Perinatal/Pediatric Haemostasis
29 June, 2006
Oslo Kongressenter, Norway
Chair: P. Massicotte, Canada
Past Chair: U. Nowak-Gottl, Germany
Co-chairs: G. Kenet, Israel; P. Matthew, USA; P. Monagle, Australia; W. Muntean, Austria; N. Schlegel, France
THROMBOSIS
A. CONGENITAL HEART DISEASE
1. Cardiopulmonary Bypass and Stroke: AKC Chan/P Massicotte
A discussion on the status of the ISTH position paper was presented.
2. Thromboprophylaxis of Mechanical Heart Valves: Point of Care testing M. Bauman/ F. Newall
An update about the ISTH position paper was discussed with the manuscript currently in preparation
3. Point of Care monitoring: Patient Education programs and outcomes.
M. Bauman/ F. Newall
Point of Care (POC ) monitoring of anticoagulant therapy represents a potential solution to the challenge of safe and effective dosing of warfarin in children. Standardized, comprehensive, education provided preceding warfarin treatment and POC monitor use positively impacts reliability of results and improves outcomes for children requiring warfarin therapy. The implementation of a formalized focused education program results in excellent correlation between lab /POC INR result r 2= 0.96, increased time in INR therapeutic range (TTR) (84%) p=0.04, increased patient knowledge p< 0.0001, and improved adherence and no thrombotic or bleeding results. POC INR monitors are a safe and effective alternative for monitoring INR in children who underwent a standardized comprehensive education program, preceding patient self testing with a POC INR monitor. Long term knowledge retention and its influence on safety and efficacy will be evaluated.
Recommendations : The education package can be provided in English and French (when translated) to those who are interested by contacting marybauman@cha.ab.ca .
B. RISK FACTORS FOR THROMBOSIS
1. Recurrent Pediatric Stroke and risk factors U. Nowak Gottl/ G. deVeber:
Data on recurrent stroke from pooled international databases held at the hospital for sick kids, Toronto , University of Munster and Great Ormond Street hospital, UK were presented. The effects of thrombophilic risk factors for the risk of recurrent stroke was evaluated. Data were available from 678 patients (age range: 1 month to 21 years) followed for a median of 36 months. Recurrence rates were significantly higher among patients with cardio vascular diseases and increased lipoprotein (a) levels. The presence of any prothrombotic risk factor doubled the risk for recurrence after adjustment for presence of cardiovascular disease, whereas the use of either antiplatelet or anticoagulant therapy significantly reduced it.
Recommendations: Due to the paucity of information regarding the risk of recurrent stroke in children, pooled international data collection and further collaborative studies were strongly encouraged.
2. Antiphospholipid Antibodies: Risk of thrombosis in children with APLA+: Results of the Israeli experience G. Kenet:
There are only few small case series regarding the issue of primary APS in the pediatric population. In Israel , a cohort of 28 patients with APS was prospectively followed for a median of 6 years. Patients were assessed for presence of any other thrombophilic risk factors and any recurrent thrombosis. The commonest presenting symptoms were thrombotic, with a small subgroup presenting with perinatal stroke. Among laboratory markers of APS, LAC prevailed. During follow up, 5 females developed SLE, 7 patients suffered recurrent thrombosis that was not associated with presence of thrombophilia, and the recurrences were inversely related to anticoagulant therapy administration. The subgroup presenting with perinatal stroke and APL antibodies had a monophasic disease with no recurrences despite lack of anticoagulant therapy. Unique features of pediatric APS and the need for proper diagnosis and early anticoagulant therapy were discussed.
Recommendations : The committee suggested a potential future joint session with the APL subcommittee to discuss diagnostic criteria for pediatric patients and guidelines for therapy. Pediatric Hematologists were encouraged to join the European APLA registry, collecting data about infants born to mothers with APS. To receive more information about the registry, contact Nicole Schlegel at schlegel@wanadoo.fr
3. Evidence that Tissue Factor Is the Driving Force in Childhood HUS, with Direct Implications for Therapy and Clinical Studies E Grabowski
Up regulation of tissue factor activity is seen on TNF α activated human glomerular endothelial cells exposed to shiga toxin on proximal tubular cells exposed to this toxin and on sections of kidney from rabbits given this toxin orally. In the last case, platelet adhesion/aggregation on the sections is tissue factor driven, as shown by full inhibition of the increase seen with shiga toxin when sections are first incubated with a monoclonal antibody directed against human rabbit factor.
These animal studies suggest that a clinical/preclinical trial to evaluate the role of the tissue factor pathway in the childhood hemolytic uremic syndrome (HUS) is warranted. The clinical/ preclinical trial would also evaluate the role of site inactivated factor VIIa in blocking this pathway and suggesting a novel therapy for the syndrome.
