Therapeutic plasma exchange as a bridge to definitive treatment in severe thyrotoxicosis with propylthiouracil-induced neutropenia

Background

Graves’ disease is a common autoimmune disorder causing hyperthyroidism due to the overproduction of thyroid hormones. While most cases are effectively managed with antithyroid drugs (ATDs), RAI or surgery, complications arising from these treatments can pose significant challenges. Among the most severe is agranulocytosis, a rare but critical side effect of ATDs characterized by severe neutropenia, which increases the risk of life-threatening infections. The estimated incidence of agranulocytosis with ATDs ranges between 0.1 and 0.5%, necessitating close monitoring of patients receiving these medications (1).

In parallel, thyroid storm, a life-threatening exacerbation of thyrotoxicosis, represents an endocrinological emergency requiring immediate intervention. Thyroid storm often results in systemic decompensation, manifesting as fever, tachycardia, gastrointestinal distress and altered mental status. When thyroid storm occurs in conjunction with ATD-induced agranulocytosis, treatment options become highly constrained, complicating clinical decision-making.

TPE has emerged as an effective tool for managing severe thyrotoxicosis in scenarios where conventional therapies are contraindicated or inadequate. By rapidly lowering circulating thyroid hormone levels and autoantibodies (2), TPE offers an immediate stabilizing effect, creating a critical window for transitioning to definitive treatments such as RAI or thyroidectomy. Despite its recognized efficacy, TPE remains underutilized in clinical practice, particularly in cases involving complex endocrine emergencies.

This case report details the management of a 67-year-old woman with Graves’ disease who developed ATD-induced agranulocytosis and impending thyroid storm. Her successful stabilization through TPE highlights the importance of this intervention as a bridging therapy and underscores the need for tailored approaches in managing severe thyrotoxicosis complicated by treatment-related adverse effects.

Case presentation

A 67-year-old Caucasian woman with a 2-year history of Graves’ disease and atrial fibrillation reported a 6-week history of watery diarrhea, nausea, vomiting, worsening palpitations, significant weight loss of 15 kg, weakness, tremors and shivering. She denied experiencing chest pain or dyspnea and reported no recent infections, exposure to iodine-containing contrast agents or use of medications known to precipitate thyroid dysfunction. Furthermore, there was no family history of thyroid disorders or other autoimmune diseases.

Initially, her Graves’ disease was managed with methimazole (MMI) at a dosage of 30 mg/day, which was discontinued due to severe urticaria. Subsequently, her treatment was switched to PTU at 300 mg/day and propranolol at 80 mg/day, 12 weeks before her current presentation. The patient did not exhibit any signs of Graves’ orbitopathy or dermopathy. Her atrial fibrillation was being managed with rivaroxaban 20 mg daily, primarily for venous thromboembolism (VTE) prophylaxis.

Upon physical examination, her vital signs were noted as follows: a heart rate of 100–110 beats per minute, blood pressure of 140/80 mmHg, oxygen saturation of 98% and a temperature fluctuating between 100 and 100.9°F. Notable findings included upper left eyelid retraction and a hand tremor. She displayed no signs of congestive heart failure or jaundice. Additional negative findings included no neurological focal deficits, confusion or signs of meningismus. Cardiovascular examination revealed no murmurs, gallops or rubs and no peripheral edema was observed. Her lungs were clear without wheezes, crackles or decreased breath sounds. The abdominal examination showed a soft, non-distended abdomen without hepatosplenomegaly, tenderness or thyroid acropachy. There were no rashes, erythema or other skin lesions apart from the previously mentioned urticaria. Musculoskeletal examination showed no proximal muscle weakness or arthralgia. No signs of anxiety or agitation were observed beyond what could be attributed to hyperthyroidism.

Investigation

Laboratory investigations (Table 1) revealed that liver and renal function tests were within normal limits. Specifically, blood urea nitrogen (BUN) was 7 mg/dL (reference range (RR): 7–20 mg/dL), creatinine was 0.8 mg/dL (RR: 0.6–1.1 mg/dL), aspartate aminotransferase (AST) was 25 U/L (RR: 10–34 U/L), alanine aminotransferase (ALT) was 30 U/L (RR: 8–37 U/L), alkaline phosphatase (ALP) was 70 U/L (RR: 44–147 U/L), total bilirubin was 0.8 mg/dL (RR: 0.2–1.9 mg/dL) and conjugated (direct) bilirubin was 0.2 mg/dL (RR: 0.0–0.3 mg/dL).

