3.3.1.1.2 Prothrombin (FII)

Heterozygosity for the 20210A allele of the common FII polymorphism 20210G/A in the untranslated 3 region of the Prothrombin (FII) gene (Poort et al, 1996) is found at a prevalence of 2.7% in the normal Caucasian population (*n* = 11.932, cumulative data from several studies). This mutant correlates with slightly elevated FII levels, suggesting a quantitative contribution to thrombophilia, and is found at a frequency of 7.1% in unselected patients with thombosis (*n* = 2884, cumulative data from several studies). The derived relative risk for thrombosis is 2.6. FII 20210A also seems to play a role in childhood stroke. Published data, however, do not give a clear picture.(Nowak - Gottl et al, 1999; Kenet et al, 2000) At least, FII 201210A does not seem to be involved in re-infarction.(Kurnik et al, 2003).

#### 3.3.1.1.3 Factor V (FV)

The FV mutation Arg506 to Gln506 (R506Q or FV Leiden) causes relative resistance against cleavage by the activated protein C (PC) complex.(Dahlbäck et al, 1993; Bertina et al, 1994) It has been identified as the most common significant genetic risk factor for thrombosis to date. The prevalence in the normal Caucasian population is on the average 5%, with prevalences in particular populations of up to 15%.(Zoller et al, 1996) The relative thrombotic risk for heterozygotes is 6- to 8-fold, whereas homozygotes carry an 80-fold relative risk. (Koster et al, 1993) In children with venous thrombosis, FV Leiden was identified in up to 30%(Aschka et al, 1996) In contrast to adults it may also play a role in childhood stroke. (Nowak - Gottl et al, 1999)

#### 3.3.1.1.4 Factor VIII (FVIII)

Elevated FVIII seems to contribute to the risk of TE in children. Furthermore, persistence of elevated FVIII after TE may also predict an unfavorable prognosis (Goldenberg et al, 2004), see Laboratory parameters.

#### 3.3.1.1.5 Von Willebrand factor

Due to its key position in platelet adhesion and aggregation under conditions of high shear forces, VWF plays a most important hemostatic role in arterial vessels and in the microcirculation.(Ruggeri, 2004) This suggests a significant contribution of VWF to arterial TE and to microangiopathies such as thrombotic thrombocytopenic purpura (TTP). An elevated level of VWF is an independent risk factor for myocardial infarction and stroke in adults.(Vischer, 2006) It has not yet been shown whether elevated VWF also plays a role in arterial thrombosis of childhood. In the neonate, supra large VWF multimers, which are the most active in primary hemostasis, are more abundant than later in life and correlate with a

Venous Thromboembolism in Neonates, Children and

**3.3.1.3 Metabolic conditions** 

3.3.1.3.2 Lipoprotein (a)

against this hypothesis.

**3.3.2.2 Childhood cancer** 

**3.3.2 Acquired prothombotic risk factors** 

measures to prevent catheter occlusion and infection.

**3.3.2.1 Central venous catheters** 

3.3.1.3.1 MTHFR polymorphism 677C/T

(Chauhan et al, 2006) which may be of future therapeutic interest.

Patients with Chronic Renal Disease – Special Considerations 55

been observed, however, their long-term prognosis is not clear. In addition to the obvious causative role of severe ADAMTS13 deficiency in TTP, the impact of milder ADAMTS13 deficiency as thrombophilic factor has not been assessed yet, but is subject of ongoing studies. ADAMTS13 has been identified as a potent antithrombotic in an animal model,

The rare condition of classical homocystinuria is most often caused by a deficiency of either cystathionine-ß-synthetase or 5-methyltetrahydrofolate-homocysteine-methyltransferase and correlates with frequent TE due to severe homocysteinemia causing endothelial cell damage. The activity of 5-methyl tetrahydrofolate-homocysteine-methyltransferase in turn depends on the availability of 5-methyl-tetrahydrofolate, regulated by 5, 10-methyl tetrahydrofolate-reductase (MTHFR). A common thermolabile MTHFR-variant (MTHFR, 677C>T) correlates with a slightly elevated level of homocysteine. Although repeatedly claimed in many studies, this variant does not seem to be an independent risk factor for TE.

Lipoprotein (a) is considered a significant venous and arterial risk factor for TE in children.(Nowak - Gottl et al, 1999; Nowak - Gottl et al, 1999) However, other reports could not confirm these findings.(Revel - Vilk et al, 2003) Levels of Lp(a), though genetically determined, vary considerably among different populations. Lp(a) has structural homology to plasminogen, suggesting a possible competitive mechanism of Lp(a) in fibrinolysis. However, the lack of correlation between severe plasminogen deficiency and TE speaks

CVCs have become critically important as medical and supportive management of various diseases and have greatly improved quality of life. They bear two serious complications: thrombotic occlusion and CVC-associated DVT as well as systemic infections. CVCs seem to be the most important risk factor for DVT. The range of reported CVC-related DVT ranges from 1% to nearly 70%, reflecting the problem of different definitions, diagnostic methods and alertness.(Mitchell et al, 2003; Male et al, 2003) However, the estimated contribution of CVCs to all thromboembolic events in newborns is as high as 90% and over 50% in older children.(Parasuraman & Goldhaber, 2006) There are only a few controlled studies on the prevalence of CVC-related DVT and infection rate as well as the efficacy of antithrombotic

TE is a well known complication in adult patients with cancer. With the exception of acute lymphoblastic leukemia (ALL), the knowledge about TE in childhood cancer is still limited. ALL has the highest rate of TE in childhood that is not necessarily related to the use of a CVC. In contrast, brain tumors have a rather low incidence of thrombosis with or without

CVC.(Tabori et al, 2006) An overall estimation looks at a risk of up to 16%.

very effective platelet dependent function of VWF in newborns.(Rehak et al, 2004) It can be speculated if these large multimers contribute to the higher rate of stroke in the perinatal period, but respective data have not been reported yet. However, it is now clear that supra large VWF multimers are responsible for the life-threatening condition of TTP (Lammle et al, 2005).
