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A model of arterial thrombus formation. (A) Initiation of thrombus formation at sites of vascular lesions is predominantly caused by TF and collagens exposed in the subendothelial matrix. TF in complex with FVII initiates thrombin formation, which promotes fibrin formation and platelet activation. The contribution of FXII in this early phase of thrombus formation is minor. (B) FXII activity on the exposed surface of the thrombus contributes to thrombin generation and additional platelet activation, propagating thrombus growth. Accordingly, FXII, as well as factor XI, deficiency severely impairs thrombus formation.
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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. We used FXII-deficient mice to study the contributions of FXII to thrombus formation i...
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Context 1
... on our results, we propose the model for patho- logic arterial thrombus formation depicted in Fig. 6. At sites of vascular injury, platelets come in contact with the exposed subendothelial ECM. Platelets are initially tethered to the ECM by von Willebrand factor through platelet glycopro- tein Ib (46). Activation and adhesion then proceeds through interactions between platelet collagen receptors such as GPVI and integrin 21 and the ...Context 2
... thrombin generation to activate newly recruited plate- lets and consolidate fibrin formation in the growing throm- bus. It is in this propagation phase that FXII / and factor XI-deficient mice appear to be defective. Therefore, we propose that FXII activation and FXII-driven thrombin for- mation might proceed on the surface of activated platelets (Fig. 6 B). Indeed, it has been suggested that "platelets can provide a surface, perhaps similar to that provided by such negatively charged substances as kaolin or glass" (48), that fa- cilitate FXII activation. Because procoagulant platelets ex- pose PS on their surface (for review see reference 49) that fa- cilitates several coagulation ...Citations
... 33 Bleeding, Thrombosis and Vascular Biology 2024; 3(s1):118 Preclinical and epidemiological evidence supporting factor XI as a safer target than factor Xa Mice deficient in FXI or FXII exhibited defective thrombus formation at sites of arterial or venous injury without evidence of increased bleeding. [34][35][36][37][38][39][40][41] Likewise, antibodies against FXI inhibited thrombosis in rodent models without affecting bleeding, and a reduction in the level of FXI with ASOs reduced shunt thrombosis in baboons. 41 Studies comparing the effects of antibodies against factor FXI or FXII in non-human primates suggested more potent antithrombotic effects with FXI-directed antibodies. ...
Venous thromboembolism (VTE) is a relatively common complication in cancer patients with potentially dire consequences. Anticoagulants are the mainstay of treatment of cancer-associated VTE. The anticoagulants most often used are low-molecular-weight heparin (LMWH) and direct oral factor (F) Xa inhibitors, which include apixaban, edoxaban, and rivaroxaban. Most guidelines recommend primary VTE prophylaxis with LMWH, apixaban, or rivaroxaban after abdominal or pelvic cancer surgery, or in high-risk ambulatory cancer patients. Both oral FXa inhibitors and LMWH have limitations. LMWH requires daily subcutaneous injections, and because of its renal clearance, its use may be problematic in patients with severe kidney disease. The risk of bleeding with oral FXa inhibitors may be higher than with LMWH in patients with intraluminal gastrointestinal or genitourinary cancers. Other problems with oral FXa inhibitors include potential drug-drug interactions and dosing issues in patients with thrombocytopenia or severe kidney or liver disease. Therefore, there remains a need for convenient and safer anticoagulants for VTE treatment in cancer patients. FXI has emerged as a potentially safer target for anticoagulants than FXa because FXI is essential for thrombosis, but mostly dispensable for hemostasis. This review summarizes the currently available therapeutic options for cancer-associated VTE, highlights knowledge gaps, and discusses the potential of FXI inhibitors to address key unmet clinical needs in this vulnerable patient population.
... There is clearly a role for FXIIdependent functions of PKa in thrombosis given that FXII-and FXI-deficient mice are also protected in models of arterial and venous thrombus formation. [45][46][47][48][49] To date, there is no direct evidence that FXII-independent functions of PKa are involved in thrombosis in vivo. Further work is required to determine the extent to which direct PKa activation of FIX contributes to thrombotic pathologies. ...
