Masseter hypertrophy is a facial feature in Asians, characterized by soft swelling around the mandibular angle. Treatment options for masseter hypertrophy range from simple medication to invasive surgical reduction [1]. Injection of botulinum toxin (BTX) into the masseter muscle is generally considered less invasive method [2]. BTX, a neurotoxin produced by Clostridium botulinum, causes muscle paralysis by inhibiting the release of acetylcholine at neuromuscular junctions. Due to its strong efficacy and safety profile, postoperative side effects such as pain, edema, and bruising at the injection site are rarely observed [3]. Herein, we report a rare case of a patient with hemophilia who developed a right-sided facial subcutaneous hematoma following BTX injection. We discuss the case and conduct a literature review to provide references for future cases.

A 33-year-old male received BTX injections into both masseter muscles at a private beauty clinic; however, the exact injection material and dosage were unknown. Six hours post-injection, the patient showed swelling on the right side of his face, accompanied by skin hyperthermia, but no special treatment was administered. Subsequently, the redness and swelling worsened, developing into blueness, local pain, and limited mouth opening. Antibiotic treatment yielded no significant improvement. Two days later, the right orbital area began to swell with cyanosis, and the patient was brought to the hospital. Initially, he did not report any significant medical or family history; however upon further inquiry, he disclosed a history of hemophilia for over ten years without any prior treatment. Physical examination revealed facial asymmetry, right-leaning lips, and a marked swelling of the right cheek. Large patches of cyanosis were observed on the right side of the face, primarily affecting the right masseter, ear and mandibular region, indicative of a subcutaneous hematoma (Fig. 1A, B). His skin temperature was elevated, with significant tenderness and restricted mouth opening. Laboratory examinations revealed factor IX at 8.4%, factor VIII at 149.7%, an activated partial thromboplastin time (APTT) of 122.1 seconds, a prothrombin time activity of 129.4%, an APTT of 3.59 seconds, and a D-Dimer of 0.51 μg/ml FEU.

Figure 1. (A) Frontal photos of the patient upon admission. (B) Right-side photos of the patient upon admission. (C) Frontal photos of the patient 7 days after infusion of clotting factor. (D) Right-side photos of the patient 7 days after infusion of clotting factor.

Upon admission, the patient received pressure dressings and anti-infective agents. After consultation with the hematology department, plasma was administered, along with factor IX infusion for a total of 7 days. By the second day of coagulation factor treatment, the patient noted slight improvement his right facial pain, though the area of facial cyanosis showed no significant change. After three days of treatment, the areas of facial cyanosis, swelling, and pain were significantly reduced. At discharge, the facial hematoma had absorbed clearly, with improved swelling and cyanosis of the right side (Fig. 1C, D). Informed consent was obtained from the patient, and the study followed the guidelines of the Declaration of Helsinki.

Since 1994, when BTX Type A was first reported to reduce facial wrinkles, it has been widely used for the treatment of facial disorders [4]. It’s indications include the removal of underarm odor and regulation of muscle dysfunction. BTX is a potent neurotoxin produced by Clostridium botulinum. The toxin inactivates synaptosome-associated protein 25 (SNAP-25), inhibiting the release of acetylcholine at the striated neuromuscular junction, leading to chemical denervation and muscle paralysis [5].

We conducted a literature review on adverse reactions or complications arising from BTX injections. The articles reviewed, published between January 2000 and October 2023, used the following terms in PubMed: “Botulinum Toxins”, “Hematoma”, and “Congestion”.

Based on our inclusion and exclusion criteria, we included 11 articles reporting 82 cases of hematoma, bleeding, congestion, and other related adverse events after BTX injections for data extraction. Table 1 [6-16] presents the results of the study. Of adverse reactions identified, 73 cases involved hematomas at the injection site. These patients were treated for various diseases, primarily muscle spasms (n=43), facial wrinkles (n=18), anal fissures (n=2), and skin hyperhidrosis (n=1). Five patients experienced bleeding at the injection site, with their treatment goals focused on managing complications from (n=3) and tears (n=2). Hematuria was noted in four cases. Most adverse events were mild or self-limiting, resolving spontaneously with conservative treatment. Two patients required surgical treatment for hematoma removal because of its specific location. These complications are categorized based on the common manifestations of local vascular damage. According to Wenninger and Wabbels [6], most hematomas occurred immediately or on the day after treatment, and only 11% of the patients with hematoma developed hematomas one or more days after injection. Overall, complications were predominantly mild and of short duration.

Table 1 . Case statistics of relevant side effects after botulinum toxin injection.

