Induced Thrombotic Thrombocytopenia in Australia

Medical education Lessons from practice The first known case of vaccine-induced thrombotic thrombocytopenia in Australia

Clinical record 3, and repeated on days 7 and 8 after admission. Despite achieving the anti-factor Xa fondaparinux level 6 hours after receiving a dose of 0.94 U/mL 44-year-old male health care worker presented (target range, 0.50–1.20 U/mL), the platelets remained with fevers, fatigue and head “fogginess” with between 6 × 109/L and 20 × 109/L for the initial 6 A abdominal discomfort and increased bowel days. The patient subsequently developed an acute frequency 8 days after receiving his first dose of the abdomen clinically and a repeat CT scan showed COVID-19 vaccine (ChAdOx1-S [recombinant]) extension and occlusive thrombus into the superior (AstraZeneca). He was previously well, with a mesenteric vein with venous outlet obstruction and past history of depression and was only taking bowel ischaemic features. He underwent an immediate escitalopram. He had no prior thrombosis or exposure laparotomy with resection of 1.8 m of ischaemic to heparin. The low platelet count, 70 × 109/L bowel. Contemporaneously, given clot extension (reference range, 150–400 × 109/L), and markedly had occurred on fondaparinux, anticoagulation was elevated D-dimer, 114 mg/L (upper limit of normal, changed to thrombin inhibitor bivalirudin, which had 0.5 mg/L), with vague abdominal pains prompted a short half-life (25 minutes) that allowed for titratable a computed tomography (CT) venogram of the perioperative anticoagulation and an intravenous abdomen, which demonstrated thrombosis with pulse of methylprednisolone 1 g administered to complete occlusion of the portal and splenic veins and augment PF4 antibody immunosuppression. protrusion of a tongue of thrombus into the superior The patient returned to the theatre 48 hours after the mesenteric vein (Box 1). CT venogram of the head did first laparotomy, where further compromised bowel not show central venous sinus thrombosis. was resected. Methylprednisolone 1 g daily was The rest of the full blood count and the blood film reinstituted for 4 days, with an immediate platelet showed no features of microangiopathic haemolytic peak to 385 × 109/L at completion of this 4-day pulse. anaemia. The prothrombin time, activated partial He was discharged after 34 days without further thromboplastin and fibrinogen levels, liver and renal complications. He has transitioned to warfarin function tests were all normal. Antiphospholipid and continues to be well while monitored in the antibodies were negative and a heterozygous haematology outpatient clinic. Box 2 summarises the prothrombin G20210A mutation was identified. time course of treatment and response. Antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein and Jay Hocking1 the respiratory polymerase chain reaction (PCR) test Discussion 2 for coronavirus disease 2019 (COVID-19) were negative, Sanjeev D Chunilal In March 2021, Australia began the roll-out of the ruling out active COVID-19 infection as a potential Vivien M Chen3 COVID-19 vaccine (ChAdOx1-S [recombinant]) to thrombosis aetiology. Tim Brighton4 combat the COVID-19 pandemic. In Europe, where Antibodies to the heparin–platelet factor 4 (PF4) more than 20 million doses of this vaccine had been 1 James Nguyen complex in the patient’s plasma was strongly positive administered by mid-March 2021, there were case Jocelyn Tan1 (optical density, 1.94) by enzyme-linked immunosorbent reports of thrombosis at unusual sites associated with Stephen B Ting5 assay (ELISA)-based test (Asserachrom HPIA IgG; Stago). Huyen Tran6,7 Three functional assays, including 1 Computed tomography venogram at presentation showing (A) a filling defect of portal vein, contrast in superior mesenteric vein and its tributaries 1 Box Hill Hospital, serotonin release assay (SRA; Melbourne, VIC. Hidex 300 SL, Hydex), multiple (arrow, coronal plane) and (B) a thrombus in the superior mesenteric vein 2 Monash Health, electrode aggregometry (MEA; (the arrow shows the contrast, axial plane) Melbourne, VIC. Roche Diagnostics) and flow 3 Concord Hospital, Sydney, NSW. cytometry (BD Fortessa, ETH

4 Prince of Wales Zürich; procoagulant assay) all MJA 215 Hospital and Community Health Services, detected heparin-independent PF4 Sydney, NSW. antibody complexes that activated ( 1 5 Eastern Health, 1 ) donor platelets. ▪ 5 July 2021 Melbourne, VIC. 6 Alfred Hospital, Immediate anticoagulation Melbourne, VIC. was started with the anti-factor 7 Monash University, Melbourne, VIC. Xa agent fondaparinux 10 mg huyen.tran@ (weight, 105 kg) subcutaneously monash.edu every 24 hours and intravenous immunoglobulin (1 g/kg) 19 doi: 10.5694/mja2.51135 administered on days 2 and Medical education

