Karen Titus
June 2025—For a relatively sleepy field of study, heparin-induced thrombocytopenia has produced more than its share of thrills in the past few years.
HIT (sometimes called HITT, with the extra “T” denoting thrombosis) gave way to urgent discussions about vaccine-induced immune thrombotic thrombocytopenia, or VITT, at one particularly panicky point in the COVID-19 pandemic.
Take another spin of the wheel: “VITT-like” is now primarily used to refer to cases in which patients have received neither heparin nor a vaccine.
Even more recently, researchers have identified a new syndrome, referred to as monoclonal gammopathy of thrombotic significance (MGTS). Publications have put this disorder into three groups:
- VITT-like MGTS (Wang JJ, et al. N Engl J Med. 2025;392[10]:995–1005; Salmasi G, et al. N Engl J Med. 2024;391[6]:570–571; Greinacher A, et al. Haematologica. 2022;107[5]:1219–1221).
- HIT-like MGTS (Kanack AJ, et al. Blood. 2023;141[14]:1772–1776).
- MGTS that is neither HIT-like nor VITT-like (Kanack AJ, et al. N Engl J Med. 2024;391[20]:1961–1963).
“I think this is going to be the biggest thing in the thrombophilia field in a long time,” predicts Anand Padmanabhan, MD, PhD, professor, Mayo Clinic. Unlike HIT and VITT, MGTS is a chronic condition. “It may end up being part of a thrombophilia profile in the coming years.”
The discipline is adding acronyms at a fast clip. Or, as Dr. Padmanabhan puts it: “The field is on fire right now.”
No one is more surprised than Theodore Warkentin, MD, coauthor of a number of articles in the field and professor of pathology and molecular medicine, McMaster University, Hamilton, Ontario. (“Which makes me sound like a pathologist, but I’m actually a clinical hematologist, though I used to run the transfusion lab,” he says.)
“And then you realize these have been around since time immemorial,” he says. “We just never recognized it. This is all in just the last four years. It’s amazing how something suddenly comes way out of the blue.”
Dr. Padmanabhan is equally spellbound by what is roiling previously becalmed waters, particularly MGTS, which is characterized by platelet-activating monoclonal antiplatelet factor 4 antibodies. “What I think has changed significantly, in my opinion,” says Dr. Padmanabhan, “is we now have a new chronic thrombophilia. And it is very severe. It’s a terrible disease.”
Anything related to VITT “is building on decades of study and knowledge of HIT,” says Kristi Smock, MD, professor of pathology, University of Utah School of Medicine, and medical director of ARUP Laboratories’ hemostasis/thrombosis laboratory. “It’s all highly related.”
The emergence of VITT, as a relative of HIT, helped initiate additional study of antibodies to PF4, says Dr. Smock, who chairs the CAP Hemostasis and Thrombosis Committee. “A lot of people are calling it anti-PF4 immune disorders, or PF4-mediated immunothrombotic disorders,” recognizing that vaccines were not the only possible culprit. “This probably has existed and we just hadn’t recognized it.”
Dr. Warkentin recently wrote an open-access review article with proposed classifications for the various entities (Warkentin TE. Int J Lab Hematol. Published online May 13, 2025. doi:10.1111/ijlh.14486). Now is the time to acknowledge differences in what he calls classic HITT (he prefers two T’s when comparing to VITT), autoimmune (also referred to as atypical) HITT, and spontaneous HITT, for example. Likewise, he says, it might make sense to refer to classic (post-vaccine) VITT and post-viral VITT—both acute disorders—in comparison with a variety of chronic anti-PF4 disorders, including MGTS.
The nomenclature is no small consideration, Dr. Warkentin says. Early in the VITT journey, the vaccine-induced immune disease was referred to as vaccine-induced “thrombotic thrombocytopenia,” which could put some folks in mind of TTP, a type of microangiopathy. VITT, on the other hand, behaves more like a consumptive, disseminated intravascular coagulation.
Though it might seem like a minor point, Dr. Warkentin says, “In the rapid recognition and publication of the first VITT papers, one didn’t really have a chance to think and ponder these subtleties of naming.”
Researchers have a little more breathing room these days. Dr. Warkentin uses terms he thinks will be useful, but he recognizes they’re not set in stone. “Whether people are going to use the term ‘spontaneous HIT’ or ‘autoimmune HIT’ or ‘VITT-like MGTS’—who knows? The world evolves as it evolves,” he says affably. “Suffice it to say it’s a rapidly shifting world.”
