Chicken or Egg? Considering the outcome of 183 patients admitted to Tongii Hospital in Wuhan in January, mean age, 54 when all patients received supportive care and antivirals. 41% had comorbis chronic diseases. 45.9% remained as inpatients with an overall mortality of 11.5%. The patients were tested for prothrombin time, activated partial thromboplastin time, antithrombin, fibrogen, D-dimer and fibrin degradation products every 3 days for the first 2 weeks as inpatients. 71.4% succumbed to the virus as non-survivors and 4% showed no evidence of disseminated intravascular coagulation. Speculation as to whether this is caused by the virus directly has been presented in the news bulletins giving COVID 19 an even more sinister characteristic or may the observed blood clotting be more due to the comorbidity conditions with a pre-existing thrombophilia tendency, than purely COVID 19. A chicken or the egg discussion of this situation needs to be addressed. Thrombosis can simply occur due to immobility, particularly postoperatively and, although patients are regularly turned intensive care treatment, this level of activity may exacerbate blood clotting complications. Clearly pre-existing cardiovascular conditions are an important factor such as arterial thrombi in MIs and Strokes. Genetic factors that interfere with the human coagulation cascade are relatively common. Thrombophilia can be caused by a severe deficiency of inhibitors (type I) or a severe elevation of coagulation factors the can be congenital or acquired also arterial, venal or combined. Venal thrombosis can be portal, renal, hepatic, Paget-Schrotter disease (upper extremity) and Thoracic outlet syndrome (unrelated to trauma). Of the congenital conditions 5% of the population have the Factor V Leiden thrombophilia condition where 95% carting this genetic mutation develop a blood clot during their life. • Prothrombin mutation (G20210A, 5’UTR) • High homocysteine levels due to MTHFR mutation (High homocysteine levels also due to vitamin deficiency B6, B12 and folic acid) • Factor VIII promoter polymorphism (high FVIII levels) • Other factors causing blood clotting are autoimmune disorders such as Anticardiolipid antibodies • Lupus anticoagulants • Renal disease (renal loss of thrombin) • Budd-Chiari syndrome Some rarer coagulation abnormalities include • Plasmogen and fibrinolysis • Paroxysmal nocturnal haemoglobinuria (haemolytic) • Protein C deficiency • Protein S deficiency • Antithrombin III deficiency Lillicrap D. Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia. J Thromb Haemost. 2020;18(4):786‐787. doi:10.1111/jth.14781 Disseminated Intravascular Coagulation Mutation Coagulation Coronary Thrombosis
Could autoimmunity be the causal link between the observed thrombosis and COVID 19 vaccine, with particular regard to convalescent patients?
An important question in the understanding of genetic consideration of different phenotypes in the population to receive the COVID 19 vaccines is, will anyone react adversely. Recognising that specific immunology with the kinetics of gene expression and form often varies between individuals. The immune response in the population can have extremely different outcomes and it is an important step to further understanding some of these processes.
Polymorphisms in immunology related genes could affect disease pathogenesis and responses to treatment/vaccines. Indeed, some patients may react completely unexpectedly to therapy. Epigenetic factors can also change gene expression and change an immune response.
The cytokine storm experienced in patients with COVID 19 produces an uncontrolled, excessive and prolonged pro-inflammatory release of cytokines. This also occurs in non-infectious diseases, such as Systemic Lupus Erythematosus (SLE), the chronic autoimmune disease that also disproportionately affects black and Hispanic populations and, similarly, causes tissue damage, lymphopenia, aberrant T-cells and proinflammatory cytokines.
Both COVID 19 and SLE cause multi-organ complications of interstitial pneumonia, cytopenia, arthralgia, myocarditis and haemophagocytic lymphohistiocytosis (HLH).
Another similarity is where Hyaluronic acid is up-regulated in the lungs of severely affected patients in both conditions associated with tissue damage, mast cell activation and histamine expression.
SLE is distinguishable by anti dsDNA autoantibodies whereas COVID 19 has anti-SARSCoV2 antibodies as well as antinuclear antibodies and other autoantigens, potentially as a result of viral cross-reactivity and molecular mimicry, in severely affected patients. Both conditions have hyperinflammatory reactions to extracellular matrix proteins causing damage to the structure and function of tissue, for example in the lungs.
As well as viral persistence in immune privilege sites with the assistance of Th17 cells, genetics, hormones and environmental factors can lead to loss of self-tolerance with aberrant immune responses of the innate and adaptive immune systems. IL-17A expression is up regulated by Th17 cells at sites of inflammation in several autoimmune diseases and these cells are increased in patients with severe disease. With reference to thrombophilia is rare vaccination reactions to the Astra Zeneca vaccine, some convalescent patients may have SARSCoV-2 induced lymphopenia and thrombocytopenia similar to SLE, where thrombosis occurs with a low platelet count, induced by autoantibodies to platelets.
Some homologous coronavirus sequences have been identified aligning to human proteins and a particular autoimmunity risk by molecular mimicry is expected in individuals with HLA*02:01 and HLA*A24:02 serotypes.
There is an expansive autoantibody landscape identified in COVID 19 patients where some distinct autoantibodies exert different clinical and immunological outcomes.
Other factors affecting hemostasis cause thrombosis in the population are genetic thrombophilic factors like, Factor V Leiden, protein S and protein C mutations.
Where convalescent patients included in the vaccination trial programme, when immune responses were investigated and identified in trial participants? Kohm AK, Fuller KG, Miller SD. Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol. 2003;11:101–105
Lule S, Colpak AI, Balci-Peynircioglu B, et al. Behcet Disease serum is immunoreactive to neurofilament medium which share common epitopes to bacterial HSP-65, a putative trigger. J Autoimmun. 2017;84:87–96.
Yekbun Adiguzel, Coronavirus associated molecular mimicry common to SARS-CoV-2 peptide
bioRxiv 2021.01.28.428642; doi: https://doi.org/10.1101/2021.01.28.428642
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