A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo (original) (raw)
Related papers
Thrombosis Research, 2010
Factor XII (FXII) is a coagulation protein that is essential for surface-activated blood coagulation tests but whose deficiency is not associated with bleeding. For over forty years, investigators in hemostasis have not considered FXII important because its deficiency is not associated with bleeding. It is because there is a dichotomy between abnormal laboratory assay findings due to FXII deficiency and clinical hemostasis that investigators sought explanations for physiologic hemostasis independent of FXII. FXII is a multidomain protein that contains two fibronectin binding consensual sequences, two epidermal growth factor regions, a kringle region, a proline-rich domain, and a catalytic domain that when proteolyzed turns into a plasma serine protease. Recent investigations with FXII deleted mice that are protected from thrombosis indicate that it contributes to the extent of developing thrombus in the intravascular compartment. These findings suggest that it has a role in thrombus formation without influencing hemostasis. Last, FXII has been newly appreciated to be a growth factor that may influence tissue injury repair and angiogenesis. These combined studies suggest that FXII may become a pharmacologic target to reduce arterial thrombosis risk and promote cell repair after injury, without influencing hemostasis. In 1955, Oscar Ratnoff and Joan Colopy described a patient, 37 year old John Hageman, who was found to have a prolonged Lee-White clotting time that was obtained during routine preoperative screening. The patient had no hemorrhagic symptoms even though he had a remarkably prolonged whole blood and plasma clotting times in glass and silicone-coated glass tubes. The prolonged clotting time was corrected by small amounts of plasma from each of the other known clotting factor deficiencies. Ratnoff concluded that his patient was deficient in an unrecognized clotting factor which he named Hageman factor, later known as Factor XII (FXII) [1]. Further experiments indicated that Hageman factor (FXII) circulates as an inactive precursor (zymogen) that becomes "activated" (FXIIa) as clotting commenced. In 1961, Ratnoff and Davie demonstrated that Factor XI (FXI) was activated by FXIIa, contributing to the presentation of their waterfall cascade hypothesis for the blood coagulation system [2]. These studies encompass the major known properties of Factor XII, a protein that autoactivates upon exposure to negatively charged surfaces to become the enzyme Factor XIIa (α-FXIIa), which then activates FXI, prekallikrein (PK), and C1 esterases (C1r, C1s), the first components of the macromolecular complex of C1 and the classic complement cascade. FXIIa
Factor XI contributes to thrombin generation in the absence of factor XII
Blood, 2009
During surface-initiated blood coagulation in vitro, activated factor XII (fXIIa) converts factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue factor, factor Xa, or α-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of factor IX reduced thrombin generat...
Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates
Blood, 2003
Thrombin, generated through activation of factor XI (FXI) and/or tissue factor (TF)–factor VIIa, is essential for thrombosis and hemostasis. We investigated the role of FXI-dependent thrombus propagation under arterial flow conditions producing rapid thrombus growth that, after the initiation phase, could limit the availability of TF at the blood/thrombus interface. Thrombosis was initiated by knitted dacron or TF-presenting teflon grafts deployed into arteriovenous shunts in baboons treated with antihuman FXI antibody (aFXI). Although aFXI did not prevent thrombus initiation, it markedly reduced intraluminal thrombus growth on both surfaces. The antithrombotic effect of aFXI was comparable with that of heparin at doses that significantly prolonged the partial thromboplastin time (APTT), prothrombin time (PT), and bleeding time (BT). aFXI also prolonged the APTT, but the PT and BT were unaffected. Thus, antithrombotic targeting of FXI might inhibit thrombosis with relatively modest ...
