Pioneering Safer Treatments: Low-Dose Sirolimus in Infantile Kaposiform Hemangioendothelioma

Pioneering Safer Treatments: Low-Dose Sirolimus in Infantile Kaposiform Hemangioendothelioma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pioneering Safer Treatments: Low-Dose Sirolimus in Infantile Kaposiform Hemangioendothelioma Hanxiang Bai, Jun Zou, Ronghua Fu, Pingliang Jin, Mengyu Huang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7713613/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Kaposiform hemangioendothelioma(KHE) is a rare and aggressive vascular neoplasm. When complicated with Kasabach-Merritt phenomenon, the condition is critical with a high mortality rate. Sirolimus (0.8 mg/m² per administration) exerts a significant therapeutic effect; however, under this conventional dosage, it is prone to induce various infections, immunosuppression and other adverse complications. This research aims to explore the efficacy and safety of low-dose sirolimus in the treatment of infants with KHE. Methods: A retrospective analysis was conducted on the treatment status of 7 infants with KHE who were treated with a low-dose stepped administration of sirolimus in our department from December 2021 to August 2024. For cases without Kasabach-Merritt phenomenon (KMP), sirolimus was used alone, and the doses were increased according to the age in months (for infants aged 1 - 3 months, 3 - 6 months, and 6 - 12 months, the initial doses were 0.1 mg/m²/time, 0.2 mg/m²/time, and 0.5 mg/m²/time respectively, all administered twice a day). For cases combined with KMP, glucocorticoid therapy was incorporated. The degree of tumor regression, hematological indexes and complications after treatment were summarized. Results: The duration of medication was from 7 months to 15 months, and the follow-up time was from 6 months to 2 years and 8 months. Among them, 2 had no KMP and 5 had KMP. For children without KMP, 1 case showed mostly regression, another had partial regression, with no adverse reactions. The 5 patients with KMP, the average time for the four indicators to return to normal was hemoglobin (26.8 ± 16.6) days, platelets (9.2 ± 3.9) days, fibrinogen (20.2 ± 15.8) days, and D-dimer (11.0 ± 10.2) days. Of these 1 case achieved complete regression, 3 cases had mostly regressed, and 1 case had partial regression. No obvious adverse reactions or recurrences were observed. Conclusion: Low-dose sirolimus is still significantly effective in the treatment of KHE in infancy. It has lower adverse reactions and higher safety. Furthermore, for cases combined with KMP, glucocorticoid therapy needs to be combined. Low-dose Kasabach - Merritt phenomenon kaposiform hemangioendothelioma Sirolimus Figures Figure 1 Figure 2 Figure 3 Background Kaposiform hemangioendothelioma is a rare vascular tumor that commonly occurs in infants and young children. When complicated with the Kasabach-Merritt phenomenon, the tumor grows rapidly, accompanied by a severe reduction in platelets and fibrinogen, presenting a critical condition with a high fatality rate [ 1 , 2 ]. For those who usually cannot undergo surgical resection, oral sirolimus is used for treatment. However, under the conventional dose, it is prone to cause various complications such as infections and immunosuppression [ 3 ]. Children under 1 year old have a higher risk of medication due to the lack of CYP3A4 enzyme for metabolizing sirolimus, and in severe cases, it can be fatal. Studies have shown that the adverse reactions caused by sirolimus are related to the dose and serum concentration. Based on this, this study treated 7 children with KHE using a low-dose stepped administration regimen of sirolimus and analyzed its efficacy and safety. This study was approved by the Medical Research Ethics Committee of our hospital and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents or guardians of the children before collecting their case data. Research Materials and Methods Research Materials Research Subjects Some patients with KHE admitted to our department from December 2021 to August 2024 were included, and the following inclusion criteria were set: (1) Diagnosed with KHE based on clinical manifestations, color Doppler ultrasound, magnetic resonance imaging (MRI), and pathological biopsy; (2) Younger than 1 year old; (3) Without severe liver or kidney function impairment or contraindications to sirolimus; (4) Without diseases affecting the observation of treatment efficacy in the blood system, cardiovascular system, etc.; (5) Excluding children with incomplete data or lost to follow-up. The clinical data of the above children were collected, including gender, age at initial diagnosis in months, lesion location, tumor size, hematological indicators (hemoglobins, platelets, fibrinogen, D-dimer count), medication time, disease outcome, and complication status. General Information After screening, a total of 7 subjects were included in the study, including 5 males and 2 females. The age at the first visit ranged from 1 day to 3 months and 13 days, with a median age of 1 month and 8 days. There were 2 cases located in the head and face, 2 in the trunk, and 3 in the limbs. The clinical manifestations were red, irregular, and rough masses protruding from the surface in 6 cases, and 1 case presented as a subcutaneous mass. Research Methods: Treatment Methods (1) KMP was defined as a platelet count < 100 × 10⁹/L, which could be combined with coagulation dysfunction or anemia; fibrinogenopenia was defined as fibrinogen < 1.0 g/L. For children with combined KMP, dexamethasone (0.5–1.0 mg/kg/d intravenous drip) or methylprednisolone (1.6 mg/kg/d) was given for shock treatment at admission. After the platelet count returned to normal, a pathological examination was performed. If the hormone shock treatment was ineffective, platelets were transfused before biopsy. For those without KMP, a direct biopsy was conducted. After diagnosis, sirolimus was added for oral administration. (2) The low-dose stepped administration regimen of sirolimus was as follows: - Weeks 1–4: Initial dose of 0.1 mg/48 h, conducting dose adjustments with reference to the target trough levels of 2–4 ng/ml; - Months 1–3: Initial dose of 0.1 mg/48 h, conducting dose adjustments with reference to the target trough levels of 2–6 ng/ml; - Months 3–6: Initial dose of 0.1 mg/24 h, conducting dose adjustments with reference to the target trough levels of 2–6 ng/ml; - Months 6–12: 0.2 mg once or twice a day, conducting dose adjustments with reference to the target trough levels of 2–6 ng/ml. (3) The drug - level of sirolimus monitoring in therapy was conducted 1 week after medication, then once every 2 weeks. After 5 weeks of medication, it was measured once a month for 2 months, and then once every 3 months. Medication was stopped when the tumor disappeared or remained stable for 12 weeks. (4) Children over 2 months old needed to take prophylactic compound sulfamethoxazole (20–30 mg/kg bid, taking it for 3 days and stopping for 4 days). Efficacy Evaluation (1) The regression degree was evaluated according to the tumor volume measured by color Doppler ultrasound, magnetic resonance, or MRI: 1) 100% regression of the tumor was regarded as complete regression; 2) 75% − 100% regression of the tumor was regarded as almost complete regression; 3) 25% − 75% regression of the tumor was regarded as partial regression; 4) No change. (2) The recovery time of hematological indicators was defined as returning to normal and remaining stable for 4 weeks without rebound, specifically with a hemoglobin ≥ 100 g/L, platelets ≥ 100×10⁹/L, fibrinogen ≥ 1.5 g/L, and D-dimer ≤ 0.5 mg/L. Results Among the 7 patients, 5 were male and 2 were female. The age at the first visit ranged from 1 day to 3 months and 13 days, with a median age of 1 month and 8 days. There were 2 cases located in the head and face, 2 in the trunk, and 3 in the limbs. The longest diameter of the tumor was 4.5 cm − 12.3 cm. The clinical manifestations were protruding or slightly protruding, red/pink/purple-red, irregular, and rough masses in 6 cases, and 1 case presented as a subcutaneous