**3.2.1 Clinical presentation**

Pain, swelling and discoloration of extremities are acute symptoms of deep vein thrombosis (DVT). Vena cava inferior thrombosis manifests with prominent cutaneous veins and possibly liver or renal dysfunction depending on the site and extension of the thrombus. Superior vena cava thrombosis leads to cyanosis and swelling of the head and upper thorax with prominent collateral veins and may finally result in acute cardiac failure. Portal vein thrombosis, in most cases due to central catheters, and renal vein thrombosis with hematuria as a frequent sign may result in functional impairment or even failure of liver and renal function, respectively. Acute chest pain and dyspnea could suggest pulmonary embolism. Acute headache, visual impairment, cerebral convulsions and signs of venous congestion may indicate sinus venous thrombosis. Signs and symptoms of central venous catheter (CVC)-associated DVT are loss of CVC patency, the need for local thrombolytic therapy or CVC replacement, CVC-related sepsis, or prominent collateral circulation over chest, neck and head.

Childhood arterial ischemic stroke (AIS) manifests in neonates preferentially with seizures and abnormalities of muscle tone, whereas in elder children hemiparesis is the most frequent neurologic sign.(Steinlin et al, 2005) Acquired or inherited severe deficiencies of protein S and protein C are disorders involving both the microcirculation and arterial vessels and may manifest with characteristic symptoms such as deep skin necrosis (purpura fulminans), blindness due to retinal vessel occlusion and arterial embolism followed by necrosis of distal extremities or whole limbs. Thrombotic thrombocytopenic purpura (TTP), a severe microangiopathic disorder is characterized by nonimmunologic hemolytic anemia and thrombocytopenia, neurologic symptoms, and renal, pulmonary and cardial involvement.

#### **3.2.2 Laboratory parameters**

Every thrombotic event initiates a particular response to re-establish the balance of the hemostatic system, e.g., by fibrinolysis. Subsequently markers of fibrinolysis such as D-

Venous Thromboembolism in Neonates, Children and

defects also cause thrombophilia.

**3.3.1.1 Coagulation factors**  3.3.1.1.1 Fibrinogen (FI)

thrombophilia are rare. 3.3.1.1.2 Prothrombin (FII)

3.3.1.1.3 Factor V (FV)

3.3.1.1.4 Factor VIII (FVIII)

see Laboratory parameters.

3.3.1.1.5 Von Willebrand factor

childhood stroke. (Nowak - Gottl et al, 1999)

Patients with Chronic Renal Disease – Special Considerations 53

genetic defects of fibrinolysis also contribute to the hypercoagulable state. Certain metabolic

In addition to being the final substrate for thrombin, FI is also an acute-phase protein that may lead to acquired thrombophilia and may also contribute to the risk of arterial TE.(Rothwel et al, 2004) Genetic defects causing dysfibrinogenemia associated with

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).

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

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),

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

dimers can be detected in the circulation. The specificity of these markers is low; however, the negative predictive value of the D-dimer test to correctly exclude DVT is as high as 89% in adult patients with likely DVT compared to 99% in patients who were categorized as unlikely to have DVT.(Wells et al, 2003) In a study on the outcome of TE in children, elevated D-dimer and/or FVIII:C were found in only 67% of the patients; however, elevation of these markers at diagnosis and during follow-up are significantly correlated with persistence or recurrence of TE and/or a post-thrombotic syndrome. (Goldenberg et al, 2004)
