Trombiinin säätely vastasyntyneillä

The coagulation system of newborn infants differs markedly from that of older children and adults. The activities of most coagulation factors and anticoagulants are low, leading to altered regulation in the formation of the key enzyme, thrombin. Timely and adequate generation of thrombin is essential, as thrombin activates platelets and many coagulation factors, cleaves fibrinogen into fibrin and activates the antithrombotic and anti-inflammatory protein C pathway. On the other hand, excess thrombin may promote thrombotic complications and exacerbate harmful inflammatory reactions. Despite the characteristic features, the newborn coagulation system can be considered physiological, since healthy newborns rarely show haemorrhagic or thrombotic complications. Sick newborns, however, often encounter clinical situations that challenge their coagulation system. The aim of this study was to clarify the behaviour of the neonatal coagulation system in selected clinical situations, with a special emphasis on the generation of thrombin. Thrombin was measured by in vivo thrombin generation markers and by thrombin generation potential in vitro. The patient groups included sick newborns undergoing intensive care and receiving fresh-frozen plasma (FFP), requiring exchange transfusions (ET) or presenting with a congenital heart defect requiring open heart surgery. Additionally, healthy newborns with inherited heterozygous factor V Leiden (FVL) mutation were studied. Thrombin generation potential was also analysed in cord plasma of healthy infants and in adults. Healthy as well as sick newborn infants showed lower total thrombin generation potential in vitro but faster initiation of thrombin generation than adults. These findings were qualitatively similar when plasma was supplemented with platelets. Platelets, however, significantly altered the effect of the major anticoagulant, activated protein C (APC), on thrombin generation potential. In accordance with previous studies, thrombin generation in healthy newborn platelet-poor plasma was resistant to the anticoagulant effects of APC, but when the plasma was supplemented with platelets APC attenuated thrombin generation significantly more in newborns than in adults. In vivo generation of thrombin was elevated in nearly all of the sick newborn infants. The low-volume FFP transfusion as opposed to the change from neonatal to adult blood in ET exerted markedly different effects on neonatal thrombin generation. FFP reduced the in vivo generation of thrombin in those newborns with the highest pretransfusional thrombin generation, thus acting as an anticoagulant agent. In those infants with lower pretransfusional thrombin generation, the effect of FFP on thrombin generation was fairly neutral. On the other hand, the combination of red blood cells and FFP, used to perform ET, significantly increased the in vivo thrombin formation and shifted the balance in the newborn coagulation system to the procoagulant direction. Cardiopulmonary bypass (CPB) also significantly increased the in vivo thrombin generation, but the thrombin generation profile during CPB differed from that previously observed in adults. Escalation of thrombin at early reperfusion was not observed in newborns; in adults, its occurrence is associated with postoperative myocardial damage. Finally, in healthy newborns with FVL heterozygosity, faster initiation of thrombin generation was observed compared with controls. Interestingly, FV level was lower in FVL-heterozygous infants, possibly to counteract the procoagulant effects induced by FVL. In conclusion, unique features regarding thrombin regulation in newborn infants were observed. These features included a novel platelet effect on the regulation of the protein C pathway. The clinical challenges mainly seemed to shift the balance in the coagulation system of newborns to the procoagulant direction. Blood component transfusions markedly affected coagulation in a manner specific to the product but that could also be altered by the clinical situation. Overall, the results highlight the need for understanding developmental haemostasis for both diagnostic and therapeutic purposes.Tämän tutkimuksen tarkoituksena oli selvittää vastasyntyneiden veren hyytymisjärjestelmän toimintaa keskittyen erityisesti sen avainentsyymin, trombiinin, tuotantoon erilaisissa kliinisissä tilanteissa. Vastasyntyneiden veren hyytymisjärjestelmä eroaa monilta osin aikuisten järjestelmästä mikä johtaa erilaiseen trombiinin säätelyyn. Riittävä trombiinin tuotanto on tärkeää sen monien veren hyytymistä edistävien vaikutusten vuoksi. Toisaalta liiallinen trombiinin tuotanto voi lisää riskiä tukoskomplikaatioille. Lasten ikäryhmässä sairaat vastasyntyneet ovat suurimmassa riskissä vuoto- ja tukoskomplikaatioille. Tutkitut potilasryhmät koostuivatkin teho-osastolla hoidetuista vastasyntyneistä, jotka saivat jääplasmasiirron tai verenvaihdon, sekä vastasyntyneistä, joilla oli avosydäleikkausta vaativa sydänvika. Lisäksi tutkittiin terveitä vastasyntyneitä, joista osa oli perinnöllisen tukostaipumusta aiheuttavan hyytymistekijä V:n Leiden-mutaation kantajia. Tutkimuksessa havaittiin, että vaikka trombiinin tuotantopotentiaali oli vastasyntyneillä matalampi kuin aikuisilla, trombiinin muodostus oli nopeampaa. Tämä todennäköisesti osaltaan tasapainottaa vastasyntyneiden hyytymisjärjestelmän toimintaa. Lisäksi verihiutaleiden todettiin muuttavan trombiinin säätelyä. Ilman verihiutaleita tärkeä luonnollinen antikoagulantti, aktivoitu proteiini C, vähensi trombiinin muodostusta enemmän aikuisilla, verihiutaleiden kanssa aktivoitu proteiini C oli tehokkaampi vähentämään trombiinin muodostusta vastasyntyneillä. Kyseinen löydös korostaa verihiutaleiden tärkeyttä mitattaessa hyytymisjärjestelmää ja arvioitaessa sen tilaa elimistön luonnollisessa ympäristössä. Lähes kaikilla sairailla vastasyntyneillä trombiinin tuotanto oli kiihtynyt ja hyytymisjärjestelmä oli aktivoitunut. Jääplasmasiirto vähensi trombiinin tuotantoa ja hillitsi hyytymisjärjestelmän aktivaatiota; vaikutus oli voimakkain niillä potilailla, joilla oli ennen siirtoa voimakkain trombiinin tuotanto. Verenvaihto taas lisäsi trombiinin tuotantoa ja verenvaihdon jälkeen vastasyntyneen veressä vallitsi hyytymistä edistävä tila, joka voi mahdollisesti altistaa tukoskomplikaatioille. Myös avosydänleikkaus lisäsi trombiinin tuotantoa mutta trombiinin tuotannon profiili leikkauksen aikana oli erilainen verrattuna aikaisempiin aikuistutkimuksiin. Aikuisilla trombiinin tuotanto lisääntyy avosydänleikkauksen loppuvaiheessa ja leikkauksen jälkeen verenkierron alkaessa palautua normaaliksi. Tämä trombiinin muodostuksen lisääntyminen liittyy leikkauksen jälkeisen sydänlihasvaurion esiintymiseen. Vastasyntyneillä samanlaista ilmiötä ei todettu. Lopuksi, hyytymistekijä V:n Leiden mutaatio liittyi vastasyntyneillä nopeampaan trombiinin muodostukseen ja matalampaan hyytymistekijä V:n tasoon, jälkimmäinen mekanismi mahdollisesti pyrkii tasapainottamaan hyytymistä edistävää tilaa veressä. Väitöskirjatyössä todettiin monia erityispiirteitä liittyen trombiinin muodostuksen säätelyyn vastasyntyneillä. Nämä erityispiirteet korostavat sitä, että arvioitaessa vastasyntyneiden hyytymisjärjestelmän tilaa tarvitaan nimenomaan vastasyntyneiden ikäryhmään kohdistuvaa tutkimusta eikä aikuisilta saatua tietoa voida suoraan soveltaa

