Thrombin activatable fibrinolysis inhibitor activation and bleeding in haemophilia A

Abstract

Individuals with haemophilia A exhibit bleeding tendencies that are not always predicted by their factor (f)VIII level. It has been suggested that bleeding in haemophilia is due not only to defective prothrombin activation but also aberrant fibrinolysis. Thrombin activatable fibrinolysis inhibitor (TAFI) activation was measured in tissue factor (Tf)-initiated blood coagulation in blood samples of 28 haemophiliacs and 5 controls. Reactions were quenched over time with FPRck and citrate and assayed for TAFIa and thrombin-antithrombin (TAT). The TAFIa potential (TP), TAFI activation rate and the TAFIa level at 20 minutes (TAFIa20min) was extracted from the TAFI activation progress curve. In general, the time course of TAFI activation follows thrombin generation regardless of fVIII activity and as expected the rate of TAFI activation and TP decreases as fVIII decreases. The magnitude of TP was similar among the control subjects and subjects with < 11% fVIII. In severe subjects with < 1% fVIII at the time of blood collection, the TAFIa20min was inversely and significantly correlated with hemarthrosis (-0.77, p=0.03) and total bleeds (-0.75, p=0.03). In all cases, TAFIa20min was more strongly correlated with bleeding than TAT levels at 20 minutes. Overall, this study shows that TAFI activation in whole blood can be quantified and related to the clinical bleeding phenotype. Measuring TAFIa along with thrombin generation can potentially be useful to evaluate the differential bleeding phenotype in haemophilia A.

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

“…Thus, a prolonged deficiency of TAFI, but not of FVIII, was required for the development of vascular abnormalities after joint injury. An indirect mechanism downstream of FVIII deficiency causing vascular abnormalities after joint injury is consistent with the notion that TAFI activation is defective in hemophilia plasma in vitro (25,27) and during hemophilic joint bleeding in vivo (28). Moreover, in vitro data show that activation of TAFI in hemophilia plasma is adequately restored by increasing TAFI zymogen levels due to TAFI's high Km value for activation by thrombin (25).…”

“…One important protein, potentially affecting vascular remodeling in the hemophilic joint, is thrombin-activatable fibrinolysis inhibitor (TAFI, also known as procarboxypeptidase U or plasma procarboxypeptidase B, gene CPB2). TAFI is a circulating proenzyme activated by thrombin or the thrombin-thrombomodulin complex (23,24), and the activation of TAFI is particularly impaired in hemophilia, as shown in hemophilia plasma in vitro (25)(26)(27) and in FVIII-gene deficient (FVIII-KO) mice after joint injury in vivo (28). Activated TAFI (TAFIa) is a basic carboxypeptidase that removes C-terminal Lys or Arg from specific proteins and peptides, resulting generally in their attenuated bioactivity (29,30).…”

Alternative Mechanism of Aspirin in Anti-Thrombotic Therapy: Inhibition of Thrombin Activatable Fibrinolysis Inhibitor

“…28 Alterations of fibrinolysis in hemophilia have recently been associated with enhanced plasmin-induced TAFI activation. [29][30][31][32] Inhibition of the carboxypeptidase activity of TAFI has been shown to modulate fibrinolysis in vivo and alter hemostatic balance toward a profibrinolytic state.…”

Global assays of fibrinolysis

“…For instance, fibrinolysis impairment in hemophilia is partially related to reduced TAFIa generation due to decreased thrombin generation. 4,5 In the paper byRuitenbeek et al, (hyper)fibrinolysis during the reperfusion stage of liver transplantation has also been shown to be linked to TAFI activity by Dr. Lisman and his colleagues. 6 In addition, the assay was able to detect a fibrinolytic defect in the case of one orphan diseaseα 2 -antiplasmin deficiency.…”

“…For instance, fibrinolysis impairment in hemophilia is partially related to reduced TAFIa generation due to decreased thrombin generation. 4,5 In the paper by…”