Dr. Padmanabhan sees this as the start of not one story, but of many. “All of this will evolve for certain. And I’ve started telling people, ‘Anything I tell you is living guidance, which will inevitably change.’” (Dr. Padmanabhan and CAP Hemostasis and Thrombosis Committee member Morayma Reyes Gil, MD, PhD, are scheduled to present a session on this topic at the CAP25 meeting in September.)
The pandemic served to advance the field in an unexpected way.
The two COVID-19 vaccines that led to cases of VITT—Johnson & Johnson/Janssen and AstraZeneca/Oxford—were adenoviral vector vaccines. In the United States, the number of VITT cases was, roughly, one in 100,000, says Dr. Warkentin. It’s rare, in other words, and in normal times would not have been identified.
The sheer number of vaccines given at the time, however, meant they were recognized quickly. “There were dozens of people within a short period of time, in a particular community or state or province, who would develop this peculiar, very dramatic reaction with a low platelet count and very unusual clotting,” Dr. Warkentin says. So even though this reaction was “super rare,” he says, its timing a week or two after the vaccine was administered drew attention, as did the distinct pattern of symptoms, including profoundly reduced platelet counts, increases in D-dimer, and other markers of hypercoagulability. While it looked similar to HIT, cerebral venous sinus thrombosis was present at a much higher level than might normally be associated with HIT.
The pandemic was the necessity that drove invention. Because VITT cases occurred at a highly visible, accelerated pace, says Dr. Warkentin, “we now know how to detect a VITT antibody because we figured it out to explain the vaccine reaction.”
The work has carried on, and the pathophysiology continues to be better understood. Dr. Warkentin points to a McMaster group publication in Nature (he’s not part of it) on VITT and HIT antibodies recognizing distinct regions on the PF4 protein. The antibodies are different, but similar—he calls them cousins. While ELISAs can spot them both, some more recently developed rapid tests only detect HIT antibodies, he says, which serves to underscore that these are indeed different antibodies.
An even more spectacular discovery—Dr. Warkentin’s word—came in 2023. For a time, VITT may have been considered a one-off—a notable, serious, but ultimately time-limited curiosity of the pandemic. The severe side effect drove the non-mRNA vaccines off the market. “So you might think VITT’s gone. It’s a historical footnote,” Dr. Warkentin says.
As it turns out, however, the identical disease can also be caused by viruses.
A New England Journal of Medicine article (Wang JJ, et al. N Engl J Med. 2024;390[19]:1827–1829) showed that the composition of the antibody in virus-induced VITT is essentially the same as the antibody composition in vaccine-induced VITT. So “VITT” remains conveniently named—no small thing at a time when vaccines seem to be facing a branding problem.
“They involved adenovirus in the manufacturing of the vaccines, and isn’t it interesting that both an adenovirus vector vaccine and natural adenovirus infection can cause acute VITT?” Dr. Warkentin says. “And Jing Jing Wang has shown that it’s the same antibody compositionally.”
HIT and VITT are both acute, transient, and self-limited, though VITT antibodies appear to linger longer than HIT antibodies. These were, in fact, thought to be reliable features of anti-PF4 disorders.
That was the thinking until researchers reported an unusual case in which the IgG monoclonal gammopathy of undetermined significance was proposed to have specificity to PF4, leading to chronic thrombocytopenia and an episode of cerebral venous thrombosis (Faille D, et al. Res Pract Thromb Haemost. 2017;1[suppl 1]:1355. doi:10.1002/rth2.12012). Since then more cases of MGTS have been reported.
These are early days, which explains why researchers are describing their work in terms of count-on-one-hand cases, rather than population studies, and raising more questions than answers.
Not surprisingly, that extends to the tests they’re using to identify these emerging disorders.
But knowledge is accumulating fairly quickly. Even though researchers have had far fewer encounters with VITT than with HIT, says Dr. Smock, “there are centers that have kind of pooled their experiences. They’ve come up with a series of patients and been able to describe the different lab test abnormalities you see in these patients.” And for MGTS and other unusual cases, “the experience is just emerging, so I wouldn’t necessarily call them well characterized.” But individual cases have benefited from deep study in basic science labs, she says. “So researchers have been able to start to understand the differences between some of these newer recognized syndromes and the antibodies. How are they different from HIT antibodies? How are they the same?”
