Perinatal/Pediatric Haemostasis

August 7, 2005
08:30 to 12:00
Sydney Convention Centre

Chairman:  P. Massicotte, Canada
Co-chairs: G. Kenet, Israel; P. Mathew, USA; P. Monagle, Australia;
W. Muntean, Austria; U. Nowak-Göttl, Germany; N. Schlegel, France

Joint Session with the Scientific Subcommittee on Control of Anticoagulation
Chairs: S Schulman/ P Massicotte

New anticoagulants for pediatric use; lessons from adults

Jeff Weitz gave an overview of the development of new anticoagulants over the past few years, with emphasis on the lessons learnt and possible implications for the pediatric population. He described the development of heparins towards lower molecular weight with problems regarding decreased clearance in case of renal impairment, lack of specific antidotes and long half-life. New, selective anticoagulant agents have usually rapid onset and offset, a wide therapeutic window and no or reduced need for monitoring, but pediatric data is lacking as well as specific antidotes. A comment from the audience was that argatroban and bivalirudin, both approved drugs, are in clinical trials in the pediatric population.

Recommendation: It is important to ensure that some of the new anticoagulants will fit the needs of the pediatric population, for example with parenteral (subcutaneous) administration, no need for monitoring, not contraindicated in case of hepatic failure etc.

Towards a unified definition of major hemorrhage in clinical trials.

I. Non-surgical studies

Report S. Schulman
The process from discussion at the previous SSC in Venice 2004 was recapitulated briefly. The recommendation was published as a full length paper in JTH in April 2005. The European regulatory authority, EMEA, has been contacted and expressed interest in possibly adopting the recommendation but preferred to have the complete set, including recommendations for orthopedic and general surgery studies. Informal contacts have also been taken with FDA, and there is a growing interest there for possible issues of harmonization.

Plan: Encourage the process for similar recommendations in surgical studies and to further develop the contacts with EMEA and FDA.

II. Surgical studies – orthopedic.

Update. G. Raskob
The Working Party on Bleeding Complications in Orthopedic Studies has identified a large variety of definitions used in their field by performing a systematic literature review. Traditional measures of severity of bleeding have limitations in the early postoperative period. There is a definite need to include the surgeon’s assessment of the surgical site bleeding.

Recommendations (preliminary): 1) There is a need for explicit reporting for the surgical site, which must be distinguished from other bleeding. 2) A blinded assessment should be done by a surgeon regarding the clinical importance of the bleeding at surgical site. 3) Bleeding index and clinically important bleeding should be reported independently as separate outcomes. 4) A clinically important bleeding at the surgical site if it leads to wound dehiscence, infection, re-operation, prolonged hospital stay or contributes to myocardial infarction, stroke or death, as assessed by an independent adjudication committee. The WP will accelerate their pace of development of the recommendations and will endeavor to get this published within the next 12 months.

III. Surgical studies – general.

Update. D. Bergqvist.
This issue is even more complicated than the orthopedic procedures, since the surgical procedures are less standardized in general surgery and the severity of the procedures vary greatly. Gynecologic procedures may differ a lot from other general surgery. The transfusion requirements are influenced by more or less conservative policies.

Recommendations (very preliminary): Major bleeding is tentatively defined as 1) leading to death, 2) leading to transfusions or endovascular hemostatic procedures, or 3) occurs in critical organs.

Plan: To form a working party within the next few months to continue the development of a unified definition.

The Use of Heparin in Children. P. Monagle

Unfractionated heparin (UFH) is the anticoagulation of choice in infants and children who are at high risk of bleeding (peri surgery, trauma, chemotherapy) because of ease of reversibility (protamine sulfate) and short half life. During cardiopulmonary bypass and extracorporeal membranous oxygenation, UFH is currently the anticoagulant agent of choice. However, infants and children do not respond to UFH in the same way as adults. The activated partial thromboplastin time (aPTT), a surrogate measure of UFH level, does not correlate to increasing levels of heparin in the same fashion as in adults. In fact, if comparing therapeutic anti factor Xa levels to corresponding aPTT levels, in infants and young children the therapeutic aPTT ranges are much high than those in older children and teenagers. This difference may relate in part to developmental haemostasis differences, but there may be other different mechanisms of interaction compared to adults.

Recommendations: The difference response to unfractionated heparin between adults and children will be determined. A subgroup lead by Dr Monagle will determine how best to monitor UFH in neonates and children. This will be submitted as a position paper to the SSC.

