Coag issues occupy COVID’s central stage

One could consider the many complexities the good old days of COVID-19 coagulopathy testing. More recently, questions about vaccine-related complications have filled laboratories’ dockets. Though the complications are rare, “they’re causing quite a hubbub,” says Dr. Smock.

It’s generally referred to as VITT (vaccine-induced immune thrombotic thrombocytopenia), although, like the names of people who arrived at Ellis Island, it may be subject to change. When Dr. Smock and her colleagues worked with the CDC to investigate a case at UHealth this spring, she noted the CDC used TTS (thrombosis and thrombocytopenia syndrome), a tag notable for the absence of the word “vaccine.”

COVID-19 itself was targeted by a geographic slur at the start of the pandemic; likewise, the variants have moved through a series of sobriquets (numbers, countries of apparent origin) that now seem to have settled on Greek letters.

Given the festering misinformation around the vaccines, Dr. Smock wonders if TTS seems less polarizing. (“There’s always some weird, new horrible aspect to the pandemic,” she says.)

Whatever the reason, or the final name, it’s worth noting that both VITT and TTS appear to be in use right now, Dr. Smock says, since “It can make it hard to find things in the literature.”

Thinking about these rare complications, she says, “To me, the biggest questions are, why does this happen in some patients and not to others? That would be useful to know. Why have these two adenovirus vector vaccine constructs been implicated in this, while other vaccines haven’t? What’s that actual mechanism? Is it something about the vaccine, like the viral capsid?” And while the two vaccines are similar, she says, they’re not identical, which raises further questions.

Vaccination is sort of the thumb on the scales with COVID-19. Says Dr. Salazar, “At this point, we’re not getting as many questions for the typical COVID-19 patient.” Early questions about the utility of viscoelastic testing, as well as lupus anticoagulants and COVID-19 patients, have receded, too.

These issues seem less pressing for now in light of worries about VITT, Dr. Salazar says. He and his colleagues developed guidance for the lab, hematology, pharmacy, and infectious disease for patients suspected of having VITT. It was also a means of letting clinical colleagues know VITT could be a possibility. This preparation helped guide the diagnosis of and treatment for a patient with VITT who presented to Houston Methodist in early June, he says.

“We have to stay on top of the literature and this rapidly evolving field—and not just VITT but also COVID-19 in general.” Dr. Salazar calls this challenge exciting, interesting, and above all necessary for the best patient care.

It’s important to get that information out there, Dr. Smock agrees. “Even very reputable journals have prepublished [information] without extensive peer review, because [VITT] can be severe and associated with fatalities.

“There is,” she continues, “this kind of balance between public confidence in the vaccines, but also making people aware of these potential complications in a way that’s transparent. We need to figure out how to prevent it and treat it,” Dr. Smock says. “But the likelihood of having severe COVID-19 and having a coagulation complication related to COVID-19 itself is still far higher than any of these vaccine complications.”

Dr. Smock echoes Dr. Salazar in saying that this needs to be tracked and learned about. “You want to get a handle on exactly which patient groups are at highest risk because you might eventually be able to identify some groups that would not be candidates for certain vaccines. And of course you have to always be transparent with patients about the potential risks, even of something rare.”

Dr. Smock points to two useful documents on VITT from the ISTH: a two-page interim guidance (https://bit.ly/ISTH-VITT-guidance) and a flow chart (https://bit.ly/ISTH-VITT-flowchart).

In cases of suspected VITT, lab testing should start with a CBC. “You want to see what their platelet count is,” Dr. Smock explains. The immune disorder causes activation of platelets, which drives the downstream actions that culminate in thrombotic events. Thrombocytopenia is a signal, in this setting, of ongoing platelet activation.

“If it’s the right timeline postvaccination, if they have symptoms of a thrombotic event, or you’ve confirmed a thrombotic event, and they have thrombocytopenia, then you should be highly, highly suspicious that it’s this disorder. You should order other coagulation testing that can give you more information,” she continues, including D-dimer, PT and aPTT, and fibrinogen assays, to look for signals that there’s activation of the coagulation system.

“You should also draw pretreatment samples for this more specialized testing, like the ELISA assay that can pick up the antibodies,” she adds. Some treatments can interfere with testing, “so you’ll need to get that sample to send to a lab like ours.” The additional testing could help guide patient monitoring and will confirm the diagnosis.

Not only is more information helpful clinically, she says, “but when the CDC investigates potential cases, it helps them to have a complete profile.”

As Dr. Smock indicates, evidence suggests certain lab tests might be superior to others in identifying VITT. Specifically, PF4  ELISAs that are complexed to polyvinyl sulfonate may be better at identifying PF4-specific IgG antibodies, Dr. Salazar says. He and colleagues have done their own evaluations and determined that such an assay was the best choice the lab could offer, though he says he’s “not yet sure how much to make” of the PVS aspect.

ARUP Laboratories has also geared up for this testing, Dr. Smock reports. The complications are similar to HIT, specifically autoimmune heparin-induced thrombocytopenia. While not an exact match, she says, this is the pathophysiology it most closely resembles.

That’s why the PF4  ELISAs are a good bet, she agrees—commercial ELISAs designed to pick up heparin PF4 antibodies in patients with HIT. “It looks like ELISAs from several different manufacturers also pick up the antibodies that are occurring in these vaccine-associated complications.” The titers are usually quite high, she notes.

But the understanding is still incomplete. Interestingly, Dr. Smock says, some non-ELISA immunoassays (automated in-solution immunoassays on a coagulometer instrument) do not pick them up. “You might hear them called in the literature rapid assays, or automated HIT immunoassays.”

