2 Cases of Pegylated Asparaginase-Associated Cerebral Venous Sinus Thrombosis in Children: Clinical Analysis and Literature Review

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Methods The clinical manifestations, laboratory findings, imaging characteristics, treatment, and prognosis of two pediatric ALL cases complicated by CVST during induction remission therapy at Guangzhou Women and Children's Medical Center were retrospectively analyzed, and relevant literature was reviewed. Results (1) Both children were treated according to the CCCG-ALL-2020 protocol and developed CVST during the induction remission phase. CVST occurred approximately two weeks after the first PEG-Asp administration in both cases. The presenting symptom was generalized tonic-clonic seizure. Platelet counts were within the normal range. Coagulation tests showed insignificant prolongation of APTT, with decreased fibrinogen (FIB) and decreased antithrombin III (AT-III) being the main abnormalities. Head magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) revealed venous sinus thrombosis with hemorrhage. After treatment with infusion of fresh frozen plasma and fibrinogen to improve coagulation function, mannitol to reduce intracranial pressure, and rivaroxaban for anticoagulation, no further thrombosis occurred. CVST symptoms did not recur upon subsequent PEG-Asp administration. Conclusion During chemotherapy for ALL, especially when using PEG-Asp, regular monitoring of coagulation function is essential. Unexplained neurological symptoms often indicate possible CVST, warranting prompt cranial contrast-enhanced MRI and MRV for early diagnosis. Anticoagulation with rivaroxaban is effective for children developing CVST, resulting in a favorable prognosis without severe permanent neurological deficits. Greater clinical attention should be paid to CVST complicating the induction remission phase of ALL to enable early prevention, diagnosis, and treatment. Child Acute Lymphoblastic Leukemia Pegylated Asparaginase Cerebral Venous Sinus Thrombosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Introduction Acute lymphoblastic leukemia (ALL) is the most common and highest incidence malignant tumor in children, accounting for about one-third of childhood malignancies 1 . With continuous advancements and optimization of treatment protocols over recent decades, the survival rate has increased from 10% to over 90% 2 . The introduction of L-asparaginase (L-Asp) in the 1970s and the application of pegaspargase (PEG-Asp) in recent years have been landmark developments in the treatment of childhood ALL. Pegaspargase (PEG-Asp) is a pegylated form of the naturally derived L-Asp from Escherichia coli (E. coli). As a new asparaginase preparation modified by polyethylene glycol (PEG) chemical conjugation, it retains the enzymatic activity of L-Asp while having a longer duration of action and significantly reduced allergic reactions compared to repeated use of L-Asp. With the widespread application of PEG-Asp in ALL chemotherapy, its drug-related adverse reactions, such as severe allergic reactions, acute pancreatitis, coagulation abnormalities, liver function impairment, and transient hyperglycemia, have emerged 3 . These adverse reactions affect the chemotherapy process and can even threaten the child's life due to severe drug side effects, particularly coagulation disorders leading to intracranial hemorrhage and cerebral venous sinus thrombosis (CVST), forcing the suspension of PEG-Asp treatment and seriously impacting treatment efficacy and prognosis. Currently, there are few reported cases of CVST occurring in ALL children after PEG-Asp chemotherapy both domestically and internationally. This article reports two cases of ALL children who developed CVST during the induction remission phase at our hospital. Both improved after anticoagulation therapy and successfully entered consolidation therapy. Object of study Case 1 A 10-year-old boy was admitted due to "swelling and pain in the left ankle for 10 days." Physical examination: Pale and sallow complexion; pea-sized enlarged lymph nodes palpable in bilateral cervical, axillary, and inguinal regions, mobile, medium consistency; liver and spleen not palpable below the costal margin; left ankle edema with significant tenderness. Laboratory tests: Blood routine: WBC 2.1×10⁹/L, NEU 1.09×10⁹/L, PLT 153×10⁹/L, HCT 28.30%, HGB 91 g/L, NEU% 52%; Coagulation profile: APTT 44.10s, PT 13.10s, INR 0.99, FIB 4.88g/L; Bone marrow cytomorphology: Considered consistent with acute lymphoblastic leukemia L2 type; Immunophenotyping: Approximately 24.40% abnormal immature B lymphocytes in the bone marrow, suggestive of acute B lymphoblastic leukemia (Com-B-ALL); Karyotype: No analyzable metaphases; Fusion genes: Negative. Head MRI: 1. No definite abnormality on plain and enhanced brain MR scan; 2. Left sphenoid sinusitis, bilateral ethmoid sinus mucosal thickening; 3. Bilateral otomastoiditis (Fig. 1). MICM diagnosis: ALL (B-cell type, intermediate risk). Treatment Course :After definite diagnosis and exclusion of chemotherapy contraindications, chemotherapy according to the CCCG-ALL-2020 induction remission protocol (VDLP group: Prednisone, Vincristine, Daunorubicin, PEG-Asp combination chemotherapy). Chemotherapy Day 5 Vincristine and Daunorubicin administered. Chemotherapy Day 6 :PEG-Asp 2500U (2500U/m²) administered. Bone marrow aspiration, lumbar puncture + intrathecal chemotherapy performed. CSF routine and biochemistry normal, no blasts, CSF MRD negative. Blood routine: WBC 3.20×10⁹/L, HB 105 g/L, PLT 293×10⁹/L, NEU 2.50×10⁹/L. Coagulation: APTT 29.90s, PT 13.30s, INR 1.01, FIB 2.05 g/L. Chemotherapy Day 13 :Blood routine: WBC 0.30×10⁹/L, HB 75 g/L, PLT 50×10⁹/L, NEU 0.09×10⁹/L. Coagulation: APTT 44.70s, PT 15.40s, INR 1.35, FIB 0.95 g/L. Plasma antithrombin (AT-III): 70%. Patient developed myelosuppression, coagulation function significantly worsened compared to pre-chemotherapy, but no obvious bleeding symptoms yet. Treated with fibrinogen infusion. Chemotherapy Day 19 :Initial evaluation. Bone marrow cytology: Blasts 1.0%. CSF routine and biochemistry normal, no blasts. Day 19 MRD < 0.01. Chemotherapy Day 21 :Developed generalized tonic-clonic seizures without fever, followed by upward gaze, unresponsiveness, frothing at the mouth, lasting 30 seconds then stopping, but persistent upward gaze with occasional blinking, still unresponsive. Pupils dilated (~ 5mm diameter), sluggish light reflex. BP 122/80 mmHg. Blood routine: WBC 0.40×10⁹/L, HB 81 g/L, PLT 184×10⁹/L, NEU 0.12×10⁹/L. Coagulation + D-dimer: APTT 35.00s, PT 15.00s, INR 1.19, FIB 0.81 g/L, D-dimer 0.35 mg/L. Plasma AT-III: 87%. Emergency head CT: 1. Consider small amount of hemorrhage in the left parietal lobe, recommend follow-up. 2. Pineal calcification (Fig. 2). Immediate treatment: Sedation and anticonvulsants, mannitol to reduce intracranial pressure, infusion of fresh frozen plasma and fibrinogen to improve coagulation, vancomycin and imipenem for infection prophylaxis, rivaroxaban for anticoagulation, levetiracetam for seizure prophylaxis. Head MRI: Large hematoma (~ 6cm*4cm) in the left parietal lobe, suggestive of possible acute hemorrhagic infarction in the left parietal lobe, recommend MRV (Fig. 3). After treatment, the child had no further seizures, no limb paralysis, normal limb muscle strength and tone, but intermittently complained of right lower limb pain. Chemotherapy Day 26 :Right lower limb pain resolved. Coagulation normal. Continued oral rivaroxaban anticoagulation. Received second dose of PEG-Asp 2500U according to protocol. No recurrence of similar symptoms. Successfully entered next phase of chemotherapy. Chemotherapy Day 35 (Approx. 