“Thromboinflammation in COVID-19: can α2-macroglobulin help to control the fire?”: Comment from Seitz et al.

Dear Editor,

An important element of progress in clinical care is the implementation of evidence-based medicine (EBM). Many clinical studies addressing COVID-19 have been conducted; a Google search on the item “covid 19 clinical study” yields >700,000,000 results. Soon after the onset of the pandemic, it was noted that a hypercoagulable state frequently occurred in patients who are severely ill [1]. For patients experiencing multiform venous or arterial thrombosis or embolism, prophylactic anticoagulation with heparins is a widely accepted recommendation [2]. The procoagulant state, flagged by elevated D-dimer levels, appears to be associated with worse prognosis [1], and therefore it was an obvious consequence that enhanced anticoagulation should be explored as a therapeutic approach to improve the overall outcome of severe COVID-19. Unfortunately, this option could thus far not be confirmed by clinical studies [3]. For instance, a recent trial [4] found that full-dose anticoagulation reduced thrombotic complications in patients who are critically-ill with COVID-19, however, with increased bleeding. There was no difference in all-cause mortality, and antiplatelet therapy with clopidogrel did not indicate an advantage.

EBM means integrating the best available research evidence with clinical expertise and patient values. However, in the case of COVID-19 thromboinflammation, the best available evidence is still insufficient. Do we need more and larger trials with heparins or anticoagulants, or should we seek other potential research targets? We may not yet sufficiently understand the nature and causes of the particular disturbance of coagulation in COVID-19, and therefore failed so far to find the appropriate weapons against it. The problem appears to be a prethrombotic condition and a very complex disorder involving multiple interactions between cellular and humoral systems. The clinical picture associated with COVID-19 was recently well characterized [5]: “The inflammatory response to SARS-CoV-2 infection commonly results in marked activation of coagulation - the process of thromboinflammation - with evidence of systemic endothelial damage and a resultant loss of normal anticoagulant properties.” Besides the direct impact of the virus on the function and integrity of endothelial cells, active host players like neutrophils are present, with their aggressive proteases such as neutrophil elastase and pronounced formation of neutrophil extracellular traps [6].

The above definition [5] gives rise to a closer look at the “loss of normal anticoagulant properties,” or in a broader sense, the impairment of natural mechanisms which usually should control any destructive overreaction of our potent and highly sensitive defense systems. Several crucial systems, such as blood coagulation, fibrinolysis, kallikrein-kinin, and complement, involve proteases, which may be part of cascades capable of rapid mutual proteolytic activation of factors, resulting in fast and strong amplification of responses. It might be a good idea to strengthen their natural counterparts, the proteinase inhibitors. Indeed, it has recently been proposed [7] to consider fresh frozen plasma or plasma derivatives to increase the level of endogenous anticoagulants. Therapeutic concentrates of, eg, antithrombin, (activated) protein C, C1-inhibitor, or α₁-antitrypsin are available but so far only used for niche indications, such as congenital deficiency.

In a previous article [8], we suggested the potential importance of another natural inhibitor and chaperone with a relatively high plasma concentration of ca. 1.5 to 3.0 g/L: α₂-macroglobulin (α₂-M) [9]. Structure and function were elucidated already in the 1980s; however, we still do not have a comprehensive understanding of its various functions, interactions, and potential pathophysiologic implications, and clinical investigations into the role of α₂-M, particularly in COVID-19, are few. The phylogenetically extremely old and conserved protein α₂-M is an acute phase reactant, capable of using a unique cache-mechanism to trap and neutralize a vast spectrum of inflammatory and hemostasis proteins, including cytokines, thrombin, and neutrophil elastase, which would make α₂-M an attractive candidate for modulation and attenuation of exaggerated activity of multiple systems involved in COVID-19 thromboinflammation. Many aspects of severe COVID-19 would be in line with sepsis, defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” [10]. One important difference to, eg, bacterial sepsis is that children rarely suffer from severe COVID-19 [10], and we provided arguments that they might be protected by their relatively high α₂-M level [8]. It is somewhat delicate to handle and prone to conformational changes affecting functionality - although it could be stabilized by sucrose [11] - and in contrast to other natural protease inhibitors mentioned above, α₂-M is not - maybe not yet? - available as a therapeutic concentrate but only as a constituent in fresh frozen or platelet-rich plasma.

Unfortunately, there has been little research so far into the role of host proteinase inhibitors in COVID-19. Suitable experimental models are lacking, and clinical studies until now have not demonstrated profoundly reduced plasma levels of inhibitors. However, maybe we could remember that decades ago, activation markers, such as enzyme-linked immunosorbent assays measuring, eg, thrombin-antithrombin complexes or neutrophil elastase-α₁-antitrypsin complexes were developed, which could provide a clue to proteolytic systems and inhibitors under stress. If one could identify a high turnover of an inhibitor, one might consider increasing its level, as suggested above [9].

We do not yet have a satisfactory solution to the problem of thromboinflammation in COVID-19, but we still have the chance to learn and elaborate by targeted experimental and clinical research as the basis for an EBM conform approach. We believe diagnostic studies focusing on the role of natural antiproteases, particularly α₂-M, would help develop new hypotheses and strategies for therapeutic approaches beyond heparin. What we urgently need was recently perfectly expressed [12]: “Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy.” We are convinced that the scientific hemostasis community should, and certainly could substantially contribute to the survival of COVID-19 patients.