Keywords platelet antigens - thrombosis - SARS-CoV-2 - vaccine
Schlüsselwörter Thrombo-zytenantigene - Thrombose - SARS-CoV-2 - Vakzin
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the novel severe
acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which can lead to systemic
multiorgan complications.[1 ] In particular, the risk of both venous and arterial thromboembolism is significantly
increased.[2 ]
[3 ] Several vaccines have been licensed and are currently being used in the European
Union to combat the COVID-19 pandemic.
On Monday, March 15, 2021, vaccinations with the COVID-19 vaccine from AstraZeneca
(AZD1222) were temporarily halted by the German Ministry of Health and other European
countries due to safety concerns regarding an elevated risk of thrombosis in vaccinated
individuals. Following the assessment of the potential risks and benefits of the vaccine
by the safety committee of the European Medicines Agency (EMA),[4 ] vaccinations were resumed on Friday, March 19, 2021. By that time, the Paul Ehrlich
Institute (PEI) had reported on 13 cases of sinus or cerebral vein thrombosis with
more than 1.6 million AstraZeneca COVID-19 vaccine doses administered. The thromboses
had occurred 4 to 16 days after vaccination with the AstraZeneca COVID-19 vaccine
in twelve women and one man aged 20 to 63 years. The patients also had thrombocytopenia,
which suggests an immunological event as the cause of the tendency to thrombosis.
However, thrombotic events may not exclusively present as intracranial thrombosis
but also manifest at other locations or vascular beds.
An important pathomechanism has meanwhile been clarified within the Society of Thrombosis
and Haemostasis Research (GTH) by the Greifswald Working Group under the leadership
of Andreas Greinacher. The vaccination is likely to induce the formation of antibodies
against platelet antigens as part of the inflammatory reaction and immune stimulation.
Depending on or independently of heparin, these antibodies subsequently cause massive
platelet activation via the Fc receptor in analogy to heparin-induced thrombocytopenia
(HIT). This mechanism (HIT mimicry) could be demonstrated in four patients with a
sinus/cerebral vein thrombosis after vaccination with the AstraZeneca COVID-19 vaccine
in Andreas Greinacher's laboratory in cooperation with other GTH members. It is currently
unclear, however, why this immunogenic thrombosis preferentially manifests in cerebral
vessels.
As with classical HIT, these antibodies appear 4 to 16 days after vaccination. This
pathomechanism does not rule out that the sinus/cerebral vein thromboses after vaccination
with the AstraZeneca COVID-19 vaccine also have other causes. However, the identified
mechanism forms the basis for the following statements and recommendations by the
GTH:
On a population basis, the positive effects of vaccination with the AstraZeneca COVID-19
vaccine outweigh the negative effects; so, the resumption of vaccinations in Germany
with this vaccine is to be welcomed.
According to the current state of knowledge, there is no evidence that thromboses
at typical locations (i.e., leg vein thrombosis, pulmonary embolism) are more common
after vaccination with the AstraZeneca COVID-19 vaccine than in the age-matched general
population.
Due to the immunogenesis of thrombosis in intracranial veins or other (atypical) locations,
patients with a positive history of thrombosis and/or known thrombophilia do not have
an increased risk of developing this specific and very rare complication after vaccination
with the AstraZeneca COVID-19 vaccine.
Flulike symptoms such as joint and muscle pain or headache that persist for 1 to 2
days after vaccination are a common side effect and not a cause for concern.
In the event of side effects that persist or recur more than 3 days after vaccination
(e.g., dizziness; headache; visual disturbances; nausea/vomiting; shortness of breath;
acute pain in chest, abdomen, or extremities), further medical diagnostics should
be carried out to clarify a thrombosis.
Important examinations include, in particular, complete blood count analysis with
determination of platelet count, blood smear, D-dimers, and, whenever indicated, further
imaging studies (e.g., cranial magnetic resonance imaging, ultrasound, computed tomography
of the chest/abdomen).
In the event of thrombocytopenia and/or evidence of thrombosis, testing for pathophysiologically
relevant antibodies should be carried out regardless of previous exposure to heparin
([Fig. 1 ]). The first test in the diagnostic algorithm is a screening test for HIT, which
is based on the immunological detection of antibodies against the platelet factor
4 (PF4)/heparin complex.
In case the screening test is negative, an HIT-like specific immunological cause of
thrombosis/thrombocytopenia can be ruled out. Importantly, not all commercially available
tests validated for the diagnosis of HIT are suitable for the detection of antibodies
involved in the specific pathogenesis of thrombosis following vaccination with the
AstraZeneca COVID-19 vaccine. Based on preliminary observations, the HYPHEN BioMed
ZYMUTEST and the Immucor GTI Diagnostics enzyme immunoassays appear to have appropriate
sensitivity for all pathophysiologically relevant antibodies.
