Complement and Thrombosis: What Is, and What Might Be

The past 12 months have brought a broader understanding of how the complement and coagulation systems are intertwined. This relationship was made apparent early in the year with emerging data in patients with antiphospholipid antibody syndrome (APS; what is), and was then suggested (but not confirmed) in preclinical and autopsy data in patients with COVID-19 (what might be).

The complement system is composed of several soluble- and membrane-bound proteins that activate components of innate immunity (e.g., via opsonization, destruction of pathogens, elimination of infected host cells, recruitment of inflammatory cells) and adaptive immunity. The three complement pathways (lectin, classical, and alternative) converge by forming a C3 convertase and subsequently a C5 convertase to mediate the inflammatory response.¹ 

There are many reported mechanisms by which the complement cascade may activate coagulation (immunothrombosis). C5a may promote the release of prothrombotic factors from platelets, induce endothelial tissue factor expression, and promote natural anticoagulant production. Other components of complement may promote the cleavage of fibrinogen and enhance XIIIa activity, among other mechanisms.²  For this reason, disorders of complement dysregulation such as atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria may result in a prothrombotic state and thrombotic microangiopathy (small vessel thrombosis).

In an earlier edition of The Hematologist this year, we reviewed a study by Dr. Shruti Chaturvedi and colleagues who investigated the role of complement dysregulation in the development of catastrophic antiphospholipid syndrome (CAPS) in patients with APS.³  They examined serum samples from patients with thrombotic APS, CAPS, and systemic lupus erythematosus for evidence of complement activation by using a modified Ham’s assay (mHam). They found that patients with CAPS and recurrent thrombosis were more likely to have a positive mHam. Moreover, they found a greater prevalence of germline mutations in complement regulatory genes in patients with CAPS than without, at a rate similar to those with aHUS. These results suggested an important role for complement activation in modulating and promoting more severe thrombotic phenotypes of APS.

It has also been suggested that complement dysregulation may also play a role in the pathophysiology of thrombosis and organ failure in patients with COVID-19.^4,5  This disease is often marked by a severe proinflammatory state, and coagulation abnormalities including elevated D-dimers, fibrinogen, and factor VIII.⁶  However, early postmortem studies from these patients have also demonstrated increased endothelial deposits of several markers of complement activation (i.e., Mannose-binding lectin, C4b, C3b, C5b-C9) within the lungs, along with C5-C9 deposition within the renal glomeruli.^7,8  Small vessel microthrombi have also been demonstrated in autopsy studies of patients who have died from respiratory failure, with evidence of pulmonary thrombotic microangiopathy as seen in aHUS.⁹  Similarly, there have been pathology reports of fibrin thrombi in glomerular capillaries of patients with COVID-19, although renal vasculopathy has been an inconsistent finding.¹⁰  In summary, while complement activation appears to be occurring in these patients, the extent to which it is responsible for their hypercoagulable state and organ dysfunction remains highly uncertain and merits intensive ongoing investigation.

What are the implications of this interaction between complement and coagulation for the practicing clinician? From the APS perspective, these data provide a rationale for the consideration of complement blockade in patients with refractory CAPS despite standard therapy with corticosteroids, anticoagulation, and intravenous immunoglobulin/plasma exchange. While drugs such as eculizumab have been used successfully in some case series, a recent report of 11 patients demonstrated inconsistent response, with the greatest benefit observed in improving thrombocytopenia.^11,12  Nevertheless, the emerging data on the role of complement in these refractory patients presents a promising avenue for additional prospective studies in this challenging disease, particularly when conventional therapy has been unsuccessful.

The implications for patients with COVID-19 are even less certain. The pathophysiology of venous thromboembolism and small vessel thrombosis in these patients is unclear, with several possible mechanisms, including complement activation/immunothrombosis. A recent report demonstrated that the SARS-CoV2 spike protein can directly activate the alternative pathway of complement, and that this effect can be abrogated by the use of an inhibitor against this pathway (factor D).¹³  In another recent proof-of-concept study in critically ill patients with COVID-19, 35 patients received eculizumab and may have had reduced oxygen requirements and improved survival relative to 45 patients who did not receive this drug.¹⁴  However, the extent to which complement activation and thrombotic microangiopathy play a role in the development of multiorgan failure and respiratory failure in COVID-19 remain highly uncertain and require further exploration.

In summary, these findings from 2020 further clarify the interplay between complement and coagulation. In a disease such as APS and CAPS, a further understanding of the mechanisms that increase the risk of severe or refractory disease may have important implications for therapy and further clinical trials. Meanwhile, in COVID-19, the role of complement activation in promoting the progression to severe or critical illness and organ failure urgently requires further investigation before complement blockade is included in the armamentarium of therapies for this disease.