mass in the parotid gland area with normal skin color on the surface. The total follow-up time ranged from 6 months to 2 years and 8 months. All patients had color Doppler ultrasound and magnetic resonance examinations upon admission. The performance of color Doppler ultrasound was similar to that of infantile hemangioma. The lesions involved the skin, subcutaneous fat, and even muscle layers, showing hypoechoic or uneven echo and rich blood supply. On MRI, the lesions mainly showed low signals on T1, with some iso-signals, irregular high signals on T2, and some adjacent to or invading the muscle layers with unclear boundaries. All cases were finally diagnosed through pathological examination. Under the microscope, the tumor tissues had various shapes, mainly composed of proliferating blood vessels and spindle-shaped endothelial cells. CD31 and CD34 were positive in all cases, GluT1 was negative, 6 cases were D2-40 positive, and 3 cases had characteristic changes, namely, glomeruloid structures(Fig. 1 ). Combining the medical history, imaging examination, and pathological results, a diagnosis of KHE could be made. The clinical data of the patients are shown in Table 1 . (1A),Microscopic findings: Tumor cells were seen in the deep dermis, distributed in a nodular pattern. Fibrous tissue and dilated blood vessels were present between the nodules. - Magnified 20 times.(1B),Microscopic findings: The tumor presented in a glomeruloid or nodular shape. The tumor cells were plump and spindle-shaped, and slit-like blood vessels could be seen. Dilated blood vessels and fibrous tissue were observed around the tumor. - Magnified 100 times.( 1C), Some tumor cells were D2-40 positive - Magnified 100 times. (1D), Diffuse positive CD31 in tumor cells - Magnified 100 times. Table 1 General clinical data and serological indicator status of infants with KHE Number Sex Age Site Size (cm) Hemoglobin (g/L) Platelets (10^9/L) Fibrinogen (g/L) D-Dimer (mg/L) 1 male 14d Left knee joint 5*5 71 30 1.18 13.41 2 male 1d Right thigh 7*5 151 60 0.82 7.41 3 female 1m8d Left face 4*4 90 63 1.16 3.4 4 male 1m13d Left upper arm 6*6 79 55 0.94 20 5 female 3m13d Nape of neck 12*10 68 19 1.15 26 6 male 1m5d abdominal 7*7 / / / / 7 male 2m Left temporal part 6*4 / / / / Mean value / 1m8d / / 91.8 ± 23.7 45.5 ± 16.7 1.1 ± 0.1 14.0 ± 7.2 d :day m :month There were 2 children without KMP. One of them was the first experimental subject in this study. Currently, the tumor has mostly regressed, and the skin color on the surface is normal. Up to now, it has been followed up for 2 years and 8 months, achieving survival with the tumor, and the tumor has not enlarged (Fig. 2 ). The other one was located on the left temporal region, had been treated for 8 months, and the tumor was gradually regressing and still under treatment. Among the 5 children with combined KMP, the average hemoglobin level at admission was (91.8 ± 23.7) g/L, platelets were (45.5 ± 16.7) × 10⁹/L, fibrinogen was (1.1 ± 0.1) g/L, and D-dimer was (14.0 ± 7.2) mg/L. During hospitalization, they were treated with glucocorticoid (dexamethasone 0.5–1.0 mg/kg/d once daily or methylprednisolone 1.6 mg/kg/d once daily intravenous drip) for shock treatment. After the platelet count was stable for 5–7 days, prednisone 2–3 mg/kg was taken orally every day, and then the dose was reduced weekly. Among them, there was a 1-day-old newborn. After hormone shock treatment, there was no significant change in platelets and fibrinogen, and then subcutaneous bleeding in the upper limb and scalp hematoma occurred. Considering the critical condition and to prevent death due to extensive bleeding, we urgently contacted the intensive care unit, hematology department, and rheumatology and immunology department for consultation. Pathological biopsy was immediately arranged after transfusing gamma globulin, fresh frozen plasma, and platelets, and the dose of methylprednisolone was increased. After diagnosis, sirolimus was used in combination, and finally, a relatively good outcome was achieved. The serological indicators of all children with combined KMP returned to normal and remained stable, and the KMP was corrected. The average time for each indicator to return to normal was hemoglobin (26.8 ± 16.6) days, platelets (9.2 ± 3.9) days, fibrinogen (20.2 ± 15.8) days, and D-dimer (11.0 ± 10.2) days. The concentration of sirolimus in serum in 4 cases was between 2–6 ng/ml, and in 1 case, it exceeded 15.4 ng/ml. After prolonging the administration time of the child, it was controlled at the target level. Finally, the tumors had different degrees of regression, among which 4 cases had mostly regressed(Fig. 3 ), and 1 case had partial regression (still under treatment). No obvious adverse reactions or recurrence were observed(Table 2 ). (3A), huge red mass on the right thigh was found at birth.( 3B), Magnetic resonance imaging (MRI) manifestations: A relatively large, irregular mass with mixed signals was observed subcutaneously in the right thigh and between the anterior and lateral muscles. It showed iso-intensity on T1-weighted images, slightly high intensity on T2-weighted images, and iso-intensity or slightly high intensity on fat-suppressed T2-weighted images. The boundary was not clearly defined. After contrast enhancement, the mass was significantly enhanced. (3C), 6 months after treatment, the mass shrank and became flat, and the erythema on the surface disappeared. The patient is still under treatment. Table 2 The reaction status of infants with KHE after being treated with low-dose sirolimus Number Time for return to normal(day) Siromo medication time(month) Retrogression degree Complic-ation Hemoglobin Platelets Fibrinogen D-Dimer 1 12 9 10 / 15 complete No 2 / 6 5 3 6 mostly No 3 60 3 59 3 7 partial No 4 19 9 21 27 9 mostly No 5 16 19 6 / 11 mostly No 6 / / / / 12 mostly No 7 / / / / 8 partial No Mean value 26.8 ± 16.6 9.2 ± 3.9 20.2 ± 15.8 11.0 ± 10.2 9.7 ± 2.5 / / Discussion Kaposiform hemangioendothelioma (KHE) is a kind of vascular endothelial cell tumor that tends to occur in infants and young children. It has low malignancy and local invasiveness [ 4 ]. This disease is rare, and the reported incidence in the literature is 9.1 per million [ 5 ]. Clinically, it mostly presents as local red masses or erythema on the skin. It frequently occurs in the limbs and is more common in the head and neck of infants and young children. It can also invade the maxilla, bone joints, pancreas, internal organs, and spine, etc., and some cases are complicated by Raynaud's phenomenon [ 6 ]. Approximately 70% of children are complicated by the Kasabach-Merritt phenomenon (KMP), which means there are coagulation disorders such as rapid tumor growth, severe reduction in platelets, and consumptive reduction in fibrinogen [ 7 , 8 ]. It often leads to a critical condition that endangers life, with a fatality rate as high as 10% − 30% [ 9 ]. In this study, the incidence of KMP was 71.4% (5/7), which was close to the above report. The common causes of death are related to bleeding in various organs, such as cerebral hemorrhage, abdominal hemorrhage, and disseminated intravascular coagulation [ 10 ]. There are also cases of death due to pulmonary infection, respiratory failure, and cardiopulmonary and renal failure. For local lesions that are isolated masses with clear boundaries, surgical resection is the preferred option. However, most infants under 1 year old are complicated by KMP, and the lesions are huge and often located in special parts such as the head and face, joints, and internal organs, so they usually cannot undergo surgical resection [ 11 – 16 ]. As a result, various drugs such as glucocorticoids, propranolol, vincristine, and sirolimus have become common treatment means. Since Blatt [ 17 ] first used sirolimus to treat KMP, more and more literature has shown that the efficacy of sirolimus is better than that of the above other drugs, evolving from an alternative treatment option to the first-line treatment drug for KHE [ 18 – 20 ]. Sirolimus can inhibit cell proliferation, metabolism, angiogenesis, and lymphangiogenesis by