Overall haemostatic potential can be used for estimation of thrombin‐activatable fibrinolysis inhibitor‐dependent fibrinolysis in vivo and for possible follow‐up of recombinant factor VIIa treatment in patients with inhibitors to factor VIII

Abstract

Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with haemophilia and/or inhibitors to factor VIII/IX could enhance generation of thrombin-activatable fibrinolysis inhibitor (TAFI), a recently described link between coagulation and fibrinolysis. TAFI is unstable and it is not easy to measure its active form in vivo. Overall haemostatic potential (OHP) is a novel method for haemostasis estimation, based on determination of the fibrin aggregation curve in which tiny amounts of thrombin are used for activation of clotting. We measured OHP in six patients with inhibitors to factor VIII before injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential (OFP) and clot lysis time (CLT) analysed by this method could be used for indirect estimation of TAFI generation. We found no change in pro-TAFI and total TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable before treatment but increased into the range of normal pooled plasma 10 and 120 min after rFVIIa treatment, as did CLT. However, after addition of potato tuber carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT was lower than that in NPP. OFP was increased in patient plasma both 10 and 120 min after treatment compared with NPP. There was a strong positive correlation between pro-TAFI concentration and shortening of CLT after PTCI addition and a negative correlation between pro-TAFI concentration and OFP 10 min after rFVIIa injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this improvement slightly decreases, but still exists after 2 hours, it suggests efficacy in bleeding prevention using a protocol based on rFVIIa administration every 2 hours.

High dose factor VIIa improves clot structure and stability in a model of haemophilia B

“…Lisman et al (2002) demonstrated that the low thrombin concentrations produced during haemophilic clot formation are insufficient for the formation of activated TAFI, and that this is the primary mechanism for the increased susceptibility to fibrinolysis and bleeding diathesis. Others have observed only a moderate effect of TAFI on the overall haemostatic potential of haemophilic plasma treated with rFVIIa (Antovic et al , 2002); while, our data suggest only a minor or no effect of TAFI. It is difficult to compare our results with these studies because of significant differences in the assay conditions used.…”

Potential role of the dynamic properties of whole blood coagulation in assessment of dosage requirements in haemophilia

“…Methods have been established that report on the entire coagulation process, the majority of which takes place during several minutes after the timepoint when the APTT was registered. By means of systems that record the continued generation of thrombin in plasma, as devised by Hemker et al [4] or by measuring the formation of fibrin aggregates [5] that occur in consequence of thrombin activity, an overall picture of the coagulation process can be studied in detail. In principle, most of the never developments have been known for several decades, but new technologies have simplified their use.…”

Thrombin activatable fibrinolysis inhibitor and its relationship to fibrinolysis and inflammation during the acute and convalescent phase of ischemic stroke

“…The method, which is more thoroughly described in Materials and methods, is a promising, inexpensive and easy-to-perform tool for the estimation of overall hemostasis. It has been shown to be sensitive for the detection of both hypocoagulable and hypercoagulable states [25][26][27][28] as well as for monitoring of anticoagulant treatment [29].…”