C-reactive protein (CRP) levels were measured at 5.6 mg/L (RR: <3 mg/L), indicating an elevated inflammatory status. Blood and urine cultures were sterile, and procalcitonin levels were within the normal range at 0.23 ng/mL (RR: <0.5 ng/mL), ruling out bacterial infection.

Thyroid function tests showed a suppressed thyroid-stimulating hormone (TSH) level of less than 0.01 mIU/L (RR: 0.4–4.0 mIU/L), elevated free thyroxine (FT4) at 52.2 pmol/L (4.07 ng/dL) (RR: 9–24 pmol/L, 0.7–1.9 ng/dL), elevated free triiodothyronine (FT3) at 11.2 pmol/L (0.87 ng/dL) (RR: 3.5–7.8 pmol/L, 0.21–0.48 ng/dL) and elevated thyrotropin receptor antibodies (TRAb) at 12.6 IU/L (RR: <1.75 IU/L). A complete blood count revealed absolute neutrophil count (ANC) of 0.42 × 10⁹/L (RR: 1.8–7.5 × 10⁹/L), indicating neutropenia; the remainder of the complete blood count was within normal limits.

An electrocardiogram confirmed atrial fibrillation with a ventricular rate of 108 beats per minute. A two-dimensional echocardiogram revealed a normal left ventricular ejection fraction of 55%, with no structural abnormalities, indicating the absence of significant heart disease despite the presence of atrial fibrillation. There were no signs of congestive heart failure, valvular abnormalities or pericardial effusion.

Treatment

Upon diagnosing an impending thyroid storm, as indicated by a Burch–Wartofsky Point Scale (BWPS) score of 40, the patient’s management strategy was promptly adjusted. The breakdown of her score included 10 points for thermoregulatory dysfunction, reflected by a temperature between 100 and 100.9°F, 10 points for severe diarrhea and vomiting, 10 points for a heart rate of 100–110 beats per minute and 10 points for the presence of atrial fibrillation.

Initial management involved the discontinuation of PTU and the initiation of empirical broad-spectrum antibiotics. A sepsis workup, including blood cultures, urine cultures and procalcitonin, was conducted before starting antibiotics, all of which were negative. The prednisone dose was increased to 80 mg/day. Despite these measures, the patient’s condition continued to deteriorate, marked by persistent fever, worsening tachycardia and escalating signs of thyrotoxicosis, including tremors, anxiety and diarrhea. The patient developed severe leukopenia, with an absolute neutrophil count (ANC) around 200/μL, raising concerns about agranulocytosis-associated complications (Table 1). To address this, G-CSF was administered at a dose of 5 μg/kg per day subcutaneously, aiming to stimulate neutrophil production and reduce the risk of infection. Despite the interventions, the FT4 and FT3 levels remained persistently elevated, prompting concern about further clinical decompensation. Given the severity of the patient’s presentation and contraindication to both PTU and methimazole due to allergy and agranulocytosis, respectively, therapeutic plasma exchange (TPE) was prioritized.

TPE was initiated on the fifth day of hospital admission after multidisciplinary consensus. Two sessions of TPE were performed on alternate days using acid citrate dextrose (ACD-A) as an anticoagulant. Each session exchanged 1.0–1.2 plasma volumes (approximately 2.5–3 liters). A replacement fluid ratio of 70:30 albumin to fresh frozen plasma (FFP) was used. FFP was chosen to replenish clotting factors and immunoglobulins, particularly in the setting of borderline coagulation parameters. No complications occurred during or after TPE. Blood pressure, electrolytes and coagulation parameters were closely monitored, and the patient tolerated both procedures well without any hemodynamic instability, bleeding or infections. In addition to TPE, several supportive therapies were implemented. Beta-blockade with propranolol was intensified to control tachycardia, with continuous telemetry monitoring to mitigate the risk of arrhythmias. High-dose hydrocortisone, at 100 mg intravenously every 8 hours, was administered to address adrenal insufficiency and suppress thyroid hormone release. Supportive care included aggressive fluid resuscitation and close monitoring in an intensive care setting.