Dr. Padmanabhan recounts his first case of MGTS (which happened to be HIT-like), tracing it back to the early days of COVID, in June 2020. The patient was previously seen by Jordan Schaefer, MD, of Michigan Medicine, who performed HIT testing on several occasions, months apart. Each time it was positive. “He noted that the patient had monoclonal gammopathy of undetermined significance, or MGUS,” says Dr. Padmanabhan. Three to five percent of people over age 50 will have these MGUS antibodies, most of whom will have no issues.
The patient then saw Dr. Padmanabhan. “Working with Dr. Schaefer, we set out to prove the hypothesis that his MGUS was an anti-PF4 antibody.”
“We developed the tools for this investigation. We had to give this disorder a name,” Dr. Padmanabhan adds. “Obviously the monoclonal antibody in this patient was not of undetermined significance. We knew it had thrombotic significance so we ended up calling it monoclonal gammopathy of thrombotic significance.”
The tools they developed came in handy, he says, because in April 2021 cases of VITT started popping up. “So we ended up consenting a large number of cases, relatively speaking—about 10 U.S. VITT patients. In rare diseases, that’s a large number. And we found the antibodies in VITT, using the techniques that we had developed to study the gentleman with MGTS,” says Dr. Padmanabhan. “We found that these antibodies the VITT patients were making are [either] monoclonal or oligoclonal.”
He says many “flavors” of MGTS have now been published on HIT-like, VITT-like, and the newest entity that is neither HIT-like nor VITT-like. He elaborated on the diagnostic complexities of this latter type in the New England Journal (Kanack AJ, et al. N Engl J Med. 2024;391[20]:1961–1963), which noted that ELISA-negative, serotonin-release assay-negative MGTS “can be challenging to diagnose . . . and requires PF4-enhanced platelet-based testing for confirmation.” In addition, this study showed for the first time that thrombocytopenia may be present only transiently in some MGTS patients.
Dr. Smock observes that VITT and other anti-PF4 immune disorders “seem to be more autoantibody-like. They’re against PF4 alone, instead of heparin PF4, and they tend to become more chronic autoantibodies. Several years out, some of the VITT patients, including a patient we have here at our hospital, still have pretty high levels of detectable antibodies. And it’s not clear if they’ll ever go away.”
MGTS is rare. It’s hard to diagnose.
It’s also not well known, which is likely adding to the diagnostic difficulty.
But clinicians are starting to take notice. Says Dr. Warkentin: “Typically, when Andreas [Greinacher, MD] and I speak at a meeting, and we talk about these new syndromes, somebody in the audience comes up and says, ‘Thanks for your talk. I think I now understand one of my cases.’ That happens more often than you might think.”
Dr. Smock says she and her laboratory colleagues have been discussing cases with their clinical colleagues. The topic has been front and center at many clinical meetings, she says, so it shouldn’t be surprising for labs to be getting questions about diagnosing anti-PF4 immune disorders.
“We’re hoping that in the clinical setting people will recognize the inpatients who have the combination of thrombosis and thrombocytopenia,” she says. “That’s what should get your suspicion up,” and perhaps prompt additional coagulation testing. Even some of the more readily available coagulation tests, including PT and PTT clotting times, fibrinogen, and D-dimer, can be helpful, she says.
At the same time, she says, “The lab can push information out to their clinical colleagues. One important aspect of this is that certain tests used for HIT do not identify the VITT antibodies. Clinicians need to know this.”
Says Dr. Padmanabhan: “I like to tell my residents that the eyes do not see what the mind does not know. And once we started publishing on MGTS, people started saying, ‘I think my patient has it.’ Of course we got a deluge of calls. Many of them were not MGTS, but some of them were. So we are now following patients from around the world.
“Right now we’re working very hard to understand what the prevalence of this is,” Dr. Padmanabhan continues. He expects several studies to come out by fall. “I really think that several patients today are going undiagnosed. Physicians aren’t aware this disorder exists. And the commonly used tools hospitals have—the ELISA for HIT—do not identify certain flavors of this disease. It’s going to be very, very interesting as we go along, and it is going to be critical to get diagnostic testing right.”
The belief initially was that solid-phase ELISAs would be useful for MGTS, though it turns out they’re not always, Dr. Padmanabhan says. “We’re finding that both ELISAs and SRAs can be dead negative. In some cases, it’s just PF4-treated platelets that unmask the antibody.”
The solid-phase HIT ELISAs are useful for VITT/VITT-like MGTS antibodies, he says, though the test is not specific. “But at least you’re not missing the VITT/VITT-like MGTS patient.” It would be helpful in some cases to have a more specific test, however, because VITT-like antibodies appear to be more severe.
