Thrombin generation in factor VIII‐depleted neonatal plasma: nearly normal because of physiologically low antithrombin and tissue factor pathway inhibitor

Abstract

Our observation provides a biochemical basis for the rare bleeding in hemophilic neonates and shows the important role of the natural inhibitors in the hemostatic system of hemophilic patients.

Normal thrombin generation in neonates in spite of prolonged conventional coagulation tests

“…Recently, investigation of plasmas from neonates with TG assays that are also capable of exploring the anticoagulant systems have contributed to develop the concept that in the neonates the coagulation balance may be restored by the concomitant deficiencies of pro-and anti-coagulants. [15][16][17][18] These studies had some limits. First, TG was measured by methods that employed the sub-sampling technique where plasma was defibrinated before assay or fibrin formation was inhibited by addition of exogenous agents; [15][16][17] these methods are cumbersome and may be subjected to artifacts.…”

“…First, TG was measured by methods that employed the sub-sampling technique where plasma was defibrinated before assay or fibrin formation was inhibited by addition of exogenous agents; [15][16][17] these methods are cumbersome and may be subjected to artifacts. Second, these studies examined plasmas pooled from many neonates instead of single donations; [15][16][17][18] in this material the variable deficiency of one or more pro-or anti-coagulants in individual plasmas might be compensated.This means that experimental conditions may not be exactly comparable to a population of individual neonates. Third, pooled plasmas were manipulated by increasing or decreasing the anticoagulant factors.…”

Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency

“…While the evidence that naturally occurring low TFPI levels could ameliorate the clinical course of patients with severe hemophilia is rather scanty, 47 newborns with hemophilia tend to be protected from bleeding by their low TFPI levels. 48 Moreover, TFPI inhibitors known as nonanticoagulant sulfated polysaccharides (NASPs) have been reported to effectively improve hemostasis in animal models of hemophilia A and B. 49,50 In conclusion, we have shown that congenital FV deficiency is associated with reduced plasma levels of free/full-length TFPI.…”

Caution in the interpretation of continuous thrombin generation assays

“…During the propagation phase of thrombin generation, when large amounts of thrombin are produced at a high rate, an exogenous thrombin substrate will interfere with thrombin inhibition by the natural inhibitors present in plasma, leading to elevated values for total thrombin as well as to higher peak thrombin concentrations. Figure 1 represents TF-initiated thrombin generation in a synthetic coagulation proteome in the absence and in the presence of 416 lM synthetic thrombin substrate Z-Gly-GlyArg-aminomethylcoumarine [1]. In a reaction initiated with 5 pM TF in the presence of 4 lM phospholipid, the addition of substrate prolongs the initiation phase from 120 s to 340 s and the time to thrombin peak from 240 to 480 s. The peak thrombin concentration increases from 330 nM in the absence of substrate to 430 nM in its presence and total thrombin generated is doubled (1210 and 2370 nM min )1 , respectively).…”