Inhibition of exogenous thrombin is impaired in neonatal compared to normal adult plasma due to neonatal antithrombin (AT) deficiency. It has been suggested that newborn infants may be resistant to antithrombotic therapy [administration of unfractionated heparin (UH), low molecular weight heparin (LMWH), antithrombin-heparin complex (ATH)] during overt thrombotic disease when the neutralisation of abnormal thrombin activity is the therapeutic goal. The effects of anticoagulant drugs on de-novo thrombin generation in both cord and adult plasma are influenced by the type of plasma activation applied. In the presence of high amounts of initiator, as usual in conventional clotting assays, cord plasma is significantly more susceptible to addition of the anticoagulant drugs UH, LMWH, ATH, and recombinant human activated protein C (rhAPC) than adult plasma due to reduced neonatal thrombin potential. It can be speculated that lower doses of these anticoagulant drugs may be required to prevent de-novo thrombin generation and possibly thrombosis in newborn infants than in older patients. In contrast, in the presence of low amounts of lipidated tissue factor (TF) to trigger clot formation, probably simulating in-vivo conditions more closely than strong activation, cord plasma is significantly less susceptible to addition of rhAPC and possibly of other anticoagulant drugs. It has been shown that the low anticoagulant efficacy of rhAPC is attributable to the low neonatal levels of tissue factor pathway inhibitor (TFPI) and AT, resulting in concomitant low anticoagulant action of TFPI, AT, and rhAPC associated with efficient thrombin generation in neonates. From this point of view, higher doses of anticoagulant drugs may be required to prevent de-novo thrombin generation and possibly thrombosis in newborn infants than in older patients.