Venous thromboembolism in childhood

There is growing awareness that venous thromboembolism (VTE) occurs in the paediatric age group and it is recognized as a critical paediatric concern 1 . The survival of children from serious underlying primary diseases such as congenital heart disease or malignancy and the use of central venous catheters have significantly contributed to the increased incidence of VTE. Additionally, some prothrombotic disorders are thought to contribute to the presentation.


Introduction
There is growing awareness that venous thromboembolism (VTE) occurs in the paediatric age group and it is recognized as a critical paediatric concern 1 .The survival of children from serious underlying primary diseases such as congenital heart disease or malignancy and the use of central venous catheters have significantly contributed to the increased incidence of VTE.Additionally, some prothrombotic disorders are thought to contribute to the presentation.
There are numerous clinical classifications of VTE.The use of precise description assists in optimizing clinical care 1 .Clinically VTE is described as first episode versus recurrent, symptomatic versus asymptomatic, acute versus chronic and idiopathic versus risk associated disease 1 .Anatomical descriptions include lower extremity versus upper extremity, distal versus proximal, deep versus superficial and peripheral versus central (cerebral and pulmonary) 1 .

Epidemiology
The incidence of VTE varies widely depending on the study design and diagnostic tests used to detect thrombosis.The incidence is remarkably lower in children compared to adults.The National Hospital Discharge survey in the United States of America (USA) (1979-2001) has disclosed an incidence of strokes approximately 4.9 cases per 100,000 children per year 2 .The age distribution of the incidence rate is bimodal with peak rates in the neonatal period and adolescence 1 .The Dutch registry, for instance, has indicated a VTE incidence rate of 14.5 per 100,000 in the neonatal period compared with an overall incidence rate of 1.4 per 100,000 children per year 3 .
Further, the VTE-specific incidence rate in USA among adolescents 15 to 17 years of age was 11 per 100,000 per year, a rate nearly threefold that observed overall in children 2 .In teenage years the incidence was greater in girls, pregnancy and oral contraceptive pills probably contributing to the difference 2 .
In the analysis of the Canadian registry data the documented VTE in upper and lower venous system was 5.3 per 1000 hospital admissions with a mortality of 2.2% 4 .The mortality rate was predominantly due to associated conditions, which were identified in 96% of children; a central (indwelling) venous line was the single most important predisposing factor for VTE, being present in 33% of cases 4 .

Pathophysiology
The pathogenesis of VTE is explained by Virchow triad 1 as shown in figure 1.

Clinical prothrombotic risk factors
Some clinical prothrombotic risk factors  In children, more than 90% of VTE is associated with more than one component of the triad 3,5 e.g.presence of an indwelling catheter in a child with infectious illness and underlying malignancy or catheter in a child with congenital heart disease and corrective surgery.
Indwelling venous catheter is the most significant risk factor for development of VTE.More than 50% of cases of deep vein thrombosis (DVT) in children and more than 80% of cases in neonates occur in association with central venous lines 4,6 .
Inherited and acquired thrombophilic conditions constitute the third component of the Virchow triad 1 .Thrombophilia in children is most often acquired but rarely may be congenital (anticoagulant deficiency) 1 .Thrombophilia is explained by any alteration in the haemostatic balance that increases thrombin production, enhances platelet activation or aggregation, mediates endothelial activation or damage or inhibits fibrinolysis 1 .Increased factor VIII activity with significant infection and inflammatory states, anticoagulant deficiencies resulting from consumption in bacterial sepsis and disseminated intravascular coagulation (DIC) or production of inhibitory antibodies in acute viral infection and parainfectious development of anti phospholipid antibodies are examples of acquired thrombophilia in children 1 .

Clinical Presentation
Clinical suspicion for acute VTE should be high in the following circumstances 1 : 1. Presence of prothrombotic risk factors.

Peripheral and periorbital oedema in older children often with nephrotic syndrome
Signs and symptoms of intracardiac thrombosis 1 1.Catheter -related or post cardiac surgery thrombosis is often asymptomatic. 1Splenomegaly 2. Anaemia 3. Gastrointestinal bleeding due to gastrooesophageal varices.

Surgical care
Thrombectomy is necessary after major cardiac surgery or if thrombolytic agents fail or are contraindicated.Paediatric haematologist, vascular surgeon, and when necessary, neurologist and oncologist should be involved with the paediatrician or neonatologist in providing care.

Diet
Vitamin K directly interferes with effectiveness of warfarin and may increase the risk for re-thrombosis.Ingestion of vitamin K rich green leafy vegetables and maternal intake of vitamin K in breast fed babies should be kept at a minimal level.Vitamin K in parenteral nutrition should be removed.

Activity
Children are given bed rest for the first 24-48 hours to decrease the risk of pulmonary embolism.Children with lower extremity DVT are fitted with compression stockings.