2 weeks post-onset) :No complaint of right lower limb pain. Follow-up imaging (Fig. 4): 1. Left parietal hemorrhage roughly same size as before. Deepened cerebral sulci bilaterally. Slightly widened lateral and third ventricles. Recommend follow-up. 2. Slightly reduced distal branches of the left superficial cerebral veins. 1 Month Follow-up (Post-onset) :Imaging (Fig. 5): 1. Left parietal hemorrhage slightly reduced compared to previous. Deepened cerebral sulci and slightly widened ventricles essentially unchanged. Recommend follow-up. 2. Slightly reduced distal branches of left superficial cerebral veins same as before. 2 Months Follow-up (Post-onset) :Imaging (Fig. 6): Left parietal hemorrhage slightly reduced compared to previous. 4 Months Follow-up (Post-onset) :Head MRI and MRV (Fig. 7): Lesion gradually absorbed and reduced. Case 2 An 11-year-old boy admitted due to "pain in limb joints for over 20 days." Physical examination: Pale and sallow complexion; left mandibular swelling, non-tender; tenderness over bilateral scapulae; soybean-sized enlarged lymph nodes palpable in cervical, axillary, and inguinal regions, limited mobility, medium consistency; liver and spleen not palpable below costal margin; left knee tenderness. Laboratory tests: Blood routine: WBC 18.30×10⁹/L, NEU 4.98×10⁹/L, PLT 70×10⁹/L, HCT 28.90%, HGB 99g/L, NEU% 28%; Coagulation: APTT 32.30s, PT 13.70s, INR 1.00, FIB 6.99g/L; Head MRI: 1. No definite abnormality on plain and enhanced brain MR scan. 2. Right ethmoid sinusitis (Fig. 8). Bone marrow cytomorphology: Considered consistent with acute lymphoblastic leukemia L2 type; Immunophenotyping: Approximately 90.10% abnormal T lymphocytes in the bone marrow, suggestive of acute T lymphoblastic leukemia (T-ALL); Karyotype: Normal; Fusion genes: Negative. MICM diagnosis: ALL (T-cell type, intermediate risk). Treatment Course After definite diagnosis and exclusion of chemotherapy contraindications, chemotherapy according to the CCCG-ALL-2020 induction remission protocol (VDLP group). Chemotherapy Day 5 :Vincristine and Daunorubicin administered. Chemotherapy Day 6 :PEG-Asp 2500U (2500U/m²) administered. Bone marrow aspiration, lumbar puncture + intrathecal chemotherapy performed. CSF routine and biochemistry normal, no blasts, CSF MRD negative. Blood routine: WBC 0.90×10⁹/L, HB 74 g/L, PLT 50×10⁹/L, NEU 0.43×10⁹/L. Coagulation: APTT 30.90s, PT 12.40s, INR 1.15, FIB 3.15 g/L. Chemotherapy Day 12 :Blood routine: WBC 0.20×10⁹/L, HB 60 g/L, PLT 25×10⁹/L, NEU 0.10×10⁹/L. Coagulation: APTT 40.70s, PT 14.40s, INR 1.05, FIB 1.50 g/L. Plasma AT-III: 80%. Patient developed myelosuppression, required packed red blood cell transfusion for anemia correction, platelet transfusion scheduled. No obvious bleeding symptoms. Chemotherapy Day 19 :Initial evaluation. Bone marrow cytology: Blasts 2.0%. CSF routine and biochemistry normal, no blasts. Day 19 MRD < 0.01. Chemotherapy Day 20 :Developed epigastric pain accompanied by vomiting approximately 15ml of light red gastric contents, followed immediately by limb convulsions, upward gaze, unresponsiveness. Pupils equal and round (~ 5mm), sluggish light reflex, no fever. BP 123/73 mmHg. Blood routine: WBC 2.20×10⁹/L, HB 101g/L, PLT 192×10⁹/L, NEU 0.63×10⁹/L. Plasma AT-III: 65%. Coagulation + D-dimer: APTT 35.50s, PT 83.00s, INR 4.8, FIB 0.49 g/L, D-dimer 0.46 mg/L. Head MRI: 1. Consider venous infarction with hemorrhage in the left frontal lobe. 2. Right sphenoid sinus submucosal cyst, right sphenoid sinusitis (Fig. 9). Head MRV: 1. Findings in the superior sagittal sinus suggestive of venous sinus thrombosis. 2. Right dominant venous sinus (Fig. 10). Immediate treatment: Sedation and anticonvulsants, hypertonic saline and mannitol to reduce intracranial pressure, infusion of fresh frozen plasma and fibrinogen to improve coagulation, rivaroxaban for anticoagulation, levetiracetam for seizure control, vancomycin and imipenem for infection prophylaxis. After treatment, the child had no further seizures, normal limb muscle strength and tone, normal limb movement. Repeat coagulation normal. Chemotherapy Day 26 :Coagulation normal. Continued oral rivaroxaban anticoagulation. Received second dose of PEG-Asp 2500U according to protocol. No recurrence of similar symptoms. Successfully entered next phase of chemotherapy. Chemotherapy Day 36 (Approx. 2 weeks post-onset) :No recurrence of symptoms. Follow-up imaging (Figs. 11, 12): Left frontal venous infarction with hemorrhage follow-up: 1. Increased blood supply in infarcted area, partial cortical neuronal necrosis, recommend follow-up. 2. Right sphenoid sinus submucosal cyst unchanged, right sphenoid sinusitis improved. Successfully entered CAT phase chemotherapy and received second dose of PEG-Asp without recurrence. 2 Months Follow-up (Post-onset) :Imaging (Figs. 13, 14): Left frontal venous infarction with hemorrhage follow-up: 1. Left frontal lesion smaller than before, peripheral hemosiderin deposition, edema improved, partial cortical neuronal necrosis unchanged; 2. Right sphenoid sinus submucosal cyst unchanged, left sinusitis; 3. Previous filling defect in superior sagittal sinus significantly reduced; 4. Head MRA showed right posterior communicating artery relatively slender (congenital variant), otherwise unremarkable. Discussion ALL is the most common hematological malignancy in childhood. With the continuous development of diagnostic and monitoring technologies and the optimization of combination chemotherapy regimens, especially the clinical application of L-Asp and PEG-Asp, the overall survival rate of children with ALL has increased to over 90% both domestically and internationally 4 . However, complications caused by combination chemotherapy remain a significant factor threatening the survival and quality of life of children with ALL. According to relevant reports, children with ALL have a higher risk of thrombosis, making ALL the malignancy most prone to thrombosis 5 . As a main drug for treating ALL, the adverse effects of PEG-Asp cannot be ignored. Besides commonly reported severe allergic reactions, acute pancreatitis, liver function impairment, and transient hyperglycemia, coagulation abnormalities are increasingly being recognized, particularly life-threatening deep vein thromboses such as CVST, which require greater attention 6 . The chemotherapeutic mechanism of PEG-Asp involves hydrolyzing asparagine to aspartic acid and ammonia, thereby inhibiting protein synthesis to suppress tumor growth. The mechanism by which PEG-Asp causes coagulation abnormalities is relatively complex and often bidirectional. Most coagulation factors in the human body are proteins synthesized by the liver. Therefore, while inhibiting tumors, PEG-Asp also