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Summary. Background: Inhibitors are rare in boys with mild hemophilia A (MHA; factor (F)VIII:C >5%) but may arise following intense FVIII exposure, e.g. continuous infusion (CI). Objectives: To determine the impact of intense FVIII exposure in inhibitor formation in MHA at our institution and to compare this with previous reports. Patients and methods: We reviewed FVIII exposure and inhibitor development in boys (ages 0-18 years) with MHA followed at our institution from 1996 to 2001 and conducted a Medline search on the experience of inhibitor development following intensive/CI exposure to FVIII. Results: We identified 54 boys with MHA. Twenty-nine (54%) had been exposed to FVIII. Seven had received FVIII by CI. Four developedinhibitors;threehightiter(atages10 years,16 yearsand 17 years) and one low titer (at 1 month old). All four had received a CI of recombinant (r) FVIII of at least 6 days within 6 weeks of developing inhibitors. Baseline FVIII levels fell to <1% in all cases and the three with high-titer inhibitors developed severe bleeding. Immune tolerance therapy (ITT) was attempted in two boys and was successful in one. Our literature search identified 35 cases (only four children) with MHA developing inhibitors following intense FVIII exposure often in the context of surgery. Conclusions: The incidence of inhibitors in our MHA population was 7.4%. If expressed according to exposure the incidence was significantly higher: 14% (4/29) for any exposure to FVIII and 57% (4/7) for exposure by CI. A prospective study to address whether CI is associated with an increased incidence of inhibitor development in MHA is warranted.

Summary.  Venous thromboembolic (VTE) events are being increasingly diagnosed in systemic and cerebral vessels in children. Systemic VTE are increasing in children as a result of therapeutic advances and improved clinical acumen in primary illnesses that previously caused mortality. The epidemiology of systemic VTE has been studied in international registries. In children older than 3 months, teenagers are the largest group developing VTE. The most common etiologic factor is the presence of central venous lines. Clinical studies have determined the most sensitive diagnostic method for diagnosing upper system VTE are ultrasound for jugular venous thrombosis and venography for intrathoracic vessels. However, the most sensitive diagnostic methods for lower system VTE and pulmonary embolism (PE) have not been established. Treatment studies for VTE consist of inadequately powered randomized controlled trials or prospective cohort studies. The long‐term outcome of systemic VTE, post‐thrombotic syndrome, has been reported in children. Cerebral sinovenous thrombosis (CSVT) is becoming increasingly diagnosed in children due to the recognition of the associated subtle clinical symptoms and improved cerebrovascular imaging. The etiology of CSVT includes thrombophilia, head and neck infections, and systemic illness. Estimates of the incidence and outcome of childhood CSVT have recently become available through the Canadian Pediatric Ischaemic Stroke Registry. Clinical studies have not yet been carried out in children to determine the best method of diagnosis or treatment. There have only been case‐series studies carried out in the treatment of CSVT. Properly designed clinical trials are urgently required in children with systemic VTE/PE and CSVT to define the best methods of diagnosis, treatment and long‐term management.

SummaryThe haemostatic system and the use of heparin during cardiopulmonary bypass (CPB) have been studied extensively in adults but not in children. Results from adult trials cannot be extrapolated to children because of age-dependent physiologic differences in haemostasis. We studied 22 consecutive paediatric patients who underwent CPB at The Hospital for Sick Children, Toronto. Fibrinogen, factors II, V, VII, VIII, IX, XI, XII, prekallikrein, protein C, protein S, antithrombin (AT), heparin cofactor II, α2-macroglobulin, plasminogen, α2-antiplas- min, tissue plasminogen activator (tPA), plasminogen activator inhibitor, thrombin-AT complexes (TAT), D-dimer, heparin (by both anti-factor Xa assay and protamine titration) and activated clotting time (ACT) were assayed perioperatively. The timing of the sampling was: pre heparin, post heparin, after initiation of CPB, during hypothermia, post hypothermia, post protamine reversal and 24 h post CPB. Plasma concentrations of all haemostatic proteins decreased by an average of 56% immediately following the initiation of CPB due to haemodilution. During CPB, the majority of procoagulants, inhibitors and some components of the fibrinolytic system (plasminogen, α2AP) remained stable. However, plasma concentrations of TAT and D-dimers increased during CPB showing that significant activation of the coagulation and fibrinolytic systems occurred. Mechanisms responsible for the activation of haemostasis are likely complex. However, low plasma concentrations of heparin (<2.0 units/ml in 45% of patients) during CPB were likely a major contributing etiology. ACT values showed a poor correlation (r = 0.38) with heparin concentrations likely due to concurrent haemodilution of haemostatic factors, activation of haemostatic system, hypothermia and activation of platelets. In conclusion, CPB in paediatric patients causes global decreases of components of the coagulation and fibrinolytic systems, primarily by haemodilution and secondarily by consumption.

SummaryThere are no validated guidelines for administering or monitoring oral anticoagulant therapy in pediatric patients. A pediatric thromboembolism program at the Hospital for Sick Children, Toronto, prospectively monitored consecutive children requiring warfarin over an 18 month period. A uniform protocol was followed and dose adjustments based upon international normalized ratios (INRs). One hundred and fifteen consecutive children; 68 males and 47 females, received warfarin. The age distribution was: <ly (19); 1-5 ys (33); 6-10ys (20); 11-18 ys (43). Warfarin was used for secondary prevention of venous thromboembolism (n = 56) and primary prevention of thromboembolism (n = 59). Underlying disorders included: congenital heart disease (CHD) without mechanical valves (MV) (49); CHD with MV (18); cancer (8); longterm total parenteral nutrition (7); renal disorders (10); other (23). Treatment length was considered as short term (3-6 mths) n = 37 (32%); longterm (> 6 mths) n = 38 (33%); and lifelong n = 40 (35%) of children. While receiving warfarin, 95 children received concurrent longterm treatment with other drugs: 1 drug (28); 2 drugs (27); 3 drugs (21); 4 or more drugs (19).The amounts of warfarin/kg required to achieve INRs of 2 to 3 decreased with increasing age. Children <1 year of age required 0.32 ± 0.05 mg/kg whereas children 11-18 yrs required 0.09 ± 0.01 mg/kg; P <0.001. Monitoring warfarin required an average of 4.0 measurements per month and 1.5 dose changes per month. Changes in warfarin doses were primarily precipitated by drugs, intermittent illness, and changes in diet. A subgroup of children (n = 21) were treated with low dose warfarin either alone (n = 14) or following a course of full dose therapy (n = 7) to achieve an INR of 1.3 to 1.8. These children had persisting predisposing causes for new or recurrent thromboembolism. After the age of 1, the average dose required was 0.08 ± 0.01 mg/kg.Complications were rare. Two children had significant bleeding events that resolved without further morbidity. There were no recurrent thrombotic events while children were receiving warfarin. In summary, warfarin therapy is age and weight dependent in children; close monitoring is necessary because of changing requirements; and complications are infrequent when management is coordinated through one service.