Outcome and follow-up

Post-TPE, there was a significant reduction in thyroid hormone levels. FT4 levels decreased from 52.2 pmol/L (4.07 ng/dL) to 31.4 pmol/L (2.42 ng/dL), and free triiodothyronine (FT3) levels declined from 11.2 pmol/L (0.87 ng/dL) to 7.1 pmol/L (0.55 ng/dL). In addition, TRAb levels decreased to 4.93 IU/L (from an elevated level of 12.6 IU/L). The patient became afebrile 10 days after admission, and her neutrophil count began to recover from day 9, with G-CSF administration contributing to the improvement.

Symptomatically, the patient showed marked improvement immediately after the first session of TPE, with a significant reduction in tachycardia, tremors and anxiety. Her overall clinical condition improved as the hypermetabolic state began to resolve, and she became more stable. This rapid recovery post-TPE indicated a favorable response to the treatment, with continued improvement observed over the following days. Despite the initial lack of significant reduction in thyroid hormones, the successful application of TPE ultimately facilitated a marked improvement in the patient’s thyroid hormone levels. This improvement allowed for her referral for RAI, marking a critical step in her recovery process.

The patient was discharged with stabilized thyroid hormone levels and underwent RAI with a dose of 15 millicuries (mCi) of I-131 2 weeks later. Ongoing management involved tapering the doses of prednisone and propranolol. One-week post-RAI, the patient experienced significant symptomatic improvement, reporting better mobility and a marked enhancement in her overall well-being. Her vital signs stabilized, with her heart rate consistently maintained at 70–80 beats per minute, reflecting the resolution of tachycardia. In addition, the patient noted reduced fatigue, improved energy levels and a decrease in anxiety and tremors. This clinical progress was a clear indication that her thyroid function was returning to normal, and she continued to recover without further complications.

Three months post-radioactive iodine therapy, the patient remained euthyroid, with TRAb levels further reduced to 2.3 IU/L. Laboratory results indicated stable electrolyte levels, and there were no signs of neutropenia or other significant abnormalities, underscoring the effective management of her condition (Table 1).

Discussion

This case illustrates the complexities of managing Graves’ disease when severe adverse reactions to ATDs, such as agranulocytosis, occur. Agranulocytosis, defined by ANC below 500/μL, is an uncommon but severe complication of ATD therapy. It typically manifests within the first few months of thionamides use but can develop at any time, significantly increasing the risk of serious infections. PTU is associated with a higher incidence of agranulocytosis compared to MMI, with reported rates of approximately 0.81% at a daily dose of 300 mg for PTU versus 0.20% at a 15 mg dose of MMI (3).

Agranulocytosis may arise from direct toxicity to myeloid precursor cells or immune-mediated destruction via antineutrophil antibodies. Certain genetic predispositions, such as specific alleles of human leukocyte antigen (HLA), including HLA-B38:02 and HLA-DRB108:03, increase susceptibility to this adverse effect. Early recognition of these risk factors is essential for timely diagnosis and management, which involves discontinuing the causative drug and initiating broad-spectrum antibiotics. In more severe cases, G-CSF may be used to expedite neutrophil recovery (1, 4).

MMI, another commonly used ATD, is associated with hypersensitivity reactions, such as urticaria, which occurs in 1–15% of patients (5). This reaction is likely mediated by the immune system, with the drug or its metabolites acting as haptens, triggering the release of histamine and other inflammatory mediators from mast cells and basophils. Management typically involves stopping the drug and switching to an alternative such as PTU. However, cross-reactivity between these medications can occur (6). In certain cases, allergist-supervised desensitization may allow for the safe reintroduction of methimazole (7).

In this patient, agranulocytosis necessitated the immediate discontinuation of PTU. Management included stopping the drug, administering broad-spectrum antibiotics and closely monitoring neutrophil counts. Neutrophil recovery began around day 9 of hospitalization, temporally correlating with G-CSF administration rather than TPE. We explicitly note that TPE was employed solely to manage thyrotoxicosis, and not intended to address neutropenia.