In case the screening test for PF4/heparin antibodies is positive, a classical heparin-induced
platelet activation (HIPA) assay or serotonin-release assay (SRA) should be ordered
as a functional confirmatory test. These two assays detect pathophysiologically relevant
antibodies, which activate platelets dependent on (typical HIT) or independent of
exogenous heparin (autoimmune HIT). A positive test result in the absence of previous
heparin exposure thus establishes the diagnosis of autoimmune HIT.
In case the classical HIPA (or SRA) does not confirm (autoimmune) HIT, a modified
HIPA assay should be ordered. This assay has recently been established in Andreas
Greinacher's laboratory in Greifswald and detects pathophysiologically relevant antibodies,
which display a reaction pattern different from that observed in (autoimmune) HIT.[5 ] Thus, a positive test result establishes the diagnosis of vaccine-induced prothrombotic
immune thrombocytopenia (VIPIT).
Until (autoimmune) HIT is ruled out as the cause of acute thrombocytopenia/thrombosis,
if the clinical situation, availability, and experience permit, anticoagulation with
heparins should be avoided and alternative, HIT-compatible anticoagulants should be
used. These anticoagulants include danaparoid, argatroban, direct oral anticoagulants
(DOACs), and possibly fondaparinux. Regarding the use of fondaparinux, treatment of
acute thrombosis occurring more than 4 days following vaccination with the AstraZeneca
COVID-19 vaccine must be differentiated from pharmacological thromboprophylaxis during
the early phase following vaccination, which is characterized by activation of inflammatory,
immunostimulatory signaling pathways and during which administration of fondaparinux
may, at least theoretically, foster the production of platelet-activating antibodies
(see later).
In patients with confirmed (autoimmune) HIT or VIPIT and critical thromboses such
as sinus/cerebral or splanchnic vein thrombosis, the prothrombotic pathomechanism
can very likely be interrupted by administration of high-dose intravenous immunoglobulins
(IVIG), for example, at a dose of 1 g/kg of body weight daily on 2 consecutive days.[6 ]
[7 ] Anticoagulation will still be necessary to treat the thrombosis. While heparins
are contraindicated in (autoimmune) HIT, parenteral anticoagulation with heparins
is likely possible in confirmed VIPIT.
Diagnostics for HIT/VIPIT should be ordered prior to the administration of IVIG, since
high-dose immunoglobulins may lead to false-negative test results.
Routine pharmacological thromboprophylaxis with anticoagulants or antiplatelet agents
to prevent (atypically located) thrombosis resulting from the specific immunological
response following vaccination with the AstraZeneca COVID-19 vaccine is not indicated.
Patients receiving oral anticoagulation (OAC) for indications such as atrial fibrillation
or venous thromboembolism (VTE) should continue OAC during and after vaccination.
In patients with no indication for OAC who are at significant risk of VTE based on
dispositional risk factors, pharmacological thromboprophylaxis over several days may
be indicated on an individual basis in case of severe flulike symptoms with fever
and immobilization (AWMF S3 guideline VTE prophylaxis[8 ]
[9 ]).
Since pathophysiologically relevant HIT-like antibodies have been described in association
with the specific immunological response following vaccination with the AstraZeneca
COVID-19 vaccine, the authors of this guidance document advise against the use of
low-molecular-weight heparin or fondaparinux for pharmacological thromboprophylaxis.
According to the current state of knowledge, it cannot be safely ruled out that such
parenteral anticoagulants foster the production of platelet-activating antibodies.
In addition to general measures (e.g., exercise, fluid replacement, compression stockings),
prophylactic dosages of DOACs, such as rivaroxaban 10 mg once daily or apixaban 2.5 mg
twice daily, maybe be considered as an alternative on an off-label basis.
Regardless of (autoimmune) HIT and VIPIT test results, alternative causes of thrombocytopenia
and/or thrombosis must be considered and further clarified accordingly. These include,
for example, thrombotic microangiopathies such as immune thrombotic-thrombocytopenic
purpura or atypical hemolytic uremic syndrome, antiphospholipid syndrome, paroxysmal
nocturnal hemoglobinuria, and underlying malignant (hematological) diseases.
Fig. 1 Diagnostic and therapeutic algorithm in patients with thrombocytopenia/thrombosis
following vaccination with the AstraZeneca COVID-19 vaccine. Based on preliminary
observations, the HYPHEN BioMed ZYMUTEST and the Immucor GTI Diagnostics enzyme immunoassays
appear to have appropriate sensitivity for all pathophysiologically relevant antibodies.
HIPA, heparin-induced platelet activation; HIT, heparin-induced thrombocytopenia;
IVIG, intravenous immunoglobulins; PF4, platelet factor 4; SRA, serotonin-release
assay; VIPIT, vaccine-induced prothrombotic immune thrombocytopenia.
The guidance statements provided here may need an update upon availability of further
evidence. Every reader is therefore advised to stay updated with the latest literature
on this topic. The GTH guidance on VIPIT will be regularly updated on https://gth-online.org .
Erratum: This article has been corrected as per Erratum (DOI 10.1055/a-1473-8284) published
online.
