Projects

• Aspirin resistance in children after interventional cardiac catheterization
  
  
• Vascular complications of Port-à-Cath devices in paediatric oncology patients
  
  
• Laboratory parameters of ITP patients
  
  
• Development of megakaryocytes and platelets
  
  
• Haemoglobin analysis
  
  
• Arterial thrombosis
  
  
• Self monitoring of oral anticoagulation
  
  
• Monitoring splenic function in children and neonates
  
  

Aspirin resistance in children after interventional cardiac catheterization

During the last 20 years, several large trials have consistently demonstrated the absolute benefit of aspirin in the prevention of arterial thrombotic events in adults. However, recurrent thromboembolic events have been reported in 5 to 45% of adult patients despite treatment with aspirin, a phenomenon that has been called “aspirin resistance”. Thus, the term “aspirin resistance” has been primarily used to describe the clinical inability of aspirin to protect individuals from arterial thrombotic events. This definition is not specific and may reflect treatment failure rather than resistance to aspirin, particularly why this definition may apply to several conditions such as poor compliance or inadequate doses possibly causing recurrent vascular events despite aspirin intake. Thus, the term “aspirin resistance” has evolved to define the failure of aspirin to produce an expected response on one or more laboratory measures of platelet activation and aggregation.

Although aspirin is increasingly administered to children to treat arterial ischemic stroke and prevent thromboembolic events following several cardiac catheterization procedures, no published data regarding aspirin resistance in children is available. We are currently studying the prevalence of aspirin resistance in a well-defined population of children undergoing interventional cardiac catheterization.

PI: Manuela Albisetti, MD, Markus Schmugge, MD Co-Investigators: Oliver Kretschmar, MD, Walter Knirsch, MD, Oliver Speer, PhD, Eva Bergsträsse, MD, Margaret L. Rand, PhD (Sick Kids Hospital Toronto)

top

Vascular complications of Port-à-Cath devices in paediatric oncology patients

Port-à-Cath (PAC) devices are essential components of modern management in paediatric oncology. However, a PAC is possibly associated with an increased risk of thrombosis, likely causing long-term morbidity. The incidence, predictors and outcome of PAC-related thrombosis are not well defined.

PAC-related thrombosis and postthrombotic syndrome (PTS) are investigated in a large paediatric oncology population. The study population is a consecutive cohort of children diagnosed with cancer, and with a PAC implanted at diagnosis or shortly after. Included children are evaluated for the presence of PAC-related thrombosis by magnetic resonance (MR) venography of the upper deep venous system, congenital prothrombotic risk factors, and PTS using a published paediatric score (Kuhle et al 2003).

Preliminary results show that PAC-related thrombosis occurs in one third of paediatric oncology patients. Thrombotic complications persist over time following PAC removal and predispose some of these children to the development of PTS. The continuation of this study will define the long term morbidity of PAC-related thrombosis in paediatric oncology.

Manuela Albisetti MD, Christian Kellenberger MD, Eva Bergsträsser MD, Huisman Terry, Felix Niggli MD, Markus Schmugge MD

top

Laboratory parameters of ITP patients

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune syndrome frequently found in children after viral infections. In the majority of patients it is self-limiting after weeks or months, and is accompanied by minor haemorrhage only and does respond well to the administration of immunoglobulines (IVIG) or steroids. Only a minority of children develop more severe bleeding or chronic ITP where patients show low platelet counts for years.

Although in its clinical presentation childhood ITP is a well described and distinct entity, still a single aethiology and a unique pathiophysiological mechanism that would be able to explain all laboratory phenomena has not been found. On the other hand most laboratory studies so far were unable to define laboratory results that help to define subgroups in this disease and to develop prognostic parameters for the occurrence of severe bleeding and the development of chronic ITP.

PI: Markus Schmugge, MD, Oliver Speer, PhD Co-Investigators: Sabine Kroiss MD, Manuela Albisetti MD, Tayfun  

Development of megakaryocytes and platelets

microRNAs are a highly conserved class of noncoding RNAs with important regulatory functions in proliferation, apoptosis, development, and differentiation. Due to the late discovery of human microRNAs, about six years ago, virtually nothing is known about their clinical importance. With the proposed project we want to set the basics to understand the role of microRNAs in the paediatric haematology. For a beginning we will focus on megakaryocyte and platelet development.

