key: cord-0742845-1xhmzttc
authors: Schramm, Wolfgang; Seitz, Rainer; Gürtler, Lutz
title: COVID‐19‐associated coagulopathy ‐ Hypothesis: Are Children protected due to enhanced thrombin inhibition by higher α(2)‐Macroglobulin (α2‐M)?
date: 2020-07-14
journal: J Thromb Haemost
DOI: 10.1111/jth.15013
sha: 00c883568bb191b556b0da3f46b175008dd19cdf
doc_id: 742845
cord_uid: 1xhmzttc

We are overwhelmed by scientific publications on clinical observations, virology and epidemiology of SARS‐CoV‐2 infections. There is a growing body of evidence that hypercoagulability complicates COVID‐19, probably contributing to poor prognosis.

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The COVID-19 pandemic raises burning questions. For instance, children's role in pandemic is still a puzzle.

Several important observations in COVID-19 [4, 5] show age-dependent differences in the clinical course; children often have milder disease than adults do and deaths have been extremely rare. Whereas the attack rate in children appears to correspond to that in adults, it is obvious that children are less frequently diagnosed having lower susceptibility to infection, lower propensity to show clinical symptoms, or both [6] . The reasons for the relative resistance of children remain obscure. It was suggested that maturational changes, more active innate immune response, or differences in the distribution, maturation, and functioning of viral receptors may play a role [6] . Immune responses in adults are generally slower, less coordinated, and less efficient, making adults and particularly the elderly more susceptible to all infectious agents, due to a process denoted as immunosenescence.

Endothelial cells play a central role in inflammation and their alteration may trigger many involved mediator systems. The endothelial lesion in COVID-19 may thus culminate in a final, destructive phase of inflammation, sending a divers army of cells and cytokines to fight invaders and mop up the debris of battle [2] . It might be reasonable to assume that children are more likely to possess "healthier" immune response and endothelial cells than adults, particularly than elderly with hypertension, diabetes or vascular diseases. However, is this already the whole story about children's' obviously more favourable course of COVID-19? We think, in order to understand this advantage, we have to explore more closely the complex interactions of the general host defence systems, particularly those against bleeding or thrombosis and pathogen invasion, since thrombin as key activator of blood coagulation, platelets and endothelial cells may have profound impact on innate immunity].

What is different in children compared to adults and older people? There are age-related fluctuations in the physiological control circuits such as coagulation, fibrinolysis, and complement system. The plasma level of the "versatile" and unique inhibitor α2-Macroglobulin (α2-M) is particularly very high in childhood, more than 200% compared to adults [7] [8] [9] . The coagulation system in children is quantitatively different from adults. Many questions remain about the true nature of the age-related differences in the proteins themselves, and how these differences are regulated has remained a total mystery.

Interestingly, α2-M is a phylogenetically very old inhibitor. All animals and plants have immune systems that protect them from diversity of pathogens. In the plasma of vertebrates and members of several invertebrates, α2-M is an abundant protein [10]. It catches with its cage-like structure a great variety of activated proteins such as thrombin and immune mediators by "Venus flytrap" and "snap-trap" mechanisms [11] , thus keeping them away from their targets. Trapped peptidases are still active, but have restricted access to their substrates such as fibrinogen due to steric hindrance. While ATIII is the

This article is protected by copyright. All rights reserved predominant antithrombin, α2-M accounts for about 25 % of the antithrombin activity of plasma, abolishing clotting activities of thrombin in the fibrinogen test, but not impairing its esterase activity with synthetic substrates [12] . α2-M regulates proteolysis in complex biological processes, such as nutrition, signalling, transport of hormones and tissue remodelling, but also defends the host organism against external attacks. One might assume that an over five hundred million years preserved protein should have a major function, and indeed, α2-M appears to be particularly important in contributing as well to thrombin inhibition and attenuation of immune reactions.

Background and trigger to our hypothesis is an old case report from 1973 of a family with hereditary AT III deficiency [13] . The 34-year-old father suffered from recurrent DVT and pulmonary embolism. Examining immunological ATIII in eight family members, we found a reduction to 45% in the father and to 50% in his 12-year-old son. The activity determined with the 1973 available two-step clotting-test "progressive antithrombin" was 50 % in the father and in contrast 75%, i.e. in the normal range, in the 12-year-old son.

For α2-M, which is an additional antithrombin as mentioned above, an age-appropriate normal low value (301 mg/dL) was found in the father and an almost twice as high value of 541 mg/dL in the son. Two other young siblings had also high α2-M values of 723 and 540 mg/dL, and normal ATIII values by both methods and we assumed a kind of "compensation mechanism". About 10 years later, the son experienced a DVT in his mid-20s. We made a similar observation of this "mechanism of compensation" in another family with hereditary AT III deficiency.

Comparing progressive antithrombin activity and plasma concentrations of three thrombin inhibitors (AT III, α2-M, Heparin Cofactor II), a strong positive correlation was found [14] in unselected adult patients and a selected low AT III activity patient group. The included three hereditary At III deficient patients had a mean age of 41 years. The authors suggested that AT III is the main inhibitor in normal plasma and more effective than α2-M in inhibiting fibrin formation, but confirmed that α2-M or possibly other inhibitors might contribute to the total progressive antithrombin activity in human plasma. It is well known that the first thrombotic manifestation in hereditary AT III deficiency occur usually not before the third decade of life, suggesting that there are protective mechanism in place for the young. In adult patients with ATIII deficiency, α2-M levels are high [30], however, the evaluation of families did not include enough younger patients for evaluation. Nevertheless, There is good reason to assume that the lower risk of thromboembolic complications in AT III-deficient children may be in part due to the protective effect of elevated α2-M levels during childhood. [15] [16] .

Our hypothesis is that similarly during SARS-CoV-2 infection the higher α2-M level in childhood may contribute to the more favourable course of COVID-19 in children. Interestingly, α2-M has been identified Accepted Article

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