Success and complications in lumbar punctures of pediatric patients with leukemia: a study protocol for a randomized clinical crossover trial of a bioimpedance needle system versus conventional procedure.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children. At present, the long-term survival from pediatric ALL is well over 90%. However, the probability of event-free survival is reduced if the lumbar puncture (LP) procedures at the beginning of the patient's intrathecal therapy cause blood leakage into the spinal canal and blast cells contaminate the cerebrospinal fluid. According to the literature, such traumatic LP procedures concern one out of five pediatric patients with ALL. Recently, a novel medical device measuring the tissue bioimpedance at the tip of a spinal needle was found feasible in pediatric patients with ALL. The LP procedure was successful at the first attempt in 80% of procedures, and the incidence of traumatic LPs was then 11%. The purpose of the present study is to compare the bioimpedance spinal needle system with the standard clinical practice resting on a conventional spinal needle and investigate its efficacy in clinical practice. METHODS: The study is a multicenter, randomized, two-arm crossover noninferiority trial of pediatric hemato-oncology patients that will be conducted within the usual clinical workflow. Patients' LP procedures will be performed alternately either with the IQ-Tip system (study arm A) or a conventional Quincke-type 22G spinal needle (study arm B). For each enrolled patient, the order of procedures is randomly assigned either as ABAB or BABA. The total number of LP procedures will be at least 300, and the number of procedures per patient between two and four. After each study LP procedure, the performance will be recorded immediately, and 1-week diary-based and 4-week record-based follow-ups on symptoms, complications, and adverse events will be conducted thereafter. The main outcomes are the incidence of traumatic LP, first puncture success rate, and incidence of post-dural puncture headache. DISCUSSION: The present study will provide sound scientific evidence on the clinical benefit, performance, and safety of the novel bioimpedance spinal needle compared with the standard clinical practice of using conventional spinal needles in the LP procedures of pediatric patients with leukemia. TRIAL REGISTRATION: ISRCTN ISRCTN16161453. Registered on 8 July 2022.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

Bioimpedance spinal needle provides high success and low complication rate in lumbar punctures of pediatric patients with acute lymphoblastic leukemia.

In this prospective single-arm study of 50 pediatric patients with acute lymphoblastic leukemia (ALL), we evaluated the clinical performance of a novel bioimpedance spinal needle system in 152 intrathecal treatment lumbar punctures (LP) of these patients. The system detects in real-time when the needle tip reaches the cerebrospinal fluid (CSF) in the spinal canal. The success was defined as getting a CSF sample and/or administering the intrathecal treatment with one needle insertion. Incidence of traumatic LP (TLP) was defined as ≥ 10 erythrocytes/µL of CSF. Post-procedural complications were monitored with a one-week diary and one-month register follow-up. The success of the first attempt was 79.5%, with the CSF detection sensitivity of 86.1%. The incidence of TLP was 17.3%. A successful first attempt was associated with a significantly lower incidence of TLP (10% vs 40%, p = 0.0015). During the week after the procedure, the incidence of post-dural puncture headache was 6%. During the follow-up, no major complications were observed. In conclusion, the novel bioimpedance spinal needle system achieved a high success rate and low incidence of TLP and other complications in pediatric patients with ALL in a real-world clinical setting, indicating clinical utility for this system in pediatric hemato-oncology.

Venous Malformations and Blood Coagulation in Children.

INTRODUCTION: Venous malformations (VMs) are congenital low-flow lesions with a wide spectrum of clinical manifestations. An increasing number of studies link VMs to coagulation abnormalities, especially to elevated D-dimer and decreased fibrinogen. This condition, termed localized intravascular coagulopathy (LIC), may pose a risk for hemostatic complications. However, detailed data on the laboratory variables for coagulation and fibrinolytic activity in VM patients are limited. We addressed this question by systematically analyzing the coagulation parameters in pediatric VM patients. METHODS: We included 62 patients (median age 11.9 years) with detailed laboratory tests for coagulation and fibrinolytic activity at a clinically steady phase. We assessed clinical and imaging features of VMs and their correlations with coagulation and fibrinolysis variables using patient records and MRI. RESULTS: D-dimer was elevated in 39% and FXIII decreased in 20% of the patients, as a sign of LIC. Elevated D-dimer and decreased FXIII were associated with large size, deep location, and diffuse and multifocal VMs. FVIII was elevated in 17% of the patients and was associated with small VM size, superficial and confined location, discrete morphology, and less pain. Surprisingly, antithrombin was elevated in 55% of the patients but without associations with clinical or other laboratory variables. CONCLUSIONS: LIC was common in pediatric patients with VMs. Our results provide a basis for when evaluating the risks of hemostatic complications in children with VMs. Further research is warranted to explore the mechanisms behind coagulation disturbances and their relation to clinical complications.

Asymptomatic Right Atrial Thrombosis After Acute Lymphoblastic Leukemia Treatment.

