C. Wermes

Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters

Abstract We prospectively evaluated the clinical relevance of genetic risk factors of thrombosis in 137 paediatric patients with solid tumours or leukaemia/lymphoma. The factor V G1691A (FV-L), the prothrombin G20210A (FII-L) and the homozygous MTHFR variant were examined. In addition, protein C, protein S and antithrombin (AT) deficiency were evaluated in patients with ALL or thrombosis. The inter-group incidence of risk factors and thrombotic events was compared. 73 of the 137 patients had ALL and 64 another form of leukaemia, lymphoma or a solid tumour. They were treated according to the established paediatric tumour protocols ALL-BFM, NHL-BFM, COSS, CWS and others. All patients had central venous lines. No patient received heparin or any other anticoagulant. Endpoints of the study were thrombosis, regular completion of chemotherapy or death. Incidence of mutations in the whole group: FV-L (7.3% heterozygous, 0.7% homozygous); FII-L (2.9% heterozygous, no homozygotes); MTHFR (51.8% heterozygous, 10.9% homozygous). Ten patients (7.3%), 6 with ALL and 4 with solid tumours, developed thrombosis. 4 of the 6 patients with ALL and thrombosis (67%) but only 21% of ALL patients without thrombosis had a genetic risk factor (P < 0.013, χ2). No genetic defect was found in the 4 patients with other malignancies and thrombosis,. However, besides a tumour, these patients had additional exogenous risk factors including diabetes insipidus and hemiparesis. Conclusion Genetic mutations appear to be additional risk factors for the development of thrombosis in patients with ALL. In contrast, these mutations do not appear to be relevant risk factors for thrombosis in the small number of children with other malignant diseases reported here. This difference may be due to asparaginase and corticosteroids being used in ALL but not in solid tumour protocols.

Gendefekte als Ursache für Thrombosen in der pädiatrischen Onkologie

Die Faktor-V:Q506-Mutation, die Prothrombin-Mutation G20210 A und die MTHFRMutation (C677T) gelten im Erwachsenenalter als signifikante Thromboserisikofaktoren [1, 2 4, 6, 9,14]. Da nach Literaturangaben bis zu 12% der Kinder mit onkologischen Erkrankungen eine Thrombose entwickeln [3, 8, 10–13, 15] untersuchten wir den Stellenwert der genannten Genmutationen als Thromboserisikofaktoren in der padiatrischen Onkologie.

Stellenwert und Prävalenz der Prothrombin-G20210A-Mutation bei Patienten mit hereditärer Thrombophilie

Kurzlich wurde eine neue Mutation im Gen des Prothrombins beschrieben (Poort 1996), die gehauft bei Patienten mit Thrombosen vorkommt und mit einer erhohten Thromboseneigung einher gehen soll (Brown 1997; Poort 1996; Cumming 1997; Hillarp 1997; von Depka Prondzinski 1997). Bei dieser Mutation handelt es sich um einen Austausch von Guanin gegen Arginin an der Position 20210 innerhalb eines nicht translatierten Bereichs des Prothrombingens. Diese kam bei 18% aller Patienten mit familiarer Thrombophilie vor, dagegen nur bei ca. 1% gesunder Kontrollen, und ist mit einem ca. 3fach erhohten Thromboserisiko gegenuber der gesunden Bevolkerung assoziiert. Inzwischen liegen auch Daten uber die Pravalenz der Prothrombinmutation bei Kindern mit thromboembolischen Komplikationen und malignen Erkrankungen vor (Wermes 1998).

Immune Tolerance in an Inhibitor Patient with Severe Hemophilia A — Comparison of two Different Treatment Schedules Including Rituximab

Up to 40 % of the patients with hemophilia A develop factor VIII inhibitors [1]. In more than 80 % of them, successful immune tolerance therapy (ITT) can be performed by the Bonn protocol [2] or the Malmoe treatment schedule [3]. Unfortunately, in a small amount of patients these treatment efforts are ineffective. Rituximab leads to B-cell depletion and has been demonstrated to be an effective tool in inhibitor patients with hemophilia A, but this effect seems to be only shortlived [4]. Based on the Malmoe treatment schedule and our experiences in the treatment of inhibitor patients with hemophilia B [5], we developed an immunosuppressive ITT regimen that includes Rituximab and mycophenolate-mofetil (MMF, Cellcept).

