Coagulation tests and COVID: inside labs, industry

January 2021— COVID-19 and coagulation testing were up for discussion on Nov. 20 when six people joined CAP TODAY publisher Bob McGonnagle to talk about that and laboratory labor, relationships with industry and hospital administration, and the distribution of testing. “We’re working with all the manufacturers to support rapid point-of-care testing to manage hot spots that will pop up once there is a vaccine,” said Orchard Software’s Curt Johnson.

With Johnson and McGonnagle on the call were Oksana Volod, MD, of Cedars-Sinai Medical Center; Neil Harris, MBChB, MD, of the University of Florida; Annie Winkler, MD, MSc, of Instrumentation Laboratory; Nichole Howard, MBA, of Diagnostica Stago; and Jason Lam, MBA, MLS, of Siemens Healthineers. Drs. Volod and Harris are members of the CAP Hemostasis and Thrombosis Committee.

The CAP’s guide to coagulation analyzers begins here.

Dr. Volod, the coagulation findings that have come out of early investigations of COVID have been interesting. What is top of mind for you as you think about coagulation and coagulation systems? What’s most important?
Oksana Volod, MD, director, coagulation consultative service, and associate professor of pathology, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA: The good quality of the reagents and the assays available and the quick turnaround time, and potentially new assays that I can bring in-house quickly during this COVID period, specifically assays for fibrinolysis. As you said, there are the specifics of COVID coagulopathy, and now they are pointing out that fibrinolysis shutdown is one of the elements of the COVID coagulopathy. However, only the reference laboratories would have this type of testing. So we are validating fibrinolysis assays on our instruments.

Dr. Harris, are you also seeing a rise in demand for this particular assay?
Neil Harris, MBChB, MD, clinical professor and core laboratory medical director, Department of Pathology, Immunology, and Laboratory Medicine, University of Florida: Yes, we’re seeing a rise in demand for D-dimers and also coagulation factors, especially factor VIII. We used to run factor VIIIs mostly during the day, except in emergencies, and now we are running them around the clock.

The other thing I’d like to point out, and it’s something we have discussed at meetings of the CAP Hemostasis and Thrombosis Committee, is that a number of clinicians have said to me they have certain criteria for D-dimers, but in fact there are different units for D-dimers. For COVID management, as with other situations, there hasn’t been a standardization of D-dimer units.

Dr. Winkler, can you give us your reaction to what you’ve just heard from the pathologists? And can you relate that to your experience at Instrumentation Laboratory in the past year?
Annie Winkler, MD, MSc, VP of reagent R&D and medical affairs, Instrumentation Laboratory: Our first priority is, and has always been, to make sure we can support our customers in these challenging times, as it not only puts challenges on them but also on us in our manufacturing facilities. We’re also investing in the future to better understand and help identify additional markers so we can bring the most innovative solutions to the market. It’s been a time of extensive literature review, working with talented investigators, looking at new markers, and even exploring some of the synergistic, nontraditional laboratory hemostasis analyzers, such as our ROTEM system and its applicability as a point-of-care whole blood test for hemostasis.

Nichole Howard, can you, too, give us your reaction to what we heard from Dr. Volod and Dr. Harris?
Nichole Howard, MBA, product manager, instruments and customer experience, Diagnostica Stago: We’re seeing the same thing. We’re seeing the increase in factor VIII and in D-dimer, and I can follow what Dr. Winkler said in terms of our focus being on manufacturing, to make sure we have the right products in the right place at the right time to meet customer demand, and on looking at how we can work with our customers to make sure they’re adopting reliable strategies.

Jason Lam, I’ll let you round out our panel of instrument and coagulation vendors with comments of your own.
Jason Lam, MBA, MLS, U.S. marketing manager, hemostasis, Siemens Healthineers: Siemens Healthineers has done the same. As soon as COVID hit and we started to see an increase in D-dimer—it was before the white papers started to come out and we even knew it was happening, we saw it happening with our volume uptick in orders—we right away went into manufacturing to ensure we did not go into any backorder situations. We wanted to make sure that the physicians and the labs could provide those results without interruption. The increase in D-dimer usage was exponential, less so for factor VIII.

We worked closely with our clinical affairs team for a full understanding of COVID—we have the chemistry portfolio too—and started to release educational information, because we’re all learning together. It was and still is an amazing event to be a part of. Everyone is trying to help patients by developing new assays and markers.

Curt Johnson, tell me from your perspective, or if you’d like to relate it more specifically to coagulation, what kind of operating burden COVID has placed on your customer laboratories and the laboratories you’re calling on.
Curt Johnson, chief operating officer, Orchard Software: Speed and timely information are paramount, even more so than in the past. We’ve always said the product of the laboratory is information, but it’s information in the hands of a provider to improve patient care. When a pandemic hits and everyone is learning at the same time, from an information perspective, we have to have the capabilities for and compatibility with the new analyzers and reagents that manufacturers are developing, to make sure we understand those parameters and can respond quickly.

For the different types of D-dimers with no standardization yet, we have to have the flexibility to handle all the different attributes of the testing labs are doing, and as they’re creating tests, be able to capture that data and have it available to be dissected and analyzed to improve patient care.

As new analyzers come out, perhaps a new point-of-care testing analyzer, we have to understand the output from that analyzer, how it will be integrated into the LIS, to ensure the information gets to where it needs to go. As the testing moves closer to the patient, the workflow changes, so it becomes important that the software works hand in hand with the analyzers to improve the providers’ experience and to improve patient care.

