Immuno-Thrombotic Complications of COVID-19: Implications for Timing of Surgery and Anticoagulation

Abstract

Early in the coronavirus disease 2019 (COVID-19) pandemic, global governing bodies prioritized transmissibility-based precautions and hospital capacity as the foundation for delay of elective procedures. As elective surgical volumes increased, convalescent COVID-19 patients faced increased postoperative morbidity and mortality and clinicians had limited evidence for stratifying individual risk in this population. Clear evidence now demonstrates that those recovering from COVID-19 have increased postoperative morbidity and mortality. These data-in conjunction with the recent American Society of Anesthesiologists guidelines-offer the evidence necessary to expand the early pandemic guidelines and guide the surgeon's preoperative risk assessment. Here, we argue elective surgeries should still be delayed on a personalized basis to maximize postoperative outcomes. We outline a framework for stratifying the individual COVID-19 patient's fitness for surgery based on the symptoms and severity of acute or convalescent COVID-19 illness, coagulopathy assessment, and acuity of the surgical procedure. Although the most common manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19 pneumonitis, every system in the body is potentially afflicted by an endotheliitis. This endothelial derangement most often manifests as a hypercoagulable state on admission with associated occult and symptomatic venous and arterial thromboembolisms. The delicate balance between hyper and hypocoagulable states is defined by the local immune-thrombotic crosstalk that results commonly in a hemostatic derangement known as fibrinolytic shutdown. In tandem, the hemostatic derangements that occur during acute COVID-19 infection affect not only the timing of surgical procedures, but also the incidence of postoperative hemostatic complications related to COVID-19-associated coagulopathy (CAC). Traditional methods of thromboprophylaxis and treatment of thromboses after surgery require a tailored approach guided by an understanding of the pathophysiologic underpinnings of the COVID-19 patient. Likewise, a prolonged period of risk for developing hemostatic complications following hospitalization due to COVID-19 has resulted in guidelines from differing societies that recommend varying periods of delay following SARS-CoV-2 infection. In conclusion, we propose the perioperative, personalized assessment of COVID-19 patients' CAC using viscoelastic hemostatic assays and fluorescent microclot analysis.

Keywords: COVID-19; elective surgical procedure; fibrinolysis; immunothrombosis; obstetrics; orthopedic procedures; thrombophilia; venous thromboembolism.

Figure 1

COVID-19 patient surgical fitness flow chart. The surgeon assesses the acuity of the procedure using the specialty-specific Elective Surgery Acuity Scale (ESAS). If the procedure is of low/intermediate acuity and can be delayed, the length of delay may follow American Society of Anesthesiologists’ recommendations. After the delay, timing of surgery is a function of both the necessity of surgery and the degree of recovery of respiratory and hemostatic derangement post-COVID-19. Post-operatively, due to a high degree of hypercoagulability in many convalescent COVID-19 patients, standard pharmacologic VTE prophylaxis may be considered in all these patients. Created using BioRender.com. *Cardiorespiratory symptoms such as shortness of breath, chest pain, and fatigue are common in patients with convalescent COVID-19 (12, 13, 18, 19). Coagulopathy, including both hyper and hypocoagulable states, should be assessed pre- and post-operatively using fibrinogen levels, platelet count, and viscoelastic hemostatic assays (e.g., thromboelastography (TEG) and rotational thromboelastometry (ROTEM)). The definition of hyper and hypocoagulability are a function of institutional preference. **This is not an exhaustive list of anticoagulant agents, nor a comprehensive dosing regimen. For inpatients acutely ill with COVID-19, those with VTE, those who undergo emergent surgery, or those at risk for hemorrhage, personalized titration of anticoagulation with adjunctive viscoelastic hemostatic assays is recommended (, –23). VTE prophylaxis for postoperative patients with acute or convalescent COVID-19 is not specifically addressed in recent expert consensus statements or society recommendations (–26). As such, this recommendation is the opinion of the authors and should be judiciously applied taking into account each individual patient’s risk and benefit to anticoagulant therapy.

