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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety reviewed information from several countries and concluded that a causal relationship between the vaccine and occurrence of blood clots with low platelets is considered plausible but it not confirmed. Specialized studies are needed to fully understand the potential relationship between vaccination and possible risk factors.(1) The key is to look at the observed incidence following>

 

Blood clots and low platelets:

Blood clots are unusual in the setting of low platelets as have been seen in patients post COVID-19 vaccines. The role of platelets is to prevent bleeding, when patients present with low platelets they are at a higher risk for bleeding. There have been 287 reports of rare blood clots (as of 4/20/2021)with low platelets after the AstraZeneca vaccine, 8 with Johnson and Johnson, 25 with Pfizer and five with Moderna. These clots have occurred in unusual locations such as cerebral venous sinus thrombosis (CVST) and splanchnic vein thrombosis. What has caused these vaccines to result in blood clots?(2)

There are two processes that can cause thrombocytopenia. The first is an immune process. Normally macrophages engulf and clear old platelets but if this process gets out of control it can lead to excess clearance and decreased platelets resulting in bleeding.(2) The second process involves consumption of platelets when they become activated and form blood clots, if this process gets out of control, the platelets continue to aggregated, get consumed resulting clotting and in thrombocytopenia.(2)

Both of these processes have been linked to vaccine associated thrombocytopenia but involve at least two different autoantibodies. ITP or immune thrombocytopenia occurs when the body produces antibodies against platelets resulting in clearing that at a must higher rate resulting in a decreased platelet count. This has been seen as a result of some medications, infection and vaccines and has been associated with a slightly increased risk of blood clots.(2)

"Vaccine-induced immune thrombotic thrombocytopenia" (VITT) has been coined to refer to cases of low platelets with unusual clots reported after COVID-19 vaccines. This is similar to an autoimmune condition called heparin-induced thrombocytopenia (HIT). In HIT, heparin caused an immune IgG reaction in which the antibody platelet factor 4 (PF4) platelet factor 4 (PF4) activates platelets leading to a reduction in platelet count resulting in clotting. This consumptive process occurs in 1-2% of patient on heparin.(2)

When it comes to management, because of the similarity of VITT to HIT, experts are advising IV immunoglobulin, use of non-heparin anticoagulants, and avoidance of platelet transfusions. The International Society on Thrombosis and Haemostasis has provided guidance (ISTH Interim Guidance for the Diagnosis and Treatment on VaccineInduced Immune Thrombotic Thrombocytopenia) for the diagnosis and treatment of VITT, as has the American Society of Hematology Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia).(2)

 

Clots After Other Vaccines

ITP has been reported in viruses like HIV and hepatitis C as well as in other vaccines, however the reports are not sufficient to cause concern and come from small numbers of case reports. After receiving the MMR vaccine 1-3 children/100,000 present with ITP, which is lower than seen in viruses. Mild ITP has been reported after vaccines given for flu, varicella-zoster, hepatitis B, DTP and Shingrix zoster vaccines.(3)

 

ASTRA ZENECA

The CDC reported on the association and causal link between AZ vaccine and rare clotting events. As of April 14th, there have been 62 cases of Cerebral Venous Sinus Thrombosis (CVST) and splanchnic vein thrombosis with thrombocytopenia, of those cases most were female under the age of 60 and occurred within 2 weeks of being vaccinated. Eighteen of those cases were fatal.(5) CVST refers to clots forming in veins that drain the brain, which can lead to hemorrhage and stroke. It is very rare, and normally affects about 5 people in 1 million per year.(6)

 

Johnson and Johnson:

The vaccine has been administered to more than 7 million people and seven have experienced CVST. The clots are rare and result in thrombocytopenia. The vaccine triggers and undesirable immune response that causes platelets to be activated. Administration was placed on a pause until further investigation, however administration has resumed and includes a warning to be aware of possible symptoms.(7)

 

Hypotheses:

When looking at both the mRNA and AVV it is believed that they could induce synthesis of the COVID spike protein within platelets which in turn may trigger an autoimmune reaction against platelets. This may be possible in all of the vaccines. It has also been speculated that ITP related to the vaccine may be a separate process involving a different autoantibody than the HIT reaction linked to the CVST cases seen in Europe.(7)

Additionally all adenoviral vector vaccine platforms are not the same and may have different biological characteristics and effects. The J&J vaccine uses human Ad.26-based vector, whereas AstraZeneca uses a chimpanzee adenovirus-based vector, ChAdOx1. They also use different host cell receptors. Also studying the anti-PF4 antibodies in recipients of all vaccines may help to provide insight into the risk of VITT as well as the pathophysiological mechanisms underlying the condition.(8)