blocking the downstream conduction of the mTOR signal [ 21 , 22 ], and thus can be used for the treatment of various vascular malformations. The conventional dose of sirolimus is 0.8 mg/m², twice a day, and maintaining a trough level of 10–15 ng/mL. Multiple literature reports have confirmed that sirolimus at this dose has a significant effect in increasing platelets, maintaining fibrinogen stability, and reducing the volume of lesions [ 7 , 8 , 21 ]. However, its complications such as pneumonia, stomatitis, fever, hyperlipidemia, pain, blood system abnormalities, diarrhea, and vomiting cannot be ignored, and some patients have to stop taking the drug due to intolerance. Kalbfell [ 3 ] reported the situation of sirolimus complications in a latest study: Among 1182 patients, 316 had infections, mainly viral upper respiratory tract infections, followed by pneumonia and skin infections. Six patients died from infections, all of whom were under 2 years old. These complication (causing pneumonia and leading to death) situations have also been reported in other literature [ 23 , 24 ]. The reason may be related to the dose of sirolimus [ 25 ]. During the medication period, the sirolimus serum content needs to be strictly monitored [ 8 ]. Some scholars believe that the main factors affecting the clearance rate of sirolimus are the CYP3A5 gene type and body weight. For a specific individual, the gene type is determined, and the body weight will change with the age in months. Therefore, it is recommended that the initial dose of medication should be determined according to the body weight situation [ 26 ]. Other scholars [ 27 ] believe that CYP3A4 is the main enzyme involved in the metabolism of sirolimus. Newborns and infants under 1 year old lack this enzyme, resulting in excessive serum sirolimus concentration in the body, severe immunosuppression, and a higher risk of medication. Mariani [ 28 ] reported the treatment situation of a 40-day-old female infant with KHE complicated by KMP using low-dose sirolimus. Initially, prednisone, propranolol, and vincristine were given, but the platelet level did not improve. After adding sirolimus at 0.4 mg/m² (twice a day) and maintaining the serum level at 2.2–3.3 ng/mL, platelets and fibrinogen returned to normal 12 days later, suggesting that low-dose sirolimus is still effective for KMP. It is worth mentioning that Veroniek [ 29 ] more systematically proposed that the treatment of KHE with sirolimus should be increased according to body weight and age in months, starting with an initial dose of 0.1 mg and controlling the serum concentration of sirolimus within 2–6 ng/mL. In his study, 5 children with KMP all responded to low-dose sirolimus. An increase in hemoglobin, fibrinogen, and platelet counts was observed in the first week, and the tumors were shrinking without serious adverse reactions. After obtaining the above information, we began to attempt the treatment of infants under 1 year old with KHE using low-dose sirolimus. Considering that we had no experience in this area at that time, we selected the KHE cases without combined Kasabach-Merritt syndrome as the first experimental subjects. Before the treatment, we had fully informed the family members of the patients about the advantages and disadvantages of the low dose. The family members were also willing to accept the new treatment method due to concerns about the high drug dose of sirolimus implying a higher risk of medication. The result was quite encouraging. Three months after the child took the medicine, the tumor of the child could be seen to be shrinking with the naked eye, and the erythema on the surface was gradually fading. When the medicine had been taken for 7 months, the skin color on the surface of the tumor had almost returned to normal. Up to now, during the follow-up, no recurrence of the tumor has been observed (Fig. 1 ). Then we also began to try using low-dose sirolimus to treat the children with combined Kasabach-Merritt syndrome. Given that glucocorticoids take effect quickly on platelets [ 30 ] and combined medication will not increase complications [ 31 ], for children with combined KMP, we first gave hormone shock treatment. After the platelet count reached > 100 × 10⁹/L, a pathological examination was performed. In one case, the child's condition was rather critical. During the treatment in the ICU, blood-related products, gamma globulin, and large-dose hormone shock treatment were transfused for many times. Subsequently, after a puncture biopsy was conducted to confirm the diagnosis, sirolimus was given orally at a dose of 0.1 mg/48 h. If the condition still could not be stabilized, we planned to adopt interventional embolization treatment to control the fatal Kasabach-Merritt phenomenon [ 7 ]. Fortunately, a satisfactory outcome was achieved, and the specific treatment details and successful treatment experience were published in the form of a case report in this journal [ 32 ]. This case suggests that not all cases of decreased platelet counts can be improved by glucocorticoid therapy.[ 20 , 33 ]. Generally, we did not routinely transfuse platelets, because this would lead to a further deterioration of platelets [ 19 , 34 ]. However, in order to confirm the diagnosis as soon as possible and provide an objective basis for the use of sirolimus, we would temporarily transfuse platelets before conducting a histopathological biopsy for cases in which hormones were ineffective to reduce the surgical risk. After having these experiences, we treated the subsequent cases in this way, and the results were also gratifying. All 7 patients responded to low-dose sirolimus, with an effective rate of 100%. The time for platelets and fibrinogen to return to normal was (3–19) days and (5–59) days respectively, which was close to the reported recovery time of 1–6 weeks under the conventional dose [ 8 , 20 , 35 – 37 ]. When monitoring the serum concentration of sirolimus, we found that for newborns and low-weight children, even if they took a very low oral dose, their durg concentration was relatively high. We had to prolong the oral medication time to control it at the target level. The phenomenon we observed was consistent with what Jason [ 38 ] described. In his report, a 26.4-week premature infant weighing only 0.59 kg with KMP was initially given 0.01 mg/d of sirolimus orally, but the measured trough concentration of sirolimus was 14.1 ng/mL. Later, the administration was changed to once every other day. As the body weight increased, the serum concentration became lower. Nine months later, the tumor shrank, and platelets returned to normal and remained stable. Shan [ 39 ] emphasized in the study that the efficacy of sirolimus was not positively correlated with its serum trough concentration. That is to say, the larger the dose of sirolimus, the better the treatment effect was not always true. This explained why good curative effects could be achieved without a large dose. If newborns and infants were given the conventional dose, it would only increase the risks of immunosuppression and infection. Conclusion Based on the above facts, it can be known that under the same dose of sirolimus, the younger the infants in months, the higher the plasma concentration in the body, and the greater the possibility and risk of causing complications. Low-dose sirolimus has lower toxicity and fewer complications. For newborns and infants under 1 year old with KHE, the dose of sirolimus should be reduced, which can reduce the risks of infection, immunosuppression, and drug-related mortality without affecting the curative effect. However, this study also has some deficiencies, such as a too small number of cases and the lack of a comparison between the low dose and the conventional dose. It cannot yet be explained that it can achieve exactly the same treatment effect as the latter. Larger sample-sized randomized controlled studies will be required in the later stage to clarify the issues. Abbreviations KHE Kaposiform hemangioendothelioma KMP Kasabach-Merritt phenomenon MRI magnetic resonance imaging Declarations Acknowledgements I