Plasma kallikrein (PKa) is an important activator of factor (F)XII of the contact pathway of coagulation. Several studies have shown that PKa also possesses procoagulant activity independent of FXII, likely through its ability to directly activate FIX. We evaluated the procoagulant activity of PKa using a mouse whole blood (WB) thrombin generation (TG) assay. TG was measured in WB from PKa-deficient mice using contact pathway or extrinsic pathway triggers. PKa-deficient WB had significantly reduced contact pathway-initiated TG compared to wild-type controls and was comparable to that observed in FXII-deficient WB. PKa-deficient WB supported equivalent extrinsic pathway-initiated TG compared to wild-type controls. Consistent with the presence of FXII-independent functions of PKa, targeted blockade of PKa with either small molecule or antibody-based inhibitors significantly reduced contact pathway-initiated TG in FXII-deficient WB. Inhibition of activated FXII (FXIIa) using an antibody-based inhibitor significantly reduced TG in PKa-deficient WB, consistent with a PKa-independent function of FXIIa. Experiments using mice expressing low levels of tissue factor demonstrated that persistent TG present in PKa- and FXIIa-inhibited WB was driven primarily by endogenous tissue factor. Our work demonstrates that PKa contributes significantly to contact pathway-initiated TG in the complex milieu of mouse WB and that a component of this contribution occurs in a FXII-independent manner.
... Epidemiologically, however, there is no data showing protection against AIS in FXII deficient subjects, while for FXI deficiency such protective effect has been observed [19,55]. Renné et al. and Kleinschnitz et al. demonstrated improved reperfusion after experimental stroke using mice with genetic deletion or pharmacological inhibition of FXII [54,56]. Pharmacological blockage of FXII by rHA-infestin-4, in a mouse and rat tMCOA model, resulted in decreased infarct sizes [57][58][59]. ...
... Virus-induced cell death, as well as activation of innate immune cells, leads to the release of potential KKS activators and are the main mechanisms proposed to stimulate this proteolytic cascade [19][20][21][22]. from thrombosis, implicating both the intrinsic coagulation pathway and KKS as major pathological mechanisms in thromboembolic development [62][63][64]. ...
Microcirculatory and coagulation disturbances commonly occur as pathological manifestations of systemic viral infections. Research exploring the role of the kallikrein–kinin system (KKS) in flavivirus infections has recently linked microvascular dysfunctions to bradykinin (BK)-induced signaling of B2R, a G protein-coupled receptor (GPCR) constitutively expressed by endothelial cells. The relevance of KKS activation as an innate response to viral infections has gained increasing attention, particularly after the reports regarding thrombogenic events during COVID-19. BK receptor (B2R and B1R) signal transduction results in vascular permeability, edema formation, angiogenesis, and pain. Recent findings unveiling the role of KKS in viral pathogenesis include evidence of increased activation of KKS with elevated levels of BK and its metabolites in both intravascular and tissue milieu, as well as reports demonstrating that virus replication stimulates BKR expression. In this review, we will discuss the mechanisms triggered by virus replication and by virus-induced inflammatory responses that may stimulate KKS. We also explore how KKS activation and BK signaling may impact virus pathogenesis and further discuss the potential therapeutic application of BKR antagonists in the treatment of hemorrhagic and respiratory diseases.
... Inhibition or deficiency of FXII also reduces thrombus formation in animal models. The effect is most striking in mice [46][47][48] but is observed in primates. 49 Because FXII deficiency does not cause abnormal bleeding, FXII inhibition could be an even safer antithrombotic strategy than FXI inhibition. ...
Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa have replaced warfarin and other vitamin K antagonists (VKA) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to under-treatment of many patients who would benefit from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on seventy years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI/XIa inhibitors experienced less bleeding than patients on DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here we review the contributions of FXI to normal and abnormal coagulation and discuss results from pre-clinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.
