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Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year's Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we're sure that you'll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.
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BACKGROUND: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process. METHODS: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined. RESULTS: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG. CONCLUSIONS: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.
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Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos , Polifosfatos , Proteínas , Animales , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Polifosfatos/toxicidad , Proteínas/metabolismo , Proteínas/genética , Supervivencia Celular/efectos de los fármacos , Ratones , Masculino , Fibrina/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Relación Dosis-Respuesta a Droga , Trombosis/prevención & control , Trombosis/inducido químicamente , Trombosis/metabolismo , Trombosis/genética , Trombosis/patología , Troponina I/metabolismo , Modelos Animales de Enfermedad , Cardiotoxicidad , Línea Celular , Electrocardiografía , Coagulación Sanguínea/efectos de los fármacosRESUMEN
ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system.
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Fibrinolisina , Ácido Tranexámico , Fibrinolisina/metabolismo , Factor de von Willebrand/metabolismo , Proteína ADAMTS13 , Proteínas ADAM/metabolismo , Ligandos , Plasminógeno/metabolismoRESUMEN
Background: Activated platelets release procoagulant factors that include Ca2+ and Zn2+. Releasable Ca2+ stores have been identified in platelet dense granules and the dense tubular system, but similar stores of free Zn2+ have not been identified. Objectives: Guided by studies of platelet Ca2+, we employed minimally disruptive methods to identify and localize concentrated free Zn2+ in human platelets. Methods: Resting platelets from normal donors (NDs), patients with gray platelet syndrome (GPS) lacking α-granules, and patients with Hermansky-Pudlak syndrome (HPS) deficient in dense granules were loaded with cell-permeant fluorescent probes specific to free Ca2+ or Zn2+. Ion concentrations were detected in fixed cells as bright puncta via high-resolution confocal microscopy. Ions were also directly detected via transmission electron microscopy and energy dispersive X-ray analysis. Levels of total platelet Ca, Zn, and Mg were measured via inductively coupled plasma optical emission spectroscopy. Results: Fluorescent Zn2+ puncta counts were similar in ND and GPS platelets and markedly lower in HPS platelets, pointing to dense granules as likely reservoirs of free Zn2+. This localization was supported by direct detection of Ca2+, Zn2+, and Na+ in platelet dense granules via transmission electron microscopy and energy dispersive X-ray analysis. Measurements of total platelet Ca, Zn, and Mg via inductively coupled plasma optical emission spectroscopy indicated that free Zn2+ represents a small proportion of total platelet zinc, consistent with the strong affinity of Zn2+ for binding proteins, including several abundant in platelet α-granules. Conclusion: We conclude that normal human platelets contain a pool of free Zn2+ concentrated in dense granules that is available for secretion upon platelet activation and potentially contributes to hemostasis.
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Oral anticoagulants are a mainstay for the prevention and treatment of arterial and venous thrombosis. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists for many indications. Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F) Xa. A new class of DOACs is under development. These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation. Anticoagulants that target FXIa have the potential to be safer than the current DOACs because there is emerging evidence that FXI is essential for thrombosis but mostly dispensable for hemostasis. In addition to the oral inhibitors of FXIa, parenteral inhibitors are also under development. These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI; abelacimab, an antibody that binds to FXI and blocks its activation; and osocimab, an FXIa inhibitory antibody. Focusing on these new agents, this article describes the unmet needs in oral anticoagulation therapy, explains why FXI is a promising target for new oral anticoagulants, reviews phase 2 clinical data on new agents, describes ongoing phase 3 trials, and provides a perspective on the opportunities and challenges for FXI inhibitors.
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Anticoagulantes , Inhibidores del Factor Xa , Humanos , Administración Oral , Anticoagulantes/química , Anticoagulantes/uso terapéutico , Dabigatrán , Inhibidores del Factor Xa/química , Inhibidores del Factor Xa/uso terapéutico , Factor XI , Rivaroxabán/uso terapéuticoRESUMEN
Factor XII (FXII) knockdown attenuates catheter thrombosis in rabbits. Because histidine-rich glycoprotein (HRG) modulates FXIIa activity, we hypothesized that HRG depletion would promote catheter thrombosis. To test this, rabbits were given either antisense oligonucleotides (ASOs) against HRG or FXII, a control ASO, or saline. The activated partial thromboplastin time (aPTT), prothrombin time (PT), and catheter-induced thrombin generation were determined in blood collected before and after treatment. Compared with the controls, the HRG- and FXII-directed ASOs reduced hepatic messenger RNA and plasma levels of HRG and FXII, respectively, by >90%. Although HRG knockdown shortened the aPTT by 2.5 fold, FXII knockdown prolonged it by fourfold; neither of the ASOs affected the PT. Catheter segments shortened the lag time and increased peak thrombin in the plasma from control rabbits; effects were significantly enhanced and attenuated in the plasma from rabbits given the HRG- and FXII-directed ASOs, respectively. Catheters were then inserted into the right external jugular vein of the rabbits, and the time for catheter occlusion was determined. The catheter occlusion times with the control ASO or saline were 62 ± 8 minutes and 60 ± 11 minutes, respectively. The occlusion time was significantly reduced to 34 ± 9 minutes, with HRG knockdown and significantly prolonged to 128 ± 19 minutes with FXII knockdown. HRG levels are decreased with sepsis or cancer, and such patients are prone to catheter thrombosis. Because HRG modulates catheter thrombosis, our findings suggest that HRG supplementation may prevent this problem.