would like to express my deepest gratitude to all those who have accompanied and assisted me throughout the research and writing process of this paper, especially my colleagues from the Department of Plastic and Aesthetic Surgery and the Department of Pathology. Authors’ contributions BHX:Study design; methodology; data curation and analysis; writing - original draft and editing. ZJ: data curation and analysis. FRH:data curation and analysis.JPL: writing - original draft and editing. HMY: methodology;critical editing. CJ: methodology;critical editing.WZP: methodology; critical editing. HXQ:methodology. HH:Provide the pathological report.YH: study design; data curation; critical editing. The author(s) read and approved the final manuscript. Funding No Funding Availability of data and materials The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Ethics approval and consent to participate This study is a retrospective study. During the data collection process, only non-identifiable information relevant to the research objectives was extracted (e.g., disease diagnosis, treatment plan, efficacy indicators, etc.), and no privacy information that could identify the subjects (e.g., name, ID number, contact information, medical record number, etc.) was involved.Although this study did not directly access the subjects' personal privacy data,it was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the research ethics committee of Jiangxi Provincial Children's Hospital and Written informed consent was obtained from the parents or caregivers of study participants. Consent for publication No applicable. Competing interests The authors declare no competing interests. Author details Department of Plastic and Cosmetic Surgery, Jiangxi Provincial Children's Hospital, Nanchang 330000, Jiangxi,China. 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Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics. 2020;48(8):300060520947627. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. New England Journal of Medicine. 2003;349(12):1157-67. Mariani LG, Schmitt IR, Garcia CD, Kiszewski AE. Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. 2019;66(8):e27810. Harbers VEM, van der Salm N, Pegge SAH, van der Vleuten CJM, Verhoeven BH, Vrancken S, et al. Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants. Br J Clin Pharmacol. 2022;88(6):2769-81. Ji Y, Chen S, Yang K, Xia C, Li L. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet journal of rare diseases. 2020;15(1):39. Ji Y, Chen S, Zhou J. Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial. 2022;139(11):1619-30. Cheng J, Zou Y, Fu R, Jin P, Huang M, Wu Z, et al. Sirolimus combined with glucocorticoids in the treatment of Kasabach-Merritt phenomenon in a neonate: A case report. Medicine (Baltimore). 2024;103(14):e37706. Burt H, Shaw L, Gómez-Villegas CP, Pérez-Téllez C, Ochoa-Gaviria J, Builes N. [Refractory kaposiforme hemangioendothelioma in the pediatric population: case report and literature review.]. Clinical and experimental dermatology. 2021;78(4):376-84. Mahajan P, Margolin J, Iacobas I. Kasabach-Merritt Phenomenon: Classic Presentation and Management Options. Journal of investigative medicine high impact case reports. 2017;10:1179545x17699849. Maza-Morales M, Valdés-Loperena S. The use of mTOR inhibitors for the treatment of kaposiform hemangioendothelioma. A systematic review. The Australasian journal of dermatology. 2023;40(3):440-5. Rana A, Das E, Sarkar S, Sherpa N, Datta S, Croteau SE, Gupta D. The clinical spectrum of kaposiform hemangioendothelioma and tufted angioma. Indian journal of pediatrics. 2016;35(3):147-52. Lackner H, Karastaneva A, Schwinger W, Benesch M, Sovinz P, Seidel M, et al. Sirolimus for the treatment of children with various complicated vascular anomalies. European journal of pediatrics. 2015;174(12):1579-84. Koury J, Brown M, Sturtevant S, Wiley C, Felton L. Use of Sirolimus in a Premature Neonate With Kaposiform Hemangioedema. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2021;26(2):205-9. Shan Y, Tian R, Gao H, Zhang L, Li J, Xie C, et al. Sirolimus for the treatment of kaposiform hemangioendothelioma: In a trough level-dependent way. 2021;48(8):1201-9. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":755720,"visible":true,"origin":"","legend":"\u003cp\u003eMicroscopic histopathological manifestations and immunohistochemistry of KHE.\u003c/p\u003e\n\u003cp\u003e(1A),Microscopic findings: Tumor cells were seen in the deep dermis, distributed in a nodular pattern. Fibrous tissue and dilated blood vessels were present between the nodules. - Magnified 20 times.(1B),Microscopic findings: The tumor presented in a glomeruloid or nodular shape. The tumor cells were plump and spindle-shaped, and slit-like blood vessels could be seen. Dilated blood vessels and fibrous tissue were observed around the tumor. - Magnified 100 times.( 1C) , Some tumor cells were D2-40 positive - Magnified 100 times. (1D), Diffuse positive CD31 in tumor cells - Magnified 100 times.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7713613/v1/03650e96a7072bb1bd3606e6.png"},{"id":94473228,"identity":"5e48deb4-4dd0-4744-94c8-393efe800e82","added_by":"auto","created_at":"2025-10-27 15:43:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130453,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment status of Case 6.( 2A) ,pre-treatment.( 2B),12months after treatment.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7713613/v1/3e679307d4030778811e6828.png"},{"id":94473378,"identity":"59356a34-bfb1-4582-89c8-17cdf64977db","added_by":"auto","created_at":"2025-10-27 15:44:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":621402,"visible":true,"origin":"","legend":"\u003cp\u003eThe imaging findings and situation of Case 2 following treatment with low-dose sirolimus.\u003c/p\u003e\n\u003cp\u003e(3A), huge red mass on the right thigh was found at birth.( 3B), Magnetic resonance imaging (MRI) manifestations: A relatively large, irregular mass with mixed signals was observed subcutaneously in the right thigh and between the anterior and lateral muscles. It showed iso-intensity on T1-weighted images, slightly high intensity on T2-weighted images, and iso-intensity or slightly high intensity on fat-suppressed T2-weighted images. The boundary was not clearly defined. After contrast enhancement, the mass was significantly enhanced. (3C), 6 months after treatment, the mass shrank and became flat, and the erythema on the surface disappeared. The patient is still under treatment.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7713613/v1/7e144c89761aa52619a35756.png"},{"id":95524649,"identity":"06636370-d783-4b64-829d-2407ace6719b","added_by":"auto","created_at":"2025-11-10 10:03:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2555844,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7713613/v1/e7f3ffc1-6d71-413d-b054-9eaa2e74b698.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pioneering Safer Treatments: Low-Dose Sirolimus in Infantile Kaposiform Hemangioendothelioma","fulltext":[{"header":"Background","content":"\u003cp\u003eKaposiform hemangioendothelioma is a rare vascular tumor that commonly occurs in infants and young children. When complicated with the Kasabach-Merritt phenomenon, the tumor grows rapidly, accompanied by a severe reduction in platelets and fibrinogen, presenting a critical condition with a high fatality rate [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For those who usually cannot undergo surgical resection, oral sirolimus is used for treatment. However, under the conventional dose, it is prone to cause various complications such as infections and immunosuppression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Children under 1 year old have a higher risk of medication due to the lack of CYP3A4 enzyme for metabolizing sirolimus, and in severe cases, it can be fatal. Studies have shown that the adverse reactions caused by sirolimus are related to the dose and serum concentration. Based on this, this study treated 7 children with KHE using a low-dose stepped administration regimen of sirolimus and analyzed its efficacy and safety. This study was approved by the Medical Research Ethics Committee of our hospital and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents or guardians of the children before collecting their case data.