affects the synthesis of coagulation factors, leading to bleeding. It can also reduce anticoagulant factor levels, disrupting the physiological balance between coagulation and anticoagulation pathways, resulting in decreased synthesis of FIB, plasminogen, AT-III, protein C, and protein S, increased thrombin formation, platelet aggregation, and endothelial cell activation, initiating the intrinsic coagulation pathway, and ultimately inducing thrombosis 7 , 8 . Current domestic and international literature reporting on coagulation changes in children with ALL treated with PEG-Asp and L-Asp is increasing, highlighting the growing concern over PEG-Asp-induced coagulation disorders. Domestic and international reports indicate the incidence of CVST ranges roughly between 0.51% and 3.34%, primarily concentrated in the induction remission and re-induction phases. It is considered that the combination of PEG-Asp with corticosteroids increases the risk of thrombosis 9 , 10 . Reported risk factors include age ≥ 10 years, initial white blood cell count > 50×10⁹/L, T-cell ALL, intermediate/high-risk patients, low antithrombin levels during treatment, and the use of prednisone (rather than dexamethasone) 11 . Case 2 in this study aligns with this report, although the initial WBC was not high (WBC 2.1×10⁹/L). Compared to international data, the risk of CVST is similar concerning gender, age, and risk stratification. However, regarding immunophenotype, domestic patients with B-cell lineage appear to have a more prominent CVST risk, possibly related to sample size, but suggesting the need for special attention to CVST risk in B-lineage patients. Case 1 in this study was a B-lineage patient who developed CVST. However, due to the small sample size of this study, it cannot fully reflect differences in CVST risk based on immunophenotype or WBC count; larger sample sizes are needed for validation. Domestic reports note many cases occurring after the second dose of PEG-Asp, reminding us to be mindful of dose accumulation 9 . However, both patients in this study developed CVST symptoms approximately two weeks after the first PEG-Asp dose, differing from reports from other institutions. Therefore, close monitoring of coagulation function after the first PEG-Asp dose and vigilance for unexplained neurological symptoms are crucial to detect CVST. The clinical manifestations of CVST in children are diverse. The main symptoms include headache, nausea, and vomiting, likely related to increased intracranial pressure. Some children may have no obvious clinical symptoms or signs. Seizures are also a common initial symptom of CVST. Both cases in this study presented with varying degrees of headache and vomiting, along with intermittent seizures, consistent with domestic and international reports 5 , 9 , 11 . Case 2 also experienced epigastric pain with vomiting light red gastric contents. This could be a side effect of prednisone (used in the regimen), where relatively high doses calculated by body surface area may stimulate increased gastric acid secretion, damaging the gastric mucosa and potentially causing gastrointestinal bleeding. International literature reports that persistent and severe headache accompanied by vomiting occurs in up to 90% of CVST cases in older children 12 . Unexplained persistent severe headache with vomiting during PEG-Asp treatment should raise suspicion for CVST. If CVST is highly suspected in an ALL child during chemotherapy, imaging should be performed promptly. Digital subtraction angiography (DSA) is the gold standard for diagnosing CVST, but its invasive nature, radiation exposure, and high cost limit its use in children. MRI combined with MRV, being non-invasive, radiation-free, and repeatable, is considered the preferred diagnostic method for CVST 13 . Both children in this study underwent MRI + MRV, yielding positive results, confirming its utility. In clinical practice, especially during PEG-Asp chemotherapy, regular monitoring of coagulation function facilitates early detection of changes. Common abnormalities include prolonged APTT, decreased FIB, and elevated D-dimer. Prompt correction of coagulation abnormalities can reduce the risk of bleeding and thrombosis during chemotherapy 14 . Anticoagulation is the established treatment. Management in children often relies on adult guidelines or experience. Low-molecular-weight heparin (LMWH) is the most commonly used drug for treating thrombosis in children and is the first choice for thrombotic events in pediatric oncology patients 15 . It is currently recommended that anticoagulation with heparin or LMWH be initiated early in the absence of specific contraindications, followed by continued oral anticoagulation. LMWH can be transitioned to rivaroxaban or warfarin. However, warfarin requires monitoring of the International Normalized Ratio (INR), demanding higher therapeutic control. Since cerebral infarction and hemorrhage often coexist, acute management requires correcting coagulation abnormalities while initiating anticoagulation. Given that LMWH was not available at our institution and frequent INR monitoring posed follow-up difficulties, both children in this study received fresh frozen plasma to correct coagulation abnormalities. Considering patient compliance and monitoring convenience, rivaroxaban, an oral anticoagulant not requiring routine INR monitoring, was chosen for anticoagulation. Rivaroxaban is an oral, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as antithrombin III) for activity. Factor Xa (FXa) plays a crucial role in the coagulation cascade, activated via both intrinsic and extrinsic pathways 16 . Symptoms resolved in both patients within about 1 week. They continued oral anticoagulants, and follow-up imaging showed reduced thrombus size. International literature suggests that PEG-Asp chemotherapy can be resumed after symptom resolution, stable hematological parameters, and normalization of coagulation factor levels 17 . In this study, after anticoagulation therapy and improvement of CVST symptoms, both children continued rivaroxaban without recurrence of CVST symptoms. Follow-up imaging showed thrombus reduction. While continuing anticoagulation and monitoring coagulation function and AT-III weekly, PEG-Asp chemotherapy was resumed according to the protocol. Therefore, after a venous thromboembolic event, PEG-Asp chemotherapy can be restarted once imaging shows thrombus stabilization or improvement, under close anticoagulation monitoring and with necessary anticoagulant use 18 , without compromising ALL treatment prognosis. Conclusion During PEG-Asp treatment, older male ALL children should undergo regular and close monitoring of coagulation function. Significant coagulation abnormalities should be promptly corrected. Unexplained manifestations of increased intracranial pressure such as headache, vomiting, or seizures should raise suspicion for CVST. MRI + MRV is recommended for prompt diagnosis, followed by active anticoagulation therapy. Rivaroxaban, as used in this study, was effective in reducing mortality and neurological sequelae. After clinical symptoms resolve and the thrombus stabilizes, PEG-Asp chemotherapy can be resumed under strict monitoring of anticoagulation efficacy. Therefore, clinicians should pay attention to CVST complicating the induction remission phase of ALL, aiming for early prevention, diagnosis, and treatment. Declarations Funding: The authors declare that this study has received no financial support. Consent to Publica: Consent to Publica declaration not applicable. Ethics Approval and Consent to Participate: Ethics approval and consent to participate declarations not applicable. Competing Interests: The authors declare no competing interests. References Chang, J. H., Poppe, M. M., Hua, C. H., Marcus, K. J., & Esiashvili, N. (2021). Acute lymphoblastic leukemia. Pediatric blood & cancer, 68 Suppl 2, e28371.https://doi.org/10.1002/pbc.28371 Elitzur S, Izraeli S. [PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA]. Harefuah. 