The simultaneous development of an impending thyroid storm, a critical escalation of thyrotoxicosis, further complicated the case. Thyroid storm is characterized by systemic decompensation, including fever, tachycardia, gastrointestinal disturbances and altered mental status. A BWPS score of 40 indicated a high risk of thyroid storm in this case. While the BWPS is highly sensitive for detecting thyroid storm, its specificity can be limited, especially in scenarios such as agranulocytosis, where infections are common and can mimic or exacerbate symptoms of thyroid storm. This limitation is significant as patients with agranulocytosis often present with fever and other systemic symptoms that could either be due to infection or the hypermetabolic state of thyroid storm, thus potentially leading to diagnostic ambiguity. Furthermore, despite a negative sepsis workup, including normal blood and urine cultures and unremarkable procalcitonin levels, suggesting the absence of infection, the risk of an occult infectious process could not be entirely dismissed. This is particularly critical in agranulocytosis, where the patient’s capacity to mount a typical inflammatory response to infection might be compromised, leading to atypically mild or absent laboratory changes. The overall clinical presentation and laboratory findings, however, strongly supported the diagnosis of an impending thyroid storm along with complications related to agranulocytosis. It is essential to consider both the advantages and the limitations of the BWPS in managing complex endocrine emergencies, recognizing that while helpful, it must be interpreted within the broader clinical context. This approach ensures comprehensive patient management, taking into account the potential for overlapping conditions that could influence both the presentation and the treatment strategy.

Our clinical decision was also informed by prior institutional experience where similar patients with ATD-induced agranulocytosis and severe thyrotoxicosis had unfavorable outcomes despite standard care. While these cases remain unpublished and inherently limited by potential selection bias, they emphasized the urgency of early intervention in life-threatening scenarios. Among these cases, two patients were treated with methimazole and two with PTU. Three patients developed agranulocytosis within 3 months of initiating therapy, with a median onset of 52 days, while one case occurred 2 years after starting treatment. Despite receiving conservative management, all four patients ultimately succumbed to severe cardiovascular and neurological complications, highlighting the critical importance of prompt and effective interventions in managing impending thyroid storm and its associated risks.

TPE was employed in this patient to address thyrotoxicosis rapidly. TPE effectively lowers thyroid hormone and autoantibody levels, providing prompt clinical stabilization and acting as a bridge to definitive treatments such as RAI or thyroidectomy (8, 9, 10, 11). In this patient, two sessions of TPE significantly reduced FT4, FT3 and TRAb, enabling the safe administration of RAI and achieving sustained euthyroid. Existing literature indicates that TPE typically reduces thyroid hormone levels by about 50%, with the most significant reductions occurring after the first session. The median number of sessions reported is four, with a range of one to ten (12).

While other options such as cholestyramine, lithium and potassium iodide were considered, these agents are known to have delayed onset and limited efficacy in acute crises. Lithium may require 1–2 weeks for effect, and cholestyramine generally acts over 24–48 h (13, 14). Given the acute severity of this case, rapid stabilization was essential, and TPE provided an effective and timely solution within a multidisciplinary care model.

This case underscores the importance of vigilance for adverse reactions during ATD therapy. Patient education about recognizing symptoms such as fever and sore throat is crucial for the early detection of complications such as agranulocytosis. While routine monitoring of blood counts is not universally recommended for all patients on drugs such as propylthiouracil (PTU) or methimazole, it may be necessarily based on individual risk factors and clinical judgment. Prompt medical evaluation should be sought if such symptoms develop, as agranulocytosis can rapidly progress and become life-threatening. Early recognition and intervention are vital to prevent progression to life-threatening conditions.

In conclusion, while TPE is not universally required, this case illustrates that it may serve as a valuable bridging therapy in select patients with severe thyrotoxicosis when conventional options are contraindicated or ineffective. A multidisciplinary, individualized approach is crucial in managing such complex endocrine emergencies.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

All authors made individual contributions to authorship. SM, VP, FT, PD, NL and VJ were involved in the diagnosis and management of the patient. VJ and PD were involved in manuscript submission. NB and MS were involved in proof reading. All authors reviewed and approved the final draft.