HIT in children A. Greinacher

The literature in adults with HIT was summarized. In neonates and children, heparin induced thrombocytopenia is rare (< 1%). Most infants who develop antibodies have underlying cardiac disease and develop antibodies post cardiac surgery. In adolescents who develop HIT, the most common indication for unfractionated heparin is the treatment of venous thromboembolism. The testing for HIT in children has not been standardized and cut off values for abnormal must be established.

Recommendations: A standardized approach to the diagnosis of HIT in children must be established. Dr Greinacher will lead a subgroup to develop a diagnostic approach in children which will be submitted as an SSC position paper.

Bleeding

Treatment of Bleeding

FVIIa use in non hemophiliac children: International Registry(ISTH Study) - P. Mathew/ J. Blatny

The use of FVIIa is increasing internationally in non haemophilac children despite the lack of properly designed studies. The establishment of an international web based registry to record and follow those children is important to provide an estimate of safety and efficacy in the absence of randomized controlled trials.

SevenBleep Registry is a web based International Registry which has just gone live. The Registry can be accessed from the ISTH home page.

Recommendations: Encourage international health professionals using FVIIa in non hemophiliac children to enter data in registry to estimate safety and efficacy of the product. Users must ensure that local research ethics boards formally accept this entry of de identified data.

Antiplatelet Therapy

ASA resistance (ISTH study proposal) - M. Rand/ M. Albisetti

A significant benefit of ASA has been demonstrated in the prevention of arterial thrombotic events in high-risk adult patients. Recurrent thromboembolic events have been reported in 5-45% of patients despite ASA therapy; this has been termed ASA ‘resistance’, but may actually reflect treatment failure. The failure of ASA to affect ASA-dependent laboratory tests has also been termed aspirin ‘resistance’. The Working Party on ASA Resistance of the Platelet Physiology Subcommittee has concluded that a clinically meaningful definition of ASA ‘resistance’ needs to be developed, based on data linking ASA-dependent laboratory tests to clinical outcomes in patients. Studies in children are required to explore ASA ‘resistance’. In an ongoing prospective study of ~100 children with arterial ischemic stroke, 20% are aspirin ‘resistant’ based on laboratory testing. A prospective study in children following interventional cardiac catheterization is undergoing ethics approval, and several other centres with appropriate patient populations have been identified.

Recommendations: Encourage international participation in this cohort study to determine the percentage of children who are ASA resistant. Further studies are required to determine alternative anti platelet agents in ASA resistant children.

Predictors of Bleeding

Coagulation tests as predictors of Bleeding in CPB:New ways to predict bleeding /When should we test – G. Kenet/ N. Schlegel

Tonsillectomy and adenoidectomy are the most common surgical procedures performed in children. Despite the progress made in this type of surgery, the operative hemorrhagic risk factors are not clearly defined. However, the occurrence of either peri or post surgery hemorrhage is considered as potentially life threatening due to the anatomical location of the palatine tonsils and the adenoids. Hemorrhage is the most common complication of such a surgery. An estimated 2-3% of patients have hemorrhage and 1 of 40,000 patients die form hemorrhage. Bleeding may occur during surgery or after surgery either within the 24 hours (primary hemorrhage) o between day 2 to 10 (secondary hemorrhage). Pre-surgery physical examination and questioning for personal and familial bleeding history are recognized to be the most informative procedures. By contrast, in absence of controlled trials, there is no consensus of opinion about the practice of pre surgery haemostasis tests. The pediatric specifics: developmental haemostasis peculiarities, risks of coagulation activation due to difficult blood drawing, risks of artifactual results due to heparin contamination, enhance the poor positive predictive value for bleeding of the screening tests for platelet functions and the limitations of INR and aPTT. The inherited haemostasis disorders associated with bleeding risks, which are rare diseases (Von Willebrands disease being more common), are mostly diagnosed early in life, but some defects might be unknown at the time of the surgery. Taking inot account the pros and cons, the most common attitude is to perform screening tests in the following situations: any child before walking age, positive personal and/or familial bleeding history, acquired disease with hemorrhagic risk, drugs associated with bleeding risk, family questioning not reliable, not relevant or not possible.

Official recommendations will be helpful from both the medical and legal points of view. The recommendations will facilitate a pre surgical estimate of the risk of bleeding and appropriate preventative therapies within the expert team (anesthesiologist, surgeon and hematologist). Platelet count and aPTT appear to be the most useful initial pre tonsillectomy and adenoidectomy tests to complete. If there are any concerns re peri surgical bleeding, Von Willebrands Disease testing should be completed pre surgery. Currently, there are no validated platelet function tests that allow a reliable assessment re peri surgical bleeding risk.