Figure 2

COVID-19-associated coagulopathy (CAC) and Fibrinolytic Shutdown. (1) The SARS-CoV-2 Spike protein binds with angiotensin converting enzyme 2 (ACE2), which causes internalization of the receptor and virus into the host cell. (2) In turn, ACE2 is not available for breakdown of angiotensin II (AT-II) leading to its build-up. AT-II causes subsequent lung injury and increases in plasminogen activated inhibitor 1 (PAI-1). Angiotensin I-7 (AT-I-7) and angiotensin I-9 (AT-I-9) are increased by other pathways involving activated platelets, but also lead to increased levels of PAI-1. (3) Increased circulating PAI-1 leads to fibrinolytic shutdown, a hypercoagulable state characterized by increased fibrin deposition and thrombus formation. (4) Among other mechanisms, widespread endotheliitis and microthrombosis can cause multi-organ injury in patients with severe COVID-19 illness. This exacerbates the acute inflammatory response, often causing a cytokine storm and worsening immuno-thrombosis. Inflammatory cytokines activate Factor XII (FXII), which subsequently increases bradykinin levels. Bradykinin increases tissue plasminogen activator (tPa) levels. (5) This subacute rebalancing of the fibrinolytic system predisposes the COVID-19 patient to both thrombosis and hemorrhage as a function of local endothelial derangement. This is particularly the case for hospitalized COVID-19 patients who are anticoagulated; these patients’ anticoagulant regimen must be judiciously titrated on a personalized basis (17, 29, 31). The spectrum of fibrinolysis is depicted as a balance whereby the predominate hypercoagulable fibrinolytic shutdown phenotype is portrayed as a balance with high levels of PAI-1, thrombin activatable fibrinolysis inhibitor (TAFI), fibrinogen, D-dimer, and lower levels of tPa and plasmin. The opposite occurs at the opposite end of the fibrinolysis spectrum when fibrinolysis predominates, which occurs much less frequently in CAC. Created using BioRender.com

Figure 3

The “rollercoaster” phenomenon of COVID-19-associated coagulopathy. The three stages of COVID-19-associated coagulopathy and their relationship to the immuno-thrombotic derangement caused by the cytokine storm are represented above by viscoelastic hemostatic assays (e.g., thromboelastography [TEG]). (A) represents the acute fibrinolytic shutdown phenotype (short R, steep α, thick MA, no lysis). (B) represents the eventual evolution to a normal physiologic fibrinolytic phenotype (normal R, α, MA, and LY30). (C) represents the TEG in evolution without anticoagulation and the subacute recovery stage where the patient is less hypercoagulable (parameters intermediate between acute and remote). (D) represents the patient with or without anticoagulant with a hypocoagulopathic phenotype due to hypofibrinogenemia and/or a thrombocytopenia in spite of persistent fibrinolytic shutdown (long R, flat α, narrow MA, no lysis) (, , , –81). Created using Adobe Illustrator.

Figure 4

Prototype spectrum of COVID-19-associated coagulopathy used to assess the patient’s coagulopathy with thromboelastography (TEG) and plasma microclot analysis. Shown above is an example of correlation between the most hypercoagulable delta (B.1.617.1) variant, intermediate hypercoagulable omicron (B.1.1.529) variant, and physiologic TEGs with corresponding plasma microclot analyses. Using Thioflavin-T as a fluorescent marker specifically for microclot staining, fluorescence microscopy demonstrates microclots in plasma with representative examples of different degrees of microclot formation as related to delta (A), omicron (B), and physiologic (C) TEGs. Previously described, Stage 1 to 4 is a qualitative numerical scoring system where a score of 4 is given for significant and widespread microclot formation and a score of 1 is given for minimal microclot formation (78, 119). In this figure, delta variant (A) equals stage 4, omicron (non-hospitalized patient) (B) is stage 3, normal physiologic non-infected individual (C) is stage 2. A hypocoagulable state either from anticoagulation of the COVID-19 patient or due to naturally acquired disease from COVID-19-associated coagulopathy is stage 1 (not pictured). Patients with Long COVID also demonstrate microclot formation, which may be used to assess platelet dysfunction and surgical candidacy in this group of patients (77, 78, 119). The omicron variant (BA.1 sub-lineage) was detected by polymerase chain reaction (PCR) based on S-gene target failure (SGTF) as a proxy for variant status (https://www.science.org/doi/10.1126/science.abn4543) (120). The TaqPath COVID-19 Combo Kit^® (Thermo Fisher Scientific) identifies SARS-CoV-2 infections by detecting 3 viral gene regions, E, RdRP, and N gene. The laboratory reported positive cycle threshold of 32 cycles for both the E gene, 35 for RdRP and 34 for the N gene. Positive N gene with negative S gene (SGTF) is an acceptable proxy of the BA.1 variant when the gold-standard whole genome sequencing is not done. The PCR result combined with reported case counts and known genomic epidemiology of the 4^th wave in South Africa has been used to track changes in transmission over time for the BA.1 variant (121, 122).