No aspect of SARS-CoV-2 infection has been more startling – or problematic – than the elevated risk for blood clotting, a concern that throughout the pandemic has been associated with severe COVID-19, frequently characterized by clotting events that have led to stroke, heart attack and organ damage.
But a team of medical scientists from a dozen institutions throughout the United States has made two key treatment-altering findings: Patients with moderate disease can also develop life-threatening clots, and need to be identified early and treated.
The same team of medical investigators has pinpointed the most effective way to address the clotting problem, a finding that may have ramifications worldwide in the treatment of COVID-19 and its impact on the blood.
Dr. Alex Spyropoulos, a professor at the Feinstein Institutes for Medical Research in Manhasset New York, found that moderately ill patients hospitalized after a COVID diagnosis and who had elevated blood levels of a protein known as d-dimer, were at especially high risk for dangerous clots.
Spyropoulos, principal investigator of the study discovered along with his team, that treating these patients with a high-dose of the blood thinner called low-molecular weight heparin (LMWH) significantly reduced the potential for clot formation and death.
The medication is readily available worldwide and is a cost-effective way to prevent clots and spare lives, the research found.
The results are expected to be practice-changing, affecting the way clinicians identify and treat hospitalized COVID patients – potentially reversing the course of the disease and increasing survival.
Reporting in JAMA Internal Medicine, Spyropoulos and colleagues sound a powerful note of caution–and hope–from the clinical study titled the HEP-COVID trial: Just because patients are hospitalized with moderate COVID symptoms doesn’t mean they’re at lower risk of life-threatening COVID-related blood clots.
“The HEP-COVID trial was able to identify an exquisite biomarker – very elevated d-dimer – that not only predicted a high risk COVID-19 inpatient population, but those whose risk was ameliorated by early use of therapeutic heparin anticoagulation for thromboprophylaxis,” Spyropoulos told Medical Xpress, referring to clot prevention.
D-dimer is a degradation product of fibrin, which is intimately involved in blood clotting. Fibrin is formed through the action of the protease thrombin on fibrinogen, which causes it to create a polymer. The polymerized fibrin combines with the tiny cells known as platelets and other cellular debris to form a clot.
As a breakdown product, d-dimer is a small protein fragment in the blood after a clot has undergone enzymatic attack through fibrinolysis, a process that attempts to prevent clots from growing. The dimer gets its name, meanwhile, because, chemically, it has two ‘D’ fragments of the fibrin protein. The amount of d-dimer present in the blood can be determined by a blood test to help diagnose clots.
Thrombosis refers to clot formation, obstructions that have been a pernicious cause of disability and death throughout the pandemic. For example, venous thromboembolism, or VTE, refers to clots that develop in a vein, such as in deep vein thrombosis.
Pulmonary embolism refers to a clot that may travel to the lungs, and arterial thromboembolism, or ATE, describes clots that can cause ischemic stroke or myocardial infarction – heart attacks. All have been common among adults hospitalized because of COVID.
“The virus can directly damage the endothelium causing endothelialitis, an immune response within the endothelium in blood vessels, as well as the host response, which in susceptible individuals, is manifested by a hyperinflammatory response and cytokine storm, activating the clotting system as well as platelets,” Spyropoulos said. Platelets are the tiny sticky disks that circulate in the blood and help the body form clots.
They’re a welcome population of cells when plugging a wound – but potentially lethal when coalescing with other factors in the blood to form clots.
The HEP-COVID randomized clinical trial recruited 253 hospitalized adult COVID patients with d-dimer levels more than four times the upper limit of normal. Patients also were recruited into the trial with a diagnosis of excessive clotting induced by sepsis. Patients were studied from May 8, 2020 through May 14, 2021 at 12 academic centers throughout the United States.
Major thromboembolism and death in patients was 28.7 percent for those given a therapeutic-dose of low-molecular-weight heparin, which again, is a high dose measuring four times the current standard of care. Major thromboembolism and death were 41.9 percent for patients receiving standard of care doses, or intermediate-dose heparins, the study found.
“The current standard has been [around] for the past 30 years or so in hospitalized medical patients – including those with pneumonia and sepsis,” said Spyropoulos, who worked with an additional international team in an arm of the study reported in the journal Thrombosis Research.