From a COVID point of view, everything sped up. Everybody needed to expand their LIS capabilities. They needed to expand their reagents, their volume, plus how they were going to distribute and use the information. We have been working with different state and county departments of health, ensuring that they have the information they need and making sure the laboratory scientists have the necessary data to allow refining of their test menus and workflows.

Dr. Volod, D-dimer is a well-known assay but one that has not always been well understood, particularly by some clinicians. Has COVID led you to additional consultation with clinicians, and talks about D-dimer with some physicians, that are a little out of the ordinary for you?
Dr. Volod (Cedars-Sinai): As Dr. Harris said, D-dimer units have been a hot topic among the CAP committee members, so I’ve been dealing with that topic for several years. Based on that, I take a more proactive approach at Cedars. First, we wanted to make sure our assay meets certain criteria. Our physicians—specifically the emergency department—wanted to switch to age-adjusted D-dimer. So I looked into the assay, comparing it to the major studies done on the age-adjusted D-dimer.

We’ve been dealing with the clinicians and D-dimer for three or four years. And then when COVID hit, our system had a series of lectures on COVID coagulopathy. We have daily updates for certain groups. We have a task force, and we were giving hospitalwide web-based talks on COVID coagulopathy. One of the first was on COVID coagulopathy from the laboratory perspective, where I went through the first data from China and said, “These are the units we’re using, and we need to make sure we are comparing those units to the units we are using.” So from the beginning I brought our doctors onto the same page—what we are using, what that measures, how that compares to the published data. More than 500 physicians attended the first talk I gave.

I do provide coagulation consultative service. Clinicians can either order a test or a panel related to COVID coagulopathies. And I’m in constant communication on this subject.

Is there now a better understanding and use of the D-dimer test at Cedars-Sinai?
Dr. Volod (Cedars-Sinai): Yes, but I was surprised. D-dimers are part of our COVID assessment protocol. When a patient comes to the institution, my expectation was that a serial D-dimer would be done. What I’m noticing is they order an initial D-dimer level, and that’s it. But you need to see a progression, where a patient is moving with his coagulopathy, if it is worsening, and I believe D-dimers play an important role in it. So my work here is to encourage them to do a serial level and to provide them meaningful feedback on the results.

Dr. Harris, can you give us the trajectory of understanding the coagulation tests that need to be used in a COVID case?
Dr. Harris (University of Florida): We’ve mostly relied on our benign nonmalignant hematology group. They’ve taken the lead in guiding the other services through the COVID coagulopathy. They have drawn up guidelines and protocols for anticoagulation and what to measure, particularly D-dimers. We don’t have the panels available as such, but D-dimer, factor VIII, and fibrinogen appear to be, for better or worse, the main analytes they’re looking at.

There has been interest among our cardiovascular anesthesiologists in viscoelastic testing, which I know Dr. Volod is involved in. Although we use the viscoelastic testing, we haven’t used it at all in the COVID cases.

So our model has been to let the clinical hematology group take the lead, and we take our guidance from them, as far as the testing goes. So far we haven’t seen supply chain issues with the coagulation testing, though we’ve seen many issues in other areas of the laboratory, particularly microbiology and virology, even for non-COVID tests.

Dr. Volod, can you give us a brief overview of where viscoelastic testing is and where it’s going?
Dr. Volod (Cedars-Sinai): I’m a strong believer in all viscoelastic assays. All of them provide important information in the right settings. Thromboelastography and thromboelastometry are similar technologies. Next-generation technologies such as the TEG 6s by Haemonetics and Quantra by HemoSonics are FDA-approved, cartridge-based point-of-care systems. We have the TEG 5000 [Haemonetics] and TEG 6s. One assay is not superior to another. They are all helpful. However, I was surprised that our team doesn’t have much interest, unfortunately, in ordering it more frequently for COVID patients. I almost insisted that they at least let us see a few patients with COVID coagulopathy, and they sent about 10 patients. The patients were on heparin because our protocol from the beginning was if these patients were admitted with COVID, they should be on heparin prophylaxis. I didn’t see them being that hypercoagulable. I had a few patients who were not on anticoagulation from the beginning, and they were significantly hypercoagulable.

So they are assays that give you a global assessment of all the hemostasis in one assay testing whole blood of the patients, versus conventional assays. There is a certain advantage. With this type of testing, we potentially can see if fibrinolysis is present or absent. With the several publications about fibrinolysis shutdown in a group of COVID patients, it’s another layer that viscoelastic assays potentially can add. However, the TEG 6s version just started to have the fibrinolysis parameter as a part of the cartridge. Both the TEG 5000 and ROTEM Delta [Instrumentation Laboratory] can assess fibrinolysis. And I think HemoSonics still validates fibrinolysis on the cartridge. But there has to be more information—how to use it, how to interpret the results—and there is still no standardization between those assays.

Dr. Winkler, can I get a comment from you on that topic?
Dr. Winkler (IL): As Dr. Volod said, there are several different viscoelastic systems with many similarities and some differences. For several centers, we’ve seen growth of ROTEM testing with COVID, and we’re sponsoring a multinational clinical trial to further investigate the coagulopathy of COVID with ROTEM testing, on both ROTEM Delta and Sigma platforms.