Coagulation Dysregulation

Presentation and Early Data

Early data from Wuhan showed an 11.5% mortality rate among 183 COVID-19 patients with pneumonia, who had a median age of 54.1 years.¹ The analysis revealed that those with higher D-dimer and fibrin degradation product (FDP) levels, longer prothrombin time, and longer activated partial thromboplastin time (aPTT) were less likely to survive (p<0.05).

Another Wuhan study in February showed that of 138 hospitalized patients with COVID-19, levels of D-dimer were higher among nonsurvivors compared with survivors.² “This was the beginning of the realization that there was unregulated coagulation taking place in some COVID-19 patients,” said Dr. Lillicrap. “Since then, our knowledge has continued to rapidly evolve, but we don’t know everything about this clinical condition yet.”

In April 2020, a study out of the Netherlands showed that, of 184 patients in intensive care units (ICUs) with COVID-19 pneumonia, 31% had thrombotic complications, which the authors called “remarkably high.”³ Another study published in April showed that D-dimers were also elevated among patients hospitalized in the New York City area.⁴

“There are several hematologic manifestations of COVID-19. In addition to low absolute lymphocyte count in most symptomatic patients with COVID-19, coagulation abnormalities are very common in COVID-19 patients with pneumonia,” said Nathan Connell, MD, MPH, Clinical Section Chief of Hematology at Brigham and Women’s Faulkner Hospital and Assistant Professor of Medicine at Harvard Medical School in Boston.

According to Dr. Lillicrap, “These patients are more prone to pulmonary embolism, although there are also reports of peripheral venous thromboembolism (VTE) and even arterial thrombosis.”

Nigel Key, MBChB, FRCP, Professor of Medicine and Pathology at the University of North Carolina (UNC) School of Medicine and Director of the UNC Hemophilia and Thrombosis Center, agreed. “The published studies so far suggest that the more profound the COVID-19 infection, the more likely that thrombotic events will occur, but that every patient who is infected with COVID-19 is likely somewhere on the [thrombosis] spectrum,” he added.

Drs. Key, Connell, and Lillicrap all recommend that patients with COVID-19 who come into the hospital receive a complete blood count and coagulation factor lab tests – as well as imaging if a clot is suspected.

“We are looking at the combination of clinical symptoms and lab results to guide imaging and treatment decisions for each patient,” said Dr. Connell. “If someone has abnormal lab results and a swollen or painful leg, for example, that might be a deep vein thrombosis. In someone who has hypoxia, that could be a suspected pulmonary embolism.”

Unique Features of COVID-19-Associated Coagulopathy

COVID-19 coagulation dysregulation has some commonalities with DIC but also some unique features, the experts noted. “This is not the traditional coagulopathy that hematologists tend to associate with bleeding,” Dr. Connell said.

Both DIC and COVID-19-associated coagulopathy are accompanied by a prolonged prothrombin time (PT) and elevated levels of D-dimer. However, patients with DIC typically have low fibrinogen levels reflective of the consumption of coagulation proteins, but with COVID-19-related coagulopathy, fibrinogen levels are often elevated, according to Dr. Key.

The abnormalities in the coagulation system may be a combination of the viral infection and the body’s innate immune response to it, the clinicians who spoke with ASH Clinical News added.

“Why this is occurring is not entirely clear, but the pathophysiology may well involve hyperactivation of the pulmonary endothelium, which expresses the ACE2 inhibitors that the coronavirus uses for cell entry,” said Dr. Lillicrap.

He cited the hypercoagulable state as one component of a dysregulated system. Patients with severe COVID-19 disease admitted to ICUs have had high plasma levels of proinflammatory cytokines, including interleukin-2, -6, -7, -8 and -10, granulocyte colony-stimulating factor, tumor necrosis factor-α, and others, according to a study out of Wuhan.⁶

“The cytokine response can go into overdrive in patients with COVID-19, resulting in a cytokine storm,” Dr. Lillicrap added. “What we are seeing in parallel is an overreaction of the coagulation system, a procoagulant hyperresponse resulting in thrombotic disease in the lungs and elsewhere.”

“Is the coagulopathy a result of an overzealous reaction by the immune system?” posed Dr. Connell. “We don’t know yet, but there is some precedent for this, including the 2009 H1N1 influenza A virus pandemic in which some patients developed hemophagocytic lymphohistiocytosis,” he said. “With COVID-19, we are seeing a thrombotic manifestation instead, but both conditions are likely related to an inflammatory immune response.”

Anticoagulation Options

The same researchers in Wuhan that published the initial observations that patients with severe COVID-19 often had evidence of coagulopathy also found, in May 2020, that use of anticoagulant therapy during hospitalization – in the form of low-molecular-weight heparin (LMWH) – appeared to be associated with better outcomes among 449 severe COVID-19 patients with markedly elevated D-dimer levels.⁵ The 28-day mortality of 99 patients who received LMWH was lower than that of the 350 patients who did not.

“The still-preliminary evidence is growing that giving anticoagulants, heparin in particular, may help patients with COVID-19 survive,” said Dr. Lillicrap.

To stay connected and informed, clinicians are taking to social media, including Twitter, and medical forums to discuss and debate therapy options for patients.

