Autoimmunity after Coronavirus Disease 2019 (COVID-19) Vaccine: A Case of Acquired
Hemophilia A
The global pandemic of coronavirus disease 2019 (COVID-19) from infection with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in high death rates
and acute and chronic morbidity in all countries.[1]
[2] The development of vaccines against SARS-CoV-2 has dramatically reduced the transmission
rate, the occurrence of COVID-19 by reducing the hospitalization rate, the severity
of disease and incidence of mortality, and the transfection rate. The Food and Drug
Administration and European Medicines Agency approved vaccines include two mRNA vaccines,
the BNT162b2 from Pfizer-BioNTech and the Moderna vaccine, and two viral vector vaccines,
the ChAdOx1 nCoV-19 (now called Vaxzevria) from AstraZeneca and the Johnson & Johnson/Janssen
vaccine.[3]
[4]
[5]
Immunothrombosis after SARS-CoV-2 Vaccines
Immunothrombosis after SARS-CoV-2 Vaccines
Vaccination against the SARS-CoV-2 may lead to immunologic reactions activating the
hemostatic system and resulting in both venous and arterial thromboembolism, of differing
severity.[6] In the present context, heparin-induced thrombocytopenia is the best known immunologic
thrombotic complication caused by immunoglobulin G (IgG) antibodies against platelet
factor 4 complexed with heparin, binding to the platelet FcRγIIA receptors, thereby
causing platelet activation, microparticle formation, and thrombosis.[7] In 2021, rare thrombotic events in atypical locations (cerebral and/or splanchnic
veins) associated with thrombocytopenia were reported 5 to 20 days after vaccination
in young patients, mainly females, who were never exposed previously to heparin.[8]
[9] This syndrome, named vaccine-induced immune thrombotic thrombocytopenia (VITT),
is associated with high fatality rate.[10] The U.S. Vaccine Adverse Event Reporting System and the U.K. Medicines and Healthcare
products Regulatory Agency established coronavirus reporting systems and have made
clear that the benefits of SARS-CoV-2 vaccination far outweigh the risk of VITT.[11]
Other Immunological Reactions to SARS-CoV-2 Vaccines
Other Immunological Reactions to SARS-CoV-2 Vaccines
In addition to immunothrombosis, other immunological reactions to SARS-CoV-2 vaccines
have been as well described. It is suggested that autoantibodies against the spike
protein S1 of SARS-CoV-2 may be responsible for these complications as reported for
immune thrombocytopenia,[12] vasculitis,[13] Schönlein-Henoch pupura,[14] autoimmune hepatitis,[15] and Guillain–Barré syndrome.[16] Additional case reports may increase the number of so far unknown immunological
reactions to the available vaccines. Of note, some of the reactions were already described
in the efficacy and safety studies of SARS-CoV-2 vaccines.[17]
Autoantibodies to Clotting Factor VIII after SARS-CoV-2 Vaccines
Autoantibodies to Clotting Factor VIII after SARS-CoV-2 Vaccines
In mid-2021, the first cases of bleeding complications were reported 15 to 19 days
(or later) after vaccination with adenoviral vector vaccine ChAdOx1.[18] Farley et al report on a case of acquired hemophilia with a large hematoma of his
left posterior leg extending from his buttock to below his left knee, 19 days after
the second dose of BNT162b2 Pfizer-BioNTech vaccine. Laboratory values revealed a
two- to threefold prolongation of the activated partial thromboplastin time (aPTT),
decrease of hemoglobin to 10 g/dL, factor VIII activity <1%, and 110 Bethesda Units/mL
of factor VIII inhibitor. Platelet count, creatinine, and other laboratory parameters
were in the normal range. The patient had no personal and family history of hemorrhagic
diseases. The patient recovered without sequelae after adequate treatment.[19]
Other case reports also described the development of acquired hemophilia after SARS-CoV-2
vaccination.[20]
[21]
[22] These reports have as common the development of hemophilia with major bleeding following
vaccination with one of the approved SARS-CoV-2 vaccines. All patients described so
far presented with prolonged aPTT values, undetectable factor VIII levels, elevated
factor VIII inhibitor concentrations, decreased platelet count, and reduced hemoglobin
levels. After adequate treatment measures, they all recovered without sequelae and
normalized coagulation values within a couple of weeks. One of these cases presented
with negative polymerase chain reaction SARS-CoV-2 test and positive SARS-CoV-2 IgG
antibodies, thus excluding with high probability that acquired hemophilia was an immunological
reaction to virus.[22] Interestingly, the development of a factor VIIIIc inhibitor was already described
in a patient with lichenoid dermatosis who had been vaccinated with BCG (Bacillus
Calmette–Guérin) and a pool of various strains of live-attenuated corynebacteria and
recovered without sequels after specific treatments.[23]
Anticoagulation and SARS-CoV-2 Vaccines
Anticoagulation and SARS-CoV-2 Vaccines
Thrombosis and hemorrhage may be a result of thromboinflammation due to viral infections,
and the role of anticoagulation is important to consider.[24] Administration of anticoagulants is of huge importance for thrombotic disease prevention
in COVID-19 patients, and heparins (unfractionated or low-molecular-weight heparins)
are the currently recommended agents for hospitalized COVID-19 patients.[25]
[26] Nevertheless, excessive doses and/or an accumulative effect of heparins may favor
bleeding, mainly in the hemorrhagic phase of the infectious disease when multiorgan
failure also occurs. Therefore, from patients' point of view, anticoagulants and SARS-CoV-2
vaccines share their capacity to induce thrombosis as well as bleeding. Thus, clinicians
are subjected to choosing between Scylla and Charybdis when they treat patients not
only with anticoagulants but also with SARS-CoV-2 vaccines ([Fig. 1]).
Fig. 1 Scylla and Charybdis phenomenon in hemostasis: similarities between anticoagulants,
SARS-CoV-2 vaccines, and selected other pathways (Copyright.com.de; deposit number:
DEP637698427981306749).
What the Future May Offer
What the Future May Offer
Several aspects will guide in future due to immunological reactions to SARS-CoV-2
vaccines:
-
Screening of patients for clinical symptoms of thrombosis and bleeding following vaccination
may be regarded as an option.[27]
-
Autoantibodies may be detected to other coagulation factors, proteins on platelet,
and endothelium surface capable to induce bleeding and/or thrombotic events.
-
Pan-sarbecovirus vaccines could seek to improve responses to this epitope by unmasking
this and other cryptic broadly neutralizing epitopes[28] aiming to reduce immunologic blood coagulation effects.
-
Careful analysis of coincidence and causality requires attention when reporting on
acquired coagulation inhibitors regarding severity, treatments, duration, and statistical
risk.[29]
-
Careful documentation of case reports on immunological reaction to SARS-CoV-2 vaccines
and of respective reactions from clinical studies in national and international registries.
