Further research will soon generate standardised approach to VTE in COVID-19 patients


At VENOUS2021 (17–20 March, virtual), the annual meeting of the American Venous Forum, Geno Merli (Thomas Jefferson University Hospital, Philadelphia, USA) gave a keynote lecture on venous thromboembolism (VTE) in COVID-19 patients, detailing an “acute and extended” risk in this clinically vulnerable group. He outlined how research has developed so far, from initial findings on pathologic mechanism, to larger studies on the acute and post-discharge patient populations. Merli also detailed how the approach at his centre, Jefferson Health System, has progressed, as well as current society recommendations. “There are a number of approaches,” Merli concluded, stressing that the volume of available data is testament to how far understanding has come, and that the continuing research will soon yield a standardised method.

Providing an overview of initial research into VTE and COVID-19, Merli highlighted a series of studies revealing that D-dimer, creatinine elevation, IL-6, and high-sensitivity troponins “all contribute to a poor prognosis in the patient depending upon their levels”. In addition, the presenter outlined research showing that rising D-dimer levels predict mortality at 28 days, coagulopathy appears to be related to the severity of the illness and the resultant thromboinflammation that occurs, and an increasing D-dimer level after admission precedes multiorgan failure.

He first referenced a paper by Dawei Wang (Zhongnan Hospital of Wuhan University, Wuhan, China) and colleagues published in February 2020 in the Journal of the American Medical Association that looked at 138 hospitalised patients with COVID-19 and focused on factors that determined prognosis. “If we look at the D-dimer levels in survivors and non-survivors, we can see that days after the onset of the disease, the higher the D-dimer level, the poorer the survival in this patient population,” he relayed to the VENOUS2021 audience.

Wang et al’s paper also highlighted that, as creatinine elevates, mortality increases in both survivors and non-survivors, Merli reported, commenting that D-dimer and creatinine levels are two factors that “all of us have experienced” in the management of COVID-19 patients.

Also in February 2020, the Journal of Thrombosis and Haemostasis published research by Ning Tang (Huazhong University of Science and Technology, Wuhan, China) and colleagues looking at elevated D-dimers and fibrin degradation products in 183 consecutive patients. Merli summarised that both factors were associated with an increased mortality in this patient group.

Merli highlighted another paper, published the following month in The Lancet, in which Fei Zhou (Peking Union Medical College, Beijing, China) et al looked again at D-dimer, but also at IL-6, lactate dehydrogenase, and high-sensitivity troponins, in 191 patients. The presenter conveyed Zhou and colleagues’ main conclusion: “The non-survivors who had high levels of these four areas had a poor outcome with respect to mortality.”

Delving into the coagulopathy features of patients with COVID-19, Merli noted that Tang and colleagues looked at the D-dimer levels and also the sepsis-induced coagulopathy (SIC) score in their paper. “If the SIC score was greater than four,” Merli explained, “the heparin users had a 40% 28-day morality versus 64% in the non-users, and if you looked at D-dimer levels above a six-fold upper limit of normal, the results were 32% mortality in the patients getting heparin versus 52% in the non-heparin users”. He remarked: “This does not tell you how to treat the patient, it just tells you [D-dimer and SIC scores] are predicting mortality.”

Key meta-analyses provide crucial data on acute and post-discharge populations

Turning the audience’s attention to meta-analyses, Merli referenced the work of David Jiménez (Hospital Ramon y Cajal, Madrid, Spain) et al, published in March 2021 in Chest, addressing the bleeding incidence in patients with COVID-19. The investigators reviewed the data of 18,000 patients assessed in 47 studies, noting a 17% incidence of VTE, he relayed. “If you break it down into DVT [deep venous thrombosis] and PE [pulmonary embolism],” the presenter elaborated, “you can see a DVT rate of 21% compared to 7% for PE”. Major bleeding, “which we are most concerned about,” he added, was 3.9%. Merli noted that Jiménez also broke the results down further into setting, with the data showing that the intensive care unit (ICU) incidence of VTE was 27.9%, compared to an incidence on the ward of 7%.

Merli cited another meta-analysis by Rui Zhang (Peking Union Medical College, Beijing, China) et al, published in March 2021 in the Journal of Vascular Surgery: Venous and Lymphatic Disorders. This study also looked at the prevalence of VTE, specifically in 13 studies in the ICU and five, non-ICU. Zhang and colleagues reported a 31% incidence of VTE prevalence in the ICU population versus 7%. “When you break it down in by setting, ICU and non-ICU” Merli explained, “what you see is that the incidence of PE was 17% and 4% respectively, clearly showing that ICU obviously is a high-risk area and the patients are much sicker.” He added that the corresponding rates for DVT were 25% vs. 7%. “Looking at these numbers, you can see where the incidence is, and maybe how we have to prophylax this population based upon the severity of illness,” Merli remarked.