Recommendations : Samples of blood and urine from patients in the acute phase of childhood HUS are required to be tested in the in vitro cell culture systems. Any interested investigators should contact Dr Eric Grabowski at eric@MGM.harvard.edu
C. TREATMENT & PROPHYLAXIS OF THROMBOSIS
1. New Anticoagulants in children. G. Young
Low molecular weight heparins have overcome some of the limitations of unfractionated heparin yet, they can not inactivate clot bound thrombin, have a long half life and do not have a specific antidote. In adults, several new anticoagulants have been licensed in recent years to prevent and treat a variety of thromboembolic complications. These agents have superior pharmacologic properties to heparin and some have shown a dramatic reduction in the risk for bleeding without compromising efficacy. These agents have properties which make them particularly attractive for evaluation in children. Data was presented on the results of 2 single centre pilot dose finding and pharmacokinetic studies using 1. bivalirudin in infants with thrombosis and 2. argatroban in children who have heparin induced thrombocytopenia (HIT). The data for dosing and safety of both agents suggests safety and efficacy in infants and children.
Recommendations : Properly designed studies including pharmacokinetic and pharmacodynamic studies are required with the new anticoagulant agents in children to determine safety and efficacy.
2. Central venous lines: thromboprophylaxis: ISTH position paper S. Revel Vilk/L. Mitchell:
An update of the manuscript status was presented; manuscript is currently in preparation.
3. Report on Diagnosis and Treatment of DVT: Survey of SSC.( Status of manuscript) L. Bomgaars/ P. Massicotte:
An update of the manuscript status was presented; manuscript is in preparation.
BLEEDING
A. TREATMENT OF BLEEDING
1. FVIIa use in non haemophilic children: International Registry update. (ISTH study) P. Mathew/J. Blatny:
Presently, n= 30 patients have been entered into the registry. Committee members were asked to increase their level of awareness and report all off-label use in pediatric patients into this registry.
2. New study : FVIIa in IVH in premature infants P. Mathew:
The rationale for this study was presented and a draft outline was discussed.
3. Acquired Purpura Fulminans: The Argentinian Data M. Bonduel
Sixty-three children with clinical diagnosis of APF related to suspected infectious diseases were retrospectively evaluated in Argentina . Neisseria meningitides was the microorganism most frequently isolated. All patients had signs of DIC, and most of them required mechanical ventilation and inotropic support.
On admission, plasma samples of 31 patients with APF associated with different infections were evaluated. There was a significant difference in PC, PS and AT levels between survivors and non- survivors. PC was significantly lower than AT or PS. In varicella associated APF (n=6) severe deficiencies of free and total PS were detected.
The patients were treated with fresh frozen plasma, protein C concentrates (n=9), or recombinant APC concentrate (n=1). No bleeding events were observed. Despite the therapies used, high percentages of mortality and severe morbidity, in some groups of patients, were found.
Recommendations : More data should be collected in APF in children to elucidate possible therapeutic measures which should ultimately be tested in clinical studies.
B. ANTIPLATELET THERAPY
1. ASA resistance (ISTH study update) M Rand/M Albisetti
The clinical efficacy and dosing of ASA in children have not been well studied. The Working Party of ASA ‘Resistance’ of the Platelet Physiology Subcommittee of the SSC has concluded that: 1) a clinically meaningful definition of ASA ‘resistance’ needs to be developed, based on data linking ASA-dependent laboratory tests to clinical outcomes in patients; and 2) the correct treatment, if any, of ASA ‘resistance’ is unknown. (Michelson et al., J Thromb Haemost 2005:3;1309).
Studies in Canada, the USA and Switzerland are now ongoing to explore ASA ‘resistance’ in children; in one of these, a prospective study of ~120 children with arterial ischemic stroke, 20% are ASA ‘resistant’ based on laboratory testing. Several other centres with appropriate patient populations have been identified.
Recommendations : To continue to work with the Platelet Subcommittee in this area. To complete studies in children to provide data to clarify the definition and clinical relevance of ASA resistance in children
C. PREDICTORS OF BLEEDING
1. Tests used to predict bleeding in children before adenoidectomy and tonsillectomy: ISTH questionnaire results G. Kenet/ N. Schlegel
Due to the lack of information there is currently no consensus regarding pre-operative screening questionnaire and screening tests for bleeding in young children undergoing various surgeries. Prior to SSC meeting a pediatric bleeding proposed questionnaire has been submitted to committee members for approval and comments. Following the correspondence, it has been suggested to use the VW questionnaire (with some pediatric modifications) as baseline screening for any child and for parents of younger children as well. The score of this questionnaire should be added to the score of surgical procedure (differentiating high and low risk surgeries, with regard to bleeding potential) and the score of abnormal laboratory screening tests (to be obtained for every child with high-risk bleeding history or high-risk surgery as well as selected cases upon clinical experts definition) in order to stratify the risk of bleeding for patients undergoing various surgical procedures.
Recommendations: A sub group led by G. Kenet/ N. Schlegel will work upon further definitions of bleeding score. The committee members have agreed to prospectively collect data of patients referred for peri-operative screening according to questionnaire and score suggested. Contact gili.kenet@sheba.health.gov.il if you are interested in participating in the sub group.
2. Pre op PFA-100 screening in 500 children W. Muntean
Peri-operative screening of 500 children referred for Hematology consultation due to potential high-risk bleeding history was performed by using 2 assays: PTT and PFA-100. Neither prolonged PTT, nor prolonged closure time of PFA-100 were associated with operative bleeding in this group despite a number of children with prolonged PTTs and closure times. This may have resulted due to limitations of both tests, as well as non-reliability of the screening questionnaire as administered by non-expert physicians.
Recommendations: To try to further define the risk for bleeding through questionnaires and laboratory predictors as suggested above.