key: cord-0725880-cwm6p5r0
authors: Seelhammer, Troy G; Plack, Daniel; Lal, Amos; Nabzdyk, Christoph G.S.
title: COVID-19 and ECMO: An Unhappy Marriage of Endothelial Dysfunction and Hemostatic Derangements
date: 2020-10-02
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2020.09.132
sha: b3d07dae658200077c767f41ed459d3efcc13263
doc_id: 725880
cord_uid: cwm6p5r0

nan

for maintenance of mechanical support (mean aPTT without stroke 41.8 seconds versus 52.8 seconds with stroke, P = 0.09) and, in all affected individuals, platelet counts greater than 130,000 per uL with fibrinogen counts > 250 mg/Dl. Similarly, systolic blood pressures appeared largely within normal limits preceding the diagnosis of intracranial hemorrhage (ICH). ICH in COVID-19 has been previously reported with an as yet to be determined incidence or underlying etiology. 3, 4 The high cerebrovascular event rate seen by Usman et al. exceeds the incidence previously reported in non-COVID-19 ECMO patients suggestive of unique aspects in this population that elevate the risk of this dreaded complication. 5 COVID-19 is understood to cause endothelial dysregulation leading to thrombosis, but also increased risk of bleeding in certain situations. The pathogenesis initially requires mechanisms of entry and action of the virus mediated by the binding of a surface glycoprotein known as spike to angiotensin converting enzyme-2. 6 Subsequent entry of the virus can cause cytopathologic changes at the epithelial alveolo-capillary interface including disruption of intercellular junctions, cellular swelling and detachment from the basal membrane. 7 Exposure of potent activators of the hemostatic cascade produces downstream activation of thrombin and, secondarily, the production of fibrin. Catalyzing the propagation of clot generation is the thrombin receptor mediated activation of platelets and degranulation of dense granules containing polyphosphates. It may be at this juncture that the linkage between the coagulation cascade and the immune system exacerbates the hyper immune state of COVID-19. Under physiologic conditions the endothelium will use mechanisms to counteract clot generation, including prostacyclin and tissue plasminogen activator secretion, to prevent vascular thrombus formation. In contrast, pathophysiological conditions may perturb this delicate balance through the secretion of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, leading to the opposite effect of anti-fibrinolysis. 8 Thus, anticoagulation strategies in COVID-19 patients are frequently deployed as chemoprophylaxis in against the genesis of these interdependent cascades.

In those critically ill patients requiring extracorporeal support, thromboembolic events in addition to high rates of hemorrhagic complications have been reported, including those delineated by Usman et al. In an effort to expand upon the genesis and importance of the concept of fibrinolysis as it relates to ECMO, further explanation is herein provided. As discussed, COVID-19 induces significant endothelial dysfunction resulting in a prothrombotic and anti-fibrinolytic state, the latter of which is due to increased PAI-1 secretion. 8 While anticoagulation may have a therapeutic role in COVID-19 patients per se, the addition of ECMO complicates the overall picture and might tip the scale towards hyperfibrinolysis in select circumstances. It is accepted that all patients will be met with varying rates of fibrinolysis which is present as an obligatory homeostatic mechanism often conceptualized as a "housekeeping" requirement to mitigate progressive thrombotic deposition that can complicate activation of the hemostatic cascade. Simply put, it counteracts progressive accumulation of fibrin clot through enzymatic cleavage into fibrin degradation products (FDP). Reflective of the regulatory nature of these cascades is the presence of modestly elevated D-dimer levels in adult ECMO patients. 15 Intriguingly, the COVID-19 literature has within it numerous reports of elevated D-dimers, which represents the most frequently assayed fibrin degradation products (FDP), and are generated during enzymatic fibrin cleavage by plasmin. 1, 16 D-dimer levels in COVID-19 patients serve as biomarkers, with elevated levels being associated with increased disease severity and higher in hospital mortality. 17 Implicit in the identification of FDPs, including D-dimers, is the action of the fibrinolytic cascade without which the generation of FDPs would be impossible. Given the frequently long ECMO runs required in COVID-19 patients superimposed upon the underlying prothrombotic state 18 and despite appropriate systemic anticoagulation, it is plausible that fibrinolysis may advance in intensity to the point of hyperfibrinolysis during mechanical support in this population. This is reflected in our cohort of COVID-19 patients on ECMO anticoagulated with bivalirudin infusion whereby hyperfibrinolysis was detected in 7% of all routine daily assays. It is worth noting that this rate is similar to the 5% recently reported in non ECMO COVID-19 patients by Yuriditsky et al receiving enoxaparin or unfractionated heparin thromboprophylaxis. 11 Routine viscoelastic monitoring may help detect subclinical coagulation abnormalities before the development of adverse events. This unostentatious statement conceals the true advantage of this diagnostic approach. Of the various coagulation derangements as it relates to viscoelastic testing, in contemporary clinical practice fibrinolysis is unique because may be ascertained by laboratory evaluation 8 in no other readily available manner. An indirect and less precise assessment of fibrinolysis can be made utilizing D-Dimers as recently reported by Besser et al. 19 Once clinically significant hyperfibrinolysis is identified, the subsequent deployment of treatment strategies to mitigate either the cause or to abate the enzymatic cascade with antifibrinolytic pharmacotherapies represents a potentially powerful strategy to optimize care for this high risk population. Our center previously reported on the utility of point-of-care TEG to identify hyperfibrinolyis during ECMO and, perhaps more interestingly, to titrate TXA dosing to effect as defined by laboratory (resolution of elevated Lysis30) and clinical (denoted by abatement of hemorrhage) findings. 20 Given our positive experience with regards to the routine use of TEG in COVID-19 patients receiving VV-ECMO therapy, we certainly support Usman et al. in their call for the integration of viscoelastic testing as a routine practice in these patients. It is the author's perspective that it is through the integration of diagnostic assessment of viscoelastic testing with dedicated management schemes, up to and including the titration of antifibrinolytic therapies, that unmasks the capacity this technology to enhance clinical outcomes. In addition, we encourage further research leveraging direct thrombin inhibitors during ECMO given its effective and predictable anticoagulation performance 21-23 as well as the high incidence of heparin induced thrombocytopenia in these patients. 24 Additional, ideally prospective, studies examining the incidence and risk factors for the manifestation of hyperfibrinolysis as well as the ideal anticoagulation and monitoring strategy as it relates to COVID-19 patients on ECMO will be needed to define best practice approaches for this challenging population. 

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