The current pandemic induced by the coronavirus COVID-19 is a good example of viral infection associated with a systemic inflammatory response and activation of coagulation in symptomatic patients. However, as has been peevishly pointed out, disseminated intravascular coagulation (DIC) is a recognised complication of bacterial infections; coronavirus infection may also cause it and condition thrombotic phenomena in diverse regions. Although the mechanism of coagulopathy has not specifically established, it is known that viral infections induce a systemic inflammatory response accompanied by a “storm of cytokines”, which alter the balance between pro and anti coagulant mechanisms and therefore promote endothelial impairment, raising of the levels of von Willebrand factor and tissue factor, promoting activation of coagulation mechanism. Changes in coagulation and thrombotic complications are common in these patients. In a retrospective series of 183 patients Tang et al. reported that 71.4% of those who died met with the DIC criteria, compared with .6% of the survivors. 16 In this, and in other series, alterations of coagulation tests have been described, including the increase of dimer D (36%–50%), prolongation of prothrombin time (30%) and partially activated thromboplastine (PATP) (16%) and thrombocytopenia (0%–30%). The patients infected by this virus, in addition to developing DIC, may present with venous thrombosis and/or pulmonary embolism, and arterial embolism, with episodes of ischemia having been described in the lower limb toes which may lead to gangrene. Very recent results obtained from patients in the area of Wuhan in China have demonstrated dimer D, a marker of thrombin generation and of fibrinolysis, which constitutes a relevant prognostic indicator of mortality. These studies indicate that dimer D levels above 1000 ng/mL s are associated with an 18 times higher risk of mortality, to the point where today this is included the screening of all positive symptomatic COVID -19 patients. The fact that there is a coagulopathy present in these patients has led to promoting antithrombotic strategies, especially in patients who are admitted to the ICU and/or show organic damage or have had ischemic episodes as previously described. Although the best antithrombotic strategy has yet to be established, it appears that low weight molecular heparins at prophylactic or intermediate doses should be administered to these patients after their admission to the ICU or when dimer D values are 4 time higher than normal.16–18

This is a clinical syndrome characterised by an exaggerated response of the host to the infection, which leads to an uncontrolled inflammatory response and generalised activation of the haemostatic system. After exposure to pathogens, toxins, microbials or PAMPs, the endothelial cells acquire a proapoptotic proinflammatory and prothrombotic phenotype. They also damage the glycocalix and impair vascular tone. A common complication of patients with sepsis is DIC, which is characterised by general activation of coagulation through the TF in response to proinflammatory cytokines. Also, this leads to a drop in the function of natural anticoagulants and suppression of fibrinolysis through an increase in PAI-1. The result is generalised microthrombosis which leads to organ damage and high mortality. Multiple evidence exists that inflammasome is involved (NLRP3) in the pathogenesis of sepsis, with an effect on the generation of IL1β, mitochondrial response, and for its cardiovascular, renal and central nervous system effects.19–21

This is a multisystemic vasculitis which causes oral and genital ulcers, skin wounds, arthritis, uveitis, gastrointestinal ulcers and venous and arterial thrombotic manifestations in 12% of cases, with those affecting the venous region being the most frequent. The participation of neutrophils and the generation of NETs has been linked to thrombotic risk. An increase in NLRP3 and IL1β22,23 expression has also been observed.

Venous thromboembolism is a common complication in patients with antineutrophil auto-antibodies (ANCA). An increase in TF and procoagulant microparticles was observed which contributed to the hypercoagulability. There is also an increase in cytokines, including IL1β y TNF-α, which lead to an increase in TF responsible for thrombosis, and a raised expression of NLRP3, NLRC5, IL1β and IL18.24,25

Together with Crohn’s disease and ulcerous colitis this is associated with an increased risk of venous and arterial thromboembolism, possibly related to cellular and molecular changes involved in the haemostatic process. This risk has been described as being 2–3 times higher than that of the general population, exacerbating during periods of activity and lowering during periods of remission. Inflammatory bowel diseases are also a risk factor for splanchnic, portal and mesenteric thrombosis and are associated with increased risk of myocardial infarction and stroke. Among the proposed mechanisms an increase in inflammatoy cytokines has been described which are involved in a prothrombotic state manifested as thromocytosis, raised TF, II, V, VII, VII and X and fibrinolysis deficiency. The frequent use of corticoids can exacerbate the prothrombotic state, to which other factors are added, including malnutrition and the insertion of central venous lines. A raised expression of NLRP3 and IL1β has been observed, together with a lowered expression of NLRP6 and NLRP12.26,27

Different autoimmune diseases, including SEL and RA are considered to be separate risk factors for the development of venous and arterial thrombosis, which play a part in increasing mortality (up to 25%) in these patients, that is partly linked with the presence of antiphospholipid antibodies.28,29 Furthermore, cardiovascular diseases of an atherosclerotic nature are a major cause of morbimortality, which has been related to immune deregulation, hyperhomocysteinaemia, inflammation and endothelial dysfunction, with expression of adhesion molecules (ICAM-1 and VCAM-1) and procoagulating factors. In both entities a raised expression of NLRP3 has been described, and an increase in caspase-1 e IL1β and IL18.30,31 Also, polymorphisms in NLRP1 have been associated with these diseases.32,33 Apoptotic deregulation is also present in patients with rheumatic disease, in such a way that in inflammatory cells such as lymphocytes the apoptosis lowers through the over-expression of BCL2, inducing tissue damage with a higher exposure of antigens and production of auto-antibodies.34

This is considered to be the most commonly acquired thrombophilic state, defined by thrombosis or gestational morbidity associated with the presence of antiphospholipid antibodies. Venous thrombosis at lower limb level and thrombosis in cerebral circulation are the most common locations for the presence of venous and arterial thrombosis, respectively. Antiphospholipid antibodies play a major pathogenic role, since they induce thrombosis through different mechanisms, including endothelial activation and monocytosis with raised TF and thromboxane A2. Furthermore, inflammasome activation through NLRP3 has been demonstrated, with increased caspase-1 and the production of IL1β.35,36 In antiphospholipid syndrome an increase in apoptosis has also been described as inducing the exposure of phosphatidylserine which would represent an additional mechanism to drive procoagulant activity.37

This is characterised by acute, recurrent fever, accompanied by polyserositis, with arterial and venous thrombosis being common as a consequence of endothelial lesion/impairment. The most current hypothesis is based on the pathogenic role of the gene MEFV, which codes a protein of the pyrin family. A mutation of this gene leads to an increase in the leukocyte expression of proinflammatory cytokines (IL1, IL6, IL18), which lead to endothelial damage and activate coagulation, triggering thrombosis. Activation of inflammasome, via NLRP3 has also been observed, with uncontrolled production of IL1β.38–40

To conclude, better knowledge regarding the association between thrombosis and inflammation may be of use in the determining new therapeutic strategies. Research of agents which act against inflammasome may be a new therapeutic pathway against thrombosis. For example, it has been demonstrated that a specific NLRP3, MCC950 inhibitor could be used in managing certain diseases with high inflammatory components.41,42

Reference to the influence of inflammasome in the context of thrombosis may, therefore, have a cross-sectional application for the prevention of cardiovascular and thrombotic manifestation associated with inflammatory processes.