Can post immunisation increase in acute phase proteins explain the recent thrombotic events with CoViD vaccines?
Dear Editor
There have been reports of haemorrhage, blood clots and thrombocytopenia following administration of CoViD-19 vaccines [1]. This has adversely affected Oxford/AstraZeneca CoViD vaccine rollout in parts of Europe and more recently in Canada [2].
In an attempt to find a potential link to recent thrombotic events, we looked at the pre-clinical safety review of CoViD-19 vaccines. The toxicity of COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) was evaluated in Wistar rats (Study 38166). An increased in circulatory white cells and acute phase proteins were found in rats that were consistent with an acute phase response [3]. This raised circulatory levels of acute-phase proteins may put the haemostatic system at an increased thrombotic potential.
The acute phase proteins that were categorically mentioned in the regulatory assessment report were fibrinogen, alpha-2 macroglobulin, and alpha-1 acid glycoprotein. Where fibrinogen (clotting factor I) is directly involved in clot formation to stop bleeding. Whereas elevated levels of macroglobulins may increase blood viscosity, which is an important factor for thrombogenesis; increased alpha-2 macroglobulin has been reported to inhibit coagulation factors that regulate anticoagulation [4]. The alpha-1 acid glycoprotein, on the other hand, has also been reported to contribute to platelet activation leading to platelets aggregation and thrombosis [5]. The potential toxicity of COVID-19 Vaccine AstraZeneca was studied in mice (Study 513351), and a similar acute phase response was noticed with increased plasma globulins (1.2x) and reduced plasma albumins (0.9x) [6]. There is, however, very limited information available so far in the public domain on both of these studies (38166 and 513351).
Some heparin-binding proteins (HBPs) are also acute-phase-reactant proteins, and it has been reported that the induction of the acute-phase response may therefore increase the plasma concentrations of HBPs [7], which in turn is known to increase the vascular permeability. Increased circulatory HBPs may also explain the recent discovery of anti-PF4/heparin antibodies in CoViD vaccinated individuals in Germany and Austria who experienced vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)[8].
The patients who developed thrombocytopenia following CoViD vaccination exhibited a favourable response to immune thrombocytopenia directed treatment (corticosteroids and IVIG) [9]. We previously proposed a likely mechanism that the genetic CoViD-19 vaccines may directly infect platelets and megakaryocytes triggering mRNA translation and consequent spike protein synthesis intracellularly. This may potentially result in an autoimmune response against platelets and megakaryocytes resulting in reticuloendothelial phagocytosis and direct CD8+ T cell lysis [10-11]. The consequent thrombocytopaenia may lead to internal bleeding and spontaneous blood clots. We, therefore, proposed that CoViD genetic vaccines may have a direct role in spurring autoimmune response against platelets that may clinically manifest in vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
As of 14th March 2021, MHRA Yellow Cards data suggested that there has been a total of ~205 thrombotic events (12 fatal) reported with Ox/AZ CoViD vaccine and ~71 (1 fatal) with Pfizer CoViD vaccine. A further 161 thrombotic events are recorded in the VAERS database in the United States with Pfizer and Moderna CoViD Vaccines as of 24th March 2021. Moreover, MHRA has reported 267 total bleeding events (6 fatal) with CoViD Vaccine AstraZeneca and 220 events (9 fatal) with Pfizer CoViD Vaccine. Another 439 bleeding events are recorded in VAERS in the USA with Pfizer and Moderna CoViD vaccines. For thrombocytopenia, there are about 60 cases (2 fatal) or 34 cases (1 fatal) reported in the UK with AstraZeneca or Pfizer CoViD vaccines respectively, with another 105 cases of thrombocytopenia reported in the United States with Pfizer and Moderna Vaccines.
It is plausible that the post-vaccination acute phase response may increase the risk of spontaneous clotting, perhaps similar to disseminated intravascular coagulation. This will in turn lead to reduced platelets and risk of bleeding in some individuals. Moreover, rare subjects with post-vaccination immune thrombocytopenia, are likely to be at increased risk of fatal thrombotic events. Vaccines are one of the great discoveries in medicine that has improved life expectancy dramatically. Nevertheless, genetic vaccines are new, and their long-term safety evaluation is a key to identify the potentially contraindicated group of subjects, for instance patients with history of blood disorders, past or current thrombocytopenia or those with pre-existing immunological conditions.
Rapid Response:
Can post immunisation increase in acute phase proteins explain the recent thrombotic events with CoViD vaccines?
Dear Editor
There have been reports of haemorrhage, blood clots and thrombocytopenia following administration of CoViD-19 vaccines [1]. This has adversely affected Oxford/AstraZeneca CoViD vaccine rollout in parts of Europe and more recently in Canada [2].
