Recurrent hemoptysis after laryngectomy-acquired hemophilia induced by laryngeal cancer surgery and chemoradiotherapy: A case report

Abstract

BACKGROUND

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by autoantibodies against coagulation factor VIII (FVIII), leading to spontaneous bleeding in patients without a personal or family history of bleeding disorders. While AHA has been reported in association with various cancers, this case represents, to our knowledge, the first reported instance of AHA following head and neck cancer surgery and subsequent chemoradiotherapy.

CASE SUMMARY

We present the case of a 65-year-old male with a history of hypopharyngeal squamous cell carcinoma (T4bN2cM0, AJCC 8^th edition) who developed AHA after extensive surgical resection and chemoradiotherapy. He presented with recurrent hemoptysis and ecchymosis. Coagulation studies showed isolated prolonged activated partial thromboplastin time of 83.8 seconds that did not correct with mixing studies. FVIII activity was < 1%, and a Bethesda assay confirmed FVIII inhibitors with a titer of 18.4 Bethesda units. Hemostasis was initially achieved with tranexamic acid and batroxobin. Immunosuppression with prednisone and cyclophosphamide was started; due to gastrointestinal bleeding, rituximab was added. Treatment was later transitioned to azathioprine with prednisone, followed by tapering. FVIII activity recovered to 188.2%, and the patient remained in remission over six years without AHA or malignancy recurrence.

CONCLUSION

This case underscores vigilance for AHA after head and neck cancer therapy to enable prompt treatment.

Key Words: Acquired hemophilia A; Hypopharyngeal squamous cell carcinoma; Surgery; Chemoradiotherapy; Paraneoplastic syndrome; Immunosuppressive therapy; Case report

Core Tip: We report a unique case of acquired hemophilia A, an autoimmune bleeding disorder due to factor VIII (FVIII) autoantibodies, occurring after head and neck cancer surgery and chemoradiotherapy—a previously unreported association. A 65-year-old male developed recurrent hemoptysis, diagnosed by prolonged activated partial thromboplastin time and high-titer FVIII inhibitors. Intensive immunosuppressive therapy achieved sustained six-year remission, demonstrating the critical role of timely diagnosis and aggressive management for this severe therapy-related complication.

INTRODUCTION

Acquired hemophilia A (AHA) is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII), leading to its functional deficiency[1]. The incidence of AHA is approximately 1.5 cases per million individuals annually[1]. While about 50% of cases are idiopathic, the remaining are associated with conditions such as autoimmune diseases, malignancies, and postpartum states. AHA has been recognized as a paraneoplastic syndrome, with FVIII inhibitors developing in association with tumors and surgical interventions[2]. Although AHA secondary to malignancies is well-documented[3], our thorough literature review found no previously reported cases of AHA specifically developing in patients with head and neck squamous cell carcinoma following extensive surgery and concomitant chemoradiotherapy. Herein, we present a unique case of AHA manifesting as hemoptysis and extensive ecchymosis after treatment for hypopharyngeal carcinoma, highlighting a previously unrecorded complication.

CASE PRESENTATION

Chief complaints

A 65-year-old male presented to the emergency department with recurrent episodes of hemoptysis.

History of present illness

Upon re-admission, coagulation studies revealed isolated prolonged activated partial thromboplastin time (APTT) of 83.8 seconds. The APTT mixing test failed to correct the prolongation. Further evaluation showed markedly reduced FVIII activity (< 1%; reference range: 60%–150%) and a high-titer FVIII inhibitor at 18.4 Bethesda units. Tests for lupus anticoagulant (dilute Russell's viper venom time) and anticardiolipin antibodies were negative. Given the absence of personal or family history of hemophilia A, a diagnosis of AHA was established.

