**1. Introduction**

#### **1.1 Venous thromboembolism in neonates**

Among children, the group of critically ill newborns presents the largest of population that suffering from thromboembolism. Making decisions regarding therapeutic strategies a challenge for the intensive care physician as the clinical significance of neonatal thrombosis varies from asymptomatic incidents to life or limb threatening events and, moreover, appropriate evidence-based treatment algorithms are lacking.

This review focuses on the incidence, pathophysiology, risks factors, diagnosis and treatment of venous thromboembolism in neonates

#### **1.2 Incidence**

The incidence of thromboembolic events in the pediatric age group is highest in neonates and infants <1 year of age (Monagle et al., 2008). Much of the published data regarding the epidemiology of neonatal venous thromboembolism (VTE) has come from national registry studies. The Canadian registry (Schmid & Andrew, 1995) reported 97 cases of wich 64 (66%) had venous involvement. The German neonatal registry (Nowak-Gottl et al., 1997) reported 79 cases of symptomatic thrombosis, including stroke. VTE accounted for 76% of cases. The overall incidence of symptomatic events was 0.51 per 10,000 births.

Male and female infants are affected with equal frecuency with the exception of renal vein thrombosis, which has a male predominance for unclear reasons (Chalmers, 2006).

#### **1.3 Pathophysiologic**

We must consider the multiple additive factors that contribute to the development of thromboembolism in neonates. Also, the hemostatic system of neonates is significantly different from that of children and adults (Veldman, 2008).

Venous Thromboembolism in Neonates, Children and

UVCs in situ (Veldman, 2008).

venous line and other medical conditions.

samples for thrombophilia diagnosis are drawn.

(Beardsley, 2007).

**1.5 Diagnosis 1.5.1 Clinical** 

Patients with Chronic Renal Disease – Special Considerations 39

inhibitors. Furthermore, plasma activity of plasminogen activator inhibitor (PAI) is increased in sepsis and levels of protein C are reduced. The latter fact has been reported to correlate with poor outcomes in adults and neonates. Ongoing consumption of coagulation factors and platelets resulting in microcirculatory thrombosis likely contributes to sepsisinduced multi-organ failure and death. Macro-circulatory thrombotic events are rare in this setting but can occur, especially in babies who have arterial umbilical catheters (UACs) or

Turebylu., 2007 reported that congenital thrombophilia not to be associated with UVC thrombosis. Revel-Vilk et al., 2003 reported that in neonates inherited prothrombotic coagulation proteins do not contribute significantly to the pathogenesis of venous TEs; they concluded that the most siginificant aetiological risk factors are the presence of a central

Heller et al., 2000 reported an elevated odds ratio for the presence of congenital thrombophilia in neonates with renal, portal or hepatic venous thrombosis and recommended that neonates with TE should undergo an extensive screening, included resistance to activated protein C ( APC-R), protein C, protein S, antithrombin activity, activities of coagulation factors VIIIC and XII, lipoprotein-A, histidine-rich glycoprotein, heparin cofactor II, antiphospholipid antibodies, lupus anticoagulants, as well as fasting homocysteine concentrations. In addition, DNA-based assays (factor V G1691A mutation or factor V Leiden, factor II G20210A variant and MTHFR C677T genotype) should be considered. Whereas DNA-based mutation analysis can be performed at any time point, protein-based assays should not be carried out in the first 6-8 months after the event and oral anticoagulation is recommended to be discontinued at 14-30 days before plasma

Deficiency of one of the important hemostasis control proteins, protein C, protein S or antithrombin, occurs less frequently, but results in a more potent prothrombotic state. Heterozygous deficiency of these proteins is difficult to diagnose in the newborn period, because the neonatal levels are much lower than the adult reference range. Homozygous deficiency of Protein C or S typically presents in the perinatal period with significant thrombosis resulting in purpura fulminans. Compoud heterozygosity of one of the natural anticoagulants in association with Factor V Leiden may cause a similar clinical picture

Intravascular catheters are responsible for more than 80% of venous thrombotic complications.Signs and symptoms of catheter-related thrombosis vary from diminished blood flow through the cateter to tenderness and swelling of the affected extremity or swelling of the neck and head associated with superior vena cava syndrome. Although clinically apparent

Renal vein thrombosis (RVT) is the most common form of non-catheter-related thrombosis (Nathan et al., 2003). Risk factors for RVT include maternal diabetes, dehydration, infection, asphyxia, polycythemia, prematurity,critical illness, femoral CVL and male gender (chest,913,veldman). Approximately 80% present within the first month and usually within

thrombi occur in less than 5% of neonates with a central line. (Beardsley, 2007).

On the pro-coagulant side, especially the vitamin K-dependent coagulation factors (II, VII, IX, and X) and the components of the contact system (FIX,FXII, prekallkreine and high molecular weight kininogen) show significantly reduced plasma activities in neonates compared to children and adults. However, the vitamin K-dependent inhibitors of coagulation, protein C and protein S, are also reduced, counterbalancing the reduced clotting potential of neonatal plasma. In fact, both antithrombin and protein C concentrantions are decreased to approximately 30% of adults values in term and even lower in preterm newborns. Neonatal platelets have been reported to be hypo-reactive; however, this deficiency seems to be balanced by increased von Willebrand factor activity, resulting in overall normal platelet function (Veldman, 2008).

The activity of the fibrinolityc system in the newborn is reduced compared to adults and older children due to both decreased plasma activity of plasminogen and increased plasma levels of plasminogen activator inhibitor (PAI). The latter fact may explain the high rate of thromboembolic event (TE) associated with intravascular devices in newborns. However, to date there is no evidence that the neonatal hemostatic system either protects from or promotes thrombus formation. Of course, additional risk factors, eg, critical illness or congenital thrombophilia, have to be considered separately from the immaturity of neonatal hemostasis (Veldman, 2008). Given the siginificant differences between the plasma factor concentrations in different age groups, a detailed knowledge on the development of hemostasis is critical for the intensivist in order to adapt pharmacological approaches and interpret results from laboratory tests in the neonate with TE (Ignjatovich et al,. 2006; Ignjatovich et al,. 2007).
