As part of an ongoing series of “Expert Perspectives”, Dr. Leon Henderson-MacLennan, Medical Advisor to inDemic Foundation and inThought Research, discusses the role of thromboembolic disease in COVID-19, and its implications for developmental therapeutics. Dr. Leon Henderson-MacLennan describes the rationale for conducting randomized, placebo-controlled trials on anticoagulants and anticomplement agents for COVID-19 associated thromboembolic disease, and highlights several agents and mechanisms of action to watch closely.
Coronavirus disease 2019 (COVID-19) is associated with a prothrombotic state and significant incidence of thrombotic events and complications during hospitalization.* Both venous and arterial circulations are affected. Pathologies are consistent with excess inflammation, platelet activation, endothelial dysfunction, and stasis.* Implicated is an ability of the SARS-CoV-2 etiologic agent to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2) expressed on endothelial cell surfaces. Subsequent endothelial inflammation, complement activation, thrombin generation, and platelet and leukocyte recruitment as well as initiation of innate and adaptive immune responses result in immunothrombosis, ultimately mediating clinical events / complications, many of which carry with them significant morbidity and mortality.*
The coagulopathy of COVID-19 frequently features findings analogous to those of more historically familiar infection-stimulated inflammatory changes including disseminated intravascular coagulopathy (DIC). Patients may present with prominent D-dimer and fibrin/fibrinogen degradation product elevations, yet early abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon.* Coagulopathy progression may be accompanied by such abnormalities, especially in cases unrecognized until clinical events / complications.* Thrombotic clinical events / complications run the range of microvascular thrombosis, venous thromboembolic disease such as deep vein thrombosis and pulmonary embolism, and stroke. Progression is associated with markers of severe COVID-19 and is accompanied by significant incidence of multiorgan failure and increased mortality.*
Further, evidence is accumulating regarding potential interaction between inflammatory and procoagulant pathways as exemplified by complement pathway components’ relationships with augmented tissue factor activity, formation of activated thrombin from prothrombin, increased platelet activity and aggregation, and stimulation of endothelial cell von Willebrand factor release and P-selectin expression.* An interesting case report, one of many, implicates complement mediation of a thrombotic microangiopathy in the setting of a Kawasaki-like COVID-associated multisystem inflammatory syndrome featuring complement inhibitor-improved renal disease.*
Vinayagam and Sattu’s graphical abstract and three (3) additional summarizing graphics well-depict many of these molecular and tissue-based concepts, and add relevant points of nuance. The first two emphasize many of the known molecular factors underlying COVID-19-associated thrombotic disease, whereas the third underscores specific, resultant clinical events contributing to morbidity and mortality. Finally, their highlighting of thrombocytopenic complications serves as reminder that, amongst other mechanisms, increased bleeding may both accompany a net thrombotic picture and undermine attempts at using primary, and even secondary, antiplatelet (and risk-raising anticoagulant) agents in certain net thrombotic clinical scenarios.
The approach to the pharmacologic management of thromboembolic disease in COVID-19 is evolving
A recent webinar reviewing thrombosis in COVID-19* emphasized the need for both aggressive prophylaxis and treatment, as well as minimizing harm to patients with an elevated bleeding risk. Retrospective analyses suggest that deployment of antithrombotic therapy has morbidity and mortality advantages.* Intense debate regarding relevant best practices rages in the absence of sufficient, well-powered, randomized, double-blind, placebo-controlled trials across an array of relevant clinical scenarios. Though numerous consensus guidelines and recommendations have been published, differences between them are notable. Endorsements of taking an “individualized approach to patient management” underscore variations in clinical practice.* * * The American Society of Hematology provides Antithrombotic Therapy in Patients with COVID-19,* and the International Society of Thrombosis and Hemostasis provides Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID‐19* in addition to related resources.*
Anticoagulants, antiplatelets, and anticomplement agents designed to address COVID-19-associated thromboembolic disease
Data from randomized, double-blind, placebo-controlled trials will hopefully aid in refining appropriate use parameters for medicines and protocols designed to address COVID-19-associated thromboembolic disease. Ongoing clinical trials will better define the roles of anticoagulants, antiplatelets, and anticomplement agents both as monotherapeutic agents and in serial or parallel combination.
High profile anticoagulant investigation* features studies of both unfractionated and low molecular weight heparins (e.g. enoxaparin, dalteparin, tinzaparin) of various prophylactic and therapeutic dosing strategies in both critical and other acute care settings in both venous and arterial circulations; parenteral alternatives such as bivalirudin, argatroban, fondaparinux in analogous settings; and novel oral anticoagulants (NOACs) such as rivaroxaban, apixaban, dabigatran, and edoxaban in hospitalized, transitional, and ambulatory settings as both prophylaxis and treatment. Both serial and parallel parenteral-oral combination studies are ongoing and planned. Other compelling developmental agents include add-on atorvastatin, long touted to have some degree of antithrombotic efficacy on top of its lipid-lowering effects as well as the short-acting anticoagulant nafamostat which inhibits multiple proteases including C1 esterase in the complement system, a pathway which may be more broadly affected by the agent than once emphasized.
It will be interesting to see if inflammatory modulation with (a) the sphingosine-1-phosphate receptor 3 (S1P3)-active agent ozanimod and (b) corticosteroids, plasma exchange, or other anti-inflammatory agents (e.g. IL-6r-active tocilizumab) add to or synergize with anticoagulants to which they are added. It is also notable that the thrombolytic tenecteplase is being investigated as an add-on to reduce the burden of COVID-19 associated respiratory failure as well as for standard acute intermediate-risk COVID-19 associated pulmonary embolism treatment.
The investigational antiplatelet landscape* is not nearly as rich as that for anticoagulants, but studies of aspirin in both acute care and ambulatory settings as both monotherapy and in combination with parenteral and oral anticoagulants will be closely watched as will investigation of dipyridamole in the acute care setting. Acute care and transitional clopidogrel as well as monotherapeutic prasugrel prophylaxis studies are generating ample interest. Aerosolized and oral isotretinoin and aerosolized all-trans retinoic acid studies shift foci of these vitamin A-based agents toward their antiplatelet and fibrinolytic potential.
Complement modulation* is receiving increased attention as an antithrombotic approach. Led by the C5 inhibitor eculizumab and its longer acting cousin, ravulizumab, it will be interesting to see their utility in pre-, intra-, and post-intensive care settings. Next generation C5 inhibition with zilucoplan is also under investigation in acute care and convalescent settings, and C3 inhibition with AMY-101 and, in a separate trial, APL-9 is being studied as Acute Respiratory Distress Syndrome (ARDS) therapy. Disease progression mitigation investigation is also ongoing with at least two recombinant human C1 esterase inhibitors, and the molecule’s peptidomimetic icatibant is being studied alone and as a remdesivir add-on to gauge its utility for ventilator support and mortality reduction. Non-specific polyclonal immunoglobulin formulations and other non-specific anti-inflammatory formulations and constructs are being studied for their complement modulating properties, and it will be interesting to see which ones emerge as simultaneously demonstrating both clinically relevant net benefit signals and evidence of significant biological activity at the level of complement.