History of past illness

One year prior, the patient was diagnosed at our institution with hypopharyngeal squamous cell carcinoma (T4bN2cM0, AJCC 8^th edition), involving the epiglottic cartilage, left aryepiglottic fold, left piriform sinus, left carotid sheath, left posterior cervical triangle, bilateral submandibular spaces, and enlarged lymph nodes in both supraclavicular fossae. Preoperative APTT was within normal limits at 27.4 seconds (reference range: 24.8–33.8 seconds). He underwent extensive surgical resection, including partial laryngectomy, partial resection of the tongue root, bilateral elective neck dissection, free flap reconstruction, left submandibular gland excision, and tracheostomy. The postoperative course was uneventful, and he was discharged on postoperative day 13. Two months postoperatively, APTT was noted to be prolonged at 35.7 seconds but was not addressed. The patient subsequently underwent chemoradiotherapy, completing 30 cycles of chemotherapy with the TPF regimen (albumin-bound paclitaxel 200 mg on day 1, cisplatin 40 mg on days 1–3, and 5-fluorouracil 1000 mg on days 1–5) and five sessions of radiotherapy totaling 60 Gy over five months. During this period, APTT progressively increased without clinical bleeding manifestations. Five months post-surgery, the patient developed spontaneous ecchymosis on the left flank and was evaluated by the hematology department. However, he did not undergo the recommended APTT mixing study at that time.

Personal and family history

Personal hemoptysis: The patient has no smoking history and drinks alcohol occasionally. He has an unremarkable social history and denies any history of intravenous drug use or illicit substance abuse.

Family hemoptysis: There is no family history of genetic diseases reported. The patient's family history is negative for heritable conditions among first-degree relatives.

Physical examination

The patient presented with mild hemoptysis, expelling small blood clots that were self-limiting. Due to the recurrent, intermittent nature of the bleeding and the admixture of blood with respiratory secretions, precise quantification of the hemoptysis volume was not feasible. There were no accompanying symptoms such as abdominal pain, distension, significant cough, sputum production, or dyspnea. Laryngoscopy revealed diffuse mucosal oozing without a single identifiable bleeding point, and physical examination showed no hemorrhage points in the pharynx and no palpable masses in the neck.

Laboratory examinations

The diagnosis was made based on severely reduced FVIII activity and the confirmed presence of a FVIII inhibitor (18.4 Bethesda Units). The normalization and subsequent overshoot of FVIII activity following immunosuppressive therapy is a hallmark of successful treatment in AHA (Table 1).

Table 1 Measurement of factor VIII activity at key clinical time points.

Time point	FVIII activity result	Clinical significance
At diagnosis (upon readmission)	< 1% (reference range: 60%–150%)	Confirmed the diagnosis of acquired hemophilia A
End of therapy (follow-up)	188.2%	Confirmed complete remission, indicating successful treatment and cure

FVIII: Factor VIII.

The line graph (Figure 1) illustrates the trends in APTT levels during the patient’s disease progression. The green shaded area denotes the normal reference range, and red dots indicate abnormal values. Key clinical milestones are annotated: Preoperative status (January 7, 2019), initiation of chemoradiotherapy (May 6, 2019), and immunosuppressive therapy for AHA beginning on March 8, 2020 (Cyclophosphamide + Prednisone). Subsequent regimen adjustments included: Cyclophosphamide + Prednisone (March 30, 2020), Azathioprine + Prednisone (April 29, 2020), discontinuation of Prednisone (May 27, 2020; monotherapy with Azathioprine), and cessation of Azathioprine (December 1, 2021). Notably, APTT levels stabilized within the normal range following the initiation of AHA-directed immunosuppressive therapy.

Figure 1 Dynamic changes in activated partial thromboplastin time levels throughout the patient’s clinical course. The line graph illustrates the trends in activated partial thromboplastin time (APTT) levels during the patient’s disease progression. The green shaded area denotes the normal reference range, and red dots indicate abnormal values. Key clinical milestones are annotated: Preoperative status (January 7, 2019), initiation of chemoradiotherapy (May 6, 2019), and immunosuppressive therapy for acquired hemophilia A (AHA) beginning on March 8, 2020 (Cyclophosphamide + Prednisone). Subsequent regimen adjustments included: Cyclophosphamide + Prednisone (March 30, 2020), Azathioprine + Prednisone (April 29, 2020), discontinuation of Prednisone (May 27, 2020; monotherapy with Azathioprine), and cessation of Azathioprine (December 1, 2021). Notably, APTT levels stabilized within the normal range following the initiation of AHA-directed immunosuppressive therapy. APTT: Activated partial thromboplastin time.

