| The Surgical Technologist | APRIL 2022 306 JUNE 202 306 progression from normal hemostasis to a relatively antifibrinolytic state (31, 38, 43–45). The SARS-CoV-2 viral saturation of ACE2 increases circulating levels of angiotensin II, leading to increased production of the important antifibrinolytic mediator, plasminogen activator inhibitor 1 (PAI-1) (46–48). Elevated PAI-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in the alveolar space have been identified in COVID-19 patients (46, 49–51). Elevated tissue plasminogen activator (tPa) levels have also been noted in COVID-19 patients. This tPa release may be due to malperfusion secondary to microvascular fibrin deposition. Despite this increase in tPa, pro-thrombosis persists in these patients, suggesting that elevated PAI-1 and TAFI overwhelm the action of tPa, resulting in microvascular deposition of fibrin (52). These factors contribute to the disruption of the tightly regulated balance between thrombosis and fibrinolysis in COVID-19 patients, leading to what is known as “fibrinolytic shutdown” (17, 46, 50, 52–58). When combined with elevated thrombin generation, it leads to adverse complications such as a type of adult respiratory distress syndrome (ARDS), multisystem organ failure, and mortality (29, 59–62). This unique type of ARDS is often associated with a localized hypercoagulability of the pulmonary vasculature due to abnormal deposition of fibrin and development of microthrombosis (63–66). Postmortem analyses confirm a similar presentation in patients with COVID-19-induced ARDS (67–70). This localized hypercoagulability is partially induced by inflammation of tissue, leading to elevated tissue factor (TF) production by epithelial cells and alveolar macrophages which results in the deposition of fibrin and the development of microthrombosis (46, 71). Thromboses are additionally potentiated by a deficient fibrinolytic response primarily induced by the overexpression of PAI-1 from activated platelets and endothelial cells (31, 72, 73). Primary hemostasis, which is accomplished via activated platelets at the site of endothelial injury, contributes to the hypercoagulable state of the COVID-19 patient. Overwhelming platelet activation is driven by many stimuli, and significantly facilitated by increased levels of von Willebrand Factor (VWF), as well as activation of the enzymatic (intrinsic) clotting pathway. COVID-19 patients have increased activation of circulating platelets as demonstrated by elevated soluble P-selectin as well as markers for endothelial activation (74). A direct stimulatory role of SARS-CoV-2 Spike protein on the COVID-19 patient’s platelets has also been described (75). Severe COVID-19 illness correlates not just with platelet activation but is also associated with enhanced platelet-monocyte aggregation. Finally, ICU admitted COVID-19 patients’ platelets induce Pselectin and αIIb/β3-dependent monocyte TF expression which may augment inflammation and hypercoagulability (76). Together, these aberrancies in hemostasis mediated by platelets and reduced fibrinolysis (documented by whole blood viscoelastic hemostatic assays [VHAs], thromboelastography [TEG] and rotational thromboelastometry [ROTEM]) inevitably lead to uncontrollable hypercoagulopathy (76–78). The TEG/ROTEM evaluates the patient’s position along the hemostatic spectrum from hypo to hypercoagulable states. The tracings resemble a shovel, whereby the length of the handle reflects coagulation factor competence, the slope of the blade reflects fibrinogen concentration, the thickness of the blade reflects clot contraction mediated by fibrin-platelet interaction, and the tapering end of the blade represents fibrinolysis. Therefore, a characteristic early COVID-19 patient with a hypercoagulable state presents with a short handle, a steep slope, and a thick blade with no tapering of the blade, which represents enhanced effect of coagulation factors, increased fibrinogen concentration, increased fibrin/platelet function, and fibrinolytic shutdown. At the other end of the spectrum lies the hypocoagulable state as manifested by a long handle, flat slope, thin blade, with significant tapering. In Figure 3, examples of this paradigm are represented along various stages of this spectrum of coagulopathies associated with COVID-19. The hypercoagulability of COVID-19 patients is clearly complex and multifactorial, but understanding these complex mechanisms allows for the pursuit of specific treatment strategies to improve patient outcomes. Management is complicated because of fibrinolytic shutdown due to the reduction of natural fibrinolysis at the level of the endothelium. While a multitude of studies have shown the detrimental effect of fibrinolytic shutdown on COVID-19 patient outcomes, bleeding complications such as gastrointestinal bleeding and hemorrhagic stroke are also common, especially in patients on therapeutic anticoagulation (17, 79, 80, 82–86). These patients tend to clot and bleed at the same time, a function of the “rollercoaster” phenomenon (77). Timing of Elective Surgery for Acute and Convalescent COVID-19 Patients Even for those patients without comorbidities or illness requiring hospitalization, a large number of convalescent COVID-19 patients at four months post-infection are reported to have one or more residual organ system impairments as defined by quantitative magnetic resonance imaging (MRI) T1 mapping (12, 87). This phenomenon is termed Long COVID (or post-acute sequelae of COVID-19 [PASC]) and can involve any organ system (88). Hypercoagulability and VTE have been described as potential complications in Long COVID patients (88). In the convalescent COVID-19 patient, it is important to understand that the timing of surgery is a function of where the patient lies within the context of their individual immuno-thrombotic state (77). Further research is necessary for determining potential biomarkers which may allow surgeons to weigh the risks and benefits of elective surgery. Multiple studies have shown persistently elevated D-dimer, fibrinogen, C-reactive protein (CRP), interleukin (IL)-4, IL-6, tumor necrosis factor (TNF)- α, interferon (IFN)-γ-induced protein 10, factor VIII, VWF, and plasma soluble thrombomodulin in patients up to six months post-recovery from COVID-19 (81, 89–94), indicating that these may serve as potential biomarkers Bunch et al. COVID-19 Immuno-Thrombosis and Surgery Frontiers in Surgery | www.frontiersin.org 6 2022 | Volume 9 | Article 889999
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