\u003c/p\u003e"},{"header":"Research Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eResearch Materials\u003c/h2\u003e\u003cp\u003eResearch Subjects\u003c/p\u003e\u003cp\u003eSome patients with KHE admitted to our department from December 2021 to August 2024 were included, and the following inclusion criteria were set: (1) Diagnosed with KHE based on clinical manifestations, color Doppler ultrasound, magnetic resonance imaging (MRI), and pathological biopsy; (2) Younger than 1 year old; (3) Without severe liver or kidney function impairment or contraindications to sirolimus; (4) Without diseases affecting the observation of treatment efficacy in the blood system, cardiovascular system, etc.; (5) Excluding children with incomplete data or lost to follow-up. The clinical data of the above children were collected, including gender, age at initial diagnosis in months, lesion location, tumor size, hematological indicators (hemoglobins, platelets, fibrinogen, D-dimer count), medication time, disease outcome, and complication status.\u003c/p\u003e\u003cp\u003eGeneral Information\u003c/p\u003e\u003cp\u003eAfter screening, a total of 7 subjects were included in the study, including 5 males and 2 females. The age at the first visit ranged from 1 day to 3 months and 13 days, with a median age of 1 month and 8 days. There were 2 cases located in the head and face, 2 in the trunk, and 3 in the limbs. The clinical manifestations were red, irregular, and rough masses protruding from the surface in 6 cases, and 1 case presented as a subcutaneous mass.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eResearch Methods:\u003c/h3\u003e\n\u003cp\u003eTreatment Methods\u003c/p\u003e\u003cp\u003e(1) KMP was defined as a platelet count\u0026thinsp;\u0026lt;\u0026thinsp;100 \u0026times; 10⁹/L, which could be combined with coagulation dysfunction or anemia; fibrinogenopenia was defined as fibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;1.0 g/L. For children with combined KMP, dexamethasone (0.5\u0026ndash;1.0 mg/kg/d intravenous drip) or methylprednisolone (1.6 mg/kg/d) was given for shock treatment at admission. After the platelet count returned to normal, a pathological examination was performed. If the hormone shock treatment was ineffective, platelets were transfused before biopsy. For those without KMP, a direct biopsy was conducted. After diagnosis, sirolimus was added for oral administration. (2) The low-dose stepped administration regimen of sirolimus was as follows:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e- Weeks 1\u0026ndash;4: Initial dose of 0.1 mg/48 h, conducting dose adjustments with reference to the target trough levels of 2\u0026ndash;4 ng/ml;\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e- Months 1\u0026ndash;3: Initial dose of 0.1 mg/48 h, conducting dose adjustments with reference to the target trough levels of 2\u0026ndash;6 ng/ml;\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e- Months 3\u0026ndash;6: Initial dose of 0.1 mg/24 h, conducting dose adjustments with reference to the target trough levels of 2\u0026ndash;6 ng/ml;\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e- Months 6\u0026ndash;12: 0.2 mg once or twice a day, conducting dose adjustments with reference to the target trough levels of 2\u0026ndash;6 ng/ml.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003e(3) The drug - level of sirolimus monitoring in therapy was conducted 1 week after medication, then once every 2 weeks. After 5 weeks of medication, it was measured once a month for 2 months, and then once every 3 months. Medication was stopped when the tumor disappeared or remained stable for 12 weeks. (4) Children over 2 months old needed to take prophylactic compound sulfamethoxazole (20\u0026ndash;30 mg/kg bid, taking it for 3 days and stopping for 4 days).\u003c/p\u003e\u003cp\u003eEfficacy Evaluation\u003c/p\u003e\u003cp\u003e(1) The regression degree was evaluated according to the tumor volume measured by color Doppler ultrasound, magnetic resonance, or MRI: 1) 100% regression of the tumor was regarded as complete regression; 2) 75% \u0026minus;\u0026thinsp;100% regression of the tumor was regarded as almost complete regression; 3) 25% \u0026minus;\u0026thinsp;75% regression of the tumor was regarded as partial regression; 4) No change. (2) The recovery time of hematological indicators was defined as returning to normal and remaining stable for 4 weeks without rebound, specifically with a hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;100 g/L, platelets\u0026thinsp;\u0026ge;\u0026thinsp;100\u0026times;10⁹/L, fibrinogen\u0026thinsp;\u0026ge;\u0026thinsp;1.5 g/L, and D-dimer\u0026thinsp;\u0026le;\u0026thinsp;0.5 mg/L.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 7 patients, 5 were male and 2 were female. The age at the first visit ranged from 1 day to 3 months and 13 days, with a median age of 1 month and 8 days. There were 2 cases located in the head and face, 2 in the trunk, and 3 in the limbs. The longest diameter of the tumor was 4.5 cm \u0026minus;\u0026thinsp;12.3 cm. The clinical manifestations were protruding or slightly protruding, red/pink/purple-red, irregular, and rough masses in 6 cases, and 1 case presented as a subcutaneous mass in the parotid gland area with normal skin color on the surface. The total follow-up time ranged from 6 months to 2 years and 8 months. All patients had color Doppler ultrasound and magnetic resonance examinations upon admission. The performance of color Doppler ultrasound was similar to that of infantile hemangioma. The lesions involved\u003c/p\u003e\u003cp\u003ethe skin, subcutaneous fat, and even muscle layers, showing hypoechoic or uneven echo and rich blood supply. On MRI, the lesions mainly showed low signals on T1, with some iso-signals, irregular high signals on T2, and some adjacent to or invading the muscle layers with unclear boundaries. All cases were finally diagnosed through pathological examination. Under the microscope, the tumor tissues had various shapes, mainly composed of proliferating blood vessels and spindle-shaped endothelial cells. CD31 and CD34 were positive in all cases, GluT1 was negative, 6 cases were D2-40 positive, and 3 cases had characteristic changes, namely, glomeruloid structures(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Combining the medical history, imaging examination, and pathological results, a diagnosis of KHE could be made. The clinical data of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e(1A),Microscopic findings: Tumor cells were seen in the deep dermis, distributed in a nodular pattern. Fibrous tissue and dilated blood vessels were present between the nodules. - Magnified 20 times.(1B),Microscopic findings: The tumor presented in a glomeruloid or nodular shape. The tumor cells were plump and spindle-shaped, and slit-like blood vessels could be seen. Dilated blood vessels and fibrous tissue were observed around the tumor. - Magnified 100 times.( 1C), Some tumor cells were D2-40 positive - Magnified 100 times. (1D), Diffuse positive CD31 in tumor cells - Magnified 100 times.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGeneral clinical data and serological indicator status of infants with KHE\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSite\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSize\u003c/p\u003e\u003cp\u003e(cm)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003cp\u003e(g/L)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlatelets\u003c/p\u003e\u003cp\u003e(10^9/L)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFibrinogen\u003c/p\u003e\u003cp\u003e(g/L)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eD-Dimer\u003c/p\u003e\u003cp\u003e(mg/L)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft knee joint\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5*5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e13.