2023 Jan;162(1):57-63. Hebrew. PMID: 36714944. Li S, Lu XT, Hua Y, et al. Clinical study of asparaginase therapy in children with acute lymphoblastic leukemia. Chinese Journal of Pediatric Hematology and Oncology. 2017(1). DOI:10.3969/j.issn.1673-5323.2017.01.006. [ Note: Original Chinese title translated ] Yang W, Cai J, Shen S, et al. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial. 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Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Thrombosis Journal → Version 1 posted Editorial decision: Revision requested 25 Aug, 2025 Reviews received at journal 22 Aug, 2025 Reviewers agreed at journal 07 Aug, 2025 Reviewers invited by journal 05 Aug, 2025 Editor assigned by journal 29 Jul, 2025 Submission checks completed at journal 29 Jul, 2025 First submitted to journal 23 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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03:53:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7201079/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7201079/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12959-025-00822-9","type":"published","date":"2026-01-07T15:58:08+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88528135,"identity":"5b93eb2e-41dc-4f10-8bd9-580b9fc4efa3","added_by":"auto","created_at":"2025-08-07 10:51:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":203564,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePre-chemotherapy Head MRI Images\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7201079/v1/17f50b7b991e787d51bfb8b1.png"},{"id":88526715,"identity":"96482fdc-ba97-4073-b410-d9f94697c409","added_by":"auto","created_at":"2025-08-07 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post-onset of Symptoms\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"13.png","url":"https://assets-eu.researchsquare.com/files/rs-7201079/v1/03bfe46cdffa5976dfacc3a3.png"},{"id":88528143,"identity":"8d3ed6b2-8d13-4670-b6b4-b5fe8d2ac891","added_by":"auto","created_at":"2025-08-07 10:51:39","extension":"png","order_by":14,"title":"Figure 14","display":"","copyAsset":false,"role":"figure","size":165578,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMRV at 2 Months post-onset of Symptoms\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"14.png","url":"https://assets-eu.researchsquare.com/files/rs-7201079/v1/b2b2d3fdb1f5ef2936b7c42f.png"},{"id":100069279,"identity":"90ccc08e-b389-4ce8-93ab-4841c99be94b","added_by":"auto","created_at":"2026-01-12 16:12:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5297319,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7201079/v1/bc6dd1e0-25b9-47e3-a89d-13209fbb8e71.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"2 Cases of Pegylated Asparaginase-Associated Cerebral Venous Sinus Thrombosis in Children: Clinical Analysis and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute lymphoblastic leukemia (ALL) is the most common and highest incidence malignant tumor in children, accounting for about one-third of childhood malignancies \u003csup\u003e1\u003c/sup\u003e. With continuous advancements and optimization of treatment protocols over recent decades, the survival rate has increased from 10% to over 90%\u003csup\u003e2\u003c/sup\u003e. The introduction of L-asparaginase (L-Asp) in the 1970s and the application of pegaspargase (PEG-Asp) in recent years have been landmark developments in the treatment of childhood ALL. Pegaspargase (PEG-Asp) is a pegylated form of the naturally derived L-Asp from Escherichia coli (E. coli). As a new asparaginase preparation modified by polyethylene glycol (PEG) chemical conjugation, it retains the enzymatic activity of L-Asp while having a longer duration of action and significantly reduced allergic reactions compared to repeated use of L-Asp. With the widespread application of PEG-Asp in ALL chemotherapy, its drug-related adverse reactions, such as severe allergic reactions, acute pancreatitis, coagulation abnormalities, liver function impairment, and transient hyperglycemia, have emerged\u003csup\u003e3\u003c/sup\u003e. These adverse reactions affect the chemotherapy process and can even threaten the child\u0026apos;s life due to severe drug side effects, particularly coagulation disorders leading to intracranial hemorrhage and cerebral venous sinus thrombosis (CVST), forcing the suspension of PEG-Asp treatment and seriously impacting treatment efficacy and prognosis. Currently, there are few reported cases of CVST occurring in ALL children after PEG-Asp chemotherapy both domestically and internationally. This article reports two cases of ALL children who developed CVST during the induction remission phase at our hospital. Both improved after anticoagulation therapy and successfully entered consolidation therapy.\u003c/p\u003e\n"},{"header":"Object of study","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 10-year-old boy was admitted due to \u0026quot;swelling and pain in the left ankle for 10 days.\u0026quot; Physical examination: Pale and sallow complexion; pea-sized enlarged lymph nodes palpable in bilateral cervical, axillary, and inguinal regions, mobile, medium consistency; liver and spleen not palpable below the costal margin; left ankle edema with significant tenderness. Laboratory tests: Blood routine: WBC 2.1\u0026times;10⁹/L, NEU 1.09\u0026times;10⁹/L, PLT 153\u0026times;10⁹/L, HCT 28.30%, HGB 91 g/L, NEU% 52%; Coagulation profile: APTT 44.10s, PT 13.10s, INR 0.99, FIB 4.88g/L; Bone marrow cytomorphology: Considered consistent with acute lymphoblastic leukemia L2 type; Immunophenotyping: Approximately 24.40% abnormal immature B lymphocytes in the bone marrow, suggestive of acute B lymphoblastic leukemia (Com-B-ALL); Karyotype: No analyzable metaphases; Fusion genes: Negative. Head MRI: 1. No definite abnormality on plain and enhanced brain MR scan; 2. Left sphenoid sinusitis, bilateral ethmoid sinus mucosal thickening; 3. Bilateral otomastoiditis (Fig. 1). MICM diagnosis: ALL (B-cell type, intermediate risk).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Course\u003c/strong\u003e:After definite diagnosis and exclusion of chemotherapy contraindications, chemotherapy according to the CCCG-ALL-2020 induction remission protocol (VDLP group: Prednisone, Vincristine, Daunorubicin, PEG-Asp combination chemotherapy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChemotherapy Day 5\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVincristine and Daunorubicin administered.