Right atrial thrombosis is a rare, but potentially serious complication of acute lymphoblastic leukemia treatment. We conducted a retrospective multicenter study to assess the incidence, treatment, and outcome of asymptomatic right atrial thrombosis detected at routine echocardiography of children after acute lymphoblastic leukemia treatment in the Nordic and Baltic countries. Eleven (2.7%, 95% confidence interval, 1.4-4.9) of 406 patients had asymptomatic right atrial thrombosis, ranging from 10 to 25 mm at detection. Three patients were treated with anticoagulation. None of the thromboses affected cardiac function, and they showed neither sign of progress nor spontaneous or treatment-related regress at follow-up.

Pulmonary embolism in acute lymphoblastic leukemia - An observational study of 1685 patients treated according to the NOPHO ALL2008 protocol.

BACKGROUND: Pulmonary embolism (PE) is a serious complication of acute lymphoblastic leukemia (ALL). We examined the cumulative incidence and clinical presentation of PE in a well-defined cohort of patients with ALL aged 1-45 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. METHODS: As part of the mandatory toxicity reporting of NOPHO ALL2008, thromboembolism including PE was reported consecutively. The cumulative incidence of first-time PE was calculated using the Aalen-Johansen estimator during a 2.5-year period from ALL diagnosis. We used Fisher's exact test to examine categorical variables and Cox logistic regression to estimate hazard ratios (HRs) for PE. RESULTS: PE was diagnosed in 32 of 1685 patients. The 2.5-year cumulative incidence of first-time PE increased with age: 0.43% (95% CI, 0.18-1.03) in children aged 1-9 years, 3.28% (95% CI, 1.72-6.22) in children aged 10-17 years, and 7.22% (95% CI, 4.61-11.21) in adults aged 18-45 years. The majority of PEs, 78% (25/32), occurred during asparaginase treatment. HRs adjusted for age and sex were associated with male sex (HR, 2.4; 95% CI, 1.0-5.6) and older age (10-17 years: HR 7.5; 95% CI, 2.5-22.2), 18-45 years: HR, 16.5; 95% CI, 6.1-44.5). In two-thirds of the patients (63%; 17/27), PE and its treatment had no impact on the administered doses of asparaginase. PE-associated 30-day mortality was 9.4% (95% CI, 1.9-25.0). CONCLUSIONS: Awareness of PE is warranted during ALL treatment. Larger multicenter studies are needed to examine predictors of PE in ALL.

Haematopoietic Stem Cell Transplantation in Children Shifts the Coagulation System towards a Pro-Coagulant State.

Coagulation system is disturbed by several mechanisms after allogeneic haematopoietic stem cell transplantation (HSCT). We evaluated the effect of HSCT on coagulation system by various conventional and investigational methods in 30 children and adolescents who received HSCT due to haematological malignancies. Pro-thrombin fragment 1 + 2, a specific measure of thrombin generation, and von Willebrand factor, a measure of endothelial activation, increased after conditioning treatment, and remained elevated until 3 months after HSCT (p < 0.05 for all comparisons to pre-conditioning treatment). D-dimer, a measure of fibrin turnover, was elevated from the second week onwards until 4 weeks after HSCT (p < 0.05). Endogenous thrombin potential was increased after conditioning, and at 2 weeks after HSCT (p < 0.05). Furthermore, the activities of acute phase reactants fibrinogen and coagulation factor VIII were increased (p < 0.05 for all comparisons to pre-conditioning treatment) from the first week onwards up to 3 weeks and 3 months after HSCT, respectively. Taken together, paediatric patients receiving HSCT demonstrate distinct and prolonged variations in the coagulation system towards a pro-coagulant state. This shift is of importance when estimating the risk of haemostatic and thrombotic complications in these children.

Coordinated release of tissue factor and tissue factor pathway inhibitor in VLBW infants.

AIM: Tissue factor (TF), a mediator between coagulation and inflammation, is upregulated in alveolar compartment and circulation in very low birthweight (VLBW) infants. We investigated the contribution of TF to systemic regulation of coagulation in VLBW infants. METHODS: We measured TF, total and free tissue factor pathway inhibitor (TFPIt, TFPIf), prothrombin fragment (F1 + 2), and thrombin-antithrombin complexes (TAT) in plasma from 51 VLBW infants during their first week of life. RESULTS: F1 + 2 in cord plasma was high (1385 pmol/mL) and decreased postnatally to 17% (p = 0.002). TAT decreased from a high cord concentration to 3% postnatally (p < 0.001). Plasma TF increased and peaked on day 3, showing no correlation with F1 + 2 or TAT. TFPIt and TFPIf increased postnatally, correlating with TF (day 1 TFPIf: R = 0.595, p < 0.001, day 3 TFPIf: R = 0.582, p < 0.001). Based on the TF/TFPIf ratio, a relative excess of plasma TF over TFPIf probably prevailed on day 3. CONCLUSIONS: In VLBW infants plasma TF fails to associate with thrombin formation. This is partly explained by release of TFPI. Despite TFPI, the newborn VLBW infant is subjected to a substantial circulating pool of TF with potential proinflammatory effects.