Author	Year	Amount	Goal	Symptom	Treatment
Tilney et al. [7]	2001	2	Anal fissure	Hematoma	Conservative treatment
Vadoud-Seyedi [9]	2004	1	Skin hyperhidrosis	Hematoma	Conservative treatment
Carruthers et al. [10]	2015	18	Facial wrinkles	Hematoma	Unknown
Lo et al. [8]	2015	1	Muscle spasm	Hematuria	Transfusion of factor VIII
LaVallee et al. [11]	2017	2	Muscle spasm	Hematoma	Untreated
Koh et al. [12]	2017	1	Muscle spasm	Hematoma	Surgery
Christiansen et al. [13]	2017	3	Muscle spasm	Hematuria	Conservative treatment
Lee et al. [14]	2017	1	Muscle spasm	Hemorrhage	Surgery
Girard et al. [15]	2018	2	Muscle spasm	Hemorrhage	Untreated
Dimitrova et al. [16]	2020	13	Muscle spasm	Hemorrhage (n=2) Hematoma (n=11)	Unknown
Wenninger et al. [6]	2022	38	Muscle spasm	Hematoma	Unknown

In this study, we reported a large facial hematoma following BTX injection, potentially related to the effect of BTX on the coagulation cascade, in addition to the mechanical damage from small-vessel injury during the injection. Studies have shown that acetylcholine can promote the release of thrombin and increase the expression of the prothrombin gene [17]. Furthermore, acetylcholine contributes to antifibrinolytic activity. Therefore, by reducing the release of acetylcholine after BTX injection, anticoagulant effects can be enhanced, resulting in increased bleeding. At the same time, since the same operator has not experienced similar situations in the past, we can think that the doctor’s injection technique is correct. In addition to the reasons for the doctor’s operation, it is also necessary to pay attention to the abnormal coagulation function of the patient. Hemophilia causes bleeding that tends to worsen gradually.

Hemophilia A and B are genetic disorders and rare congenital recessive X-linked diseases caused by the absence or dysfunction of coagulation factors VIII and VIII, respectively. The lack of coagulation factor IX caused by hemophilia B leads to poor coagulation function, leading to increased bleeding from damaged blood vessels and the accumulation of blood under the skin, forming a facial hematoma. A stratified model of bleeding risk showed that a combination of antiplatelet and anticoagulant drugs, a shorter duration of anticoagulation, and a history of poorly controlled anticoagulation therapy significantly increase the bleeding risk. Lo et al. [8] reported a patient with a history of hemophilia A who developed hematuria after BTX injection; the symptoms disappeared after self-infusion of factor VIII. They suggested that unstable blood clots after BTX injection may convert clinically insignificant microhematuria into macroscopic hematuria. Rodriguez-Merchan and De la Corte-Rodriguez [18] believes that the patient’s history of factor VIII deficiency and poor coagulation ability after injection may contribute to post-injection bleeding.

Currently, improper injection levels, sites, doses, and drug dispersion are the primary causes of complications. Due to the widespread use of BTX and its low risk, many practitioners do not conduct a systematic preoperative evaluation before injection, potentially increasing the incidence of postoperative complications [3]. Therefore, a thorough preoperative evaluation is essential, including careful inquiries into the patient’s medical history and presence of coagulation disorders.

To reduce these complications, it is necessary to accurately evaluate the muscle distribution and activity of the patient. In addition, practitioners should master and carefully observe the distribution of facial blood vessels prior to injection. During the injection procedure, the technique should be gentle, and the injection level must be clear. During injection, the needle should be withdrawn to avoid penetrating blood vessels and to reduce the possibility of vascular damage. If a small hematoma appears shortly after the injection, it can be stopped by applying slight pressure to the tissue or leaving it untreated to subside naturally. When treating patients with massive hematomas in unknown origin after injection therapy, the possibility of abnormal coagulation function should be considered. Healthcare providers must detect promptly assess relevant laboratory indicators and provide clotting factor replacement therapy based on each patient’s individual situation. It is necessary to observe the recovery situation at any time and adjust the dosage of clotting factors to achieve a better therapeutic effect. Hemophilia serves as a relative contraindication for BTX injections and is generally not recommended.

This study reports a rare complication in a patient with hemophilia who developed a large subcutaneous facial hematoma after a BTX injection. By analyzing this case and reviewing the relevant literature, we provide valuable insights for managing similar complications after BTX. It is crucial to conduct a thorough inquiry into the patient’s medical history and to identify any contraindications prior to injection. In cases where such complications arise, consultation with the hematology department should occur once a definite diagnosis is established. Under these circumstances, the infusion of clotting factor replacement therapy is the most effective option for managing hematoma-related complications and promoting timely recovery.

None.

The authors have nothing to disclose.