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 6\u003c/strong\u003e:PEG-Asp 2500U (2500U/m\u0026sup2;) administered. Bone marrow aspiration, lumbar puncture\u0026thinsp;+\u0026thinsp;intrathecal chemotherapy performed. CSF routine and biochemistry normal, no blasts, CSF MRD negative. Blood routine: WBC 3.20\u0026times;10⁹/L, HB 105 g/L, PLT 293\u0026times;10⁹/L, NEU 2.50\u0026times;10⁹/L. Coagulation: APTT 29.90s, PT 13.30s, INR 1.01, FIB 2.05 g/L.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 13\u003c/strong\u003e:Blood routine: WBC 0.30\u0026times;10⁹/L, HB 75 g/L, PLT 50\u0026times;10⁹/L, NEU 0.09\u0026times;10⁹/L. Coagulation: APTT 44.70s, PT 15.40s, INR 1.35, FIB 0.95 g/L. Plasma antithrombin (AT-III): 70%. Patient developed myelosuppression, coagulation function significantly worsened compared to pre-chemotherapy, but no obvious bleeding symptoms yet. Treated with fibrinogen infusion.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 19\u003c/strong\u003e:Initial evaluation. Bone marrow cytology: Blasts 1.0%. CSF routine and biochemistry normal, no blasts. Day 19 MRD\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 21\u003c/strong\u003e:Developed generalized tonic-clonic seizures without fever, followed by upward gaze, unresponsiveness, frothing at the mouth, lasting 30 seconds then stopping, but persistent upward gaze with occasional blinking, still unresponsive. Pupils dilated (~\u0026thinsp;5mm diameter), sluggish light reflex. BP 122/80 mmHg. Blood routine: WBC 0.40\u0026times;10⁹/L, HB 81 g/L, PLT 184\u0026times;10⁹/L, NEU 0.12\u0026times;10⁹/L. Coagulation\u0026thinsp;+\u0026thinsp;D-dimer: APTT 35.00s, PT 15.00s, INR 1.19, FIB 0.81 g/L, D-dimer 0.35 mg/L. Plasma AT-III: 87%. Emergency head CT: 1. Consider small amount of hemorrhage in the left parietal lobe, recommend follow-up. 2. Pineal calcification (Fig.\u0026nbsp;2). Immediate treatment: Sedation and anticonvulsants, mannitol to reduce intracranial pressure, infusion of fresh frozen plasma and fibrinogen to improve coagulation, vancomycin and imipenem for infection prophylaxis, rivaroxaban for anticoagulation, levetiracetam for seizure prophylaxis. Head MRI: Large hematoma (~\u0026thinsp;6cm*4cm) in the left parietal lobe, suggestive of possible acute hemorrhagic infarction in the left parietal lobe, recommend MRV (Fig.\u0026nbsp;3). After treatment, the child had no further seizures, no limb paralysis, normal limb muscle strength and tone, but intermittently complained of right lower limb pain.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 26\u003c/strong\u003e:Right lower limb pain resolved. Coagulation normal. Continued oral rivaroxaban anticoagulation. Received second dose of PEG-Asp 2500U according to protocol. No recurrence of similar symptoms. Successfully entered next phase of chemotherapy.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 35 (Approx. 2 weeks post-onset)\u003c/strong\u003e:No complaint of right lower limb pain. Follow-up imaging (Fig.\u0026nbsp;4): 1. Left parietal hemorrhage roughly same size as before. Deepened cerebral sulci bilaterally. Slightly widened lateral and third ventricles. Recommend follow-up. 2. Slightly reduced distal branches of the left superficial cerebral veins.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003e1 Month Follow-up (Post-onset)\u003c/strong\u003e:Imaging (Fig.\u0026nbsp;5): 1. Left parietal hemorrhage slightly reduced compared to previous. Deepened cerebral sulci and slightly widened ventricles essentially unchanged. Recommend follow-up. 2. Slightly reduced distal branches of left superficial cerebral veins same as before.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003e2 Months Follow-up (Post-onset)\u003c/strong\u003e:Imaging (Fig.\u0026nbsp;6): Left parietal hemorrhage slightly reduced compared to previous.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003e4 Months Follow-up (Post-onset)\u003c/strong\u003e:Head MRI and MRV (Fig.\u0026nbsp;7): Lesion gradually absorbed and reduced.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn 11-year-old boy admitted due to \u0026quot;pain in limb joints for over 20 days.\u0026quot; Physical examination: Pale and sallow complexion; left mandibular swelling, non-tender; tenderness over bilateral scapulae; soybean-sized enlarged lymph nodes palpable in cervical, axillary, and inguinal regions, limited mobility, medium consistency; liver and spleen not palpable below costal margin; left knee tenderness. Laboratory tests: Blood routine: WBC 18.30\u0026times;10⁹/L, NEU 4.98\u0026times;10⁹/L, PLT 70\u0026times;10⁹/L, HCT 28.90%, HGB 99g/L, NEU% 28%; Coagulation: APTT 32.30s, PT 13.70s, INR 1.00, FIB 6.99g/L; Head MRI: 1. No definite abnormality on plain and enhanced brain MR scan. 2. Right ethmoid sinusitis (Fig.\u0026nbsp;8). Bone marrow cytomorphology: Considered consistent with acute lymphoblastic leukemia L2 type; Immunophenotyping: Approximately 90.10% abnormal T lymphocytes in the bone marrow, suggestive of acute T lymphoblastic leukemia (T-ALL); Karyotype: Normal; Fusion genes: Negative. MICM diagnosis: ALL (T-cell type, intermediate risk).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Course\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter definite diagnosis and exclusion of chemotherapy contraindications, chemotherapy according to the CCCG-ALL-2020 induction remission protocol (VDLP group).\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 5\u003c/strong\u003e:Vincristine and Daunorubicin administered.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 6\u003c/strong\u003e:PEG-Asp 2500U (2500U/m\u0026sup2;) administered. Bone marrow aspiration, lumbar puncture\u0026thinsp;+\u0026thinsp;intrathecal chemotherapy performed. CSF routine and biochemistry normal, no blasts, CSF MRD negative. Blood routine: WBC 0.90\u0026times;10⁹/L, HB 74 g/L, PLT 50\u0026times;10⁹/L, NEU 0.43\u0026times;10⁹/L. Coagulation: APTT 30.90s, PT 12.40s, INR 1.15, FIB 3.15 g/L.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 12\u003c/strong\u003e:Blood routine: WBC 0.20\u0026times;10⁹/L, HB 60 g/L, PLT 25\u0026times;10⁹/L, NEU 0.10\u0026times;10⁹/L. Coagulation: APTT 40.70s, PT 14.40s, INR 1.05, FIB 1.50 g/L. Plasma AT-III: 80%. Patient developed myelosuppression, required packed red blood cell transfusion for anemia correction, platelet transfusion scheduled. No obvious bleeding symptoms.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 19\u003c/strong\u003e:Initial evaluation. Bone marrow cytology: Blasts 2.0%. CSF routine and biochemistry normal, no blasts. Day 19 MRD\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 20\u003c/strong\u003e:Developed epigastric pain accompanied by vomiting approximately 15ml of light red gastric contents, followed immediately by limb convulsions, upward gaze, unresponsiveness. Pupils equal and round (~\u0026thinsp;5mm), sluggish light reflex, no fever. BP 123/73 mmHg. Blood routine: WBC 2.20\u0026times;10⁹/L, HB 101g/L, PLT 192\u0026times;10⁹/L, NEU 0.63\u0026times;10⁹/L. Plasma AT-III: 65%. Coagulation\u0026thinsp;+\u0026thinsp;D-dimer: APTT 35.50s, PT 83.00s, INR 4.8, FIB 0.49 g/L, D-dimer 0.46 mg/L. Head MRI: 1. Consider venous infarction with hemorrhage in the left frontal lobe. 2. Right sphenoid sinus submucosal cyst, right sphenoid sinusitis (Fig.