Bolus Injection of Recombinant Factor VIIa (NovoSeven) can be More Effective than Continuous Infusion in Inhibitor Patients with Severe Hemophilia A

Although in most inhibitor patients with hemophilia A, immune tolerance therapy (ITT) according to the Bonn protocol [1] is successful, a small number of patients does not reach a remission. These patients suffer from relapsing severe bleedings and are at high risk to develop hemophilic arthropathy. Bleedings have to be treated either by an activated prothrombin complex (FEIBA) [2, 3] or by recombinant activated factor VII (rFVIIa, NovoSeven), given as bolus injections (BI) [4–8] or continuous infusion (CI). Because of its short half-life, rFVIIa requires infusions every 2 hours in the immediate post-operative period [9, 10]. Then, time intervals can be increased but infusions often have to be continued for days. Treatment schedules are shown in Table 1 and 2. The administration of rFVIIa by continuous infusion is a wide-spread practice since several authors have shown that it is effective, less expensive [11–15], and more convenient than bolus injections.

Elevated Fibrinogen is a Risk Factor for Arterial Thrombosis in Children

Several authors reported about the role of an elevated fibrinogen level as a risk factor for arterial and venous thromboembolism in adults [1, 2, 3, 4, 5]. In children elevated fibrinogen levels also are discussed to be a risk factor for thrombus development, but no special pediatric studies exist, which confirm this hypothesis [6].

Expression of Protease-activated Receptors in Neuroblastoma Cells

Children with cancer are on high risk to develop thrombosis. The underlying pathophysiological Mechanisms are not completely understood. Most coagulation factors are expressed in liver or endothelial cells. Some of them, e.g. thrombin, Plasminogen activator inhibitor-1 and tissue factor, have been detected in neuroblastoma cells as well, suggesting that tumor cells directly take part in thrombogenesis [5,9].

Severe Neonatal Thrombosis in a Patient with Factor V Q:506 Mutation and the G20210A Prothrombin Mutation

In childhood, thromboses are most common in neonates and adolescents. Well- known hereditary risk factors are the factor V Q:506 mutation manifesting itself as APC resistance, and a reduced level of protein C, protein S, and antithrombin and dysfibrinogenemia. Also, the forming of abnormal plasminogen and disturbances in the release of fibrinolytic substances from the endothelium are discussed as risk factors for the development of thrombosis. Further prothrombotic newly described risk factors are the prothrombin G20210A mutation, an increased level for lipoprotein(a), and the MTHFR mutation (methylenetetrahydrofolate reductase), as well as the intron 16 ACE polymorphism (angiotensin-converting enzyme).

Thrombophilie bei akuter lymphoblastischer Leukämie (ALL) und Mukoviszidose

Die Koinzidenz von ALL und Mukoviszidose ist sehr selten (ca. 1: 6,5 · 107), daher ist in Deutschland nur alle 5 Jahre mit der Kombination beider Erkrankungen zu rechnen. In der Literatur wurden bisher nur vereinzelt Patienten mit beiden Erkrankungen beschrieben, von denen einer im Rahmen der Chemotherapie (ALL-BFM-95) einen rechtsartrialen Thrombus entwickelte [18], wohingegen bei den ubrigen Patienten die Thrombose als Komplikation nicht erwahnt wird [9, 10].

Keine Dosisreduktion des vWF-Konzentrates trotz kontinuierlicher Infusionstherapie bei erworbenem von-Willebrand-Syndrom

Die Entwicklung eines erworbenen von-Willebrand-Syndroms mit Verlust der grosen Multimere ist bei Herzvitien ein bekanntes Phanomen [2–4]. Die Ursache fur diese Storung ist bisher ungeklart. Die Behandlung dieser Patienten im Rahmen von Blutungskomplikationen oder Operationen besteht in der Substitution von vonWillebrand-Faktor-haltigen Faktor-VIII-Konzentraten, ublicherweise als Bolusapplikation alle 8–12 h. Durch kontinuierliche Infusionstherapie konnte der Verbrauch von Faktor-Konzentraten bei Patienten mit kongenitalem von-WillebrandSyndrom um bis zu 50% reduziert werden [1].