Blood clots, inherited thrombophilia and COVID-19 – 25 March 2021

Recent reports in the media from a collection of European countries suggest that there may be cause for concern with regards to the Oxford AstraZeneca COVID-19 vaccine and abnormal blood clotting. According to Norway’s medicines agency (NoMA), four new cases of “serious blood clotting in adults” have been identified following a recent review (1). Austria have suspended the use of one particular batch of the vaccine after two events, including an individual diagnosed with multiple blot clots who ultimately died 10 days after receiving the vaccine (2). Overall, more than a dozen European countries suspended their use of the AstraZeneca vaccine (3).

Following these reports, AstraZeneca issued an update on the safety data for their COVID-19 vaccine. Based on the available scientific evidence from the vaccination of over 17 million people across the European Union (EU) and UK, the company reports that there is “no evidence of an increased risk of pulmonary embolism, deep vein thrombosis (DVT) or thrombocytopenia, in any defined age group, gender, batch or in any particular country.” Reassurances have also come from The World Health Organization (WHO), who are currently undertaking their own investigation. Dr. Mariangela Simao, WHO Assistant Director-General for access to medicines and health products, commented ‘WHO is very much aligned with the position that we should continue immunization until we have clarified the causal relationship,’. The European Medicines Agency (EMA) has released a statement saying the benefits of taking the AstraZeneca-Oxford vaccine outweigh the risks of not taking it. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) said there was no evidence the vaccine had caused problems, and people should still go and get vaccinated when asked to do so.

Despite these reassurances, many will have concerns around their personal risk of a thrombotic event. The predisposition to form blood clots, a so called ‘hypercoagulable condition’, can arise from underlying genetic mutations, or acquired changes in the clotting mechanism. More commonly it is a combination of both genetic and acquired factors.  In the general population, the prevalence of an inherited thrombotic syndrome is presently estimated to be 1 individual in 2500-5000; the prevalence increases to 4% in patients with a past history of thrombosis (4). Inherited hypercoagulable conditions include:

  • Factor V Leiden mutation (G1691A/R506Q)
  • Prothrombin mutation (Factor II) (G20210A)
  • Elevated levels of homocysteine
    • MTHR (677 C>T)
    • MTHR (1298 A>C)
  • Deficiencies of natural clotting proteins e.g. protein C

A thrombophilia laboratory ‘screen’ often includes a range of tests, including both functional clotting assessments and genetic analysis. The choice of which genetic mutations to test for often depends on the ethnic admixture of the population being served and local guidelines taking into account clinical utility.

Factor V Leiden (FVL) is the most common of these heritable causes. It is caused by a single nucleotide substitution resulting in an R506Q mutation, resulting in factor V resistance to activated protein C (APC) inactivation. Heterozygosity for Factor V Leiden occurs in 3–8% of the US and European populations, and accounts for 40-50% of all cases of heritable hypercoagulable conditions (5). The lifetime risk of a clot in heterozygotes is around 10%, and this rises to 80% in homozygotes (6). The prevalence of a heterozygous G20210A prothrombin mutation is thought to be about 1.5% in the UK (7).

The ARUP laboratories testing directory (6) suggests testing for FVL should be considered in:

  • One unprovoked venous thromboembolism, particularly before age 50
  • Recurrent blood clots
  • Blood clots in unusual locations
  • Personal history of clots and one family member with clot before age 50 or two or more family members with clots
  • Individuals with low activated protein C (APC) resistance activity

These guidelines are broadly in line with those issued by NICE and the British Society for Haematology (BSH) in the UK for thrombophilia screening. However, in many countries a thrombophilia screen may also be considered in women who sadly experience recurrent miscarriage. Thrombophilia is a common cause of recurrent miscarriage, and has been reported in up to 40–50% of cases (8). Pregnancy is in and of itself an acquired form of hypercoagulable state that is exacerbated when a woman has an underlying predisposition such as FVL.

Identifying individuals with an underlying genetic predisposition is important for both understanding recurrence risk, and guiding treatment options. For example, there are specific recommendations for prophylactic use of anti-clotting agents in pregnant women with FVL. Testing can also offer reassurance for patients, or may prompt them to make lifestyle changes in light of a known inherited risk. Obesity is known to be a significant acquired risk factor for a clotting event, as is smoking and the use of some oral contraceptive pills (9).

Many trusted safety and advisory committees, including those from the EMA and the WHO, have presented compelling evidence that the benefits of the AstraZeneca vaccine still outweigh the risks despite possible a link to abnormal blood clotting events. Such events are very rare – around 20 million people in the UK/EEA have received the vaccine (as of 16/03/21) with only 25 cases presented to the EMA for review (10). An inherited predisposition to form blood clots, however, is not rare. Identifying those with an underlying predisposition is important to enable appropriate clinical decision making, and to allow individuals to make informed lifestyle choices in light of their personal risk.

At Yourgene Health we look to support our trusted laboratory partners to provide the testing services that offer most value to the patients they serve. Our Thrombophilia panel, TRP-Fplus, covers 4 of the most common mutations associated with thrombophilia:

  • Factor V Leiden (G1691A/R506Q)
  • Factor II (G20210A)
  • MTHR (677 C>T)
  • MTHR (1298 A>C)

Our assay therefore enables laboratories to provide a rapid, high-quality thrombophilia screen and identify those individuals with a predisposition to clotting events such as DVT.