Higher Concentrations of Heparin and Hirudin Are Required to Inhibit Thrombin Generation in Tissue Factor–Activated Cord Plasma Than in Adult Plasma

Abstract

Neonatal plasma clots slower than adult plasma, and only 30 -50% of peak adult thrombin activity can be produced in neonatal plasma when high amounts of tissue factor (TF) are added to trigger clotting, as used in standard clotting assays. Plasma activation by addition of low amounts of TF probably better reflects conditions in vivo. Under these conditions, cord plasma clots faster than adult plasma. In the present study, we show that after activation with low amounts of TF, higher amounts of the anticoagulants heparin and hirudin are required in cord plasma for effective inhibition of thrombin generation compared with adult plasma. After strong activation with high amounts of TF (30 M), the thrombin potential was significantly more suppressed in cord plasma compared with adult plasma in the presence of 0.4 IE/mL heparin (Ϫ92 versus Ϫ75%; p Ͻ 0.01) and in the presence of 2 IE/mL hirudin (Ϫ18 versus Ϫ8%; p Ͻ 0.01). In contrast, after weak activation with low amounts of TF (30 pM), the thrombin potential was significantly more suppressed in adult plasma compared with neonatal plasma in the presence of 0.025 IE/mL heparin (Ϫ93 versus Ϫ8%; p Ͻ 0.01) and in the presence of 2 IE/mL hirudin (Ϫ89 versus Ϫ48%; p Ͻ 0.01). Our results show that in neonates, effects of anticoagulants very much depend on the type of activation used to initiate clotting, and doses of anticoagulants should not be derived from studies done in adults, because potentially higher doses of anticoagulants may be required. The hemostatic system of neonates is different from that of children and adults. Neonates have lower levels of most procoagulant factors, especially prothrombin, other factors of the prothrombin complex (VII, IX, and X), and contact factors. This is reflected in prolonged prothrombin time and activated partial thromboplastin time. Physiologic low levels of anticoagulant proteins in neonatal plasma might compensate for low levels of coagulation factors and allow sufficient thrombin generation. In neonatal plasma, antithrombin (AT) is reduced to~50% of adult values (1). These physiologic low AT levels result in an impaired ability of neonatal plasma to inhibit thrombin compared with adult plasma (2).It has been suggested that decreased concentrations of heparinoids are required to inhibit thrombin generation in cord plasma to the same extent as in adults as a result of reduced neonatal thrombin potential (TP) (3). The thrombin generation curve, i.e. the course of appearance and disappearance of thrombin in triggered plasma, gives information on the process of blood coagulation that is difficult to obtain otherwise. The TP is the area under the thrombin generation curve and has been shown to be a valid parameter for detection of possible hypo-or hypercoagulable states (4 -6). However, thrombin generation is delayed only in cord plasma compared with adults after addition of high amounts of activator, as is usually done in the conventional clotting assays activated partial thromboplastin time or prothrombin time. Strong activators were ...

An evaluation of the procoagulant action of recombinant activated factor VII in cord whole blood versus adult whole blood using thromboelastography

“…These findings are in agreement with our recent study revealing that higher amounts of heparin and hirudin are required in cord plasma than in adult plasma to suppress thrombin generation to the same extent, an effect attributable to the low thrombin inhibiting capacity of cord plasma [25].…”

Thrombin generation before and after multicomponent blood collection

“…Using CAT, we could also explain why hemophilic neonates have better hemostasis than in later life 19 . CAT has also been applied in hypocoagulable states such as the control of heparin therapy, to detect the influence of various ACs including direct thrombin inhibitors, and to monitor hemophilia treatment 12,20‐27 …”

Pilot dose‐finding and safety study of bivalirudin in infants <6 months of age with thrombosis

“…The inter‐ and intra‐individual variability of heparin pharmacokinetics has been well described in both adults [4] and children [5]. This problem is compounded in young children (especially below the age of 6 months) because of the reduced concentration of antithrombin as compared to adults, leading to relative heparin resistance [6]. Furthermore, the concentration of antithrombin changes rapidly in the first 6 months of life, making the adequate control of heparin more difficult [7].…”