\u0026nbsp;9). Head MRV: 1. Findings in the superior sagittal sinus suggestive of venous sinus thrombosis. 2. Right dominant venous sinus (Fig.\u0026nbsp;10). Immediate treatment: Sedation and anticonvulsants, hypertonic saline and mannitol to reduce intracranial pressure, infusion of fresh frozen plasma and fibrinogen to improve coagulation, rivaroxaban for anticoagulation, levetiracetam for seizure control, vancomycin and imipenem for infection prophylaxis. After treatment, the child had no further seizures, normal limb muscle strength and tone, normal limb movement. Repeat coagulation normal.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 26\u003c/strong\u003e:Coagulation normal. Continued oral rivaroxaban anticoagulation. Received second dose of PEG-Asp 2500U according to protocol. No recurrence of similar symptoms. Successfully entered next phase of chemotherapy.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy Day 36 (Approx. 2 weeks post-onset)\u003c/strong\u003e:No recurrence of symptoms. Follow-up imaging (Figs.\u0026nbsp;11, 12): Left frontal venous infarction with hemorrhage follow-up: 1. Increased blood supply in infarcted area, partial cortical neuronal necrosis, recommend follow-up. 2. Right sphenoid sinus submucosal cyst unchanged, right sphenoid sinusitis improved. Successfully entered CAT phase chemotherapy and received second dose of PEG-Asp without recurrence.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cstrong\u003e2 Months Follow-up (Post-onset)\u003c/strong\u003e:Imaging (Figs.\u0026nbsp;13, 14): Left frontal venous infarction with hemorrhage follow-up: 1. Left frontal lesion smaller than before, peripheral hemosiderin deposition, edema improved, partial cortical neuronal necrosis unchanged; 2. Right sphenoid sinus submucosal cyst unchanged, left sinusitis; 3. Previous filling defect in superior sagittal sinus significantly reduced; 4. Head MRA showed right posterior communicating artery relatively slender (congenital variant), otherwise unremarkable.\u003c/p\u003e\n \u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Discussion","content":"\u003cp\u003eALL is the most common hematological malignancy in childhood. With the continuous development of diagnostic and monitoring technologies and the optimization of combination chemotherapy regimens, especially the clinical application of L-Asp and PEG-Asp, the overall survival rate of children with ALL has increased to over 90% both domestically and internationally\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. However, complications caused by combination chemotherapy remain a significant factor threatening the survival and quality of life of children with ALL. According to relevant reports, children with ALL have a higher risk of thrombosis, making ALL the malignancy most prone to thrombosis\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. As a main drug for treating ALL, the adverse effects of PEG-Asp cannot be ignored. Besides commonly reported severe allergic reactions, acute pancreatitis, liver function impairment, and transient hyperglycemia, coagulation abnormalities are increasingly being recognized, particularly life-threatening deep vein thromboses such as CVST, which require greater attention\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe chemotherapeutic mechanism of PEG-Asp involves hydrolyzing asparagine to aspartic acid and ammonia, thereby inhibiting protein synthesis to suppress tumor growth. The mechanism by which PEG-Asp causes coagulation abnormalities is relatively complex and often bidirectional. Most coagulation factors in the human body are proteins synthesized by the liver. Therefore, while inhibiting tumors, PEG-Asp also affects the synthesis of coagulation factors, leading to bleeding. It can also reduce anticoagulant factor levels, disrupting the physiological balance between coagulation and anticoagulation pathways, resulting in decreased synthesis of FIB, plasminogen, AT-III, protein C, and protein S, increased thrombin formation, platelet aggregation, and endothelial cell activation, initiating the intrinsic coagulation pathway, and ultimately inducing thrombosis\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Current domestic and international literature reporting on coagulation changes in children with ALL treated with PEG-Asp and L-Asp is increasing, highlighting the growing concern over PEG-Asp-induced coagulation disorders.\u003c/p\u003e\u003cp\u003eDomestic and international reports indicate the incidence of CVST ranges roughly between 0.51% and 3.34%, primarily concentrated in the induction remission and re-induction phases. It is considered that the combination of PEG-Asp with corticosteroids increases the risk of thrombosis\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Reported risk factors include age\u0026thinsp;\u0026ge;\u0026thinsp;10 years, initial white blood cell count\u0026thinsp;\u0026gt;\u0026thinsp;50\u0026times;10⁹/L, T-cell ALL, intermediate/high-risk patients, low antithrombin levels during treatment, and the use of prednisone (rather than dexamethasone)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Case \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e2\u003c/span\u003e in this study aligns with this report, although the initial WBC was not high (WBC 2.1\u0026times;10⁹/L). Compared to international data, the risk of CVST is similar concerning gender, age, and risk stratification. However, regarding immunophenotype, domestic patients with B-cell lineage appear to have a more prominent CVST risk, possibly related to sample size, but suggesting the need for special attention to CVST risk in B-lineage patients. Case \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e1\u003c/span\u003e in this study was a B-lineage patient who developed CVST. However, due to the small sample size of this study, it cannot fully reflect differences in CVST risk based on immunophenotype or WBC count; larger sample sizes are needed for validation. Domestic reports note many cases occurring after the second dose of PEG-Asp, reminding us to be mindful of dose accumulation\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. However, both patients in this study developed CVST symptoms approximately two weeks after the first PEG-Asp dose, differing from reports from other institutions. Therefore, close monitoring of coagulation function after the first PEG-Asp dose and vigilance for unexplained neurological symptoms are crucial to detect CVST.