PI: Oliver Speer, PhD, Markus Schmugge, MD  

top

Haemoglobin analysis

Hemoglobin, the oxygen-carrying polypeptide tetramer of the erythrocytes, consists of two pairs of globin chains (i.e. plus α, β, γ, δ) and four oxygen-binding heme that are covalently linked to globin chains. In healthy adults, about 95 % of the Hb is HbA _(α2β2), whereas the remaining 5 % consists of minor fractions such as HbA_1c α₂β^GLYC₂), HbF (α_2γ2), or HbA₂ (α₂δ₂). Hemoglobinopathies are a group of disorders affecting red blood cells with abnormal Hb. Thalassemia, in contrast, results from quantitative reductions in globin chain synthesis. Structural Hb variants typically are based on a point mutation in a globin gene that produces a single amino acid substitution in a globin chain. Although most of these variants are of limited clinical significance, some of them, such as homozygous Hb S, or Hb C, produce severe clinical manifestations. Furthermore, variants with no clinical manifestations could cause erroneous results in HbA_1c determination, the common diabetes index. Worldwide, an estimated 150 million people carry Hb variants, and hemoglobinopathies are the commonest inherited disorders and constitute a significant healthcare problem. Therefore, sensitive detection and identification methods are necessary.

Karin Zurbriggen, Marlis Schmid, Heinz Troxler, PhD, Oliver Speer, PhD, Markus Schmugge, MD  

top

Arterial thrombosis

Venous and arterial thromboembolic events (TE) are increasingly recognized in infants and children. Similarly to adults, these TE may cause serious long-term morbidity in children including the post-thrombotic syndrome following venous TE or claudication following arterial TE. However, children may be impaired over a much longer period of time by these complications, which may have a negative impact on their development as normal healthy adults. Thus, early and optimal treatment strategies of TE in children are extremely important to potentially avoid such complications.

Manuela Albisetti, MD, Markus Schmugge, MD  

top

Self monitoring of oral anticoagulation

Portable monitors allow the measurement of the prothrombin time (PT) at home from capillary blood obtained from a finger prick. Studies in adults have demonstrated that this method provides a reliable and safe self-monitoring in patients requiring oral anticoagulation (OA). Compared to adults, oral anticoagulation in children requires more frequent monitoring, which is often difficult to perform due to poor venous access. Thus, capillary whole blood monitoring potentially offers advantages over monitoring from venous blood samples to children on oral anticoagulation.

Since 2002, paediatric cardiac patients on long term oral anticoagulation and/or their parents have been offered the possibility of monitoring oral anticoagulation at home using the portable PT monitor (CoaguCheKR). After a theoretical and practical instruction, motivated children and/or parents self-monitored and self-adjusted oral anticoagulation, taking any time phone contact with the staff in the hospital when INR values were outside the target range or in cases of any uncertainty. At a regular basis, INR records were collected, and a venous INR was performed in the clinical laboratory and compared with the capillary INR measured at the same time.

A total of 24 cardiac patients at a median age of 6.98 years (range, 1.5-18.49 years) had received a portable PT monitor for a median of 1.76 years. Overall, patients performed a mean of 4.07 capillary INR tests per months, achieving individual target INR ranges in 72.1% of INR tests. Capillary INR values were above individual target INR ranges in 10.7% and below in 17.1% of all INR tests (p=0.07). The correlation coefficient between capillary and venous INR was r = 0.87 (95%CI, 0.76-0.93). Based on individually defined target INRs, the concordance between capillary and venous INR was 80%. No patients experienced significant haemorrhagic or any thrombotic complications. These results indicate that self-control of oral anticoagulation is reliable and safe. The portable PT monitor offers an accurate and safe self-monitoring to motivated paediatric cardiac patients requiring long term oral anticoagulation.

Albisetti M, Schmugge M, Kägi E, Bauersfeld U, Fasnacht M

top  

Monitoring splenic function in children and neonates

Children with splenic dysfunction and asplenia are at increased risk for life threatening bacterial sepsis. So far there is no quantitative laboratory test for the immuno-logical function of the spleen available. The absence of Howell Jolly inclusion bodies (HJB) in red blood cells and low levels of pocked (pitted) erythrocytes (PE) can be used to assess the phagocytic or filtration function of the spleen. The percentage of PE is determined by differential interference contrast microscopy.

Currently we investigate whether the determination of PE is a simple and reliable method for the assessment of the splenic function. So far we find that in contrast to HJBs, the level of PE allows to distinguish between partial and complete absence of functional splenic tissue in a semiquantitative way. The determination of PE can help to identify patients at increased risk for bacterial sepsis.

Sabine Kroiss MD, Karin Zurbriggen, Monica Ceresetti, Manuela Albisetti MD, Janine Reichenbach MD, Oliver Speer PhD, Markus Schmugge MD

top