Clotting brought about by the COVID-19 infection can cause autoimmune associated thrombocytopenia and thrombosis, but clotting occurs as a DVT or a PE. Clotting in VITT occurs in the brain and the abdomen which are atypical locations for clotting. Despite being speculation, lower extremity veins belong to different vascular beds then those in the abdomen and brain, which may express different proteins which play a role in clot development.(9)

German scientists have a theory that encompasses a two-step mechanism regarding how the AstraZeneca vaccine causes the consumption of platelets resulting in blood clots. Their hypothesis is that in regard to the adenoviruses and how they ferry instructions for producing the viruses spike protein into cells. Previous studies have shown that adenoviruses can cause this type of platelet activation. This study describes a cascade of events that occurs in the body prior to the vaccine developing these large clots. The mechanism of the immune system that leads to these clots is almost always kept in balance. In some cases where there is a perfect storm where each stage progresses to the next and the end result is very hard to control and this autoimmune attack causes the body to enter a hypercoagulable state. When patients receive rapid treatment the condition will resolve.(10)

In the first step of the clotting process, the adenovirus shell in the vaccine along with proteins from the cells where the vaccine is grown come in contact with platelets. When they are activated, they surround invaders, undergo a shape change and release chemical signals from their granules. This can happen both when certain patients take heparin, and as was seen in the AV vaccine. It results in a hard to control branch of the immune response. It alerts B-cell which then produce massive amounts of antibodies against the PF4 protein. The body believes that it is reacting to pathogens, so the immune system reacts, antibodies bind to platelets which then recruit white blood cells.(10)

The second step of a reaction may be caused by EDTA, which is a calcium binding agent and stabilizer which is present in the AZ vaccine, but not the J&J vaccine. The EDTA causes the walls of blood vessels to become leaky which allows giant complexes formed by proteins and platelets to enter blood circulation where they can trigger bodywide alarm.(10)

 

CONCLUSION:

When the vaccines were distributed, they were received with both hope and skepticism. No one would have thought that the possibility of a blood clot would occur when they rolled up their sleeve to get vaccinated. A formal review from the WHO and EMA both issued statements that the overall risk for clotting is no higher than in the general population and the benefits outweigh the clotting risk. Making people aware of the signs and symptoms of these rare clotting events is very important, since they are treatable. Since the events seem to occur in people below the age of 55, several countries have placed age limits on who can get the vaccine.

On a personal note, I do believe that vaccination will be the only way to achieve a return to our new normal- but best of all, when people are vaccinated, you can HUG!

 


 

REFERENCES:

  1. LabLINE, EMA finds possible link to unusual blood clots with AstraZeneca COVID-19 vaccine Apr 8th, 2021 MLO EMA finds possible link to unusual blood clots with AstraZeneca COVID-19 vaccineu>
  2. Veronica Hackethal, Why Clotting Happens When Platelets Are Low, MedPage Today April 23, 2021 Why Clotting Happens When Platelets Are Low | MedPage Today
  3. Hackethal, V., Vaccines and Rare Clotting Disorders: What's the Link? MedPage Today March 25, 2021 Vaccines and Rare Clotting Disorders: What's the Link? | MedPage Today
  4. Eun-Ju Lee1 | Douglas B. Cines2 | Terry Gernsheimer3 | Craig Kessler4 | Marc Michel5 | Michael D. Tarantino6 | John W. Semple7 | Donald M. Arnold8 | Bertrand Godeau5 | Michele P. Lambert9,10 | James B. Bussel1, Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination, Am J Hematol. 2021;1–4. wileyonlinelibrary.com/journal/aj
  5. Dr. Beth Bell, Work Group Chair, ACIP COVID-19 Vaccines Work Group, April 14, 2021, https://www.gov.uk/government/publications/use-of-the-astrazeneca-covid-19-vaccine-jcvi-statement/jcvi-statement-on-use-of-the-astrazeneca-covid-19-vaccine-7-april-2021
  6. Hackethal, V., Vaccines and Rare Clotting Disorders: What's the Link? MedPage Today March 25, 2021 Vaccines and Rare Clotting Disorders: What's the Link? | MedPage Today
  7. Godoy, M., Johnson & Johnson Vaccine And Blood Clots: What You Need To Know, https://www.npr.org/sections/health-shots/2021/04/13/986767069/johnson-johnson-vaccine-and-blood-clots-what-you-need-to-know, April 13, 2021.
  8. Walker, M., J&J Tries to Distance Itself From AstraZeneca Vax MedPage Today April 16, 2021, J&J Tries to Distance Itself From AstraZeneca Vax | MedPage Today
  9. Hackethal, V., From VIPIT to VITT: Thrombosis and COVID Vaccines MedPage Today April 9, 2021
  10. 10. Goodman.B., Scientists Reveal How the AstraZeneca Vaccine Causes Unusual Clots. Scientists Reveal How AstraZeneca Vaccine Causes Unusual Clots (medscape.com), April 20, 2021.