Keywords
kaposiform hemangioendothelioma - Kasabach–Merritt phenomenon - sirolimus - neonate
- thrombocytopenia
Importance for the Pediatric Surgeon
This case reinforces sirolimus as a lifesaving salvage therapy for refractory neonatal
KHE-KMP. Pediatric surgeons must advocate for early sirolimus initiation, coordinate
multidisciplinary care, and prioritize coagulopathy stabilization over theoretical
infection risks in critical settings.
Introduction
Kaposiform hemangioendothelioma, a rare borderline vascular tumor with an estimated
incidence of 0.91 per 100,000,[1] predominantly manifests during infancy. A subset of cases may develop severe thrombocytopenia
and consumptive coagulopathy, triggering the Kasabach–Merritt phenomenon, a life-threatening
complication associated with high mortality if untreated. This study retrospectively
analyzes the diagnostic and therapeutic management of a neonate with kaposiform hemangioendothelioma
(KHE) complicated by Kasabach–Merritt phenomenon (KMP) treated at our institution.
Case Presentation
A male neonate, first-born of a singleton pregnancy delivered vaginally at 40 weeks'
gestation with a birth weight of 3,150 g, had Apgar scores of 9 (deducted 1 point
for cyanosis) at 1 minute and 10 at 5 minutes. Prenatal ultrasound performed 5 days
prior to delivery revealed right upper limb thickening (subcutaneous tissue thickening
with enhanced echogenicity). Postnatally, a dark red mass on the right upper limb
was noted within 1 hour, prompting referral to pediatric surgery with a provisional
diagnosis of KHE. Physical examination demonstrated a swollen, violaceous, firm mass
with elevated skin tension, ill-defined borders, limited mobility, and blanchable
discoloration upon pressure; distal finger mobility was preserved ([Fig. 1]). Laboratory tests revealed hemoglobin 127 g/L, severe thrombocytopenia (platelets:
16 × 109/L), neutrophil ratio 60.3%, and hypofibrinogenemia (1.70 g/L). Magnetic resonance
imaging (MRI) of the right upper limb confirmed vascular endothelial neoplasia with
minimal hemorrhage ([Fig. 2]), supporting a diagnosis of KHE complicated by KMP. Due to recent Bacillus Calmette–Guérin
(BCG) vaccination, initial management excluded sirolimus and included topical tacrolimus,
compression therapy, vitamin K, and corticosteroids. Platelet counts transiently improved
to 23 × 109/L on day 2 but declined to 11 × 109/L on day 3, accompanied by worsening hypofibrinogenemia (0.72 g/L) and hemoglobin
drop (111 g/L). After parental consent, oral sirolimus (0.25 mg/m2/day) was initiated, and the infant was transferred to the neonatal intensive care
unit. Re-examination shows a drop in hemoglobin, suggesting bleeding. Two fibrinogen
transfusions stabilized coagulation parameters. By day 13, platelets normalized (283 × 109/L), and sirolimus was continued alongside transitioning corticosteroids from intravenous
to oral. On day 21, fever and diarrhea emerged but resolved with anti-inflammatory
agents, rehydration, and symptomatic care. At discharge (day 27), platelets stabilized
at 183 × 109/L, with marked tumor regression ([Figs. 3] and [4]). Postdischarge, oral sirolimus and prednisone were maintained. Prophylactic trimethoprim-sulfamethoxazole
(20 mg/kg twice daily, 3 days/week) was added at 2 months to prevent Pneumocystis
infection. Three-month follow-up demonstrated sustained platelet stability (268–532 × 109/L), no infections, and significant clinical improvement. Ongoing monitoring confirms
favorable outcomes.
Fig. 1 Postnatal clinical presentation of the right upper limb.
Fig. 2 Magnetic resonance imaging findings of vascular tumor infiltration with hemorrhage.
Fig. 3 Clinical assessment at 2-month follow-up demonstrating significant tumor regression.
Fig. 4 Radiological and clinical evaluation at 4-month follow-up confirming complete tumor
resolution.
Discussion
KHE is a rare, locally aggressive borderline vascular tumor with a multifactorial
pathogenesis. Current evidence suggests that KHE may be associated with mitogen-activated
protein kinase pathway alterations caused by the GNA14 c.614A > T (p.Gln205Leu) mutation.
Additionally, germline TP53 single-nucleotide variants in the context of coexisting
oncogenic drivers may contribute to KHE development, while somatic second-hit mutations
likely play a critical role in disease progression.[2]
[3]
KHE has an estimated incidence of 0.7 per 10 million neonates, accounting for approximately
2% of all vascular tumors. Over 90% of cases manifest within the first year of life,
with 60% presenting within the first month. Cutaneous or subcutaneous lesions typically
appear as firm, violaceous nodules or plaques displaying heterogeneous pigmentation
and ill-defined borders secondary to ecchymosis or telangiectasia. KHE can trigger
KMP, a life-threatening coagulopathy initiated by abnormal vascular endothelial cell
proliferation within KHE lesions. These cells sequester platelets, promoting platelet
adhesion, aggregation, and activation. This process locally activates the coagulation
cascade, leading to excessive fibrin deposition and microthrombus formation. Subsequent
consumption of platelets and clotting factors exacerbates coagulopathy, culminating
in disseminated intravascular coagulation and potential mortality.[2]
The diagnosis of KHE requires a multidisciplinary approach integrating clinical evaluation,
imaging studies, and histopathological examination. Prenatal ultrasound serves as
a diagnostic modality, with some cases detectable during the third trimester of pregnancy.
