Question 3 from the second paper of 2021 asked about VITT in some considerable detail. This was an unexpected and welcome departure from the routine practice, where the appearance of the SAQ lags the trends in evidence and prevalence by about a year or so. For this SAQ from 2021, the most effective revision resource would have to be the TSANZ statement on VITT from August 2021. The UpToDate article is also good, made all the better by the uncharacteristically socialist decision to make it free to access. Greinacher et al (2021) and Schultz et al (2021) are also free (courtesy of NEJM). As it is not clear whether NEJM and UpToDate will continue to extend this courtesy after the kudos-rich pandemic period is behind us, Chen (2021) or Macris et al (2021) are offered to the reader as alternatives.
At a fundamental level, this is an immune-mediated thrombocytopenia. Schultz et al (2021) described it as "a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia". The mechanism and pathophysiology can be described as follows:
Why only the adenoviral vaccines? Why anything. However, it is clear that the mRNA vaccines are not likely to cause this, because of the hundreds of millions of doses, there have been no case reports of thrombocytopenia and thrombosis, apart from a single case report with the Moderna vaccine, which could also have been spontaneous HITT. McGonagle et al (2021) dive deep into the immunology of this thing, and their article is full of some interesting theories. An unforgivably glib reinterpretation would focus on the promiscuity of PF4 molecules, which can interact with all kinds of negatively charged substrates, among which is DNA and RNA. It is thought that the adenoviral nucleotides bind to this receptor and - very rarely - break self-tolerance, resulting in an autoimmune reaction.
Exposure to the two implicated adenoviral vector vaccines is the main risk factor for VITT.
In addition to this, "female sex and younger age" were proposed as risk factors; some case series reported mainly female and mainly younger patients ( younger than 55 years of age). Older and male-er patients are also being reported, and because the case numbers are so low, we may never know whether there is a real trend, or just some kind of play chance.
Question 3 from the second paper of 2021 specifically asked for an outline of the clinical presentation, which suggests that they were mainly looking for the constellation of signs and symptoms which would be found on the initial assessment of the patient, rather than laboratory data or the response to therapy. However, sometimes, when the college examiners say "clinical presentation", they also mean "biochemistry and imaging".
This is based on TSANZ, who give the following list of Ts and Rs:
TSANZ is not the only body making these guidelines and recommendations. For example, the American Society of Hematology have this list of criteria, all five of which must be satisfied:
VITT is rare, whereas thrombocytopenia in general is common and has numerous differentials. Any discussion of VITT would have to include some mention of the mechanisms one might use to exclude the much more common differentials. Statistically, the most likely explanation for all these clinical features is just some other cause of thrombocytopenia in a person who also happens to have received a vaccination in the last forty days. The rapid escalation of vaccine delivery around the world has massively increased the size of the susceptible population, and apart from the vanishingly small risk of VITT all of these people have brought with them all of their pre-existing risk factors for thrombocytopenia, their huge spleens and haematological malignancies and their alcoholism. In short, for exam purposes, you need to demonstrate that you will not jump on the zebra, thoughtfully considering the other possibilities.
From these differentials, it follows that a fairly broad range of tests might need to be launched. Obviously not everyone needs an ADAMTS13 level, but the list of investigations needs to reflect the need to exclude all the usual suspects. Thus:
TSANZ subclassifies the VITT presentations into possible and probable, reflecting that confirmatory tests need to be sent away and that a definitive diagnosis may take some days. The rationale for this is that one should not waste time, and start treatment while waiting for these tests (as a delay in treatment may be criticised, considering this condition can have a 40% mortality).
The management of probable VITT is basically the same as the management of confirmed VITT; with the exception of anticoagulation drug choices. If VITT is not confirmed, i.e. if the ELISA comes back negative, one could theoretically continue to manage the thrombus conventionally, i.e with heparin.
Why do we want to avoid heparin? There is a belief that in "true" VITT, the use of heparin can produce enhanced platelet activation. This comes from Greinacher et al (2021), who recommended people use non-heparin agents, "given the parallels with autoimmune heparin-induced thrombocytopenia". The implication is that all subsequent guidelines have been recommending the use of non-heparin anticoagulants mainly because this condition resembles HIT, rather than any specific data. Certainly, if you accidentally happen to treat VITT with heparin, the patient does not seem to come to any heparin-attributable harm. UpToDate authors point to a 220-patient case series by Pavord et al (2021), who reported no major difference in outcomes for VITT patients who received heparin while the diagnosis had not been established or even considered. There was a mortality difference (20 vs 16%), but this could be attributed to other things, and none of the heparinised patients seemed to develop any major complications, which suggests that heparin might in fact be perfectly fine for VITT. Still, local guidelines reflect the opinions of thrombosis gurus, who hold that on the balance of things it is safer to give a non-heparin product (considering that, at the point of making that decision, often HIT is also one of the differentials).
According to Lentz (2021), the use of polyclonal immunoglobulin for VITT is also recommended on the basis of the rationale that VITT and HIT are very similar, and IVIG seems to work in HIT. Theoretically this makes sense. Some abnormal adenoviral RNA fragments are causing all the problems, and there's a lot of COVID in the community, which means there should be plenty of antibodies in donated blood which should specifically target those RNA fragments. Wiping them out of the bloodstream should theoretically prevent them from binding to the PF4 protein and therefore prevent worsening thrombocytopenia and thrombosis. Beyond that, IVIG can also block platelet activation by anti-PF4 antibodies by competing for binding to Fcγ receptors, which is the platelet surface receptor responsible for platelet activation in VITT. For this competitive effect to be useful, a fairly large amount of immunoglobulin needs to be given - 1-2g/kg over two days is the recommended dose. Logically, this therapy should follow plasmapheresis.
Though follow-up and long term management of these patients in the community is really not the province of intensivists, they should probably still be aware of what tends to be the standard. Specifically, they should be aware that nobody really knows how long the anti-PF4 antibodies can hang around, which means the patient may be at some hard-to-estimate risk of recurrence for a prolonged period of time. Local guidelines recommend surveillance for thrombocytopenia and repeat ELISA and functional testing at 6 weeks, 3 months and 6 months.