**1.4 Risk factors**

Neonatal VTE is frecuently associated with presence of significant underlying risk factors. As in older children central venous lines (CVLs) are the single most important contributing factor. Excluding cases of renal vein thrombosis (RVT), CVLs-related thrombosis accounted for 89% and 94% of VTE in the Canadian and Dutch registries, respectively (Schmidt and Andrew, 1995; van Ommen et al., 2001). These events involve the large vessels most frequently used for catheterization including the umbilical vein. Neonatal VTE related to the use of the umbilical venous catheter (UVC) has been the subject of studies involving sequential imaging. Using venography, Roy et al.,1997 documented UVC-associated thrombosis in 14 of 48 neonates (29%). As in older children, many of these events were asymptomatic and the incidence of thrombosis was highly dependent on the imaging modality used (Chalmers, 2006).

Critical illness is a well-recognized risk factor for TE in all age groups. Inmobilization, rapid changes in intravascular volume and extensive intravascular instrumentation contribute to the enhanced risk of venous and arterial thrombosis in patients in intensive care units. (Veldman, 2008). Additional risk factors include, but are not limited to, asphyxia, maternal diabetes, poor cardiac output and dehydration. Neonates are born with a high hematocrit and tend to contract their intravascular volume within the first days of life, making them even more prone to thromboembolic events (Veldman, 2008).

In the neonatal population, sepsis is particularly devastating, as it causes 45% of late deaths in the neonatal intensive care unit (NICU). Neonates with sepsis develop an acquired prothrombotic state due to increased consumption of already limited supplies of coagulation Pathophysiology and Clinical Aspects of 38 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

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,

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;

Neonatal VTE is frecuently associated with presence of significant underlying risk factors. As in older children central venous lines (CVLs) are the single most important contributing factor. Excluding cases of renal vein thrombosis (RVT), CVLs-related thrombosis accounted for 89% and 94% of VTE in the Canadian and Dutch registries, respectively (Schmidt and Andrew, 1995; van Ommen et al., 2001). These events involve the large vessels most frequently used for catheterization including the umbilical vein. Neonatal VTE related to the use of the umbilical venous catheter (UVC) has been the subject of studies involving sequential imaging. Using venography, Roy et al.,1997 documented UVC-associated thrombosis in 14 of 48 neonates (29%). As in older children, many of these events were asymptomatic and the incidence of thrombosis was highly dependent on the imaging

Critical illness is a well-recognized risk factor for TE in all age groups. Inmobilization, rapid changes in intravascular volume and extensive intravascular instrumentation contribute to the enhanced risk of venous and arterial thrombosis in patients in intensive care units. (Veldman, 2008). Additional risk factors include, but are not limited to, asphyxia, maternal diabetes, poor cardiac output and dehydration. Neonates are born with a high hematocrit and tend to contract their intravascular volume within the first days of life, making them

In the neonatal population, sepsis is particularly devastating, as it causes 45% of late deaths in the neonatal intensive care unit (NICU). Neonates with sepsis develop an acquired prothrombotic state due to increased consumption of already limited supplies of coagulation

resulting in overall normal platelet function (Veldman, 2008).

Ignjatovich et al,. 2007).

modality used (Chalmers, 2006).

even more prone to thromboembolic events (Veldman, 2008).

**1.4 Risk factors** 

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 UVCs in situ (Veldman, 2008).

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 venous line and other medical conditions.

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 samples for thrombophilia diagnosis are drawn.

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 (Beardsley, 2007).