In an attempt to find a potential link to recent thrombotic events, we looked at the pre-clinical safety review of CoViD-19 vaccines. The toxicity of COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) was evaluated in Wistar rats (Study 38166). An increased in circulatory white cells and acute phase proteins were found in rats that were consistent with an acute phase response [3]. This raised circulatory levels of acute-phase proteins may put the haemostatic system at an increased thrombotic potential.
The acute phase proteins that were categorically mentioned in the regulatory assessment report were fibrinogen, alpha-2 macroglobulin, and alpha-1 acid glycoprotein. Where fibrinogen (clotting factor I) is directly involved in clot formation to stop bleeding. Whereas elevated levels of macroglobulins may increase blood viscosity, which is an important factor for thrombogenesis; increased alpha-2 macroglobulin has been reported to inhibit coagulation factors that regulate anticoagulation [4]. The alpha-1 acid glycoprotein, on the other hand, has also been reported to contribute to platelet activation leading to platelets aggregation and thrombosis [5]. The potential toxicity of COVID-19 Vaccine AstraZeneca was studied in mice (Study 513351), and a similar acute phase response was noticed with increased plasma globulins (1.2x) and reduced plasma albumins (0.9x) [6]. There is, however, very limited information available so far in the public domain on both of these studies (38166 and 513351).
Some heparin-binding proteins (HBPs) are also acute-phase-reactant proteins, and it has been reported that the induction of the acute-phase response may therefore increase the plasma concentrations of HBPs [7], which in turn is known to increase the vascular permeability. Increased circulatory HBPs may also explain the recent discovery of anti-PF4/heparin antibodies in CoViD vaccinated individuals in Germany and Austria who experienced vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)[8].
The patients who developed thrombocytopenia following CoViD vaccination exhibited a favourable response to immune thrombocytopenia directed treatment (corticosteroids and IVIG) [9]. We previously proposed a likely mechanism that the genetic CoViD-19 vaccines may directly infect platelets and megakaryocytes triggering mRNA translation and consequent spike protein synthesis intracellularly. This may potentially result in an autoimmune response against platelets and megakaryocytes resulting in reticuloendothelial phagocytosis and direct CD8+ T cell lysis [10-11]. The consequent thrombocytopaenia may lead to internal bleeding and spontaneous blood clots. We, therefore, proposed that CoViD genetic vaccines may have a direct role in spurring autoimmune response against platelets that may clinically manifest in vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
As of 14th March 2021, MHRA Yellow Cards data suggested that there has been a total of ~205 thrombotic events (12 fatal) reported with Ox/AZ CoViD vaccine and ~71 (1 fatal) with Pfizer CoViD vaccine. A further 161 thrombotic events are recorded in the VAERS database in the United States with Pfizer and Moderna CoViD Vaccines as of 24th March 2021. Moreover, MHRA has reported 267 total bleeding events (6 fatal) with CoViD Vaccine AstraZeneca and 220 events (9 fatal) with Pfizer CoViD Vaccine. Another 439 bleeding events are recorded in VAERS in the USA with Pfizer and Moderna CoViD vaccines. For thrombocytopenia, there are about 60 cases (2 fatal) or 34 cases (1 fatal) reported in the UK with AstraZeneca or Pfizer CoViD vaccines respectively, with another 105 cases of thrombocytopenia reported in the United States with Pfizer and Moderna Vaccines.
It is plausible that the post-vaccination acute phase response may increase the risk of spontaneous clotting, perhaps similar to disseminated intravascular coagulation. This will in turn lead to reduced platelets and risk of bleeding in some individuals. Moreover, rare subjects with post-vaccination immune thrombocytopenia, are likely to be at increased risk of fatal thrombotic events. Vaccines are one of the great discoveries in medicine that has improved life expectancy dramatically. Nevertheless, genetic vaccines are new, and their long-term safety evaluation is a key to identify the potentially contraindicated group of subjects, for instance patients with history of blood disorders, past or current thrombocytopenia or those with pre-existing immunological conditions.
References:
[1] https://doi.org/10.1186/s40545-021-00315-w
[2] https://www.bmj.com/content/373/bmj.n883
[3] https://www.gov.uk/government/publications/regulatory-approval-of-pfizer...
[4] https://www.karger.com/Article/Pdf/48038
[5] https://pubmed.ncbi.nlm.nih.gov/19806255/
[6] https://www.ema.europa.eu/en/documents/assessment-report/vaxzevria-previ...
[7] https://www.ahajournals.org/doi/full/10.1161/01.ATV.17.8.1568
[8] https://doi.org/10.21203/rs.3.rs-362354/v1
[9] https://doi.org/10.1002/ajh.26132
[10] https://www.bmj.com/content/372/bmj.n699/rr-6
[11] https://www.bmj.com/content/372/bmj.n699/rr-20
Competing interests: No competing interests