The treatment benefit from low-molecular-weight-heparin therapy was not seen in patients who were critically ill requiring ICU care, a discovery during the research that Spyropoulos said can be understood within the context of the findings. “They were too far advanced in their hyperinflammatory/cytokine storm/coagulopathic state to see any treatment effects by simply increasing heparin dosing.”
Regarding the data published in JAMA Internal Medicine, he noted that “HEP-COVID now presents compelling data that we should, in high-risk hospitalized patients with elevated d-dimers, use therapeutic doses of heparins to prevent clots. This is a major change in hospital guidelines.”
Anticoagulation was associated with improved survival of hospitalized coronavirus disease 2019 (COVID-19) patients in large-scale studies. Yet, the development of COVID-19-associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low-molecular-weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence.
In this observational multicentre investigation of 586 patients hospitalized for COVID-19 in Austria, we were able to show that the use of LMWH was associated with curtailed viral persistence in COVID-19 leading to a reduction of virus shedding of 4 days. LMWH use war further associated with increased survival and diminished circulating markers of cell death, while no differences in biomarkers of CAC development and thromboinflammation were observed between LMWH users and non-users.
Coagulation and the development of a hypercoagulable state play a central role in COVID-19 pathophysiology.3,13–17 In fact, CAC as depicted by D-dimer increase during hospitalization majorly evolved in patients requiring ICU and in non-survivors.
While the mechanisms leading to CAC are a matter of ongoing investigations, increased D-dimer levels were postulated as a surrogate marker for presence of CAC, development of thrombotic complications, and ultimately as a predictor of mortality in COVID-194,18 As previously reported, analysis of D-dimer and other haemostatic biomarkers revealed that these markers are of limited prognostic value for prediction of mortality in COVID-19.19 This indicates that more specific biomarkers are necessary to reliably predict patient outcome.
Thromboinflammation represents a central link between systemic hypercoagulability, respiratory failure, and mortality in COVID-19 patients, and NETs are frequently observed in CAC20,21 Investigation of post-mortem biopsies in COVID-19 patients showed occluding thrombi positive for citrullinated histone 3 as a specific marker for NETs not only in pulmonary tissue but also in kidney and cardiac tissue.20
In the present study, increased circulating markers of NET formation were observed in patients with higher COVID-19 disease severity at admission, which was paralleled by increased D-dimer levels, indicating that thromboinflammation might be a potential determinant of disease severity, as previously suggested.21
However, patients in the ICU and in the non-survivor sub-groups showed increased levels of H3Cit-DNA in circulation throughout the entire hospitalization. To our knowledge, this study is the first to assess markers of NET formation in a longitudinal approach, while previous studies focused on only one time point during disease onset.
Intriguingly, we observed a general decrease in H3Cit-DNA regardless of outcome. This finding stands in clear contrast to the observed increase in D-dimer in patients requiring ICU treatment and non-survivors, suggesting a minor role of NET formation in CAC development or in later phases of COVID-19. In fact, there was no direct correlation of H3Cit-DNA and D-dimer in our study. Accordingly, while a role of NETs in COVID-19 pathophysiology could be validated, the contribution of thromboinflammation to CAC has to be questioned.
Importantly, we found that anticoagulation was associated with improved survival upon multivariable Cox regression analysis including age, cardiovascular diseases, chronic renal insufficiency, and concomitant treatment with other drugs affecting the course of COVID-19 as potential confounders, as well as in all evaluated sub-groups.
This finding is in line with previous observational studies in COVID-19 patients, showing comparable effects of prophylactic and therapeutic anticoagulation on survival of COVID-19 patients.6,7,17 The use of anticoagulation and LMWH in particular entered the guidelines for treatment of COVID-19 in July 2020. Accordingly, we observed an increase in probability of LMWH use throughout the study period (Supplementary material online, Figure S5).
Importantly, we could not evaluate an influence of the inclusion time point on the association of LMWH and improved survival, even though the biggest proportion of patients in the no-LMWH sub-group was included in the beginning of the study period. Intriguingly, in our cohort, anticoagulation with either LMWH or NOAC was not associated with altered dynamics of D-dimer indicating a minor effect of LMWH on CAC development.