\u003c/p\u003e\u003cp\u003eThe clinical manifestations of CVST in children are diverse. The main symptoms include headache, nausea, and vomiting, likely related to increased intracranial pressure. Some children may have no obvious clinical symptoms or signs. Seizures are also a common initial symptom of CVST. Both cases in this study presented with varying degrees of headache and vomiting, along with intermittent seizures, consistent with domestic and international reports\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Case \u003cspan refid=\"FPar3\" class=\"InternalRef\"\u003e2\u003c/span\u003e also experienced epigastric pain with vomiting light red gastric contents. This could be a side effect of prednisone (used in the regimen), where relatively high doses calculated by body surface area may stimulate increased gastric acid secretion, damaging the gastric mucosa and potentially causing gastrointestinal bleeding. International literature reports that persistent and severe headache accompanied by vomiting occurs in up to 90% of CVST cases in older children\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Unexplained persistent severe headache with vomiting during PEG-Asp treatment should raise suspicion for CVST.\u003c/p\u003e\u003cp\u003eIf CVST is highly suspected in an ALL child during chemotherapy, imaging should be performed promptly. Digital subtraction angiography (DSA) is the gold standard for diagnosing CVST, but its invasive nature, radiation exposure, and high cost limit its use in children. MRI combined with MRV, being non-invasive, radiation-free, and repeatable, is considered the preferred diagnostic method for CVST\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Both children in this study underwent MRI\u0026thinsp;+\u0026thinsp;MRV, yielding positive results, confirming its utility. In clinical practice, especially during PEG-Asp chemotherapy, regular monitoring of coagulation function facilitates early detection of changes. Common abnormalities include prolonged APTT, decreased FIB, and elevated D-dimer. Prompt correction of coagulation abnormalities can reduce the risk of bleeding and thrombosis during chemotherapy\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAnticoagulation is the established treatment. Management in children often relies on adult guidelines or experience. Low-molecular-weight heparin (LMWH) is the most commonly used drug for treating thrombosis in children and is the first choice for thrombotic events in pediatric oncology patients\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. It is currently recommended that anticoagulation with heparin or LMWH be initiated early in the absence of specific contraindications, followed by continued oral anticoagulation. LMWH can be transitioned to rivaroxaban or warfarin. However, warfarin requires monitoring of the International Normalized Ratio (INR), demanding higher therapeutic control. Since cerebral infarction and hemorrhage often coexist, acute management requires correcting coagulation abnormalities while initiating anticoagulation. Given that LMWH was not available at our institution and frequent INR monitoring posed follow-up difficulties, both children in this study received fresh frozen plasma to correct coagulation abnormalities. Considering patient compliance and monitoring convenience, rivaroxaban, an oral anticoagulant not requiring routine INR monitoring, was chosen for anticoagulation. Rivaroxaban is an oral, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as antithrombin III) for activity. Factor Xa (FXa) plays a crucial role in the coagulation cascade, activated via both intrinsic and extrinsic pathways\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Symptoms resolved in both patients within about 1 week. They continued oral anticoagulants, and follow-up imaging showed reduced thrombus size.\u003c/p\u003e\u003cp\u003eInternational literature suggests that PEG-Asp chemotherapy can be resumed after symptom resolution, stable hematological parameters, and normalization of coagulation factor levels\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In this study, after anticoagulation therapy and improvement of CVST symptoms, both children continued rivaroxaban without recurrence of CVST symptoms. Follow-up imaging showed thrombus reduction. While continuing anticoagulation and monitoring coagulation function and AT-III weekly, PEG-Asp chemotherapy was resumed according to the protocol. Therefore, after a venous thromboembolic event, PEG-Asp chemotherapy can be restarted once imaging shows thrombus stabilization or improvement, under close anticoagulation monitoring and with necessary anticoagulant use\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, without compromising ALL treatment prognosis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDuring PEG-Asp treatment, older male ALL children should undergo regular and close monitoring of coagulation function. Significant coagulation abnormalities should be promptly corrected. Unexplained manifestations of increased intracranial pressure such as headache, vomiting, or seizures should raise suspicion for CVST. MRI\u0026thinsp;+\u0026thinsp;MRV is recommended for prompt diagnosis, followed by active anticoagulation therapy. Rivaroxaban, as used in this study, was effective in reducing mortality and neurological sequelae. After clinical symptoms resolve and the thrombus stabilizes, PEG-Asp chemotherapy can be resumed under strict monitoring of anticoagulation efficacy. Therefore, clinicians should pay attention to CVST complicating the induction remission phase of ALL, aiming for early prevention, diagnosis, and treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: The authors declare that this study has received no financial support.\u003c/p\u003e\n\u003cp\u003eConsent to Publica: Consent to Publica declaration not applicable.\u003c/p\u003e\n\u003cp\u003eEthics Approval and Consent to Participate: Ethics approval and consent to participate declarations not applicable.\u003c/p\u003e\n\u003cp\u003eCompeting Interests: The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChang, J. H., Poppe, M. M., Hua, C. H., Marcus, K. J., \u0026amp; Esiashvili, N. (2021). Acute lymphoblastic leukemia. Pediatric blood \u0026amp; cancer, 68 Suppl 2, e28371.https://doi.org/10.1002/pbc.28371\u003c/li\u003e\n\u003cli\u003eElitzur S, Izraeli S. [PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA]. Harefuah. 2023 Jan;162(1):57-63. Hebrew. PMID: 36714944.\u003c/li\u003e\n\u003cli\u003eLi S, Lu XT, Hua Y, et al. Clinical study of asparaginase therapy in children with acute lymphoblastic leukemia. Chinese Journal of Pediatric Hematology and Oncology. 2017(1). DOI:10.3969/j.issn.1673-5323.2017.01.006. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eYang W, Cai J, Shen S, et al. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2021;22(9):1322-1332. DOI: 10.1016/S1470-2045(21)00328-4.\u003c/li\u003e\n\u003cli\u003eZheng QH, Wu XD. Two cases of cerebral venous sinus thrombosis in children with acute lymphoblastic leukemia and literature review. Asian Pediatric Case Research. 2020;8(4):7. DOI:10.12677/ACRP.2020.84007. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eGuo XM, Sun L, Zhang YY. Four cases of early intracranial venous sinus thrombosis during chemotherapy in children with acute lymphoblastic leukemia. Chinese Journal of Pediatric Hematology and Oncology. 2024;29(04):261-263+268. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eBender C, Maese L, Carter-Febres M, et al. Clinical utility of pegaspargase in children, adolescents and young adult patients with acute lymphoblastic leukemia: a review. Blood Lymphat Cancer. 2021;11:25-40. DOI: 10.2147/BLCTT.S245210.