Recommendations: A subgroup lead by Gili Kenet and Nicole Schlegel will explore the institution of pre surgical questionnaires that indicate a potential peri surgical bleeding risk. The subgroup will liase with Francesco Rodeghiero and the European Union re the validated and pre existing questionnaire for bleeding associated with Von Willebrands Disease. This established questionnaire may have potential application to tonsillectomy and adenoidectomy bleeding risk.

Cardiopulmonary Bypass (CPB) and Stroke: Update – A. Chan /P. Massicotte

Arterial ischemic stroke (AIS) is likely to be an important complication arising from cardiopulmonary bypass in children. The best estimated incidence of AIS at the present time is 0.4%. The three parameters that have been associated with an increase incidence of AIS are older age at the time of CPB, longer bypass time and lower pre-op activated partial thromboplastin time. Forty-eight percent of the patient with AIS had severe to moderate neurological deficit However, large multicentre prospective studies are necessary to determine the incidence, risk factors and long term outcome of such complications. Optimization of anticoagulation therapy and cardiopulmonary bypass techniques, and development of neuroprotective agents are necessary in order to prevent the devastating long term complications associated with CPB, such as AIS.

Recommendations: The subcommittee has submitted a position paper to the SSC and awaits comments/approval. This position paper will facilitate properly designed incidence studies.

Thromboprophylaxis of mechanical heart valves: Point of Care Testing (ISTH position paper) – M. Bauman / F. Newall

Children with mechanical prosthetic heart valves require oral antithrombotic therapy using vitamin K antagonists. Monitoring vitamin K antagonists in children is difficult as they usually have complex underlying health problems, are on multiple medications and are often difficult to venesect. The cohort of children requiring primary thromboprophylaxis for the management of mechanical prosthetic heart valves is further challenging due to their lifelong need for thromboprophylaxis. This position paper will discuss the rationale for point-of-care capillary monitoring of vitamin K antagonists and provide an overview of POC monitoring. Clinical recommendations will be made regarding the use of POC testing generally, and use of this technology in home monitoring programs. POC INR monitoring, including home INR monitoring, in children has been demonstrated to be safe and efficient with the setting of dedicated paediatric anticoagulant clinics. Whether such monitoring remains safe and efficient when implemented within other models of care has not been determined. Implementation of strategies to reduce the risk associated with reduced reliability of POC INR results greater than 5.0 can optimize this management strategy. Consideration should be given to the education program upon which home INR monitoring programs are built.

Recommendations: The position paper is ready for comments/review by the subcommittee members. This will facilitate properly designed studies to determine safety and efficacy, quality of life and cost effectiveness of POC monitoring in children.

Risk factors for Venous Thrombosis/Thromboprophylaxis

Factor VIII, lipoprotein (a)and other risk factors in Thrombosis Recurrence in children. Update of StudiesU. Nowak Gottl/ M. Manco Johnson

In children FVIII assays must have cut off values for abnormal which are dependent upon age and blood group. If FVIII is persistently increased, there is controversial data as to whether this is associated with an increased risk of VTE. Goldenberg et al show an increased risk of recurrence while Nowak Gottl et al demonstrate no increased risk of recurrence (unpublished data).

In children lipoprotein a cut off values for abnormal are age related. Increased lpa is associated with an increased risk of recurrent stroke. It is unclear whether recurrent VTE is associated with increased lpa.

Recommendations: More studies to determine the relationship of FVIII to the development of VTE in children are necessary.

Antiphospholipid Antibodies: Risk of Thrombosis in Children with APLA+: Status of manuscript (ISTH position paper)C. Male

Antiphospholipid antibodies (APLA) occur in children with a variety of conditions, most frequently following infections. However, APLA associated with thrombotic events (TE) are essentially limited to children with underlying autoimmune disease. The best evidence on the risk of TE associated with APLA comes from studies in children with systemic lupus erythematosus (SLE). Multiple laboratory tests for APLA are available but there are conflicting reports which test best predicts an increased risk of TE.

A recent cohort study of 58 consecutive children with SLE determined lupus anticoagulants (LA), anticardiolipin antibodies (ACLA), anti- b 2 -glycoprotein-I (anti- b 2 GPI), anti-prothrombin (anti-PT) in serial samples and prospectively (and retrospectively) assessed patients for symptomatic TE, confirmed by objective radiographic tests. Ten TE occurred in 7 patients (12%). Lupus anticoagulant showed the strongest association with TE since no LA-negative patient had TE. LA remained the only significant factor in multivariable analysis. Persistent ACLA, anti- b 2 GPI, and anti-PT were all significantly associated with TE. Considering all positive (persistent and transient) antibodies, the strength of association remained similar for LA and anti- b 2 GPI, while ACLA and anti-PT were no longer associated with TE. P ositivity for multiple APLA subtypes showed substantially stronger associations with TE than for individual APLA subtypes because of improved specificity.

