Thrombin activatable fibrinolysis inhibitor (TAFI) in different hemorrhagic and thrombotic conditions

Abstract

Until recently the coagulation and fibrinolytic systems were usually considered as separate entities. Accounts of a fibrinolysis inhibitor that is generated by thrombin shed more light on this field and changed the concept by giving thrombin, the pivotal enzyme in hemostasis, another important role in the down-regulation of fibrinolysis. Thrombin Activatable Fibrinolysis Inhibitor (TAFI), also known as procarboxypeptidase B and procarboxypeptidase U, is a relatively recently described inhibitor of fibrinolysis that can be converted into its activated form which is a carboxypeptidase B- like enzyme, by the thrombin/thrombomodulin complex.

In this study, the precursor of TAFI is denominated proTAFI (instead of TAFI or procarboxypeptidase U). Since this "inhibitor" of fibrinolysis is functional only in its active form, we reserve the term TAFI for the active form of the enzyme and suggest the term TAFli for the inactive form. Although the role of TAFI in pathology is not completely known, it is reasonable to expect that the level of TAFI is altered in various thrombotic and hemorrhagic diseases.

Objective: The aim of the study is to investigate possible changes in different forms of TAFI and their influence on fibrinolysis in different clinical conditions associated with hypocoagulable states and decreased thrombin generation (e.g. hemophilia A and von Willebrand disease (VWD) as well as in hypercoagulable states such as APC resistance and conditions associated with complicated pregnancy and diabetes mellitus.

Methods: Different forms of TAR were determined in patients with APC resistance due to FV Leiden mutation, in patients with hemophilia A and VWD, in patients with diabetes mellitus type I and in women with preeclampsia. Data were obtained on total thrombin activatable fibrinolysis inhibitor antigen (including pro-TAFI, its active form TAFI and its inactive form TAFIi), pro-TAFI activity, TAFl/TAFIi antigen, overall hemostatic potential (OHP) and overall fibrinolytic potential (OFP) in plasma, and clot lysis time (CLT) derived from this test. OHP and TAFI-dependent fibrinolysis were also determined in vitro in variously deficient plasmas after addition of different concentrations of rVIIa (NovoSeven).

Results: A decrease in pro-TAFI, accompanied by no change in total TAFI antigen, was found in APC resistant patients. A significant decrease in TAFI antigen and impaired fibrinolysis that was not TAFI dependent were observed in women with preeclampsia compared to those with a normal pregnancy. Pro-TAFI levels did not differ between diabetic patients with or without microvascular complications and controls. TAFI antigen was lower (though not significantly so) in both groups of diabetic patients, while OHP was increased (significantly in the group with microvascular complications). Neither fibrinolysis itself nor TAFI-dependent fibrinolysis differed between the two groups of diabetic patients compared to controls. Pro-TAFI was decreased in hemophilia A, hemophilia B and VWD patients, together with no changes in total TAFI antigen. An increase in TAFI/TAFIi antigen was found in both hemophilia and VWD patients compared to controls. rFVIIa in a concentration of 2.4µg/mL improved the overall hemostasis in FV, FVIII and FIX deficient plasmas. Not even very high concentrations of rFVIIa (9.6µg/mL) induced hypercoagulation in deficient plasmas or in normal pooled plasma (NPP). It seems that flbrinolysis is also regulated by factors other than TAFI but higher concentrations of rVIIa do, at least partly, induce (most probably through increased thrombin generation) a TAFI-dependent down-regulation of fibrinolysis in FVIII and FIX deficient plasmas.

Conclusions: TAFI contributes to an impairment of fibrinolysis in patients with APC resistance. TAFI does not induce a further down-regulation of initially impaired fibrinolysis in preeclampsia, most probably because it is reduced as a result of renal and hepatic disturbances. In patients with type I diabetes mellitus and microvascular complications, TAFI does not induce an impairment of fibrinolysis despite the presence of increased overall coagulation and hemostasis. The transformation of pro-TAFI into TAFI and TAFIi in hemophilia and VWD is most probably induced by plasmin and could partly counterbalance the up-regulation of fibrinolysis in these conditions. rVIIa improves overall hemostasis and fibrinolysis in hemophilia patients and in FVIII and FIX deficient plasma, but the improved down-regulation in overall fibrinolysis is only partly TAFI-dependent. The OHP assay seems to be a handy and inexpensive tool not only for the determination of overall hemostasis, coagulation and fibrinolysis but also for indirect estimation of TAFI-dependent fibrinolysis. TAFI obviously has a role as a link between coagulation and fibrinolysis but since it is activated by both thrombin and plasmin and is also inactivated by plasmin, both enzymes could regulate TAFIs role and influence the TAFI-dependent regulation of fibrinolysis. The definitive role of TAFI therefore remains to be proven.