Abnormal Clotting and COVID-19

Author: Gina Shaw

Anesthesiology News

Abnormal clotting, apparently resulting from endothelial damage, has been described in patients with severe COVID-19 disease, and Chinese clinicians recommend initiating prompt anticoagulation therapy in all severe COVID-19 patients.

Bin Cao, MD, with the National Clinical Research Center for Respiratory Diseases in Beijing, described “clots in the small vessels of all organs, not only the lungs but also including the heart, the liver, and the kidney,” in a March 19 webinar on the disease cosponsored by the Chinese Cardiovascular Association and the American College of Cardiology.

High D-dimer levels seen in these patients, Dr. Cao said, point to abnormal coagulation throughout the body. ”The virus can bind to the endothelial cells and may cause damage to the blood vessel, especially the microcirculation of the small blood vessels.”

In a March 11 paper in Lancet involving 191 COVID-19 patients in Wuhan, Dr. Cao and colleagues reported that D-dimer levels over 1 mcg/L at admission predicted an 18-fold increase in the odds of death before discharge (Lancet 2020;395[10229]:1054-1062).

However, American clinicians advised caution in interpreting these data. “Elevation of D-dimers may be a VTE [venous thromboembolism] risk signal to consider,” said William Dager, PharmD, BCPS, a pharmacist specialist at UC Davis Medical Center, in Sacramento, and a clinical professor of medicine at UC Davis School of Medicine and clinical professor of pharmacy at UC Davis College of Pharmacy. “But more [data are] needed to know the significance of this association alone to drive initiating antithrombotic prophylaxis that otherwise would not be considered.”

Dager added that due to the rapid pace of COVID-19 developments, “we are learning so much as we go. But it would be difficult to provide much more comment than this: There are notable signals suggesting an increased risk for thromboembolism in patients being managed for COVID-19.”

As for the causes, “it may be multifactorial, from being sedentary to the impact of management approaches in the more critically ill [patients],” he said.

“Checking D-dimer levels and fibrinogen and then initiating anticoagulation is controversial in based on the American Society for Hematology guidelines right now,” acknowledged Anthony Proli, PharmD, BCPS, clinical pharmacy specialist: Bone Marrow Transplant at Memorial Sloan Kettering Cancer Center, in New York City. (The ASH recommendations on COVID-19, as of April 1, state “Blood component therapy should not be instituted on the basis of laboratory results alone.”

“But in our ICU, when D-dimers are elevated in COVID-19 patients, we initiate full-dose anticoagulation,” Proli said. “Some of our hematologists are even wondering if there’s a potential for defibrotide [Defitelio, Jazz Pharmaceuticals] as a fibrinolytic in these patients who have potential to go into hypercoagulable DIC [disseminated intravascular coagulopathy].”

Katelyn Sylvester, PharmD, BCPS, CACP, the pharmacy manager for anticoagulation services at Brigham and Women’s Hospital, in Boston, agreed there are multiple possible underlying mechanisms for abnormal clotting and cardiac damage in COVID-19. “It’s interesting to consider the direct damage they’re seeing in endothelial cells. Is the virus attacking those cells and causing microvascular damage, and is that leading to some of the acute coronary syndromes being reported in these patients? Does that suggest that we need to consider therapeutic anticoagulation versus prophylaxis? Although we are seeing endothelial tissue damage, so far there are not a lot of VTE events being reported.”

Sylvester also noted that angiotensin-converting enzyme 2, which is involved in COVID-19 viral entry, is expressed in cardiomyocytes, suggesting that some of the myocarditis that has been seen in COVID-19 could be related to the virus inhabiting those cells and causing cell death. In a case series of 21 critically ill patients with COVID-19 in Washington state, 33% of these intensive care patients developed cardiomyopathy (JAMA 2020 March 19. doi:10.1001/jama.2020.4326).

“Also, since the disease’s primary target is the lungs, if a patient is not oxygenating their tissue well, we would see acute coronary syndromes due to lack of oxygen. This makes sense since we are primarily seeing myocarditis toward the end of the disease,” Sylvester said. “”In addition, the cardiotoxicity seen at this stage of the disease may involve stress/cytokine-mediated cardiomyopathy, a Takotsubo’s effect—it’s most likely these three factors acting in concert.”

A Risky Constellation

Any patient who has a significant underlying illness and thus is at risk to be more severely affected by COVID-19 is also at higher risk for clotting and diffuse intravascular coagulopathy in the first place, Sylvester said. “We need to treat COVID-19 patients like other critically ill patients and use standardized risk assessment scores for prophylactic anticoagulation.

Patients with mild disease who are at home likely do not need VTE prophylaxis. Patients in the ICU, and even if on a step-down unit for multiple days, should have pharmacologic prophylaxis if there is not a contraindication. That’s my take from looking at the data that has been published to date.”

Clotting problems and antiplatelet therapy should be included in the daily COVID-19 management process, rather than just focusing on the infection, Dager said. “Any symptoms consistent with a thromboembolic process such as a [pulmonary embolism] should be addressed and not be presumed to be from the infection.”

Guidelines on COVID-19 and Coagulation

In late March, the International Society on Thrombosis and Haemostasis issued an interim guidance document

recommending that all hospitalized COVID-19 patients should get prophylactic-dose low molecular weight heparin (LMWH), unless they have contraindications (active bleeding and platelet count <25×109/L). (They acknowledged that this is an interim guidance.)

Other key points include:

D-dimers: Patients with markedly elevated D-dimers (which they suggest as a 3-4 fold increase) should be considered for hospital admission even absent other signs of disease severity
Low platelets: They note that some data suggests that thrombocytopenia may be a predictive factor for mortality, but this finding has not been consistent.
Routine coagulation tests: Monitoring of PT, D-dimer, platelet count and fibrinogen can be helpful in determining prognosis in COVID-19 patients requiring hospital admission.
Management of bleeding: Bleeding is rare in the setting of COVID-19 infection. If bleeding occurs, general ISTH guidance with respect to transfusions may be followed.
Experimental therapy: Other treatments, such as antithrombin concentrate, recombinant thrombomodulin, and hydroxychloroquine, can only be considered to be experimental at present.

These recommendations differ from those updated by the American Society for Hematology (ASH) on April 1, which state that therapeutic anticoagulation should be reserved for those with active bleeding, requiring an invasive procedure, or who are otherwise at high risk for bleeding complications.

“In patients with CAC/DIC who are not bleeding, there is no evidence that correction of laboratory parameters with blood products improve outcomes,” their guidelines state. “Replacement might worsen disseminated thrombosis and further deplete scarce blood products.”