“So we’re in the process of developing and deploying a new diagnostic test for VITT,” Dr. Padmanabhan says. “Having said that, the new flavor of MGTS we found late last year and published on is even negative on the VITT ELISA. It needs platelets that are treated with PF4 to confirm” the antibody is present.
Much of the testing is still in development, not surprisingly.
Dr. Warkentin notes that the typical PF4 polyanion ELISAs are good screening tests for almost all of the HIT and VITT syndromes. However, the rapid HIT assays do not detect VITT antibodies.
Moreover, he says, the platelet activation test known as the SRA sometimes needs to be “tweaked” by adding PF4 in order to detect the VITT antibodies with high sensitivity. “Which basically means you’ve got to send the sample to a reference lab.”
Dr. Smock agrees, saying that automated immunoassays are convenient for HIT, which is much more common, and they perform well in that setting. “But if you don’t have something that’s sensitive to VITT or PF4 syndromes outside of HIT, you might have to do a send-out test,” she says.
The emerging PF4 syndromes, says Dr. Smock, “are just much more variable in the lab tests.”
With a functional test like an SRA, she says, “People are very programmed to think of that as the gold standard test for HIT, with high sensitivity and high specificity. And then you take VITT or one of these other PF4 syndromes and you get much more variable results. I’ve seen patients, they’re totally negative in the SRA, or very barely weak positive, or multiple results over time are extremely variable.”
Dr. Smock continues: “You have to be really wary—is the negative you’re seeing a false-negative? The functional assays that might do better with VITT are assays that don’t use heparin, and that might be supplemented with PF4. That seems to be a good construct for VITT. But its availability is very limited.”
Her hope is that manufacturers will develop commercially available immunoassays that can look for antibodies against PF4 alone. Until that happens, “daunting” will continue to be a laboratory watchword for this field, alongside “amazing.”
Doing variations on functional assays, such as the SRA, to validate a version of the test that doesn’t use heparin and that supplements PF4 can be done, says Dr. Smock, but she’s skeptical whether many laboratories would undertake that kind of validation, in part because so few VITT samples are available.
“To me, the most important point right now in clinical practice is to be on the lookout for patients who present with thrombosis and thrombocytopenia in combination or an unusual thrombotic disorder without an identified cause,” she says. “And think about this group of syndromes and if they should be worked up further.”
Dr. Warkentin offers insights into other subtleties in this slowly unfolding, curious tale.
One is heparin-independent reactivity. “Classically we think of HIT—the heparin reaction—as a heparin-dependent antibody,” he says. But nearly a quarter of a century ago, he and other research colleagues began to note that HIT triggered by heparin can have atypical features. “The explanation was that although heparin triggered the antibodies, they now had both heparin-dependent and heparin-independent properties. Even if there was no heparin around anymore, the antibody was still pathogenic—it still bound to PF4.” That would explain why a patient could receive heparin during heart surgery, do fine, and be discharged on day four or five, only to return to the hospital on day 12 or 15, say, with a pulmonary embolism, stroke, or deep vein thrombosis, and have a low platelet count. He terms this autoimmune HIT or atypical HIT.
Another subset, first reported by Dr. Warkentin and collaborators in 2008, is referred to as spontaneous HIT. Patients had HIT antibodies, including those with heparin-independent platelet-activating antibodies and no proximate exposure to heparin. As it turns out, some of these patients had had knee replacement surgery; others had had recent infections of some sort, including bacterial.
(When heparin was given regularly to patients during knee and hip replacements, as was standard in the 1980s and 1990s, HIT was common in both groups, Dr. Warkentin notes. Now that it’s been replaced by other types of blood thinners, spontaneous HIT occurs only very rarely, and only in knee, not hip, replacement, though one case of it occurred in shoulder arthroplasty. One possible explanation, says Dr. Warkentin, is that in knee replacement, the surgeon places a tourniquet around the thigh to create a bloodless field. Once it’s released, the bolus of negatively charged molecules, perhaps mimicking heparin, is released into the bloodstream. “We think something there might be immunizing the patient,” he says.)
The removal of adenoviral vector COVID-19 vaccines from the market has quieted, but not ended, conversations about the “vaccine” version of VITT.
