Recurrent hypofibrinogenemia with interleukin-6 inhibitors tocilizumab and sarilumab: A case report

INTRODUCTION

Hypofibrinogenemia is a recognized complication of interleukin-6 (IL-6) receptor blockade, particularly with tocilizumab, a humanized anti-IL-6 monoclonal antibody widely used in the treatment of rheumatoid arthritis (RA) and other inflammatory diseases.^[1-3]

While IL-6 inhibition predictably downregulates acute-phase reactants, including fibrinogen, clinically significant hypofibrinogenemia rarely develops. Most of the literature on this effect focuses on tocilizumab, with hypofibrinogenemia typically presenting as an asymptomatic laboratory finding.^[1-4] However, bleeding complications have been reported, especially in patients facing hemostatic challenges such as surgical interventions.^[5,6]

Interestingly, evidence for hypofibrinogenemia associated with sarilumab, another IL-6 receptor blocker, remains sparse despite its mechanistic similarity to tocilizumab.^[7]

CASE REPORT

An 83-year-old man presented to the emergency department with presyncope. Electrocardiography revealed atrial flutter with concurrent bradycardia and pauses exceeding 3 s. He was admitted to the cardiology department and underwent pacemaker insertion. Following the procedure, apixaban 5 mg twice daily was initiated.

Four days later, he developed a pacemaker pocket hematoma, prompting temporary discontinuation of apixaban. A local infection, necessitating pacemaker extraction, further complicated the hematoma. Apixaban was restarted on discharge.

Six weeks later, the patient experienced another episode of symptomatic bradycardia. A second pacemaker was implanted after 48 h of apixaban therapy. However, 1 week later, another pocket hematoma developed. Despite the discontinuation of apixaban, bleeding persisted for 10 days. The hematoma was complicated by Pseudomonas infection, ultimately requiring pacemaker extraction.

A hematology consultation was sought due to bleeding diathesis. The patient had no personal or family history of abnormal bleeding. His medical history was significant for hypertension, hyperlipidemia, diabetes mellitus, and seronegative RA treated with tocilizumab at the time [Figure 1].

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Figure 1:

Timeline of treatments for rheumatoid arthritis and corresponding patient outcomes.

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Laboratory evaluation revealed a hemoglobin of 16.3 g/dL, mild thrombocytopenia of 130 × 10⁹/L, a mildly elevated prothrombin time of 15.3 s (reference range: 9–14 s), normal partial thromboplastin time, and low fibrinogen levels, with a nadir of 123 mg/dL [Figure 2]. Thromboelastography (TEG) demonstrated prolonged clotting time and clot formation time, consistent with hypofibrinogenemia as the underlying cause of bleeding. Further workup revealed a stable immunoglobulin G/Kappa clone, present since 2017. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Factor I inhibitor testing was negative. Next-generation sequencing of the fibrinogen gene did not identify pathogenic variants, suggesting an acquired rather than inherited etiology. Tocilizumab was implicated as the likely cause of hypofibrinogenemia and was subsequently discontinued. Notably, factor XIII activity was assessed to rule out tocilizumab-induced deficiency but was found to be normal.

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Figure 2:

Fibrinogen levels during periods of treatment with anti-interleukin-6 inhibitors and other interventions.

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Before pacemaker implantation, cryoprecipitate was administered, restoring fibrinogen levels to normal (up to 230 mg/dL) and markedly improving TEG parameters. A leadless pacemaker was inserted uneventfully, and the patient was eventually discharged on apixaban 5 mg twice daily.

Following discontinuation of tocilizumab, the patient was transitioned to etanercept, then abatacept, both of which failed to control his RA. He was subsequently switched to sarilumab, which improved arthritis symptoms but led to recurrent hypofibrinogenemia, with a nadir of 111 mg/dL. Despite adjusting dosing intervals from every 2 weeks to every 4 weeks, hypofibrinogenemia persisted, necessitating discontinuation of sarilumab. The patient was then switched to adalimumab, resulting in prompt resolution of hypofibrinogenemia.

DISCUSSION

IL-6 receptor blockade predictably reduces fibrinogen as part of its suppression of hepatic acute- phase reactants. Tocilizumab-induced hypofibrinogenemia has been well described,^[1,2,4] most frequently within the first 3 months of therapy.^[1,2] Although many patients remain asymptomatic and tocilizumab is usually continued,^[1-3] bleeding complications can occur, particularly in perioperative settings.^[5,6]

Notably, IL-6 blockade disrupts the standard inflammatory stimulus for fibrinogen synthesis and, in some cases, may further impact clot stability through concurrent acquired Factor XIII deficiency.^[5,8]

Despite accumulating evidence of hypofibrinogenemia associated with tocilizumab, documentation of this adverse effect with sarilumab remains extremely limited. Achleitner et al. compared the impact of tocilizumab and sarilumab on fibrinogen levels, demonstrating similar rates of hypofibrinogenemia but no associated bleeding events.^[7]

Our patient’s experience of recurrent, clinically significant hypofibrinogenemia under both tocilizumab and sarilumab suggests that fibrinogen depletion should likely be regarded as a class effect of IL-6 receptor blockade rather than a phenomenon limited to tocilizumab.

This case underscores the importance of individualized risk assessment in patients treated with IL-6 inhibitors. While hypofibrinogenemia is often clinically inconsequential, select patients - particularly those with additive bleeding risk such as anticoagulation, invasive procedures, or underlying coagulopathies - may develop clinically meaningful bleeding complications.^[5,6]

Given the increasing use of IL-6 inhibitors, further studies are needed to clarify the incidence and clinical relevance of hypofibrinogenemia, particularly with sarilumab. Until such data become available, clinicians should maintain a high index of suspicion for hypofibrinogenemia-related bleeding in high-risk patients.

CONCLUSION

Although tocilizumab-induced hypofibrinogenemia is well recognized, we report that clinically significant hypofibrinogenemia can also occur with sarilumab. This finding suggests that fibrinogen depletion is likely a class effect of IL-6 receptor blockade, and switching between IL-6 inhibitors may not resolve the risk.