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRight thigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7*5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e7.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1m8d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft face\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4*4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1m13d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft upper arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6*6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003efemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3m13d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNape of neck\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12*10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1m5d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eabdominal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7*7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003emale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2m\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLeft temporal part\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6*4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1m8d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e91.8\u0026thinsp;\u0026plusmn;\u0026thinsp;23.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e45.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e14.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003ed\u003c/b\u003e:day \u003cb\u003em\u003c/b\u003e:month\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThere were 2 children without KMP. One of them was the first experimental subject in this study. Currently, the tumor has mostly regressed, and the skin color on the surface is normal. Up to now, it has been followed up for 2 years and 8 months, achieving survival with the tumor, and the tumor has not enlarged (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The other one was located on the left temporal region, had been treated for 8 months, and the tumor was gradually regressing and still under treatment.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAmong the 5 children with combined KMP, the average hemoglobin level at admission was (91.8\u0026thinsp;\u0026plusmn;\u0026thinsp;23.7) g/L, platelets were (45.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7) \u0026times; 10⁹/L, fibrinogen was (1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1) g/L, and D-dimer was (14.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2) mg/L. During hospitalization, they were treated with glucocorticoid (dexamethasone 0.5\u0026ndash;1.0 mg/kg/d once daily or methylprednisolone 1.6 mg/kg/d once daily intravenous drip) for shock treatment. After the platelet count was stable for 5\u0026ndash;7 days, prednisone 2\u0026ndash;3 mg/kg was taken orally every day, and then the dose was reduced weekly. Among them, there was a 1-day-old newborn. After hormone shock treatment, there was no significant change in platelets and fibrinogen, and then subcutaneous bleeding in the upper limb and scalp hematoma occurred. Considering the critical condition and to prevent death due to extensive bleeding, we urgently contacted the intensive care unit, hematology department, and rheumatology and immunology department for consultation. Pathological biopsy was immediately arranged after transfusing gamma globulin, fresh frozen plasma, and platelets, and the dose of methylprednisolone was increased. After diagnosis, sirolimus was used in combination, and finally, a relatively good outcome was achieved. The serological indicators of all children with combined KMP returned to normal and remained stable, and the KMP was corrected. The average time for each indicator to return to normal was hemoglobin (26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6) days, platelets (9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9) days, fibrinogen (20.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8) days, and D-dimer (11.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2) days. The concentration of sirolimus in serum in 4 cases was between 2\u0026ndash;6 ng/ml, and in 1 case, it exceeded 15.4 ng/ml. After prolonging the administration time of the child, it was controlled at the target level. Finally, the tumors had different degrees of regression, among which 4 cases had mostly regressed(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), and 1 case had partial regression (still under treatment). No obvious adverse reactions or recurrence were observed(Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e(3A), huge red mass on the right thigh was found at birth.( 3B), Magnetic resonance imaging (MRI) manifestations: A relatively large, irregular mass with mixed signals was observed subcutaneously in the right thigh and between the anterior and lateral muscles. It showed iso-intensity on T1-weighted images, slightly high intensity on T2-weighted images, and iso-intensity or slightly high intensity on fat-suppressed T2-weighted images. The boundary was not clearly defined. After contrast enhancement, the mass was significantly enhanced. (3C), 6 months after treatment, the mass shrank and became flat, and the erythema on the surface disappeared. The patient is still under treatment.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe reaction status of infants with KHE after being treated with low-dose sirolimus\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eNumber\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e\u003cp\u003eTime for return to normal(day)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSiromo medication time(month)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRetrogression degree\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eComplic-ation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003ePlatelets\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFibrinogen\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eD-Dimer\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ecomplete\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003emostly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003epartial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003emostly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003emostly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003emostly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003epartial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKaposiform hemangioendothelioma (KHE) is a kind of vascular endothelial cell tumor that tends to occur in infants and young children. It has low malignancy and local invasiveness [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This disease is rare, and the reported incidence in the literature is 9.1 per million [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Clinically, it mostly presents as local red masses or erythema on the skin. It frequently occurs in the limbs and is more common in the head and neck of infants and young children. It can also invade the maxilla, bone joints, pancreas, internal organs, and spine, etc., and some cases are complicated by Raynaud's phenomenon [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Approximately 70% of children are complicated by the Kasabach-Merritt phenomenon (KMP), which means there are coagulation disorders such as rapid tumor growth, severe reduction in platelets, and consumptive reduction in fibrinogen [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It often leads to a critical condition that endangers life, with a fatality rate as high as 10% \u0026minus;\u0026thinsp;30% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In this study, the incidence of KMP was 71.4% (5/7), which was close to the above report. The common causes of death are related to bleeding in various organs, such as cerebral hemorrhage, abdominal hemorrhage, and disseminated intravascular coagulation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There are also cases of death due to pulmonary infection, respiratory failure, and cardiopulmonary and renal failure. For local lesions that are isolated masses with clear boundaries, surgical resection is the preferred option. However, most infants under 1 year old are complicated by KMP, and the lesions are huge and often located in special parts such as the head and face, joints, and internal organs, so they usually cannot undergo surgical resection [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. As a result, various drugs such as glucocorticoids, propranolol, vincristine, and sirolimus have become common treatment means. Since Blatt [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] first used sirolimus to treat KMP, more and more literature has shown that the efficacy of sirolimus is better than that of the above other drugs, evolving from an alternative treatment option to the first-line treatment drug for KHE [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Sirolimus can inhibit cell proliferation, metabolism, angiogenesis, and lymphangiogenesis by blocking the downstream conduction of the mTOR signal [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and thus can be used for the treatment of various vascular malformations.