key: cord-0944113-a84d751x
authors: Makris, Michael; Pavord, Sue; Lester, William; Scully, Marie; Hunt, Beverley
title: Vaccine‐induced Immune Thrombocytopenia and Thrombosis (VITT)
date: 2021-06-01
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12529
sha: 87904fdd69da795e95ad515605b48849d8383b7e
doc_id: 944113
cord_uid: a84d751x

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Concerns about a high number of unusual thrombotic events following vaccination with the AZ vaccine started to grow in early March 2021. On March 11, 2021 , both the MHRA and the EMA provided reassurance that the number of events observed was no higher than expected and advised the continued use of this vaccine as the benefits outweighed the risks. 1,2 Within a week, however, researchers from Norway, Germany, and the United Kingdom reported on a group of patients who had been previously healthy but were admitted within 3 weeks of AZ vaccination with an unusual combination of cerebral venous sinus thrombosis (CVST) and thrombocytopenia. All three groups independently identified that their patients had circulating antibodies against platelet factor 4 (PF4), which were detected using the heparin-induced thrombocytopenia (HIT) ELISA assay. Schultz and colleagues 3 from Norway reported on five patients admitted to the hospital with thrombosis (four CVST, one portal vein) and thrombocytopenia 7 to 10 days after AZ vaccination. In Norway, health care personnel younger than 65 years were selected to receive the AZ vaccine first, and the five cases appeared after 132 686 first doses of the vaccine were administered. Three of the women were on hormonal therapy. All five patients had high levels of IgG against PF4-polyanion complexes and also had platelet activation detected with a functional assay. 3 Greinacher and colleagues 4 from Germany and Austria reported on 11 patients who presented 5 to 16 days after AZ vaccination with multiple thromboses and thrombocytopenia. Nine of the patients had CVST, three had splanchnic vein thrombosis, three had pulmonary embolism, and other types of thrombosis were detected in four patients. In one patient who died from cerebral bleeding, CVST could not be excluded. Using an ELISA assay, the authors showed also that there was platelet activation which could be inhibited by immune globulin providing support for a proposed treatment for this condition. 4 In a report of the early UK experience, Scully and colleagues 5 described 23 patients presenting 6 to 24 days after AZ vaccination with thrombosis and thrombocytopenia. CVST was the most common type of thrombosis, with many patients presenting with thrombosis in several locations. Although the thrombotic events were primarily venous, two patients had ischemic strokes in the middle cerebral artery territory, one had a myocardial infarction, and one had an aortic thrombus.

Patients were positive for anti-PF4 antibodies on two HIT ELISA tests, findings that were confirmed using a functional assay. A case of thrombocytopenia without thrombosis was also described in this paper with equivalent laboratory findings to those with thrombosis, distinguishing it from a typical postvaccine immune thrombocytopenia. 5 Although these three papers described cases after AZ vaccination, a case report VITT shares many similarities with a condition in which hematologists are well versed called heparin-induced thrombocytopenia. HIT is a highly prothrombotic condition that develops 4 to 10 days after heparin exposure and presents with a falling platelet count, which is often associated with venous or arterial thrombosis. The etiology is the formation of antibodies against the complex of PF4 with heparin, which activate platelets through the Fc gamma RIIA receptor. The condition is managed by avoiding any further heparin exposure and using a nonheparin product as either primary or secondary thromboprophylaxis. 7 Guidelines recommend that prophylactic platelet transfusions are avoided 8 It was noted more than 10 years ago that a condition similar to HIT could rarely occur without heparin exposure, and the condition was termed spontaneous 9 or autoimmune HIT. 10 Arterial events such as bilateral leg ischemia, myocardial infarction, or stroke constitute at least 10% of acute admissions. Overall age of presentation is <60 years, and although in the reports from Norway and Germany it was mostly women, in the United Kingdom we are seeing a more equal sex distribution. One possible reason for this variation is the different national rollout schedules, which in Norway and Germany concentrated on health care workers, where there is a female excess. A further striking similarity between the current published cases is the significant mortality, ranging from 30% to 60% (Table 1) . The platelet count tends to be lower than that seen with HIT, and there is often a reduction in fibrinogen and a marked elevation in the D-dimer levels. Patients have strongly positive anti-PF4polyanion or anti-PF4-heparin antibodies detected by the HIT ELISA, but the HIT chemiluminescence assays are often negative. This most likely reflects the different specificities of the assays to heparin itself.

The management of patients is extrapolated from the treatment of autoimmune HIT, consisting of avoiding platelet transfusions and heparin exposure and using intravenous immunoglobulin (IVIG). 11 Our UK experience is that it is important to give high-dose IVIG early to turn off the prothrombotic process. Given the similarities to HIT, anticoagulation is currently provided through nonheparin anticoagulants such as argatroban, fondaparinux, or the direct oral anticoagulants.

Anticoagulation is more challenging in patients with marked thrombocytopenia such as those with platelet counts <30 × 10 9 /L since severe bleeding into the brain is more common than with non-vaccinationrelated CVST or with HIT. In many of the patients who died with VITT, the cause of death was intracerebral hemorrhage. Intervention in very extensive CVST with thrombectomy and/or neurosurgery should be considered, and an early discussion with neurosurgery is advised. 12 Transfusion to correct hypofibrinogenemia and thrombocytopenia are recommended before invasive procedures. Uncertainties remain, such as the value of steroids, whether heparin can be used safely in all cases and the benefits versus risks of prophylactic platelet transfusion other than for surgery.

It is important to appreciate that it is <6 weeks since the possibility of an unusual thrombotic pattern after the AZ vaccination was considered. We are bound to learn more in the next few weeks or months, including the true incidence, the optimal management, and, importantly, the length of time the antibodies persist as well as whether or not antibody persistence will be associated with recurrence of VITT. In particular, we do not know the natural history of the antibody in terms of persistence and expression of disease. We are concerned that it may persist for months and we may need to give repeated treatment for thrombocytopenia. Thus, any patients who present with this condition need close follow-up, with measurement of anti-PF4 antibodies and routine laboratory parameters, such as platelet count and Ddimer and fibrinogen levels. 

Thrombosis and thrombocytopenia after ChAdOx1 nCoV vaccination

Thrombotic thrombocytopenia after ChAdIx1 nCov-19 vaccination

Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19

Thrombotic thrombocytopenia after Ad26.COV2.S vaccination

Heparin induced thrombocytopenia

Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition

A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia

Autoimmune heparininduced thrombocytopenia

High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review

Current endovascular strategies for cerebral venous thrombosis: report of the SNIS Standards and Guidelines Committee

Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT)

The authors declare no conflicts of interest.

All authors contributed equally to this article.

https://orcid.org/0000-0001-7622-7939Beverley Hunt https://orcid.org/0000-0002-4709-0774

Beverley Hunt @bhwords