Factor XI contributes to thrombin generation in the absence of factor XII (original) (raw)
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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
Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma
Proceedings of the National Academy of Sciences, 2010
The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
Objective-Feedback activation of factor XI by thrombin is a likely alternative for tissue factor-dependent propagation of thrombus formation. However, the hypothesis that thrombin can initiate and propagate its formation in a factor XI-dependent and platelet-dependent manner has not been tested in a plasma milieu. Methods and Results-We investigated thrombin generation in recalcified platelet-rich plasma activated with varying amounts of thrombin or factor VIIa. Thrombin initiates and propagates dose-dependently thrombin generation only when platelets and plasma factor XI are present. Incubation of thrombin-activated platelets with a tissue factor neutralizing antibody had no effect on thrombin formation, indicating that platelet-associated tissue factor, if present at all, is not involved. In the absence of factor VIII, thrombin could not initiate its own formation, whereas factor VIIa-induced thrombin generation was reduced. Collagen strongly stimulated both thrombin-initiated and factor VIIa-initiated thrombin generation. Conclusions-These findings support the notion that platelet-localized feedback activation of factor XI by thrombin plays an important role in maintaining normal hemostasis as well as in sustaining thrombus formation when the TF pathway is inhibited by tissue factor pathway inhibitor. (Arterioscler Thromb Vasc Biol. 2004;24:1138-1142.)
The role of factor XI in thrombin generation induced by low concentrations of tissue factor
Thrombosis and Haemostasis, 2001
Thrombin generation has been studied in the plasma of severely factor XI deficient patients under conditions in which contact activation did not play a role. In platelet-rich as well as platelet-poor plasma, thrombin generation was dependent upon the presence of factor XI at tissue factor concentrations of between 1 and 20 pg/ml i.e. ~ 0.01 to 0.20% of the concentration normally present in the thromboplastin time determination. The requirement for factor XI is low; significant thrombin generation was seen at 1% factor XI; at 10%, thrombin formation was nearly normalised. A suspension of normal platelets in severely factor XI deficient plasma did not increase thrombin generation. This implies that there is no significant factor XI activity carried by normal platelets, although the presence of factor XI and factor XI inhibitors in platelets cannot be ruled out.
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
A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo
Blood, 2010
Mice lacking factor XII (fXII) or factor XI (fXI) are resistant to experimentally–induced thrombosis, suggesting fXIIa activation of fXI contributes to thrombus formation in vivo. It is not clear whether this reaction has relevance for thrombosis in pri mates. In 2 carotid artery injury models (FeCl3 and Rose Bengal/laser), fXII-deficient mice are more resistant to thrombosis than fXI- or factor IX (fIX)–deficient mice, raising the possibility that fXII and fXI function in distinct pathways. Antibody 14E11 binds fXI from a variety of mammals and interferes with fXI activation by fXIIa in vitro. In mice, 14E11 prevented arterial occlusion induced by FeCl3 to a similar degree to total fXI deficiency. 14E11 also had a modest beneficial effect in a tissue factor–induced pulmonary embolism model, indicating fXI and fXII contribute to thrombus formation even when factor VIIa/tissue factor initiates thrombosis. In baboons, 14E11 reduced platelet-rich thrombus growth in collagen-coated graf...
Blood Coagulation & Fibrinolysis, 2000
We used a cell-based, in-vitro model of normal hemostasis and hemophilia to address the question of whether factor (F) X concentration affects the hemostatic response to high-dose activated factor VII (FVIIa). Under conditions designed to mimic normal tissue factorinitiated hemostasis in vivo, we found that only a very small amount of FX-equivalent to about 3% of the normal plasma level-was required to support a 'normal' level of thrombin generation. This suggests that, under normal conditions in vivo, the level of FX does not significantly affect hemostatic function. By contrast, in experiments designed to mimic the hemophilic condition, the level of FX had a significant effect on the level of thrombin generated in the presence of high-dose FVIIa. This finding suggests that the plasma level of FX could affect the hemostatic response of hemophilic patients to high-dose FVIIa therapy. Blood Coagul Fibrinolysis 11 (suppl 1):S3-S7
Epidemiologic and clinical data linking factors XI and XII to thrombosis
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program, 2014
Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The poss...
British Journal of Haematology, 1996
The variable bleeding tendency associated with a genetic deficiency of factor XI (FXI) and the lack of bleeding disorders in individuals with a genetic deficiency of factor XII (FXII) suggest an alternative mechanism for FXI activation in vivo. Recently, thrombin has been shown to activate FXI. However, in plasma this activation has been shown to occur only with exogenous FXI and a non-physiological cofactor (sulphatides), and the occurrence of this reaction in a plasma environment has been questioned. Using recently developed sensitive assays for FXIa-inhibitor complexes we found thrombin-mediated and FXII-independent activation of endogenous FXI in plasma in the presence of heparan sulphate, heparin, dermatan sulphate or dextran sulphate. Using heparan sulphate, which is present in the human vascular system, activation of about 1-2% of plasma FXI was observed, however, only after addition of very high amounts (500 nmol/l) of human ®-thrombin to FXII-deficient plasma (at a 1 to 4 final dilution). We conclude that endogenous FXI in plasma can be activated by thrombin in the presence of various glycosaminoglycans, including the physiological compounds heparan sulphate and dermatan sulphate, but only at very high concentrations of thrombin, corresponding to 100% prothrombin activation in undiluted plasma.