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Adenovirus vaccines and thrombosis
safety profile with no difference in severe reactions between study arms.69,70 In a phase III trial with a recom- binant, replication-incompetent human Ad-26 vector encoding the SARS-CoV-2 spike protein, with 43,783 par- ticipants, 11 venous thromboembolic events were observed in the vaccine group compared to three in the placebo group (Table 1); however, most subjects had underlying medical conditions that might have con- tributed to these events. In the vaccine group there were six cases of lower leg deep venous thrombosis and four cases of pulmonary embolism. Interestingly, however, a CVST, with cerebral hemorrhage and thrombocytopenia, occurred 21 days after vaccination in a 25-year-old male who had multiple predisposing factors, including pre- existing cerebral sigmoid sinus stenosis and infection from an unknown pathogen. Subsequent testing identi- fied anti-PF4 antibodies at the time of the event. The patient recovered.71
In a phase III controlled randomized clinical trial with a recombinant Ad-26-vectored and a recombinant Ad-5- vectored vaccine (Sputnik V) among 16,501 participants, ten vascular events (0.061%) were observed including: one deep vein thrombosis (0.006%), one transient ischemic attack (0.006%), one cerebral circulation failure (0.006%), one vascular encephalopathy (0.00659%) and two acute myocardial infarctions (0.012%) (4 additional events were non thrombotic)72 (Table 1).
The vaccine-induced immune thrombotic thrombocytopenia syndrome
When the anti-SARS-CoV-2 vaccination campaign was well underway worldwide a few cases of spontaneous, severe thromboembolic events in otherwise healthy sub- jects began to be reported, leading to a pause in the admin- istration of the Vaxzevria vaccine in several European countries (https://www.ema.europa.eu/en/news/emas-safety- committee-continues-investigation-covid-19-vaccine-astrazeneca- thromboembolic-events). Soon after several case reports were published, mainly concerning young females, with new ones continuing to accrue, although many were not subject to rigorous central review and with anti-PF4 antibodies measured using disparate methods, not allowing to con- clude that all were typical VITT cases
Up to July 17, 2021, 105 such cases with two Ad-vec- tored vaccines had been published (Table 2) with some common clinical features characterizing a new syndrome, including thrombocytopenia, often severe, venous throm- bosis at unusual sites, in particular of the cerebral sinuses but also of the splanchnic veins, frequently associated with thromboses in multiple sites, both venous and arte- rial, and sometimes DIC combined with hemorrhage. A comparative evaluation of the clinical characteristics of the published ChAdOx1 or Ad26.CoV2.S VITT cases suggests that while clinical symptoms are comparable, Ad26.CoV2.S-associated cases show more thrombosis and intracerebral hemorrhage, lower D-dimer and less altered aPTT, but a similar mortality.9 In a recent, large nationwide healthcare register-based study in Denmark and Norway involving 281,264 ChAdOx1-S-vaccinated subjects aged 18-65 and as controls the entire age- matched populations of the two countries studied in the period 2016-2019, the standardized morbidity ratio for CVST was 20.25 (8.14-41.7), with an excess of 2.5 events
per 100,000 vaccinations, particularly evident in women 18-44 years old,73 confirming the crucial relationship between Vaxzevria administration and occurrence of VITT. The catastrophic syndrome, burdened by a 20-50% mortality rate, has the time course and tumultuous evolu- tion of an acute immunological reaction and indeed three groups of investigators identified, in several of their patients, circulating antibodies to PF4/heparin complexes using an enzyme-linked immunosorbent assay (ELISA) and a heparin-induced platelet activation assay,2-4 and thus proposed that this disorder is a peculiar form of autoimmune HIT.
The autoimmune heparin-induced thrombocytopenia hypothesis
HIT is a rare immune-mediated adverse drug reaction that may occur after exposure to heparin. Circulating heparin binds to PF4, a positively charged platelet protein released in plasma upon activation. PF4 normally binds to negatively charged glycosaminoglycans on the endotheli- um, displacing antithrombin and thus activating coagula- tion. However, PF4 binds with greater affinity to heparin, forming heparin/PF4 complexes which become neoanti- gens inducing the formation of autoantibodies. Heparin- PF4-IgG immune complexes in turn bind to platelet FcgRIIA receptors causing activation, aggregation, and additional release of PF4, with ignition of a positive feed- back loop leading to further platelet activation and con- sumption. Moreover, these complexes also activate monocytes, which release tissue factor, thus promoting concomitant activation of coagulation.
HIT is a potentially fatal condition, associated with the development of arterial or venous thrombosis.74 Thrombocytopenia occurs in more than 85% of HIT patients and is usually of moderate severity, with median platelet counts of approximately 50-60×109/L, although values <20×109/L can be found in approximately 10% of cases. Typically, the platelet count starts to decrease 5-10 days after initiation of heparin, but early-onset thrombo- cytopenia (rapid-onset), within 24 h of exposure, can develop in 25-30% of cases if patients have been treated with heparin in the preceding 3 months.75 Thromboembolic complications occur in 35-75% of HIT patients and are usually severe. They can be venous (i.e., deep vein thrombosis and pulmonary embolism, but rarely also CVST or splanchnic thrombosis), arterial (ischemic stroke, myocardial infarction, acute occlusion of limb arteries) or microvascular (digital infarction).76
Recently, another clinical picture not triggered by expo- sure to heparin has been recognized and defined as autoimmune HIT.77 The main characteristic of this condi- tion is the presence of circulating antibodies able to acti- vate platelets also in the absence of heparin. Polyanion molecules potentially involved in the development of autoimmune HIT are typically bacteria and virus compo- nents, hypersulfated chondroitin sulfate, DNA and RNA and polyphosphates.78 Patients with this syndrome show slightly different clinical features from those with classi- cal HIT, including severe thrombocytopenia (<20x109/L), sometimes in combination with DIC, microvascular thrombosis and CVST in up to 40% of cases.78 From a therapeutic standpoint, besides the indication for an alter- native anticoagulant, valid also for HIT, the intravenous
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