Clinical trials to test treatments for COVID-19-associated coagulopathy are underway but, until the results are in, there are two main opinions for how to use anticoagulation therapy for COVID-19 patients, says Dr. Key. “The first is to do what is usually done with sick patients in the hospital: use anticoagulation as VTE prophylaxis without going overboard on the dose. The second is to believe that there is something fundamentally different about these patients with COVID-19 and that the higher rates of coagulopathy warrant higher anticoagulation doses.”

According to Dr. Key, the rationale for using a higher anticoagulation dose is the emerging evidence of microvascular thrombosis among patients with COVID-19, which can affect the lungs, kidney, and potentially the heart. “This is all unfolding very quickly, and we don’t know the best way to treat the coagulopathy in these patients,” noted Dr. Key.

Drs. Key, Lillicrap, and Connell agree that patients with COVID-19, if hospitalized, should receive at least a prophylactic dose of anticoagulation in the form of either LMWH or unfractionated heparin. Increasing D-dimer levels, fibrinogen levels, and aPTT are indicators of progressing severity that likely requires increasingly aggressive treatment and care, the experts concurred.

Dr. Connell warned of potential confusion caused by the May study from Wuhan that showed anticoagulation was associated with improved survival in patients with severe COVID-19. “Many people are using those data to support use of a therapeutic, larger dose of anticoagulation in these patients,” he said, but prophylactic anticoagulation therapy is not routinely provided in hospitals in China, where the study was conducted. Only the most severely ill patients received prophylactic anticoagulation in the study, while in the U.S. and Europe, anticoagulation prophylaxis is standard of care in the hospital.

“So far, I think the hematology community is in agreement that you need some form of anticoagulant for prophylaxis in hospitalized COVID-19 patients,” Dr. Connell told ASH Clinical News. “At our hospital,” he added, “we make sure that every patient is receiving prophylactic doses of anticoagulation, either LMWH or unfractionated heparin as appropriate, to prevent VTE.”

Dr. Key agreed. “There’s currently an important debate about the anticoagulation dosing intensity that is sufficient and necessary and the risk-benefit ratio of aggressive prophylactic anticoagulation,” he said. “The downside to too much anticoagulation is bleeding risk. Patients with this coagulopathy do not appear to have an extraordinarily high bleeding risk, but anyone can bleed when on anticoagulation therapy.”

The American Society of Hematology (ASH) is in the process of developing clinical practice guidelines on the use of anticoagulation in patients with COVID-19. The recommendations for clinicians will be rapidly developed based on available evidence, including indirect evidence from non-COVID-19 patients and early reports from observational studies. ASH expects to incorporate data from clinical trials as they are reported. In addition, the ASH Research Collaborative’s Data Hub recently launched a COVID-19 Registry for Hematology, a global registry with clinical data on people with COVID-19 and a current or past diagnosis of a hematologic disease. Editor’s note: Learn more about the COVID-19 Registry for Hematology or submit a case here.

Rapidly Evolving Knowledge

Whether there are risk factors other than severe disease for developing COVID-19-related coagulopathy is still unclear. “This was identified only 2 months ago, so we just don’t know yet,” said Dr. Lillicrap. “So far, the patients who develop this coagulopathy tend to be males and to have a pre-existing condition, such as hypertension or chronic lung disease, and a high body mass index.”

Dr. Connell noted that he and his colleagues Brigham and Women’s Hospital and other institutions are conducting retrospective analyses to determine whether there are certain factors that are associated with blood clotting in COVID-19. “Anyone that has previously had a thrombosis is at higher risk,” he said, “but whether the clotting is due to the virus or severity of the disease is still being teased apart.”

Prospective clinical trials are underway to understand the most effective VTE prophylaxis dosing necessary to prevent thrombosis, all three experts told ASH Clinical News. There are at least 10 clinical trials in the U.S., Canada, and Europe posted to ClinicalTrials.gov assessing whether various doses of heparin and other anticoagulants can prevent coagulation complications and death among patients infected with COVID-19. One such trial at St. Michael’s Hospital in Toronto, Canada, led by Michelle Sholzberg, MD, in partnership with the University of Vermont Medical Center, is comparing therapeutic doses of anticoagulation (either LMWH or unfractionated heparin) with the standard-of-care thromboprophylactic doses of anticoagulant as part of a two-arm, randomized, open-label trial.⁷

“We’ve started to see the importance of adherence to institutional protocols for VTE prophylaxis,” Dr. Connell noted.

While most clinical trials are testing doses of heparin or LMWH, there is also interest in alternative agents including fibrinolytic therapy, antiplatelet therapies, and agents that interfere with the high von Willebrand factor levels seen in these patients, noted Dr. Lillicrap.

“It will also be important to understand how patients with hematologic malignancies who have a dysregulated immune system do if they develop COVID-19,” said Dr. Connell.

All three experts noted that there are emerging lessons to apply to future widespread viral illnesses.

According to Dr. Lillicrap, a major focus should be on research to understand the biology of viral and other infectious agents.

“Every viral infection is different,” noted Dr. Connell, “so it’s hard to say whether everything we learn about one infection is going to apply to future infections, but this pandemic has shown us areas in the health-care system infrastructure that need to be improved.” For instance, he noted, many patients on warfarin therapy require periodic lab monitoring of their clotting time, yet many labs are turning away patients that could potentially have COVID-19.

Above all, Dr. Key stressed, “this situation is a day-to-day and week-to-week evolution of knowledge.” —By Anna Azvolinsky