Anticoagulant treatment
Heparin and warfarin are the most commonly used anticoagulants in children 1 .Heparin includes unfractionated heparin (UFH) and low molecular weight heparin (LMWH) 1 .Heparin enhances the activity of antithrombin, an intrinsic anticoagulant protein that serves as a key inhibitor of thrombin 1 .Warfarin acts through antagonism of vitamin K, thereby interfering with gamma-carboxylation of the vitamin K-dependent procoagulant factors II, VII, IX and X and intrinsic anticoagulant proteins C and S 1 .UFH is given intravenously whilst LMWH is given subcutaneously and vitamin K is given orally 1 .LMWH has a decreased risk for the development of thrombocytopenia compared with UFH 1 .UFH has a shorter half-life than LMWH and is preferred in circumstances of heightened bleeding risk or labile acute clinical status 1 .Heparin can be reversed with protamine and warfarin with vitamin K.The lab must be made aware of the type of heparin used so that appropriate assay standard is used.Warfarin therapy is started after therapeutic anticoagulation is achieved with heparin.
Recommended antithrombotic therapy for first and recurrent episodes according to the seventh ACCP guidelines 8 is shown in table 2 Anti thrombotic therapy with anticoagulants has been used for many years but thrombolytic therapy is now gaining recognition especially in children with significant PE or extensive limb-threatening VTE 1 .These drugs promote fibrinolysis whereas anticoagulants attenuate hypercoagulability 1 .Tissuetype plasminogen activator is administered as a recombinant agent by different routes (e.g.systemic bolus, short-duration infusion, low-dose continuous infusion, local catheter-directed infusion with or without mechanical thrombectomy) 1 .Thrombolysis regimen followed by standard anticoagulation may reduce the risk for post thrombotic syndrome substantially compared with standard anticoagulation alone 9 .
Other antithrombotic agents include factor Xa inhibitors and thrombin inhibitors 1 .Hirudin is a direct thrombin inhibitor 1 .Protein C concentrate is still undergoing clinical trials.It may be useful in the treatment of purpura fulminans resulting from microvascular thrombosis in children with sepsis especially meningococcaemia 10 .Antithrombin replacement combined with daily prophylactic LMWH during induction and consolidation phases of therapy in acute lymphoblastic leukaemia (ALL) has a potential benefit for VTE risk reduction 11 .Antithrombin also has a role to play in nephrotic syndrome associated VTE (antithrombin deficiency prevents achievement of therapeutic anti-Xa levels i.e. heparin resistance) and in neonates with clinical conditions when antithrombin consumption is high 1 .
The use of vena caval filters should be considered in children of appropriate size in whom recurrent VTE (especially PE) occurs on therapeutic anticoagulation in the presence of a persistent prothrombotic risk factor 1 .In addition, temporary vena caval filters may be considered during times of especially heightened risk of PE 1 .With regard to long-standing vena caval filters, the impact of such non-retrievable devices on the vena cava of developing children has not been studied 1 .Children seem to have a lower risk for recurrent thromboembolism than adults 1 .The risk for PTS in children who have DVT of the limbs, however, is as great as that in adults 1 .VTE specific mortality in children is low, ranging from 0% to 2% 13 .A considerably higher all-cause mortality reflects the severity of underlying conditions (e.g.sepsis, cancer and congenital cardiac disease) in paediatric VTE 1 .Neonate-specific outcomes data in paediatric non-RVT VTE reflect an all-cause mortality of 12% to 18% 14 .

Short term adverse outcomes of VTE
Outcomes of VTE in children differ with the anatomic site involved.In a Canadian study of CRT in children 15 , VTE-specific mortality was 4% among all children and 20% among those children in whom CRT was complicated by PE 15 .
Persistence of thrombosis after anticoagulation is recognised.This is associated with venous valvular insufficiency but does not increase the risk of recurrent VTE or PE 16 .The prevalence of residual thrombosis despite adequate anticoagulation in neonatal VTE has ranged from 12% in a small series of premature newborns who had CRT 17 to 62% in full-term neonatal VTE survivors 4 .
Prediction of long term outcome of VTE during acute phase helps in planning out the antithrombotic management 1 .
APA syndrome, homozygous anticoagulant deficiencies and presence of multiple thrombophilia traits are associated with recurrent VTE 18 .The radiologic finding of complete veno-occlusion at diagnosis of DVT is associated with an increased risk for persistent thrombosis 19 .Plasma factor VIII activity greater than 150 U/dl and D-dimer concentration greater than 500 ng/ml at the time of diagnosis of VTE in children and after 3-6 months of standard anticoagulation are shown to predict a composite adverse thrombotic outcome, characterized by persistent thrombosis, recurrent VTE or the development of PTS 20 .
VTE has become an important and critical problem in the paediatric age group.Paediatric recommendations are mainly derived from adult trials and therefore need further evaluation by studies undertaken in children.