Says Dr. Smock, “We’re getting calls about hospitals that may have some of these versions of the test that are not adequate for this particular disorder, so they need to bypass their own testing and send ELISAs to another lab.”

That comes with logistical difficulties. “You have to be able to identify when you’re receiving testing from one of these patients versus a patient with HIT, because in one scenario your assay will work correctly and in one scenario it wouldn’t.”

Understanding the full picture entails one more layer of testing: platelet activation tests, such as the serotonin release assay. But these are much more specialized, with limited availability, and technically difficult. Nor are they necessarily sensitive.

During the surge in the Houston area last summer, the overwhelming majority of patients in the hospital and presenting to the ED, according to Dr. Salazar, were COVID-19 patients. “So the high likelihood was that the sample we received in the laboratory was from a COVID-19 patient.”

That had ramifications for how the laboratory prepared. Dr. Salazar, like so many others, recalls the concerns he had about supply shortages and trying to predict volumes. “I can recall especially checking in with the lab to make sure we had enough reagents to run D-dimers, for fibrinogen levels, for anti-Xa assays, seeing that it was likely that many of these patients were going to be treated with some type of anticoagulation.”

Thankfully, he says, supplies held out, but the laboratory continues to deal with the ramifications, including occasional shortages of blue-top tubes.

He’s hardly alone. Dr. Wool says that on a recent conference call, a vendor reported significant rises in use of D-dimer reagents as demands for the test balloon. It’s also been fueled by the high D-dimer rates seen in COVID-19-related coagulopathy—depending on how labs report values, this can require a second dilution. “Some places are even reporting above 20 microgram per mL FEU or the equivalent,” which leads to those aforementioned offline dilutions and use of even more reagents.

Shortages have become a perpetual pandemic aftershock. As labs look beyond their primary vendors, that in turn creates more shortages with new vendors. “It’s a major domino effect,” Dr. Smock says. UHealth is helped by its size, but smaller systems may be in more dire straits, she suspects.

And while the reference lab isn’t drawing patients, its clients are. “We don’t need to supply the blue-top tubes for all those patients, but our clients need to. So we’ve been having calls and conversations with them to discuss approaches and brainstorm ideas,” says Dr. Smock.

The recommendations of the CAP, including members of the Hemostasis and Thrombosis Committee, are at https://bit.ly/CAP_bluetop.

Marching alongside that search for supplies is the lab’s ageless quest for knowledge.

Dr. Wool’s group described its work recently in a paper on the impact of COVID-19 on platelets and coagulation (Wool GD, et al. Pathobiology. 2021;88[1]:15–27). “So we’ve gotten a bit published,” he says, “but some of my colleagues who’ve published these large, well-done cohort studies describing their work have been really valuable in the field. I take my hats off to them to be able to get these giant studies done during the pandemic.”

The pandemic has put a quantum mechanics gloss on research: It’s only been a year! and We’ve had a whole year! are both fair characterizations of the growth in knowledge.

“We want to practice based on peer-reviewed, properly designed studies,” says Dr. Goodwin. “And a year is often not enough to do it.” It’s even harder in the midst of a global pandemic.

Nevertheless, he applauds the solid science that has started to emerge from the roller derby that was 2020. “We’re learning a lot from it,” he says. “I remember reading articles that weren’t even peer reviewed, and you were making your best assessment of the data” to see if it could be applied clinically. The literature and data are being reviewed more rigorously these days, he says. “Finally.”

He, like the others, says he would love to understand more about the pathophysiology of COVID-19-related coagulopathy. “It has been proposed that this is some variant of a lupus anticoagulant or antiphospholipid antibody syndrome. Some have hypothesized that this is more like a heparin-induced thrombocytopenia,” a notion that has drawn revived interest because of VITT.

“If we can better understand the true pathophysiology, then the laboratory testing can mirror what needs to be done,” Dr. Goodwin says.

That knowledge would also help explain the testing mysteries he and others have encountered, including with viscoelastic assays, which did not detect expected fibrinolytic components. “That generated a lot of questions,” Dr. Goodwin recalls. “Is there something about the disease where they truly aren’t lysing—which was hard for us to understand, because the fibrin degradation products and the D-dimers were so high—or was the assay system itself not sensitive enough to detect that lytic component?” He echos Dr. Wool’s mention of D-dimer elevation in association with infections. “D-dimer, while sensitive to fibrinolysis, lacks specificity for fibrinolysis, meaning it is elevated in many other settings, including in association with infections,” Dr. Goodwin says.

At Houston Methodist, Dr. Salazar and colleagues continue to evaluate the potential role for viscoelastic testing. “More studies are needed,” Dr. Salazar says. “When we did viscoelastic tests in our COVID-19 patients, we saw that the maximum amplitude was usually quite high, consistent with the sort of hypercoagulable state that many patients were in,” as well as with their very high fibrinogen levels.

Houston Methodist also has a long-COVID clinic. “So far we haven’t been getting a lot of coag-related questions, but it doesn’t mean we’re not going to get them in the future.” The lab also offers an algorithm for ambulatory patients to determine whether they are at high risk for progression and to determine eligibility for monoclonal antibody therapy.

Knowledge, always the lab’s strongest currency, offers the best chance for everyone to reattach to normalcy, even amid the always shifting demands of COVID-19.

Says Dr. Salazar, “The needs continue to evolve, even as we’re hopefully progressing to a stage where we don’t have an acute surge of patients.” The vaccines have been immensely successful, he notes. “But we need a far greater percentage of the population to get fully immunized. Until that happens,” he says, “COVID-19-related coagulation problems will continue to be problems.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.