... Следующим вопросом, который заинтересовал ученых, было влияние протективного эффекта дефицита XII фактора на риск образования венозных и артериальных тромбозов без сопутствующих геморрагических проявлений. По данным исследований, проведенных на мышах, дефицит XII фактора, а также прекалликреина и высокомолекулярного кининогена связан со сниженным риском тромбоза без повышенной кровоточивости [6]. В эксперименте, проведенном в 2005 г. на мышах, было показано, что дефицит XII фактора защищает от образования артериальных, венозных тромбозов, а также ишемического инсульта [7]. ...
В статье обсуждается роль фактора Хагемана (XII фактора свертывания крови, FXII) в тромбообразовании и формировании риска кровотечений при его дефиците. Представлены результаты исследования причин синдрома изолированно удлиненного активированного частично тромбопластинового времени АЧТВ (СИУ АЧТВ) и частоты выявления при этом дефицита FXII фактора. Установлено, что второй по частоте встречаемости причиной СИУ АЧТВ является дефицит FXII (25%), что говорит о недостаточности знаний истинной частоты встречаемости дефицита FXII. Полученные данные позволяют сделать вывод о том, что в первую очередь при положительном тесте коррекции удлиненного АЧТВ (нормализация при добавлении контрольной плазмы) и при отсутствии геморрагического синдрома необходимо исключить дефицит FXII, так как он является наиболее частой причиной нарушения свертывания крови (помимо присутствия волчаночного антикоагулянта (ВА)), удлинения АЧТВ в амбулаторной практике. Полученные результаты позволили сформировать алгоритм лабораторного диагностического поиска при синдроме изолированно удлиненного АЧТВ.
The article discusses the role of the FXII blood coagulation factor (Hageman factor) in the process of blood coagulation, its role in the formation of thrombosis and the risk of bleeding in its deficiency. The results of a study of the causes of isolated prolonged APTT syndrome (SIU APTT) and the frequency of detection of FXII factor deficiency are presented. FXII deficiency (25%) was found to be the second most common cause of IRS APTT, which indicates a lack of knowledge of the true incidence of FXII deficiency. The data obtained allow us to conclude that, first of all, with a positive test for the correction of a prolonged APTT (normalization with the addition of control plasma) and in the absence of a hemorrhagic syndrome, it is necessary to exclude FXII deficiency, since it is the most common cause, in addition to the presence of lupus anticoagulant (LA), prolongation of APTT in outpatient practice. The results obtained made it possible to develop an algorithm for laboratory diagnostic search for isolated prolonged APTT syndrome.
... FXI activation during hemostasis may also involve contact pathway activation on collagen [4] or soil [5,6]. Finally, activation of FXI was demonstrated in pathophysiologic thromboembolic and inflammatory events [7][8][9][10][11], through mechanisms that are likely mediated by FXII, high molecular weight kininogen (HK) and prekallikrein (PK) on cell polyphosphates [12], RNA [13], misfolded proteins [14], and βamyloid peptides [15]. ...
... The aPTT test, which uses artificial contact activators like silica or ellagic acid to activate FXII and measure plasma clotting time, helps physicians identify anomalies concerning the plasma levels of certain coagulation factors [15]. Despite its deficiency causing a mild bleeding disorder known as hemophilia C, FXI was similarly deemed irrelevant for preventing venous thromboembolism (VTE), very similar to other contact factors [16]. However, recent times have seen a surge in interest in FXI, as it is now believed that it is more significant for thrombosis than for hemostasis. ...
... However, recent times have seen a surge in interest in FXI, as it is now believed that it is more significant for thrombosis than for hemostasis. Accordingly, compounds inhibiting FXI function, like ASOs or blocking antibodies, reduced thrombosis in preclinical animal studies [16][17][18]. Recently, several contact activators linked to the onset of VTE, such as DNA, RNA, platelet polyphosphates, and misfolded proteins, have been suggested as physiological FXII activators [19][20][21]. ...
Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.
