麻豆传媒

Of COVID-19's hallmark symptoms, clotting may not rank high in the national consciousness. But it has made quite an impression in-hospital.

"I have never, ever, ever seen such high levels of D-dimer in any of the hundreds of other patients with venous thrombosis that I've seen over the past 15 years," said Behnood Bikdeli, MD, of NewYork-Presbyterian Hospital/Columbia University Irving Medical Center in New York City. "It's just mind-blowing."

Clinicians treating COVID-19 patients have described pervasive clots in the lungs on autopsy, breakthrough clotting clogging dialysis lines despite antithrombotic medication, and even for ischemic stroke.

"At this point, even though our knowledge is limited, what we know is highly suggestive of a prothrombotic milieu -- an excess of thrombotic events in the setting of COVID-19, specifically severe COVID-19," said Bikdeli.

Whether coagulopathy in COVID-19 is a of what's happening in the lungs remains unclear. However, consensus has formed on anticoagulation treatment for hospitalized patients and sending them home with an empiric regimen.

from Bikdeli's consensus group of the International Society on Thrombosis and Haemostasis (ISTH) and other professional societies recommended risk stratifying COVID-19 patients in the hospital for venous thromboembolism (VTE) prophylaxis using the normal risk tools, noting that once-daily dosing of unfractionated heparin gives it the leg up on other options for reducing personal protective equipment use and healthcare worker exposure.

Previously, ISTH had recommended prophylactic-dose low molecular weight heparin (LMWH) for all hospitalized COVID-19 patients, even those not in the ICU, unless they have contraindications such as active bleeding or low platelet count (<25×10⁹/L).

New guidance out last week from the National Institute for Public Health of the Netherlands, released in a report in Radiology, advocated prophylactic-dose LMWH with or suspected to have COVID-19, irrespective of risk scores.

"One of the big questions... is whether when we see such elevated D-dimer levels, do we have to empirically up our game and give more intense antithrombotic agents or do we have to routinely screen for deep vein thrombosis? There is no good answer at the moment," Bikdeli told 麻豆传媒.

Some centers are going ahead with full therapeutic dosing or intermediate doses, based on subgroup analysis from a single retrospective study from China suggesting high D-dimer predicted VTE with over 85% specificity and sensitivity.

"The majority of [consensus group] panel members consider prophylactic anticoagulation, although a minority consider intermediate-dose or therapeutic dose to be reasonable," Bikdeli's group .

The University of North Carolina at Chapel Hill is one such center that has been using intermediate or full-dose anticoagulation for COVID-19 patients, depending on their risk factors. Those with D-dimer over 2,500 ng/mL get an intermediate dose, and full dose is used for those with high suspicion of VTE without objective documentation possible or who have repetitive clotting of dialysis tubing.

The Dutch group proposed a more nuanced algorithm for anticoagulation dosing based on initial and rising D-dimer levels in hospital.

Elevated D-dimer levels, while common with COVID-19, do "not currently warrant routine investigation for acute VTE in absence of clinical manifestations or other supporting information," Bikdeli's group argued, although urging a high index of suspicion in case of typical deep vein thrombosis symptoms, hypoxemia disproportionate to known respiratory pathologies, or acute unexplained right ventricular dysfunction.

How long inflammation and after recovering from the symptoms of COVID-19 remains unclear as well.

Bikdeli's consensus group's recommendations advocated extended prophylaxis with LMWH or direct oral anticoagulants (DOACs) as reasonable after hospital discharge, with individualized risk stratification for thrombotic and hemorrhagic risk.

Up to 45 days of prophylaxis could be considered for low-bleeding-risk patients at elevated VTE risk due to reduced mobility or comorbidities such as active cancer. Elevated D-dimer more than twice the upper limit of normal was also suggested as a high-risk group to get post-discharge extended prophylaxis, although without full consensus from the writing group.

UNC's algorithm calls for 30 days of DOAC use after discharge with COVID-19. However, "our outpatient management in the algorithm is purely empiric and non-evidence based!" cautioned Stephan Moll, MD, who helped design the algorithm there.

Bikdeli agreed that the evidence isn't solid, which is why it had to be an international collaborative to form some interim consensus-based guidance rather than the standard guideline process. "It wasn't easy to address."

Still, "to some extent we can extrapolate to people with milder COVID-19 who are homebound or people who have multiple risk factors for venous thrombosis who are homebound," Bikdeli noted, acknowledging that the evidence was even scarcer for them.

For quarantined patients with mild COVID-19 but significant comorbidities or who are being less active because of quarantine, prophylaxis is uncertain, according to Bikdeli's group: "These patients should be advised to stay active at home. In the absence of high-quality data, pharmacological prophylaxis should be reserved for those highest risk patients, including those with limited mobility and history of prior VTE or active malignancy."

VTE can be challenging to diagnose for many reasons in hospitalized COVID-19 patients, particularly for those in prone positioning. It's likely underdiagnosed, Bikdeli and colleagues noted.

Research letters from France in Radiology recently reported that 23% to 30% of pulmonary CT angiograms performed for COVID-19 patients showed acute pulmonary embolus (PE) -- much higher than the 1.3% typical for critically ill patients without COVID-19 infection or 3% to 10% seen in emergency department patients. Notably, and 67% specificity for PE on CT angiography. Patients with PE were .

Longer-term outcomes for such patients, incidence of events during recovery outside the hospital, and other important questions haven't been looked at yet, Bikdeli noted.

"We are currently in a war zone," he said, so it's hard to follow-up patients longitudinally. "It's a critically important part of the care, but just because of the priorities, many of the cardiology and critical care-trained people in institutions across the country are being asked to take care of those priorities in critically ill patients. But addressing the thrombotic events in the inpatient and outpatient setting are similarly important."

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