\u003c/p\u003e\u003cp\u003eThe conventional dose of sirolimus is 0.8 mg/m\u0026sup2;, twice a day, and maintaining a trough level of 10\u0026ndash;15 ng/mL. Multiple literature reports have confirmed that sirolimus at this dose has a significant effect in increasing platelets, maintaining fibrinogen stability, and reducing the volume of lesions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, its complications such as pneumonia, stomatitis, fever, hyperlipidemia, pain, blood system abnormalities, diarrhea, and vomiting cannot be ignored, and some patients have to stop taking the drug due to intolerance. Kalbfell [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] reported the situation of sirolimus complications in a latest study: Among 1182 patients, 316 had infections, mainly viral upper respiratory tract infections, followed by pneumonia and skin infections. Six patients died from infections, all of whom were under 2 years old. These complication (causing pneumonia and leading to death) situations have also been reported in other literature [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The reason may be related to the dose of sirolimus [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. During the medication period, the sirolimus serum content needs to be strictly monitored [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Some scholars believe that the main factors affecting the clearance rate of sirolimus are the CYP3A5 gene type and body weight. For a specific individual, the gene type is determined, and the body weight will change with the age in months. Therefore, it is recommended that the initial dose of medication should be determined according to the body weight situation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Other scholars [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] believe that CYP3A4 is the main enzyme involved in the metabolism of sirolimus. Newborns and infants under 1 year old lack this enzyme, resulting in excessive serum sirolimus concentration in the body, severe immunosuppression, and a higher risk of medication. Mariani [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] reported the treatment situation of a 40-day-old female infant with KHE complicated by KMP using low-dose sirolimus. Initially, prednisone, propranolol, and vincristine were given, but the platelet level did not improve. After adding sirolimus at 0.4 mg/m\u0026sup2; (twice a day) and maintaining the serum level at 2.2\u0026ndash;3.3 ng/mL, platelets and fibrinogen returned to normal 12 days later, suggesting that low-dose sirolimus is still effective for KMP. It is worth mentioning that Veroniek [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] more systematically proposed that the treatment of KHE with sirolimus should be increased according to body weight and age in months, starting with an initial dose of 0.1 mg and controlling the serum concentration of sirolimus within 2\u0026ndash;6 ng/mL. In his study, 5 children with KMP all responded to low-dose sirolimus. An increase in hemoglobin, fibrinogen, and platelet counts was observed in the first week, and the tumors were shrinking without serious adverse reactions.\u003c/p\u003e\u003cp\u003eAfter obtaining the above information, we began to attempt the treatment of infants under 1 year old with KHE using low-dose sirolimus. Considering that we had no experience in this area at that time, we selected the KHE cases without combined Kasabach-Merritt syndrome as the first experimental subjects. Before the treatment, we had fully informed the family members of the patients about the advantages and disadvantages of the low dose. The family members were also willing to accept the new treatment method due to concerns about the high drug dose of sirolimus implying a higher risk of medication. The result was quite encouraging. Three months after the child took the medicine, the tumor of the child could be seen to be shrinking with the naked eye, and the erythema on the surface was gradually fading. When the medicine had been taken for 7 months, the skin color on the surface of the tumor had almost returned to normal. Up to now, during the follow-up, no recurrence of the tumor has been observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Then we also began to try using low-dose sirolimus to treat the children with combined Kasabach-Merritt syndrome. Given that glucocorticoids take effect quickly on platelets [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and combined medication will not increase complications [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], for children with combined KMP, we first gave hormone shock treatment. After the platelet count reached\u0026thinsp;\u0026gt;\u0026thinsp;100 \u0026times; 10⁹/L, a pathological examination was performed. In one case, the child's condition was rather critical. During the treatment in the ICU, blood-related products, gamma globulin, and large-dose hormone shock treatment were transfused for many times. Subsequently, after a puncture biopsy was conducted to confirm the diagnosis, sirolimus was given orally at a dose of 0.1 mg/48 h. If the condition still could not be stabilized, we planned to adopt interventional embolization treatment to control the fatal Kasabach-Merritt phenomenon [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Fortunately, a satisfactory outcome was achieved, and the specific treatment details and successful treatment experience were published in the form of a case report in this journal [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This case suggests that not all cases of decreased platelet counts can be improved by glucocorticoid therapy.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Generally, we did not routinely transfuse platelets, because this would lead to a further deterioration of platelets [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, in order to confirm the diagnosis as soon as possible and provide an objective basis for the use of sirolimus, we would temporarily transfuse platelets before conducting a histopathological biopsy for cases in which hormones were ineffective to reduce the surgical risk. After having these experiences, we treated the subsequent cases in this way, and the results were also gratifying. All 7 patients responded to low-dose sirolimus, with an effective rate of 100%. The time for platelets and fibrinogen to return to normal was (3\u0026ndash;19) days and (5\u0026ndash;59) days respectively, which was close to the reported recovery time of 1\u0026ndash;6 weeks under the conventional dose [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. When monitoring the serum concentration of sirolimus, we found that for newborns and low-weight children, even if they took a very low oral dose, their durg concentration was relatively high. We had to prolong the oral medication time to control it at the target level. The phenomenon we observed was consistent with what Jason [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] described. In his report, a 26.4-week premature infant weighing only 0.59 kg with KMP was initially given 0.01 mg/d of sirolimus orally, but the measured trough concentration of sirolimus was 14.1 ng/mL. Later, the administration was changed to once every other day. As the body weight increased, the serum concentration became lower. Nine months later, the tumor shrank, and platelets returned to normal and remained stable. Shan [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] emphasized in the study that the efficacy of sirolimus was not positively correlated with its serum trough concentration. That is to say, the larger the dose of sirolimus, the better the treatment effect was not always true. This explained why good curative effects could be achieved without a large dose. If newborns and infants were given the conventional dose, it would only increase the risks of immunosuppression and infection.