Blood Clots Caused By SARS-CoV-2 Infections Poses A Threat For Fatal Vascular Events For Up To 49 Weeks After Diagnosis

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A British new study by researchers from the University of Bristol,  University of Cambridge, Swansea University, National Health Service Digital- Leeds, University College London, King’s College London, Glasgow Caledonian University, University of Leicester, University of Edinburgh and the British Heart Foundation Data Science Centre has found that blood clots caused by SARS-CoV-2 infections poses a threat for fatal vascular events for up to 49 weeks after diagnosis.

The study findings were published in the peer reviewed journal: Circulation (A Journal of the American Heart Association or AHA).

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.060785

In this cohort of 48 million adults, a markedly higher incidence of arterial thromboses in the first weeks after COVID-19 diagnosis, relative to no COVID-19 diagnosis, declined rapidly with time after diagnosis. The excess incidence of VTEs in the first weeks after COVID-19 diagnosis declined less rapidly than for arterial thromboses and was twofold higher for up to 49 weeks after COVID-19 diagnosis.

For both arterial thromboses and VTEs, relative incidence was higher, and remained elevated for longer, after hospitalized than nonhospitalized COVID-19. Associations between COVID-19 and thrombotic events did not vary markedly by age or sex, but were greater in people of Black or Asian race than those of White race, and in people without than with a history of vascular events.

We estimate that by December 2020, COVID-19 led to >10 500 additional arterial thromboses and VTEs in England and Wales.

Like other studies of vascular disease risk after COVID-19 infection, 4,7,8,16 this study found that incidence of arterial thromboses and VTEs was markedly elevated in the first 1 to 2 weeks after COVID-19 diagnosis and declined with time from diagnosis. Two self-controlled case series studies found that excluding cases of arterial thromboses or VTEs recorded on the first day of COVID-19 diagnosis attenuated the early relative incidence associated with COVID-19.4,7

This may have been attributable to ascertainment of COVID-19 at the time of hospitalization for a vascular event or to limited resolution of date coding of COVID-19 and vascular events in the same hospital admission.

Incidence of arterial thromboses and VTEs is also elevated after non–COVID-19 infections. In general, the relative increases in these events are greatest soon after infection and fall within a month toward baseline, although elevated incidence of VTEs may persist for longer. The mechanism for this may relate to persistence of a postinfection inflammatory response that predominantly affects the venous rather than arterial circulation, although whether this is predominantly driven by endothelial, leukocyte, or other components of inflammation is not clear.17

Relative increases after non–COVID-19 infections have been shown to be similar to this study’s estimates 2 weeks after COVID-19 diagnosis.18–21 Hospital admissions attributable to MI22 or stroke23 fell during the height of the COVID-19 pandemic in England and Wales, which suggests that increases in hospitalizations for arterial thromboses or VTEs after COVID-19 were small compared with the substantial reductions in diagnoses and health care use at that time.

The large number of COVID-19 infections in England and Wales during 2020 and 2021 is likely to have caused a substantial additional burden of arterial thromboses and VTEs. Strategies to prevent vascular events after COVID-19 will therefore be important at a population level. These will include early review in primary care, risk factor management, and ensuring adherence and preventative therapies in high-risk individuals.

However, during the pandemic, there have been substantial reductions in primary care contacts for a number of conditions, including cardiometabolic diseases. These reductions have limited the ability of primary health care professionals to provide routine health checks for people with chronic conditions.24,25 The pandemic also led to reductions in prescriptions of antihypertensives and lipid-lowering medication and many patients will have missed reviews of vascular risk modification after COVID-19 diagnosis.26

Randomized trials of short courses of antithrombotic interventions with a low risk of harm might be the next step to reduce longer-term risks after hospital discharge. Emerging evidence for this approach is promising,27 although its longer-term benefits are uncertain.

Observational studies suggest a protective effect of statins and blood pressure lowering against post–COVID-19 vascular events.28,29 The risks of arterial thromboses could be mitigated by review of known vascular risk factors soon after a COVID-19 diagnosis.

The excess incidence of thromboembolic events was higher in Black or Asian people than in White people. Black or Asian people have had higher rates of COVID-19 mortality, which appears to be related to geography, deprivation, occupation, household composition, living arrangements, and preexisting health conditions.30 Prepandemic differences in control of vascular risk factors between racial groups may also explain these findings.31

Our study has a number of strengths. We included almost all of the adult English and Welsh populations; therefore, the results reflect the total population effect of COVID-19 on the incidence of major vascular events, and are generalizable to other settings with comprehensive health care.

Linkage with primary care records and national COVID-19 testing data allowed us to study vascular diseases after both hospitalized and nonhospitalized COVID-19 and adjust for a wide range of potentially confounding factors. We used a widely agreed-on set of codes in electronic health records to identify arterial thromboses and VTEs recorded in the first position in hospital and death records. The protocol was prespecified and all code lists are available.

This study has several limitations. First, the survival analyses allowed for variations in diagnoses with calendar time, so should control for the reductions in hospital attendance during the period of maximum disruption (March and April 2020). However, some vascular events may not have been recorded either because patients died in nursing homes with few diagnostic resources or were so unwell that MI, stroke, PE, or DVT diagnoses would have been difficult to make.

Second, people may have avoided health care facilities after minor vascular events because of fear of COVID-19. If this was more likely in people without COVID-19, then estimated HRs would have been biased upwards.

Third, because the English primary care dataset did not include information on PE and DVT, the incidence of milder nonhospitalized VTEs may have been underestimated.

Fourth, we had limited resolution to determine the date order of COVID-19 diagnosis and arterial thromboses or VTEs for some hospitalized patients. Some patients hospitalized with a vascular event either developed a nosocomial infection or had a COVID-19 diagnosis after routine testing on admission. For some patients, a raised troponin level with COVID-19 may have led to a diagnosis of MI.31 Therefore, the very high HRs within 1 week of COVID-19 diagnosis may have been inflated by reverse causality.

Fifth, there was underascertainment of COVID-19 infection before testing for SARS-CoV-2 became widely available for mild or asymptomatic infections. Such underdiagnosis would bias estimated post–COVID-19 HRs toward the null.

Sixth, identification of exposures, covariates, and outcomes relies on the accuracy of data recorded in electronic health records during routine health care and we were unable to validate these against fuller health records.

Seventh, unmeasured confounding may explain some findings, because there is a substantial overlap between risk factors for vascular disease and COVID-19. Risk factors for vascular events (eg, body mass index) are not systematically recorded for all patients and are subject to measurement error.

The difference between maximally-adjusted and age-/sex-/region-adjusted HRs was more marked longer after COVID-19 diagnosis: the HRs for major arterial events >13 weeks (HR 1.3) after diagnosis could be attributable to unmeasured confounding. However, the higher HRs for VTEs after 13 weeks are less plausibly explained by unmeasured confounding and are consistent with the risk of VTEs after other infections.18

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