Thrombin formation and effect of unfractionated heparin during pediatric cardiac catheterization.

OBJECTIVES: To assess the strength of thrombin formation and determine the effects of unfractionated heparin (UFH) in children during cardiac catheterization. BACKGROUND: UFH reduces the thrombotic risk related to catheterization but the effects of UFH on the coagulation system in children, and proper monitoring of UFH remain unclear. METHODS: We studied 42 patients aged 3-12 years undergoing catheterization. Twenty-seven received UFH (group A) and 15 patients did not (group B). Anticoagulation was assessed by measurements of plasma prothrombin fragment F1 + 2, thrombin-antithrombin (TAT) complexes, D-dimer, activated partial thromboplastin time (APTT), anti-FXa, and prothrombinase-induced clotting time (PiCT). RESULTS: Markers of thrombin generation remained low during catheterization in group A. In group B, both F1 + 2 and TAT had increased significantly (P < 0.05) by the end of the procedure versus baseline and versus respective levels in group A. In group A, 15 min after heparinization, APTT was over 180 sec (in all patients), anti-FXa 1.4 U/ml (1.1-2.4 U/ml) and PiCT 1.5 U/ml (1.3-2.4 U/ml). Anti-FXa and PiCT were correlated (R = 0.84, P < 0.0001). CONCLUSIONS: Thrombin generation was enhanced in patients who did not receive UFH, which may increase the risk of thrombotic complications. In group A, routine heparinization seemed excessive by all monitoring methods. UFH prevented an increase in prothrombin to thrombin conversion, resulting in unaltered fibrin formation. The current UFH protocol seemed to have no effect on postprocedural activation of coagulation. Further studies are needed to clarify adequate heparin dosing for children during cardiac catheterization to prevent thrombotic complications without predisposing the patient to bleeding complications.

Enhanced thrombin generation and depressed anticoagulant function in children with pneumonia.

AIMS: To clarify the status of the coagulation system in children with community-acquired pneumonia. METHODS: Coagulation activation markers (prothrombin fragment F1 + 2, thrombin-antithrombin complexes, D-dimer), the natural anticoagulants (antithrombin, protein C and S) and tissue factor were measured in 28 consecutive children with pneumonia on admission to the hospital. Patients were divided into those with either bacterial-type pneumonia (at least two of the following three criteria: plasma C-reactive protein (CRP) >80 mg/L, white blood cell count >15 × 10(9) /L and alveolar infiltrates on the chest radiograph) or viral-type pneumonia. RESULTS: The majority of the patients (79%) showed elevation of at least one of the three coagulation activation markers. Plasma CRP concentration correlated with F1 + 2 (R = 0.44, p < 0.05) and D-dimer (R = 0.71, p < 0.0001). Patients with bacterial-type pneumonia (n = 17) had higher D-dimer levels (p < 0.05) and lower levels of antithrombin (p = 0.005) and protein C (p = 0.08) than the patients with viral-type pneumonia. CONCLUSIONS: Children with community-acquired bacterial-type pneumonia show distinctive changes in their coagulation system. The finding of coagulation system activation and depressed function of natural anticoagulants in uncomplicated pneumonia helps to understand the rapid and unpredictable changes observed in the coagulation status in patients with more severe forms of disease.

Exchange transfusion activates coagulation and alters the coagulation profile in newborn infants.

Exchange transfusion (ET) with adult blood is a standard procedure for neonates with severe hyperbilirubinemia. How ET affects newborn coagulation system remains, however, largely unknown. Thus, we prospectively evaluated the effect of ET on thrombin formation and coagulation profile in 18 newborns (22 ETs). Prothrombin fragment F1+2 and thrombin-antithrombin complexes increased considerably during ET while platelets were significantly reduced. Protein C increased less (p < 0.001) and factor VIIIc more (p < 0.001) than expected based on their levels in the infused blood. Further, in vitro thrombin generation initiated by 5 pM tissue factor was analysed. Before the first ET, newborn endogenous thrombin potential (ETP) and thrombin peak remained at approximately 60% of adult control plasma levels, but the lag time to thrombin burst in newborn plasma was approximately 45% shorter than the lag time in adult plasma. At the end of the first ET, the thrombin burst still started approximately 35% earlier in newborn than adult plasma, whereas ETP and thrombin peak were increased to > 90% of adult levels. ETP and peak remained elevated at adult levels until the beginning of the second ET. APC-induced reductions in newborn ETP remained unaltered throughout the first ET. The reductions of ETP by APC were less pronounced in newborn than adult plasma (p < 0.0001). We conclude that ET is associated with multiple procoagulant changes and increased in vivo thrombin formation. This ET-induced procoagulant challenge may be of clinical significance in sick newborns already prone to bleeding and thrombotic complications.