\u003c/li\u003e\n\u003cli\u003eWang JT, Du YG, Wang L, et al. Efficacy of PEG-Asp and L-Asp in the treatment of children with acute lymphoblastic leukemia and their effects on coagulation function. Experimental and Laboratory Medicine. 2023;41(03):297-299+303. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eYan YY, Liu HY, Yu LH, et al. Clinical analysis of 8 cases of cerebral venous sinus thrombosis caused by pegaspargase. Chinese Journal of Neuromedicine. 2022;21(5):7. DOI:10.3760/cma.j.cn115354-20220211-00074. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eMateos MK, Trahair TN, Mayoh C, et al. Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia. Thromb Res. 2019;177:32-37. DOI:10.1016/j.thromres.2019.04.011. [\u003cem\u003eNote: Volume/Pages added as likely based on common citation\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eZheng Y, Yang W, Estepp J, Pei D, Cheng C, Takemoto CM, Inaba H, Jeha S, Pui CH, Relling MV, Karol SE. Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries. Haematologica. 2023 Jul 6. doi: 10.3324/haematol.2022.281582. Epub ahead of print. PMID: 37408475.\u003c/li\u003e\n\u003cli\u003eKlaassen ILM, Lauw MN, Fiocco M, et al. Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: Risk factors and effect on prognosis. Res Pract Thromb Haemost. 2019;3(2):234-241. DOI:10.1002/rth2.12182.\u003c/li\u003e\n\u003cli\u003eCarducci C, Colafati GS, Fig\u0026agrave;-Talamanca L, et al. Cerebral sinovenous thrombosis (CSVT) in children: what the pediatric radiologists need to know. Radiol Med. 2016;121(4):329-341. DOI:10.1007/s11547-016-0630-9.\u003c/li\u003e\n\u003cli\u003eZhu P, Xin Q, Liao X, et al. Effects of pegaspargase and L-asparaginase on coagulation function in patients with acute lymphoblastic leukemia. Chinese and Foreign Medical Research. 2019;17(30):3. DOI:10.14033/j.cnki.cfmr.2019.30.013. [\u003cem\u003eNote: Original Chinese title translated\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eGeorge C, Rahman M, Monagle P. Challenges and Opportunities in the Pharmacological Treatment of Acute Venous Thromboembolism in Children. Paediatr Drugs. 2020;22(4):385-397. doi: 10.1007/s40272-020-00403-5. PMID: 32519267.\u003c/li\u003e\n\u003cli\u003eJaffray JA, Goldenberg NA. Current approaches in the treatment of catheter-related deep venous thrombosis in children. Expert Rev Hematol. 2020;13(12):1349-1362. DOI:10.1080/17474086.2020.1756260.\u003c/li\u003e\n\u003cli\u003eBordbar M, Haghpanah S, Dabbagh A, et al. Thrombosis in pediatric malignancy: a review and future perspectives with focus on management. Blood Coagul Fibrinolysis. 2018;29(8):689-695. DOI: 10.1097/MBC.0000000000000772. [\u003cem\u003eNote: Author list corrected based on DOI\u003c/em\u003e]\u003c/li\u003e\n\u003cli\u003eBrown P, Inaba H, Annesley C, et al. Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(1):81-112. doi: 10.6004/jnccn.2020.0001. PMID: 31910389.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Child, Acute Lymphoblastic Leukemia, Pegylated Asparaginase, Cerebral Venous Sinus Thrombosis","lastPublishedDoi":"10.21203/rs.3.rs-7201079/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7201079/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo investigate the risk factors and prognosis of cerebral venous sinus thrombosis (CVST) occurring in children with acute lymphoblastic leukemia (ALL) during chemotherapy with pegylated asparaginase (PEG-Asp).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThe clinical manifestations, laboratory findings, imaging characteristics, treatment, and prognosis of two pediatric ALL cases complicated by CVST during induction remission therapy at Guangzhou Women and Children's Medical Center were retrospectively analyzed, and relevant literature was reviewed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e(1) Both children were treated according to the CCCG-ALL-2020 protocol and developed CVST during the induction remission phase. CVST occurred approximately two weeks after the first PEG-Asp administration in both cases. The presenting symptom was generalized tonic-clonic seizure. Platelet counts were within the normal range. Coagulation tests showed insignificant prolongation of APTT, with decreased fibrinogen (FIB) and decreased antithrombin III (AT-III) being the main abnormalities. Head magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) revealed venous sinus thrombosis with hemorrhage. After treatment with infusion of fresh frozen plasma and fibrinogen to improve coagulation function, mannitol to reduce intracranial pressure, and rivaroxaban for anticoagulation, no further thrombosis occurred. CVST symptoms did not recur upon subsequent PEG-Asp administration.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eDuring chemotherapy for ALL, especially when using PEG-Asp, regular monitoring of coagulation function is essential. Unexplained neurological symptoms often indicate possible CVST, warranting prompt cranial contrast-enhanced MRI and MRV for early diagnosis. Anticoagulation with rivaroxaban is effective for children developing CVST, resulting in a favorable prognosis without severe permanent neurological deficits. Greater clinical attention should be paid to CVST complicating the induction remission phase of ALL to enable early prevention, diagnosis, and treatment.\u003c/p\u003e","manuscriptTitle":"2 Cases of Pegylated Asparaginase-Associated Cerebral Venous Sinus Thrombosis in Children: Clinical Analysis and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-07 10:35:33","doi":"10.21203/rs.3.rs-7201079/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-25T09:40:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T14:36:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190389311475689582731674133576634847903","date":"2025-08-07T17:20:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-05T05:42:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-30T03:06:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-30T03:05:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"Thrombosis Journal","date":"2025-07-24T03:38:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"thrombosis-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"thrj","sideBox":"Learn more about [Thrombosis Journal](http://thrombosisjournal.biomedcentral.com/)","snPcode":"12959","submissionUrl":"https://submission.nature.com/new-submission/12959/3","title":"Thrombosis Journal","twitterHandle":"@Thrombosis_J","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16f42fc2-8bdb-4180-8a0f-a95d962dfd8c","owner":[],"postedDate":"August 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:03:28+00:00","versionOfRecord":{"articleIdentity":"rs-7201079","link":"https://doi.org/10.1186/s12959-025-00822-9","journal":{"identity":"thrombosis-journal","isVorOnly":false,"title":"Thrombosis Journal"},"publishedOn":"2026-01-07 15:58:08","publishedOnDateReadable":"January 7th, 2026"},"versionCreatedAt":"2025-08-07 10:35:33","video":"","vorDoi":"10.1186/s12959-025-00822-9","vorDoiUrl":"https://doi.org/10.1186/s12959-025-00822-9","workflowStages":[]},"version":"v1","identity":"rs-7201079","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7201079","identity":"rs-7201079","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}