TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy

Abstract

An important component of severe COVID-19 disease is virus-induced endothelilitis. This leads to disruption of normal endothelial function, initiating a state of failing normal clotting physiology. Massively increased levels of von Willebrand Factor (VWF) lead to overwhelming platelet activation, as well as activation of the enzymatic (intrinsic) clotting pathway. In addition, there is an impaired fibrinolysis, caused by, amongst others, increased levels of alpha-(2) antiplasmin. The end result is hypercoagulation (proven by thromboelastography® (TEG®)) and reduced fibrinolysis, inevitably leading to a difficult-to-overcome hypercoagulated physiological state. Platelets in circulation also plays a significant role in clot formation, but they themselves may also drive hypercoagulation when they are overactivated due to the interactions of their receptors with the endothelium, immune cells or circulating inflammatory molecules. From the literature it is clear that the role of platelets in severely ill COVID-19 patients has been markedly underestimated or even ignored. We here highlight the value of early management of severe COVID-19 coagulopathy as guided by TEG®, microclot and platelet mapping. We also argue that the failure of clinical trials, where the efficacy of prophylactic versus therapeutic clexane (low molecular weight heparin (LMWH)) were not always successful, which may be because the significant role of platelet activation was not taken into account during the planning of the trial. We conclude that, because of the overwhelming alteration of clotting, the outcome of any trial evaluating an any single anticoagulant, including thrombolytic, would be negative. Here we suggest the use of the degree of platelet dysfunction and presence of microclots in circulation, together with TEG®, might be used as a guideline for disease severity. A multi-pronged approach, guided by TEG® and platelet mapping, would be required to maintain normal clotting physiology in severe COVID-19 disease.

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

“…Coagulopathies [ 84–102 ], and especially the formation of extensive microclots in vivo , are a hallmark of both COVID [ 85 , 103–115 ] and long COVID [ 116 , 117 ], and we have demonstrated that these microclots too are amyloid in character [ 108 , 109 , 116 ]. Importantly, the addition of purified, recombinant SARS-CoV-2 S1 spike protein to coagulation-competent normal plasma is sufficient to induce the formation of anomalous clots [ 118 ] that adopt amyloid states that are also resistant to fibrinolysis [ 108 ].…”

“…The size of these amyloid microclots, that can be observed microscopically and stained e.g. with thioflavin T [ 108 , 109 , 116 ] ( Figure 4 ; control vs LC plasma), are typically anywhere from 1–200 µm; this means that they can effectively block up, and inhibit blood flow through, all kinds of microcapillaries, thereby strongly lowering the availability of oxygen in tissues. As expected, they consist mainly of fibrin, but also contain many other proteins, including α2-antiplasmin [ 108 ] (and even the virus itself [ 119 ]).…”

“…The TEG is a well-known point-of-care method, lately suggested as a good method for following blood clotting status in acute COVID-19, especially when anticoagulation regimes are prescribed to patients [ 109 ]. However, in our experience, it is not useful for determining (hyper)coagulation status in Long COVID, and should be reserved for those Long COVID patients where there is either a bleeding concern or actual bleeding.…”

“…Interestingly, it is now accepted that DIC-bleeding events are uncommon in acute COVID-19 [ 111 ]. Even in this event, TEG is still of more use to manage this situation [ 109 ].…”

Fibrin Strands Will Grow from Soluble Fibrin and Hang Up In an ex vivo Microcirculatory Viscoelastic Model: Is This a Major Cause of Covid-19 Associated Coagulopathy?

“…Consequently, it is very difficult to provide laboratory guidance in a number of clinical situations such as liver transplantation, cardiac trauma and obstetrics and particularly with regard to the care of the COVID-19 patient. Viscoelestic testing (VET) methods such as Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) provide deeper insight into these subtle coagulopathic changes and have demonstrated that COVID-19 patients develop a propensity for hypercoagulation [6][7][8][9][10][11][12][13][14]. Herein we provide structural images of what may connect the COVID-19 patient's hypercoagulopathy with pneumonia and other organ system failure.…”