Using pharmacokinetics for tailoring prophylaxis in people with hemophilia switching between clotting factor products: A scoping review

Abstract The objective of this scoping review is to summarize the current use of pharmacokinetics for tailoring prophylaxis in hemophilia patients switching between clotting factor products. Patients with hemophilia may require switching of clotting factor concentrates due to a variety of factors, but there have been perceived risks associated with switching, such as inhibitor development or suboptimal protection due to inadequate dosing while titrating treatment. Studies that look at patients switching from one clotting factor concentrate to another are categorized in terms of their primary and/or secondary objectives, notably biosimilarity and comparative pharmacokinetic studies and inhibitor development studies. Research on how best to switch concentrates with respect to dosing regimen are lacking, and currently a trial-and-error approach is used for dosing the new factor concentrate. In the future, studies looking at the predictability of pharmacokinetics (PK) of a new factor concentrate based on individual PK knowledge of the original factor concentrate may offer clinical benefit by providing a safer switching approach and protocol.Peer reviewe

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.Peer reviewe

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.Peer reviewe

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

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.Peer reviewe

Lasten suonipoikkeavuuksien diagnostiikan on oltava tarkkaa

Vertaisarvioitu.• Lasten yleisin hyvänlaatuinen kasvain on infantiili hemangiooma eli mansikkaluomi. Valtaosa häviää itsestään, mutta lisätutkimuksia ja hoitoa vaativat on tärkeää tunnistaa. • Suoniepämuodostumat ovat suonten synnynnäisiä kehityshäiriöitä. Ne luokitellaan suonityypin mukaan. • Jos lapsella todetaan suonipoikkeavuuden lisäksi raajojen eriparisuus, poikkeava kasvu tai muita anomalioita, on syytä epäillä oireyhtymää.Peer reviewe

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

BackgroundAcute 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.MethodsThe 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.DiscussionThe 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.Peer reviewe

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

Abstract 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

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.Peer reviewe