Postnatal magnetic resonance imaging is pivotal for distinguishing KHE from other
vascular malformations, defining lesion extent, and assessing therapeutic response
during follow-up.[3] The diagnosis of KHE involving the right upper limb, complicated by KMP, was confirmed
postnatally through comprehensive evaluation, including physical examination, MRI,
hematologic profiling (e.g., blood cell analysis), and coagulation function studies.
Although biopsy remains the diagnostic gold standard, it was not performed in this
case due to the potential to exacerbate the infant's consumptive coagulopathy.
A study involving six pediatric patients with superficial KHE treated with topical
tacrolimus demonstrated an overall response rate of 100%, with no rebound growth of
KHE observed at the final follow-up after treatment cessation. The therapeutic mechanism
may be attributed to tacrolimus-mediated calcineurin inhibition, which reduces the
production of T cell-derived cytokines and suppresses angiogenic factor synthesis,
thereby impeding pathological vascular proliferation.[4]
Glucocorticoids are employed in combination therapy for KMP to mitigate thrombocytopenia
and suppress fibrinolysis. However, prolonged glucocorticoid use may result in transient
growth impairment, heightened infection susceptibility, and behavioral changes. Gradual
tapering and discontinuation are advised once clinical stabilization is achieved.[2]
Sirolimus, an inhibitor of the mammalian target of rapamycin, exerts therapeutic effects
by suppressing the mTOR/PI3K/AKT signaling pathway and downregulating vascular endothelial
growth factor production. This dual mechanism effectively inhibits vascular endothelial
cell proliferation and angiogenesis, establishing sirolimus as the first-line systemic
therapy for KHE.[5] However, a case report documented disease recurrence in a pediatric patient following
sirolimus treatment.[6] Due to the immunosuppressive effects of sirolimus, patients are at increased risk
of upper respiratory tract infections, pneumonia, and cutaneous infections. Additionally,
the potential for Pneumocystis pneumonia necessitates prophylactic administration
of trimethoprim-sulfamethoxazole to mitigate infection risks.[7]
A neonate presented with right upper limb KHE complicated by KMP. Given the patient's
recent BCG vaccination, immediate sirolimus administration posed significant risks
of immunosuppression-related complications, including disseminated tuberculosis (e.g.,
tuberculous meningitis). Therefore, topical tacrolimus was initiated as primary therapy
at doses maintained within established safety thresholds. KHE lesions exhibited a
significant clinical response to twice-daily topical application.[2] First-line therapies, including topical medications, compression therapy, and corticosteroids,
failed to improve symptoms, prompting eventual sirolimus administration (0.25 mg/m2/day) to control KMP. TMP-SMX prophylaxis was deferred until 2 months of age due to
the infant's immature acetyltransferase system, which elevates free sulfonamide levels
and increases kernicterus risk. During hospitalization, transient fever and diarrhea
resolved with anti-inflammatory and antidiarrheal therapies. At 2 months of age, TMP-SMX
was initiated for infection prevention. Platelet transfusion was deliberately withheld
in this patient. Platelets contain pro-angiogenic growth factors that may potentiate
vascular lesion progression. Furthermore, transfused platelets can become sequestered
within the lesion, precipitating acute expansion with concomitant activation and consumption
of coagulation factors.[8] Thyroid function tests were not performed in this case. Routine thyroid screening
will be systematically incorporated into the management protocol for subsequent patients.
Follow-up confirmed sustained clinical stability, with no recurrence and age-appropriate
developmental progress. Thyroid function tests were not performed in this case. Routine
thyroid screening will be systematically incorporated into the management protocol
for subsequent patients.
Conclusion
KHE is a rare and complex vascular disorder often complicated by KMP. Prenatal ultrasound
can detect KHE prenatally, while postnatal diagnosis is confirmed through clinical
manifestations, MRI, hematologic and coagulation profiles, and histopathological examination.
Timely treatment is critical, with current therapeutic options including local compression
therapy, glucocorticoids, and oral medications such as sirolimus. Clinicians must
tailor treatment strategies based on individual contraindications and disease severity.
This case aims to provide clinical insights to guide evidence-based management of
KHE and KMP.
Erratum: This article was published with incorrect page numbers. The page numbers have been
corrected subsequently with the publication of an erratum (DOI: 10.1055/a-2706-9632).