In conclusion, the criteria to best predict the risk of TE associated with APLA in children are: 1. underlying autoimmune disease, e.g. SLE; 2. persistent presence of APLA; 3. presence of LA, and 4. positivity for multiple APLA subtypes.

Recommendations: The risk of thrombosis in children with APLA+ will be submitted to the SSC for publication.

Open Prospective International Registry: Infants of mothers with APLA syndrome M. H. Aurosseau, Lachassinne E, Fain O, Biasini-Rebaioli C, Derenne S, Boinot C, Schlegel N, Avcin T, Le Toumelin P, Nicaise P, Faden D, Tincani A, Uzan M and Boffa MC.

The aim of this register is to evaluate the correlation between maternal disease / treatments and the clinical events, neuro-developmental features and immunological status of the babies. The prevalence, type and kinetics of disappearance of antiphospholipid antibodies (APLA) in infants and children born to mothers with primary or secondary APS can be determined, according to Sapporo criteria. The potential effects of these antibodies will be evaluated in children until the age of 5.In 54 babies already included, we observed a higher prematurity rate than in the normal neonatal population. All types of APL antibodies were found in 39% of the neonates and in 5/54 neonates, new specificities of antibodies, different from maternal antibodies, were present. The time of disappearance of these antibodies is prolonged to 6-18 months. Furthermore, we observed 8 children, negative at birth who subsequently became positive. The registry is expected to recruit 300 neonates and mothers within the next 3 years.

To download the data base and to send the form please contact: philippe letoumelin@avc.ap-hop-paris.fr

Treatment and Prophylaxis of Thrombosis

Treatment of venous thrombosis - E. Chalmers/ H. Van Ommen

There are no new studies determining the safety and efficacy of medical therapy for venous thrombosis in infants and children. The differing treatment practices for venous thrombosis in infants and children were determined in an international survey (see below).

Recommendations: The results of the survey to be published will facilitate the design of treatment studies in infants and children with venous thrombosis.

Central Venous Lines: Thromboprophylaxis: Status of manuscript (ISTH position paper )S. Revel-Vilk / L. Mitchell

The two high risk groups with CVL related thrombosis that have been identified are children with ALL and children with congenital heart disease (CHD). Need summary

Recommendations: The recommendations for thromboprophylactic studies in these high risk groups will be submitted as a position paper to the SSC.

Report on Diagnosis and Treatement of DVT in children: Survey of the Pediatric Perinatal SSC (ISTH publication). L. Bomgaars

The Pediatric Perinatal subcommittee (30 members) was surveyed re the diagnosis and treatment of VTE in infants and children. There were 17 questions in the survey which was completed by 72% of the members (18 centres, 9 countries). The conclusions are :

1. LMWH as part of therapy in neonates is considered standard of care by all surveyed.

2. Objective testing schedule and duration of therapy is highly variable.

2. Thrombophilic work ups are more often performed in children as compared to neonates and most commonly included the measure of Protein C, S, Antithrombin, Factor V Leiden, and prothrombin 20210 defect.

3. Further RCTs are needed to define optimal therapy and evaluation in children.

Recommendations: The determination of international expert practice for the diagnosis and treatment of thrombosis in infants and children will facilitate the design of proper safety and efficacy studies. The results of this survey will be submitted as a position paper to the SSC.

Antiphospholipid Antibodies

Risk of thrombosis in children with APLA – C. Male

There is good evidence of a high risk of thrombosis in children with SLE and APLA.. The association of APLA with TE found in pediatric cohorts are stronger than those found in adult studies. Few children with SLE who are negative for APLA develop TE. Lupus anticoagulant is a stronger predictor of the risk of TE than anticardiolipin antibodies, anti beta 2 glycoprotein antibodies and anti prothrombin antibodies.

In children without underlying SLE case reports describe associations of APLA and severe thrombotic complications (primary APLA syndrome). Currently, it is unknown what the risk of TE is in well children with APLA. Increased prevalence of APLA are found in children who suffered from stroke compared to controls .However, recent evidence suggests, in general, APLA presence is not associated with an increased risk of recurrent stroke.

Recommendations: The subcommittee recommends that the data on stroke and APLA in children be published in a Position paper with the recommendations that more studies are urgently needed in this area especially in primary prophylaxis of patients with APLA and SLE.