... FXIa is a crucial component of the intrinsic pathway of blood coagulation activation [25]. FXIa and the intrinsic pathway have a limited role in hemostasis, but they are suspected to be contributors to thrombosis because FXI activation in blood has been demonstrated in both thromboembolic and inflammatory events [26][27][28][29][30][31][32]. Indeed, several pharmacological inhibitors that target FXIa are being developed for prevention of thrombosis with the hope of achieving anticoagulation with a reduced risk of bleeding [33,34]. ...
Citation: Liang, Y.; Tarandovskiy, I.; Surov, S.S.; Ovanesov, M.V. Comparative Thrombin Generation in Animal Plasma: Sensitivity to Human Factor XIa and Tissue Factor. Abstract: Preclinical evaluation of drugs in animals helps researchers to select potentially informative clinical laboratory markers for human trials. To assess the utility of animal thrombin generation (TG) assay, we studied the sensitivity of animal plasmas to triggers of TG, human Tissue Factor (TF), and Activated Factor XI (FXIa). Pooled human, mouse, rat, guinea pig, rabbit, bovine, sheep, and goat plasmas were used in this study. TF-or FXIa-triggered TG and clotting were measured via fluorescence and optical density, respectively. Thrombin peak height (TPH) and time (TPT), clot time (CT), and fibrin clot density (FCD) were all analyzed. The trigger low and high sensitivity borders (LSB and HSB) for each assay parameter were defined as TF and FXIa concentrations, providing 20 and 80% of the maximal parameter value, unless the baseline (no trigger) value exceeded 20% of the maximal, in which case, LSB was derived from 120% of baseline value. Normal human samples demonstrated lower TPH HSB than most of the animal samples for both TF and FXIa. Animal samples, except mice, demonstrated lower TPT LSB for FXIa versus humans. Most rodent and rabbit samples produced baseline TG in the absence of TG triggers that were consistent with the pre-activation of blood coagulation. FCD was not sensitive to both TF and FXIa in either of the plasmas. Animal plasmas have widely variable sensitivities to human TF and FXIa, which suggests that optimization of trigger concentration is required prior to test use, and this complicates the extrapolation of animal model results to humans.
... FIX is activated in wounds in the hemostasis phase, and it is thought to play an essential role in the inflammatory phase, as gene targeting of vitamin K-dependent coagulation factors, including FIX, was shown to result in impaired wound healing. Retarded re-epithelialization and reduced inflammatory cell infiltration are found in vitamin Kdependent coagulation factor-knockout mice (41)(42)(43)(44). In the present study, the decreased collagen deposition induced by F9-LC treatment suggests that F9-LC plays a role in inflammation or remodeling. ...
Background/aim:
Fibrosis is an essential process for wound healing, but excessive fibrosis, such as keloids and hypertrophic scars, can cause cosmetic and functional problems. These lesions are caused by abnormal deposition and shrinkage of collagen fibers. The light chain of FIX, a plasma protein essential for hemostasis, has the amino acid sequence CXDXXXXYXCXC in the EGF domain. Peptides containing this sequence inhibited stromal growth in a mouse transplant tumor model. In this study, the effect of the FIX light chain on wound healing was studied.
Materials and methods:
A full-layer wound was made on the back of each mouse, and cDNA encoding the light chain of mouse FIX (F9-LC) in an expression vector was injected locally once each week using a non-viral vector. Histochemical analysis of the wound was then performed to assess the effects on wound healing. Moreover, the effect of F9-LC on fibroblasts was studied in vitro.
Results:
Macroscopic observation showed that wounds with forced expression of F9-LC appeared flatter and had fewer wrinkles than control wounds. Tissue collagen staining and immunostaining revealed that administration of F9-LC suppressed collagen 1 and 3 deposition and decreased α-smooth muscle actin expression. Electron microscopy revealed sparse and disorganized collagen fibers in the F9-LC-treated mice. In experiments using fibroblasts, addition of a recombinant protein of the FIX light chain disrupted the typical spindle shape and alignment of fibroblasts.
Conclusion:
F9-LC is a new candidate for use in treatments to regulate excessive fibrosis and contraction in wound healing.
