By K Srinath Reddy
A critical but really uncommon adverse impact. This is the scientific consensus that has emerged immediately after each the European and British regulators examined the association of uncommon blood clotting events reported in some persons vaccinated with AstraZeneca’s Covid-19 vaccine. Jonathan Van Tam, Britain’s Deputy Chief Medical Officer was more colourful in calling it “a vanishingly rare but sadly a very serious adverse event.” At an estimated incidence of 1 in one hundred,000, it is certainly really uncommon. However, with quite a few deaths amongst these impacted, it is also really critical.
Causal or coincidental? This is the query that is normally addressed when adverse events are reported in persons who are administered a vaccine. After initial expressions of scepticism about a doable causal hyperlink, the scientific neighborhood and regulators have now concluded that a causal hyperlink is recommended by a constant association, even even though the mechanistic pathway is not clear as however.
Younger persons, under 50 years of age, appear to be impacted, amongst the vaccine recipients. Women predominate amongst the impacted. This has led to lots of nations decreeing that the vaccine need to not be administered to persons below 60 years of age. This was an ironical turn about from a time when some European nations had decided that older persons (above 65 years in some nations and above 55 years in other people) need to not be offered the vaccine since the multi-nation AstraZeneca trial had integrated only smaller numbers of older persons.
A later substantial American trial of the vaccine helped to override that objection. By the time the European nations removed the bar on employing that vaccine for older persons, reports began flowing in of critical blood clots in young persons getting the vaccines. The position reversed swiftly with the vaccine now permitted only for older persons and barred for young persons! Indian regulators have stated that related adverse events have not been reported so far in India and have not imposed any restrictions.
The pathological manifestations of this adverse occasion are really uncommon. Clots happen in the veins, but at uncommon areas. The cerebral sinus vein of the brain and the splanchnic veins (which drain the blood from the intestines and other abdominal organs) have been the web pages exactly where substantial clots formed. This phenomenon was accompanied by a low platelet count. Platelets are blood cells which aid to kind clots to quit bleeding. Usually, a low platelet count manifests as a bleeding tendency, not as a clotting dilemma. That is what we see, for instance, as a complication of serious dengue fever. The paradox of blood clotting combined with a low platelet count tends to make this a really uncommon complication, in addition to the uncommon web pages exactly where the venous thrombosis is occurring.
The puzzle relating to the mechanism underlying these manifestations remains, even as the situation has acquired a health-related name. Since it is akin to a previously described situation referred to as heparin induced thrombocytopenia (HIT), German and Austrian scientists have named it Vaccine Induced Prothrombotic Immune Thrombocytopenia (VIPIT). This new entity also has capabilities of venous blood clotting linked with a low platelet count but is not linked to the use of heparin, an anti-coagulant blood thinner. Describing related instances, Norwegian scientists have labelled it vaccine-induced immune thrombotic thrombocytopenia (VITT). Whichever name lastly stays on in the scientific literature (I choose VIPIT), the situation has thrown up a critical challenge to vaccine rollout globally.
Antibodies directed at the platelets have been described in these instances, indicating that an auto-immune reaction is accountable. While the trigger is administration of heparin in HIT, it is the AstraZeneca vaccine that seems to set off this uncommon reaction in VAPIT. Treatment with intravenous immunoglobulin and prednisolone (a steroid) proved valuable in some instances, buttressing the suggestion of an autoimmune causal pathway. Further research will be required to determine susceptibility markers, early diagnostic tests and helpful treatment options. The situation getting so uncommon, that will take time. In the meanwhile, nations are employing younger age as a threat predictor to stop VIPIT, by avoiding administration of this vaccine.
Why need to there be improved clotting rather of bleeding, when the platelet count is low? Why is the clotting noticed largely in veins and not in arteries? Why does clotting happen in uncommon areas like the cerebral sinus vein and splanchnic veins, rather than in the legs which are the usual web pages of deep vein thrombosis (as in extended distance fliers or immobilised hospital patients)? These are some clinical conundrums that need to have to be clarified even as the immuno-pathology pathways are getting identified.
Clotting mechanisms in veins and arteries are various. The veins are thin walled and carry blood at a low stress, with low shear anxiety on the walls. Arteries are thicker, with more smooth muscle in their walls and can withstand the shear anxiety of a higher stress blood flow. Coagulation things are proteins developed by the liver which circulate in the blood and initiate clot formation to staunch bleeding. The cascade of activation of these things ends up in a fibrin clot. This is the more dominant clotting pathway on the venous side. Platelets are circulating blood cells which clump collectively to kind platelet plugs about an injured arterial wall.
They are most frequently initiated by the rupture of an atherosclerotic plaque. Platelet activation is the principal pathway of clot formation on the arterial side. Anticoagulant drugs are used to stop venous thrombosis as they are very best suited for the low stress circuit even though anti-platelet drugs are used to stop arterial thrombosis as they are helpful in the higher stress circuit.
Both these pathways are complementary, even if their relative value varies amongst arteries and veins. When platelet count goes down markedly, bleeding can happen. However, if the coagulation cascade is activated by the body as a counter measure, it may perhaps lead to clotting in the veins if that response is excessive. Some of the instances of VAPIT had each cerebral bleed and cerebral sinus vein thrombosis. Treatment of the thrombosis with heparin was unhelpful and possibly counterproductive, since of the autoimmune pathway shared with HIT.
The uncommon areas of venous thrombosis also need to have additional elucidation. Deep vein thrombosis happens in the legs when the legs are immobile for a extended time. When mobile, the calf muscle pump does not permit the venous blood to stagnate. The patients of VAPIT have been young, mobile and would not have had venous blood stagnation in the legs. The splanchnic veins and cerebral veins have no such muscle pumps enclosing them. Did the autoimmune response to the vaccine causing a low platelet count trigger the coagulation cascade, top to clots in veins which have no muscle pumps to stop stagnation? This believed that arose in my thoughts is speculative.
If an autoimmune reaction directed at the platelets is the explanation why a chain reaction is initiated that proceeds to venous thrombosis, why is it noticed only with the AstraZeneca vaccine? Is it since it is the only Covid vaccine employing a chimpanzee adenovirus as a carrier of the spike protein code, even though other virus vector vaccines are employing human adenoviruses? If that is so, why is such an adverse reaction occurring in a minuscule proportion of persons getting the AstraZeneca vaccine? Many concerns stay for scientists to investigate and unravel.
Being really uncommon, treatment options of established efficacy are however to be identified. Intravenous immunoglobulin infusion appears to aid. Being an autoimmune manifestation, steroids are most likely to be valuable. Heparin and heparin-like anticoagulants need to be avoided. However, prevention would stay a higher priority. In the meanwhile, the AstraZeneca need to be utilised in accordance with national suggestions.
The author, a cardiologist and epidemiologist, is resident, Public Health Foundation of India (PHFI) Views are private