Finally, Merli outlined the findings of a registry of arterial and venous thromboembolic complications in COVID-19 patients by Gregory Piazza (Harvard Medical School, Boston, USA) et al, published in November 2020 in the Journal of the American College of Cardiology. “What I like about this registry is the fact that every single one of the events is adjudicated, and so we know these events actually happen,” he remarked. Piazza and colleagues reported that, in the symptomatic VTE group, the figures were 27% ICU and 2.2% non-ICU—numbers that Merli remarked look “pretty similar” to Zhang’s and Jiménez’s papers.

The presenter also detailed research into the post-discharge patient population. He cited in particular a study by Richard Salisbury (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) et al published in Blood Advances in December 2020. In this retrospective analysis, Salisbury looked at the rate of symptomatic VTE in 152 patients discharged without any indication for anticoagulation. At 42 days post discharge, the rate was 2.6%. “If you look more closely at Salisbury’s paper,” Merli noted, “at patients that were intubated, patients on non-invasive ventilation, and then patients on just oxygen alone, the data clearly show that patients who had been ventilated had a lower survival rate than those patients that were not”.

Risk stratification central to Jefferson Health System approach

Relaying his own approach and that of the wider team at the Jefferson Health System, Merli explained: “Patients who come into the ICU with a platelet count greater than 25,000 are looked at based upon their creatinine clearance, which we have established is an important factor in predicting outcome”. He specified that if a patient’s creatinine clearance is greater than 30ccs, they are prescribed intermittent pneumatic compression plus enoxaparin, noting that enoxaparin is dosed based upon the kilogram weight of the patient. “If a patient’s creatinine clearance is impaired,” Merli continued, “the team use unfractionated heparin, also dosing this based upon the weight of the patient”. The presenter noted that, in patients who have a platelet count less than 25,000, pneumatic compression sleeves without pharmacologic prophylaxis are used.

“We decided to increase prophylaxis based upon the renal function and also the weight of the patient,” the presenter informed the VENOUS2021 audience. He noted that the team added rivaroxaban as part of their management of this patient population once they are transferred to the wards.

Risk stratification is crucial to the approach at Jefferson Health System, Merli conveyed. In the patients going home, he specified that the team needed to risk-stratify based upon the IMPROVEDD VTE risk score and the IMRPROVE bleeding risk score. “We thought this was very important because we know that the symptomatic incidence is low,” he remarked, “and therefore we had better select the right patient population”. A patient with a high VTE risk but low bleeding risk, as well as a creatinine clearance of greater than 30ccs, will receive enoxaparin to take at home, he described. On the other hand, if a patient’s liver function tests are normal, the team then use 10mg of rivaroxaban once daily for the post-discharge management of this patient.

Finally, Merli detailed that patients at high risk of both VTE and bleeding need to have knee-high compression stockings. These patients are assessed upon signs and symptoms, secondary to a phone call that was done on day seven and day 30, and ambulation is encouraged, Merli communicated.

Variations in society recommendations highlight need for more data

Concluding his lecture, Merli outlined the recommendations of various organisations, including the American College of Chest physicians (ACCP), the International Society on Thrombosis and Haemostasis (ISTH), the National Institutes of Health (NIH), the Italian Society of Thrombosis and Haemostasis, and the Anticoagulation (AC) Forum. Detailing the guidelines of the ISTH, Merli explained that the society recommends intermediate dosing of low molecular weight heparin (LMWH) in this patient population if they are on ventilation, while in non-ventilated ICU patients “[the ISTH] were not very specific”. In the ward population, Merli said that the ISTH “did not specify particularly what the best approach would be”. For high-risk patients in the post-discharge population, the society recommends 14 days of LMWH versus a DOAC. The NIH, on the other hand, recommend standard dosing “across the board,” said Merli, and suggest prophylaxis in high-risk patients. “The AC Forum said intermediate dose for the ICU patients, standard prophylaxis for the ward population, and for patients who had prolonged illness or were in rehab, LMWH,” he added.

“You can see there are a number of approaches,” Merli summarised, noting that more studies are needed in order to reach standardisation.


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