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on the above facts, it can be known that under the same dose of sirolimus, the younger the infants in months, the higher the plasma concentration in the body, and the greater the possibility and risk of causing complications. Low-dose sirolimus has lower toxicity and fewer complications. For newborns and infants under 1 year old with KHE, the dose of sirolimus should be reduced, which can reduce the risks of infection, immunosuppression, and drug-related mortality without affecting the curative effect. However, this study also has some deficiencies, such as a too small number of cases and the lack of a comparison between the low dose and the conventional dose. It cannot yet be explained that it can achieve exactly the same treatment effect as the latter. Larger sample-sized randomized controlled studies will be required in the later stage to clarify the issues.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eKHE \u0026nbsp; \u0026nbsp;Kaposiform hemangioendothelioma\u003c/p\u003e\n\u003cp\u003eKMP \u0026nbsp; \u0026nbsp;Kasabach-Merritt phenomenon\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI \u0026nbsp; \u0026nbsp;magnetic resonance imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI would like to express my deepest gratitude to all those who have accompanied and assisted me throughout the research and writing process of this paper, especially my colleagues from the Department of Plastic and Aesthetic Surgery and the Department of Pathology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBHX:Study design; methodology; data curation and analysis; writing - original draft and editing. ZJ: data curation and analysis. FRH:data curation and analysis.JPL: writing - original draft and editing. HMY: methodology;critical editing. CJ: methodology;critical editing.WZP: methodology; critical editing. HXQ:methodology. HH:Provide the pathological report.YH: study design; data curation; critical editing. The author(s) read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo Funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a retrospective study. During the data collection process, only non-identifiable information relevant to the research objectives was extracted (e.g., disease diagnosis, treatment plan, efficacy indicators, etc.), and no privacy information that could identify the subjects (e.g., name, ID number, contact information, medical record number, etc.) was involved.Although this study did not directly access the subjects\u0026apos; personal privacy data,it was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the research ethics committee of Jiangxi Provincial Children\u0026apos;s Hospital and Written informed consent was obtained from the parents or caregivers of study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Plastic and Cosmetic Surgery, Jiangxi Provincial Children\u0026apos;s Hospital, Nanchang 330000, Jiangxi,China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKhoei AA, Arias-Shah A, Kralik S, Mahajan P, Iacobas I, Fernandes CJ. 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Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics. 2020;48(8):300060520947627.\u003c/li\u003e\n\u003cli\u003eKearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. New England Journal of Medicine. 2003;349(12):1157-67.\u003c/li\u003e\n\u003cli\u003eMariani LG, Schmitt IR, Garcia CD, Kiszewski AE. Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. 2019;66(8):e27810.\u003c/li\u003e\n\u003cli\u003eHarbers VEM, van der Salm N, Pegge SAH, van der Vleuten CJM, Verhoeven BH, Vrancken S, et al. Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants. 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Sirolimus for the treatment of kaposiform hemangioendothelioma: In a trough level-dependent way. 2021;48(8):1201-9.\u003cstrong\u003e\u003cstrong\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Low-dose, Kasabach - Merritt phenomenon, kaposiform hemangioendothelioma, Sirolimus","lastPublishedDoi":"10.21203/rs.3.rs-7713613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7713613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eKaposiform hemangioendothelioma(KHE) is a rare and aggressive vascular neoplasm. When complicated with Kasabach-Merritt phenomenon, the condition is critical with a high mortality rate. Sirolimus (0.8 mg/m² per administration) exerts a significant therapeutic effect; however, under this conventional dosage, it is prone to induce various infections, immunosuppression and other adverse complications. This research aims to explore the efficacy and safety of low-dose sirolimus in the treatment of infants with KHE.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA retrospective analysis was conducted on the treatment status of 7 infants with KHE who were treated with a low-dose stepped administration of sirolimus in our department from December 2021 to August 2024. For cases without Kasabach-Merritt phenomenon (KMP), sirolimus was used alone, and the doses were increased according to the age in months (for infants aged 1 - 3 months, 3 - 6 months, and 6 - 12 months, the initial doses were 0.1 mg/m²/time, 0.2 mg/m²/time, and 0.5 mg/m²/time respectively, all administered twice a day). For cases combined with KMP, glucocorticoid therapy was incorporated. The degree of tumor regression, hematological indexes and complications after treatment were summarized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The duration of medication was from 7 months to 15 months, and the follow-up time was from 6 months to 2 years and 8 months. Among them, 2 had no KMP and 5 had KMP. For children without KMP, 1 case showed mostly regression, another had partial regression, with no adverse reactions. The 5 patients with KMP, the average time for the four indicators to return to normal was hemoglobin (26.8 ± 16.6) days, platelets (9.2 ± 3.9) days, fibrinogen (20.2 ± 15.8) days, and D-dimer (11.0 ± 10.2) days. Of these 1 case achieved complete regression, 3 cases had mostly regressed, and 1 case had partial regression. No obvious adverse reactions or recurrences were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eLow-dose sirolimus is still significantly effective in the treatment of KHE in infancy. It has lower adverse reactions and higher safety. Furthermore, for cases combined with KMP, glucocorticoid therapy needs to be combined.\u003c/p\u003e","manuscriptTitle":"Pioneering Safer Treatments: Low-Dose Sirolimus in Infantile Kaposiform Hemangioendothelioma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-27 14:26:37","doi":"10.21203/rs.3.rs-7713613/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"600048b2-2610-4ac8-b41f-f4bce0e16d3d","owner":[],"postedDate":"October 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-07T06:08:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-27 14:26:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7713613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7713613","identity":"rs-7713613","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}