All coagulation assays were performed at our hospital's clinical laboratory. The APTT was measured using a silica-based reagent on an automated coagulation analyzer. The APTT mixing study was conducted following standard protocol, incubating the patient's plasma with normal pooled plasma (1:1 ratio) for 2 hours before re-assaying the APTT. Factor VIII activity (FVIII: C) was determined using a one-stage, factor-deficient plasma-based clotting assay. The FVIII inhibitor titer was quantified using the Nijmegen-Bethesda assay. Lupus anticoagulant was tested using the dilute Russell's viper venom time test, and anticardiolipin antibodies were detected by an enzyme-linked immunosorbent assay.

Imaging examinations

No imaging studies are available for this case.

FINAL DIAGNOSIS

AHA.

TREATMENT

The therapeutic approach focused on hemostasis and inhibitor eradication. Hemostatic management with tranexamic acid and batroxobin effectively controlled bleeding. Initial immunosuppressive therapy comprised prednisone (1 mg/kg/day) and cyclophosphamide (1.5 mg/kg/day) for four weeks. Due to the development of hematemesis, the regimen was modified to cyclophosphamide combined with rituximab. The patient's bleeding symptoms improved significantly. After one month, the treatment was adjusted to azathioprine and prednisone. Prednisone was discontinued after another month, and azathioprine was tapered based on APTT results until cessation (Figure 1). Follow-up tests showed normalization of APTT and FVIII activity (188.2%).

OUTCOME AND FOLLOW-UP

The patient achieved complete remission from AHA with the normalization of coagulation parameters. To vigilantly monitor for potential tumor recurrence, a rigorous, multi-modal follow-up protocol was implemented for over six years. This protocol included: Morphological surveillance with annual contrast-enhanced computed tomography of the neck and thorax. This was critical for assessing deep-tissue structures and regional lymph nodes for any signs of recurrence or metastasis. Endoscopic evaluation performed biannually (every six months). Each examination consisted of: Conventional white-light laryngoscopy to directly visualize the mucosal surfaces of the operative site and pharynx. Narrow-band imaging laryngoscopy to enhance the detection of abnormal vascular patterns suggestive of early neoplastic changes, which might be imperceptible under white light alone. Immunosuppressive therapy with azathioprine was successfully discontinued on December 8, 2021. Since then, the patient has had no further bleeding episodes, and his factor VIII activity has remained supranormal (> 180%). Throughout this entire follow-up period, all endoscopic and imaging examinations have shown no evidence of local recurrence or distant metastasis.

DISCUSSION

This case report has several strengths, including the detailed longitudinal documentation of the patient's clinical course with a comprehensive timeline (Figure 1), and the long-term follow-up period of six years which clearly demonstrates the efficacy of the treatment and the durability of remission. However, our findings must be interpreted in the context of the inherent limitations of a single case report. The observations and conclusions are based on one individual, which limits the generalizability of our results. Furthermore, the retrospective nature of the analysis may introduce potential biases in data collection and interpretation. Despite these limitations, we believe this case provides valuable insights into a rare but serious complication.

AHA is an uncommon bleeding disorder characterized by the sudden development of autoantibodies against FVIII, leading to its functional deficiency. It is associated with various conditions, including autoimmune diseases, malignancies, and postpartum states[2]. While AHA has been reported in association with solid tumors such as prostate, lung, and gastrointestinal cancers, its occurrence in head and neck cancers is rare[2]. In the present case, the patient exhibited a gradual prolongation of APTT following surgery, which became more pronounced during chemoradiotherapy. This progression suggests that surgical intervention may have triggered the release of FVIII-like antigens into circulation, prompting autoantibody production. Subsequent chemoradiotherapy may have exacerbated this immune response, leading to significant inhibitor development. Notably, there is a paucity of reports linking radiotherapy or the TPF chemotherapy regimen commonly used in head and neck cancers to the onset of AHA.