There has been one case involving a VITT-like syndrome following human papillomavirus vaccination (Kanack AJ, et al. Am J Hematol. 2022;97[10]:E363–E364. Dr. Padmanabhan is a coauthor). “We don’t know what to make of it,” says Dr. Warkentin. And even as he spoke with CAP TODAY, a new case had just been published in the British Journal of Haematology, of which he is a coauthor, involving a patient with a recent cytomegalovirus infection whose anti-PF4 antibodies tested as both VITT- and HIT-like in different assays (Nicolson PLR, et al. Br J Haematol. Published online April 29, 2025. doi:10.1111/bjh.20092).
At this point, all cases are rare. The sporadic cases involving other viruses and vaccines will depend on what researchers learn about those characteristics. The CMV case is compelling because it’s a different virus and antibody, though still related to PF4.
“These are evolving syndromes,” Dr. Warkentin says.
One hypothesis is that an adenoviral infection triggers VITT in some cases, such as spontaneous thrombotic thrombocytopenia. Dr. Warkentin and colleagues offered data to suggest it, though it’s too early to know for sure.
And as Dr. Padmanabhan notes, “I’m not saying it’s not possible; it’s certainly possible but we haven’t had, for example, rigorous demonstrations of this in a mouse model that these types of infections can trigger anti-PF4 antibody production. The stories presented are quite convincing that the patients have an anti-PF4-mediated thrombotic thrombocytopenia.”
Dr. Padmanabhan continues: “Now, many of my patients who have developed these kinds of acute reactions have told me, ‘Oh yeah, I felt a little sick before this came on. I had some diarrhea; I had a cold.’ So, I mean, we always had been thinking this is possibly related to an infection, maybe a viral infection. But we don’t have that proof yet. The adenoviral hypothesis is an attractive hypothesis but needs more data to convincingly prove it.”
The stories surrounding vaccines also have their limitations, Dr. Padmanabhan concedes. The aforementioned HPV-related case is a case in point.
He explains: “The biggest question in that case is, is this related? Is this because of the vaccine this woman got? Or is it coincidental? The rate of VITT after HPV and other non-COVID adenoviral vaccines is so low, it can be hard to tease out the spontaneous background rate of spontaneous VITT, versus a vaccine-induced reaction.
“One hypothesis,” he continues, “is that vaccination induces some level of inflammation that may cause antibody production in a ‘susceptible’ person.” It’s also possible the patient was sick with another viral infection at the time of vaccination. “So I would say even if HPV is implicated, the rate of VITT is very low, such that easily the risk-benefit profile is in favor of getting those shots, rather than skipping them.”
He concludes: “From my perspective, we’re not really thinking of VITT antibodies solely in the context of vaccines. I have not consented a post-vaccination VITT patient in several years now.”
Given the inverted conversations around vaccines currently, Dr. Smock adds another word of caution. “It’s important to say that when you think about vaccines as a stimulus to the immune system, VITT and other reports of this are extremely, exceedingly rare. It’s far more likely to have a complication from the viral diseases themselves than to have this complication from vaccination.”
Though everyone agrees these cases all seem to be exceptionally rare, pathologists have to be aware they exist.
“You can’t recognize something if you don’t know it exists, or if you’re not able to think out of the box,” says Dr. Warkentin. Suspicion might arise either in the lab or on the clinical side. In the best scenarios, the lab is collaborative and can discuss puzzling cases with clinical colleagues, rather than simply send out a result, he says.
At Mayo, says Dr. Padmanabhan, “We’re making the recommendation now if you have unexplained thrombosis recurrence, you can’t explain what’s going on, even if the patient is not thrombocytopenic, you may need to test further.”
He recognizes this could potentially be a double-edged sword, with an abundance of testing not necessarily in the interest of health economics or resource use. But the severity of these cases should not be ignored, he says.
Dr. Padmanabhan continues: “Right now I get a lot of calls and emails, almost every week now. So definitely there’s going to be questions coming to pathologists. I would say at this point they should probably contact an expert center that has experience with this, because again, the story is evolving. It may not be one solution, or, say, Run this one test. It might be multiple things that we have to do.” Indeed, he and his colleagues are now using mass spectrometry to help identify cases, though only in the research setting (Kanack AJ, et al. Blood. 2022;140[1]:73–77. Dr. Padmanabhan and Dr. Smock are coauthors).
“It’s all so new,” says Dr. Padmanabhan. “But I would say the biggest thing pathologists need to know is, this is an entity you need to think about. It could be acute or persistent. And if you see this, talk to somebody because it can present in unusual ways. There are many flavors of this, and probably some flavors we haven’t seen yet. These are the conversations that I am having now with my colleagues.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.