**3.3.1.3 Metabolic conditions**

Pathophysiology and Clinical Aspects of 54 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

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,

The hemostatic process is tightly regulated by specific inhibitors that act on coagulation factors and on the factors of primary hemostasis. Functionally most important are tissue factor pathway inhibitor, the PC system, antithrombin (AT) and the VWF cleaving protease ADAMTS13. Clinically, to date only the latter three are important. Involvement of the coagulation inhibitors AT, PC and Protein S (PS) is rare with a prevalence in unselected patients with thrombosis of 0.019 for AT, 0.037 for PC, and 0.023 for PS deficiency.(Pabinger & Schneider, 1996; Koster et al, 1995) Recently, severe deficiency of ADAMTS13 has been identified as the causative factor of the rare TTP in most TTP patients (Lammle et al, 2005).

The PC system comprises PC, PS and FV as co-factors. PC is activated to APC by thrombin, which changes its substrate specificity from FI to PC by being bound to thrombomodulin at the endothelial cell surface. APC cleaves and inactivates aFV and aFVIII at specific proteolytic sites, thereby regulating the formation of thrombin. Severe PC deficiency as well as severe PS deficiency correlates with purpura fulminans, a life-threatening thromboembolic disorder of the microcirculation and larger vessels. Heterozygous deficiency of either inhibitor correlates with venous TE. PC also binds plasminogen activator inhibitor 1 (PAI1) which then facilitates fibrinolysis. This dual function of PC suggests a

When bound to heparan sulfate on endothelial cells, AT inhibits thrombin but also aFXI, aFIX and aFX. Its action on thrombin is enhanced 1000-fold by heparin through an allosteric conformational change. In contrast, low-molecular-weight heparin makes AT more aFX specific. These effects are the basis for prophylactic or therapeutic anticoagulation by heparin. Even mild hereditary deficiency of AT function may correlate with thrombophilia

ADAMTS13 regulates the size of VWF multimers and thereby its functional activity in primary hemostasis. Its deficiency has clearly been assessed as playing the causative role in TTP.(Lammle et al, 2005) An acquired form, caused by autoantibodies against ADAMTS13, and an inherited form called Upshaw Schulman syndrome (USS) due to mutations in the gene, exist. Lack of the protease correlates with persistence of supra large VWF multimers and, on an adequate trigger (infection, stress, hypoxia), these large multimers will induce platelet adhesion and aggregation in the microcirculation with subsequent microangiopathy, finally resulting in organ failure and death in 80% of cases when untreated. Thrombosis of larger venous and arterial vessels has also been observed. In childhood, TTP is rare and seems more often inherited.(Schneppenhim et al, 2004) Oligo-symptomatic courses have

2005).

**3.3.1.2 Inhibitors of hemostasis** 

3.3.1.2.1 Protein C system

3.3.1.2.2 Antithrombin

3.3.1.2.3 ADAMTS13

central role in the regulation of thrombus formation.

with a penetrance higher than in PC and PS deficiency.
