3.3.1.2.1 Protein C system

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 central role in the regulation of thrombus formation.

#### 3.3.1.2.2 Antithrombin

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 with a penetrance higher than in PC and PS deficiency.

#### 3.3.1.2.3 ADAMTS13

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

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