Thrombin Activates Factor XI on Activated Platelets in the Absence of Factor XII
—Thrombin can activate factor XI in the presence of dextran sulfate or sulfatides. However, a physiological cofactor for thrombin activation of factor XI has not been identified. We examined this question in a cell-based, tissue factor–initiated model system. In the absence of factor XII, factor XI enhanced thrombin generation in this model. The effect on thrombin generation was reproduced by 2 to 5 pmol/L factor XIa. A specific inhibitor of factor XIIa did not diminish the effect of factor XI. Thus, factor XI can be activated in a model system that does not contain factor XIIa or nonphysiological cofactors. Preincubation of factor XI with activated platelets and thrombin or factor Xa enhanced subsequent thrombin generation in the model system. Preincubation of factor XI with thrombin or factor Xa, but without platelets, did not enhance thrombin generation, suggesting that these proteases might activate factor XI on platelet surfaces. Thrombin and factor Xa were then directly tested for their ability to activate factor XI. In the presence of dextran sulfate, thrombin or factor Xa activated factor XI. Thrombin, but not factor Xa, also cleaved detectable amounts of factor XI in the presence of activated platelets. Thus, thrombin activates enough factor XI to enhance subsequent thrombin generation in a model system. Platelet surfaces might provide the site for thrombin activation of functionally significant amounts of factor XI in vivo. (Arterioscler Thromb Vasc Biol. 1999;19:170-177.) Key Words: factor XIa factor XIIa factor IXa human blood coagulation contact system C oagulation factor XI circulates as a homodimer consisting of 2 identical disulfide-linked polypeptide chains (M r 80 000 each). 1 The zymogen protein is activated by a single cleavage of each polypeptide chain to give rise to the activated form (factor XIa). 2 Factor XIa activates zymogen factor IX to factor IXa. 3–5 Unlike classic hemophilia A or B (factor VIII or factor IX deficiency), one cannot predict whether patients with factor XI deficiency will exhibit a bleeding diathesis based on their level of factor XI activity alone. Some patients who are homozygous for factor XI deficiency show a severe bleeding tendency while others are asymptomatic. 6,7 Although the bleeding tendency of patients who are heterozygous for factor XI is controversial, 1 recent study showed that up to half of these patients have a bleeding tendency. 8 Attempts have been made to correlate bleeding in factor XI– deficient patients with low levels of von Wille-brand factor, 8 blood group, 8 and lack of an alternatively spliced form of platelet factor XI. 9,10 Activated factor XII can activate factor XI both in plasma 11,12 and on activated platelets. 13,14 However, deficiency of factor XII is not associated with a bleeding tendency. 15 This led investigators to propose an alternate mechanism for activation of factor XI based on the observation that thrombin can activate factor XI in a purified system 16,17 or in plasma. 18,19 It remains unclear whether or not thrombin is a physiologically relevant activator of factor XI. In most studies, factor XI activation by thrombin has required the presence of dextran sulfate (DS) or nonphysiological concentrations of sulfatide cofactors. It has also been suggested that high-molecular-weight kininogen, which strongly associates with factor XI, and fibrinogen, which is the preferred sub-strate for thrombin, would block thrombin activation of factor XI in plasma. 20 Another study showed that factor XI was not activated by thrombin in plasma in the presence of kaolin. 12 However, 1 group suggested that thrombin activation of minute amounts of factor XI in plasma protected fibrin clots from fibrinolysis, presumably by increasing the amount of thrombin generated within the clot. 21 If thrombin is a physiological activator of factor XI, it is not known what the in vivo cofactor for this activity might be. It has been hypothesized that endogenous glycosaminogly-cans 22 or platelets 23 might promote activation of factor XI by thrombin in vivo. One study found that a physiological glycosaminoglycan, heparan sulfate, could support activation of factor XI in plasma, but only when unphysiologically high levels of thrombin were added. 19 Platelets can bind factor XI and provide a site for activation of factor IX by factor XIa. 5 We hypothesized that platelets could serve as a cofactor for activation of small but physiologically important amounts of factor XI by thrombin. We have tested this hypothesis by using a defined, tissue factor–initiated, cell-based model of coagulation to examine factor XI activation by mechanisms
The Journal of pharmacology and experimental therapeutics, 2016
Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa needed for efficacy, and impact of FXIIa inhibition on cerebral embolism. A selective FXIIa inhibitor, recombinant human albumin-tagged mutant Infestin4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin4 (rHA-WT-inf) (human FXIIa KI = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against FXa and plasmin. rHA-Mut-inf binds FXIIa, but not FXII zymogen, and competitively inhibits FXIIa protease activity. Its mode of action is hence akin to typical small molecule inhibitors. Plasma shift and aPTT studies with rHA-Mut-inf demonstrated that calculated enzyme occupancy for FXIIa in achieving a putative aPTT doubling target in human, non-human primate, and rabbit is more than 99.0%. Effects of rHA-Mut-inf in carotid arterial thrombosis and microembolic signal (M...
Blood, 2012
Coagulation factor XII (FXII, Hageman factor, EC ؍ 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by "contact" to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Con-sistent with their human counterparts, FXII ؊/؊ mice have a normal hemostatic capacity. However, thrombus formation in FXII ؊/؊ mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic poly-mer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology. (Blood. 2012;120(22):4296-4303)
Defective thrombus formation in mice lacking coagulation factor XII
The Journal of …, 2005
Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)mediated fibrin formation is not believed to play an important role for coagulation in vivo. ...
Dual role of collagen in factor XII-dependent thrombus formation
Blood, 2009
dependent thrombus formation − Dual role of collagen in factor XII http://bloodjournal.hematologylibrary.org/content/114/4/881.full.html Updated information and services can be found at: (608 articles) Thrombosis and Hemostasis Articles on similar topics can be found in the following Blood collections http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub\_requests