Paraneoplastic syndromes are a group of disorders triggered by a cancerous tumor but not caused by the direct effects of the tumor mass or its metastases. They occur when the immune system, in its response to the tumor, or due to substances released by the tumor, inadvertently attacks normal cells. In the context of AHA, it is considered a paraneoplastic phenomenon wherein the underlying malignancy disrupts immune homeostasis and leads to a loss of self-tolerance. This dysregulated immune response results in the production of autoantibodies that mistakenly target coagulation factor VIII, culminating in the clinical manifestations of AHA[4]. The temporal relationship in our patient, where coagulation abnormalities emerged following cancer treatment, strongly supports the hypothesis that AHA was a paraneoplastic event triggered by the malignancy and its subsequent therapy.

Furthermore, we propose that the major surgical intervention itself played a direct 'triggering' role in the pathogenesis. Extensive tissue trauma from surgery leads to the release of a substantial load of intracellular antigens into the circulation[5], antigens that are typically shielded from the immune system. In a host with an already compromised or dysregulated immune system, such as our patient with malignancy and a history of chemoradiotherapy, this acute exposure to a flood of self-antigens can break immune tolerance. This process may occur through the presentation of previously 'cryptic' epitopes of FVIII or via molecular mimicry, activating autoreactive lymphocytes and culminating in the production of anti-FVIII autoantibodies[6]. Therefore, the surgical trauma likely acted as a 'second hit' that unmasked the clinical presentation of AHA on the underlying background of a paraneoplastic syndrome.

The diagnostic approach to AHA involves identifying isolated prolonged APTT, performing mixing studies to distinguish between factor deficiencies and inhibitors, measuring FVIII activity, and quantifying inhibitor titers using the Bethesda assay[7,8]. In this case, the diagnostic process adhered to established guidelines, effectively ruling out other potential causes such as lupus anticoagulant.

Management of AHA centers on controlling bleeding and eradicating inhibitors. Hemostatic agents include bypassing agents like recombinant activated FVII and activated prothrombin complex concentrates, as well as FVIII concentrates and antifibrinolytics[7,8]. Given the patient's mild bleeding manifestations, tranexamic acid and batroxobin were sufficient. Immunosuppressive therapy is crucial for inhibitor eradication, with first-line treatments comprising corticosteroids alone or in combination with cyclophosphamide[7,8]. Rituximab is considered in cases where first-line therapy is ineffective or contraindicated[7,8]. In this patient, the initial regimen was modified due to gastrointestinal bleeding, and subsequent therapy with cyclophosphamide and rituximab proved effective. Maintenance therapy with azathioprine and prednisone facilitated sustained remission.

This case highlights the necessity of considering AHA in patients with head and neck malignancies who develop unexplained bleeding and prolonged APTT, particularly following surgical and chemoradiotherapeutic.

CONCLUSION

This case illustrates a rare but critical complication of AHA following multimodality therapy for advanced head and neck cancer. The temporal association between extensive surgical resection, subsequent chemoradiotherapy, and the development of FVIII inhibitors suggests a paraneoplastic mechanism potentially triggered by tissue trauma and immune dysregulation. The diagnosis of AHA should be considered in any patient with unexplained bleeding and isolated prolonged APTT, particularly in the context of recent oncologic treatment. Early recognition, appropriate hemostatic management, and prompt initiation of immunosuppressive therapy are essential for achieving remission. Importantly, this patient maintained long-term remission from both AHA and malignancy over six years, demonstrating the efficacy of a tailored immunosuppressive regimen and vigilant follow-up. This report underscores the need for heightened clinical awareness of AHA as a possible late adverse event in head and neck cancer patients undergoing aggressive treatment.

ACKNOWLEDGEMENTS

We sincerely thank the patient for providing consent to publish his case details. We also thank the anonymous reviewer for his/her insightful comments which greatly improved the manuscript.