are no reported VITT cases 2 Time course and management associated with mRNA COVID-19 vaccines. It is doctrine in the management of heparin- induced thrombocytopenia that, in addition to immediate cessation of all heparins, a non-heparin anticoagulant is commenced to prevent (further) thrombosis. Given the pathogenic similarities of VITT cases to heparin- IV = intravenous; IVIg = intravenous immunoglobulin; SC = subcutaneous. ◆ induced thrombocytopenia, we initially used fondaparinux, as our patient thrombocytopenia, which occurred at day 4–28 after was clinically stable with normal renal function at vaccination and had a mortality rate of up to 25%, at an presentation. It is unclear if the clinical deterioration estimated rate of 1:100 000.2 in our patient, despite achieving favourable In Australia, the COVID-19 vaccine (ChAdOx1-S therapeutic fondaparinux drug level, was resultant of [recombinant]) was initially offered to people working anti-factor Xa drugs non-efficacy and/or because of in high risk professions without age restrictions. By the severity of the venous outflow obstruction with the end of March 2021, about 350 000 first doses of the compromised ischaemic small bowel. In principle, the COVID-19 vaccine (ChAdOx1-S [recombinant]) had been surgical removal of any ischaemic tissue would be administered Australia-wide. associated with clinical improvement. This is the first reported case of thrombosis at an The benefit of intravenous immunoglobulin unusual site with thrombocytopenia following remains debatable, but in vitro spiking experiments vaccination with the COVID-19 vaccine (ChAdOx1-S and observation of platelet increment after its [recombinant]) in Australia. The temporal association, administration suggest that there may be a role.3,4 the detection of anti-PF4 antibodies with platelet It is possible that intravenous immunoglobulin activation in the absence of heparin, which is displaces the binding of anti-PF4 antibody complex neutralised at high dose heparin, is consistent with the to FcgammaRIIA (an Fc receptor for IgG) receptors 3 most recent reports. This entity, currently labelled as on platelets.5 In our patient, it is difficult to ascribe a vaccine-induced thrombotic thrombocytopenia (VITT) specific clinical and platelet recovery to intravenous — also known as thrombosis with thrombocytopenia immunoglobulin solely given the simultaneous syndrome (TTS) — has pathological similarity to timing of surgical removal of ischaemic intestine, autoimmune heparin-induced thrombocytopenia the commencement of alternate anticoagulation with but without prior heparin exposure. More evidence bivalirudin, and pulsed high dose steroids. It is noted is needed to demonstrate if the serum of patients that pulsed methylprednisolone was prescribed in the with VITT contains antibodies that can bind to PF4 majority of recently reported cases.3 independent of heparin following vaccination for COVID-19. Furthermore, the mechanism responsible In line with evolving guidance documents, clinicians for profound platelet activation following vaccination assessing patients who present with organ-specific with the COVID-19 vaccine (ChAdOx1-S [recombinant]), thrombotic symptoms 4–28 days following vaccination as evidenced by ELISA high optical densities, with the COVID-19 vaccine (ChAdOx1-S [recombinant]) remains to be established.3 While the COVID-19 should look for any combination of thrombocytopenia vaccine (ChAdOx1-S [recombinant]) is delivered via and elevated D-dimer, and/or low fibrinogen, with a adenovirus vector, to the best of our knowledge, there low threshold for requesting imaging of the appropriate organ — in particular, the brain central venous sinus and abdominal splanchnic venous systems — for Lessons from practice thrombosis plus anti-PF4 ELISA testing in consultation • Vaccine-induced immune thrombotic thrombocytopenia (VITT) with haematology. is rare but potentially life-threatening. • VITT should be considered when patients present at day 4–28 Competing interests: No relevant disclosures. after vaccination with unusual site thrombosis: splanchnic and/ or central venous sinus thrombosis, or thrombocytopenia (or Provenance: Not commissioned; externally peer reviewed. ■ falling platelets) and markedly elevated D-dimer. The unedited version of this article was published as a preprint on mja. Specific testing to detect anti-platelet factor 4 (PF4) antibody ▪ 5 July 2021 • com.au on 7 May 2021. )

MJA 215 platelet transfusions. References are available online.

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1 Favaloro EJ, Mohammed S, Donikian https://www.gov.uk/government/news/ 4 Brodard J, Kremer Hovinga JA, Fontana P, D, et al. A multicentre assessment of m h r a - i s s u e s - n e w - a d v i c e - c o n c l u d i n g et al. COVID-19 patients often show high- contemporary laboratory assays for -a- possi ble- link- betwe en- covid - 19- vacci titer non-platelet-activating anti-PF4/ heparin induced thrombocytopenia. ne-astra zenec a- and- extre mely- rare- heparin IgG antibodies. J Thromb Haemost Pathology 2021; 53: 247–256. unlikely-to-occur-blood-clots (viewed 2021; 19: 1294–1298. 2 Medicines and Healthcare products May 2021). 5 Warkentin TE. High-dose intravenous Regulatory Agency. MHRA issues 3 Schultz NH, Sørvoll IH, Michelsen AE, et al. immunoglobulin for the treatment new advice, concluding a possible link Thrombosis and thrombocytopenia after and prevention of heparin-induced between COVID-19 vaccine AstraZeneca ChAdOx1 nCoV-19 vaccination. N Engl J thrombocytopenia: a review. and extremely rare, unlikely to occur Med 2021; https://doi.org/10.1056/NEJMo Expert Rev Hematol 2019; 12: blood clots [press release]. 7 Apr 2021. a2104882 [Epub ahead of print]. 685–698. ■ MJA 215 ( 1 ) ▪ 5 July 2021

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