Alternatively, D-dimer levels in patients who received LMWH could be suppressed to levels observed in patients who did not receive LMWH, which was previously suggested by Blasi et al.9 Nonetheless, the observations made in this longitudinal approach do not allow to link improved CAC or altered haemostasis in LMWH treated COVID-19 patients to the observed improved survival. Accordingly, we aimed for investigation of potential off target effects of anticoagulation. We observed a decrease in the cell death marker cfDNA in patients using LMWH and NOAC during hospitalization.
This is of specific interest, as an increase in cfDNA was only observed in non-survivors. Noticeably, a correlation of cfDNA and D-dimer could already be observed at baseline, potentially linking cell death to haemostatic derangements. Yet, these findings have to be interpreted with caution due to the observational character and the low number of patients not receiving anticoagulation in this evaluated sub-group. Nonetheless, our data are suggestive for a potential protective role of anticoagulants in COVID-19 beyond haemostasis.
In this context, direct factor Xa inhibitors and heparin were shown to reduce oxidative stress and to yield anti-inflammatory properties, thereby potentially altering the inflammatory environment in vivo and affecting cell death in COVID-19.22,23 Preservation of vascular integrity via inhibition of endothelial cell heparinase or impairment of hepcidin formation and concomitant reduction of hyperferritinaemia might be other potential mechanisms by which LMWH exerts its beneficial effects.24,25
Importantly, we observed curtailed SARS-CoV-2 viral persistence upon qPCR in patients treated with LMWH, when compared to patients without anticoagulation or those using NOAC. These data provide exploratory clinical evidence compatible with a direct effect of LMWH on virus pathology, which was previously suggested in in vitro studies, where heparin was found to interfere with SARS-CoV-2 binding on ACE2 expressing cells, thereby limiting its infectivity.26
The effect on viral persistence was specific for LMWH in our analyses and increased odds for curtailed SARS-CoV-2 infection culminated in a median 4-day reduction of viral shedding. While direct interaction of LMWH with SARS-CoV-2 binding is one potential mechanism explaining the observed viral dynamics,27 the underlying study design does not allow to evaluate the exact pathomechanism responsible for these observations.
Notably, our study has certain limitations. In particular, the retrospective character of the study only allows to hypothesize a potential interaction of LMWH with SARS-CoV-2 which diminishes viral persistence. This limitation is further important for the interpretation of survival analyses, as the retrospective study design is associated with a notable amount of missing data. Accordingly, interventional studies are necessary to establish causality.
In the light of the ongoing clinical trials, we aim to raise awareness for these potentially beneficial off-target effects of anticoagulants and encourage further research within this area. Moreover, we did not analyse effects of different doses of LMWH in our cohort, as only nine patients (2.2% of LMWH-treated patients) received therapeutic doses of LMWH and the statistical power for the respective analyses was not sufficient.
Of note, previous reports were not able to assess a difference between prophylactic and therapeutic uses of LMWH in more than 4,000 patients.6 Further, recent data from interventional studies comparing therapeutic doses of LMWH to standard of care thromboprophylaxis showed a beneficial effect of high-dose treatments on hospital survival in non-critically ill patients, while critically ill patients did not benefit from these schemes.28,29
However, we cannot rule out that a difference in LMWH dosage might affect the data obtained for SARS-CoV-2 viral persistence in the present study. Ultimately, we want to point out that patients using NOAC were underrepresented in our cohorts, which renders the findings for this sub-cohort explorative and hypothesis generating. While we tried to take various possible confounders, for example comorbidities and age, into account, we cannot exclude that our data only reflect the situation in Austria and the virus mutations present.
Taken together, the present investigation confirms an association of anticoagulants with improved survival of COVID-19 patients in a large Central European Multicentre Cohort and suggests a beneficial effect of LMWH use on SARS-CoV-2 viral persistence.
While the exact pathomechanisms underlying these observations cannot be investigated due to the retrospective observational study design, the present study encourages the evaluation of viral persistence in randomized controlled trials assessing the effect of LMWH in COVID-19 patients in order to establish a causal relation of the presented findings. Limiting viral persistence, thereby shortening hospitalization and contagiousness is a relevant aspect during this pandemic.
reference link : https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvab308/6381563
More information: Alex C. Spyropoulos et al, Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19The HEP-COVID Randomized Clinical Trial JAMA Internal Medicine (2021) DOI: 10.1001/jamainternmed.2021.6203