disruption of the normally antithrombotic endothelium adds to this prothrombotic state.9 Second, evidence suggests that COVID-19 infection leads to a hypofibrinolytic state, in which dysregulated fibrinolysis leads to reduced clot dissolution, again shifting the hemostatic balance towards thrombosis. This dysregulated fibrinolysis also contributes to acute respiratory distress syndrome, one of the leading causes of morbidity and mortality in COVID-19. Notably, the CAC is distinct from disseminated intravascular coagulation, though patients with very severe COVID-19 illness can be affected by disseminated intravascular coagulation.

In response to early data of high rates of thrombotic complications and observed CAC, randomized trials of antithrombotic strategies in COVID-19 were conducted. To date, three completed randomized trials compared the intensity of anticoagulation (therapeutic versus prophylactic) for patients hospitalized with COVID-19. The pooled data demonstrated that escalating to therapeutic intensity was not efficacious in patients with critical COVID-19 illness, for which prophylactic dose anticoagulation remains standard,10 and therapeutic dose had a higher efficacy than prophylactics in increasing organ support-free days for patients with moderate illness, without significantly affecting  thrombotic rate or survival to hospital discharge.11 The use of thromboprophylaxis has not been shown to be beneficial in outpatients with COVID-19.12

Emerging guidance

Based on available data, professional societies have published guidance on thromboprophylaxis for patients hospitalized with COVID-19.13-16 Consensus from both American Society of Hematology (ASH) and Chest guidelines recommend prophylactic over intermediate or therapeutic anticoagulation for patients with critical COVID-19 illness, and therapeutic over prophylactic anticoagulation for hospitalized patients that did not have critical illness.14, 15 These guidance statements were based on available evidence at the time of publication, and in the case of the ASH guidelines, are to be updated as more data emerge. Additional ongoing studies include those investigating the role of post-discharge thromboprophylaxis, as well as other antithrombotic therapies.

The IR impact

Early in the pandemic, there was concern amongst the endovascular community that the increase in thrombosis events would lead to a commensurate increase in procedures to address these events. Procedures that were anticipated to increase included deep venous and pulmonary arterial thrombectomy, and the need for a greater number of inferior vena cava filters. However, there have been no large or medium sized series of such patients reported thus far. A review of the literature finds numerous case reports of catastrophic thrombosis, including cerebral venous thrombosis, splanchnic venous thrombosis and more typical deep venous thrombosis and pulmonary embolism. Thus far, these thrombotic events seem to anecdotally occur, however, there is not a clear, discernable trend of increased risk of these entities that would benefit from endovascular intervention. Despite the lack of procedures specifically for COVID-19 related thrombosis, however, interventional radiology (IR) has seen a shift in other procedures performed during the pandemic. The large number of patients with critical illness, particularly during surges, has necessitated IR resources for procedures that are needed to support such patients, including central venous access, percutaneous cholecystostomy and gastrostomy tube placement.17 Further, there have been shifts in outpatient IR procedures, particularly in the early stages of the pandemic, where there was a focus on saving resources and limiting unnecessary exposure aside for urgent and/or emergent procedures.18

Vaccine-associated thrombosis

One other issue that has arisen in the midst of the COVID-19 pandemic is vaccine-associated thrombosis. One rare syndrome, termed vaccine-induced immune thrombotic thrombocytopenia has been reported with ChadOx1 nCoV-19/AZD1222 (AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson), with an estimated incidence of about 3.8 cases per 1 million doses.19 The syndrome presents with thrombosis at unusual sites, including within splanchnic and cerebral sinus veins, in the setting of thrombocytopenia. It typically presents approximately 2 weeks after vaccination and is due to autoantibodies directed against the platelet factor 4 antigen. While data are limited, one study reported data which did not demonstrate increase in deep venous thrombosis development following COVID-19 vaccination.

Conclusion

In conclusion, COVID-19 coagulopathy is multifactorial, and manifests as increased rates of thrombotic complications for patients hospitalized with COVID-19, driven by particularly high rates of thrombotic complications in the ICU, as well as an increased risk of bleeding. Management currently involves antithrombotic therapy for those hospitalized for COVID-19, with selected interventions performed for patient support or in line with prior guidelines for a specific pathology. Studies are ongoing to optimize treatment and improve outcomes for patients with COVID-19.

References

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