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Coagulación Sanguínea , Trombosis , Animales , Conejos , Catéteres/efectos adversos , Factor XII/genética , Trombina , Trombosis/etiología , Trombosis/prevención & controlRESUMEN
BACKGROUND: Central venous catheters are prone to clotting, particularly in patients with cancer. Although low-molecular-weight heparin and direct oral anticoagulants, such as apixaban and rivaroxaban, have been evaluated for the prevention of catheter thrombosis, their efficacy remains uncertain. OBJECTIVES: Compare apixaban and rivaroxaban with enoxaparin for the prevention of catheter-induced clotting in vitro. METHODS: To address this uncertainty, we used a well-established microplate-based assay to compare the effects of enoxaparin, apixaban, and rivaroxaban on catheter-induced thrombosis and thrombin generation in human plasma. RESULTS: Consistent with our previous findings, catheter segments shortened the clotting time and promoted thrombin generation. When compared at concentrations with similar anti-factor Xa activity as enoxaparin, apixaban and rivaroxaban were >20-fold less potent than enoxaparin for the prevention of catheter-induced clotting and thrombin generation. CONCLUSION: The prevention of catheter thrombosis in patients with cancer is challenging. Clinical trials are needed to compare the efficacy of low-molecular-weight heparin with that of direct oral anticoagulants both for the prevention and treatment of catheter thrombosis.
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Neoplasias , Trombosis , Humanos , Enoxaparina/farmacología , Enoxaparina/uso terapéutico , Rivaroxabán/uso terapéutico , Anticoagulantes/uso terapéutico , Trombina , Piridonas/farmacología , Piridonas/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Trombosis/etiología , Trombosis/prevención & control , Catéteres , Neoplasias/tratamiento farmacológico , Inhibidores del Factor Xa/uso terapéuticoRESUMEN
BACKGROUND: Polyphosphate (polyP) promotes feedback activation of factor (F) XI by thrombin by serving as a template. The contribution of thrombin's exosites to these interactions is unclear. OBJECTIVES: To determine the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation by thrombin. METHODS: The affinities of α-thrombin; K109E/110E-thrombin, an exosite 1 variant, or R93E-thrombin, an exosite 2 variant; FXI; and FXIa for polyP-70 were quantified using surface plasmon resonance in the absence or presence of exosite ligands. FXI was activated with α-thrombin or thrombin variants in the absence or presence of polyP-70 and exosite ligands. RESULTS: α-Thrombin, K109/110E-thrombin, FXI, and FXIa bound polyP-70, whereas R93E-thrombin exhibited minimal binding. Exosite 1 and exosite 2 ligands attenuated thrombin binding to polyP-70. PolyP-70 accelerated the rate of FXI activation by α-thrombin and K109E/110E-thrombin but not R93E-thrombin up to 1500-fold in a bell-shaped, concentration-responsive manner. Exosite 1 and exosite 2 ligands had no impact on FXI activation by thrombin in the absence of polyP-70; however, in its presence, they attenuated activation by 40% to 65%. CONCLUSION: PolyP-70 binds FXI and thrombin and promotes their interaction. Exosite 2 ligands attenuate activation because thrombin binds polyP-70 via exosite 2. Attenuation of FXI activation by exosite 1 ligands likely reflects allosteric modulation of exosite 2 and/or the active site of thrombin because exosite 1 is not directly involved in FXI activation. Therefore, allosteric modulation of thrombin's exosites may represent a novel strategy for downregulating FXI activation.
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Factor XI , Trombina , Humanos , Factor XI/metabolismo , Trombina/metabolismo , Polifosfatos/química , Dominio Catalítico , CatálisisRESUMEN
BACKGROUND: Previously, we showed that histidine-rich glycoprotein (HRG) binds factor (F) XIIa with high affinity, inhibits FXII autoactivation and FXIIa-mediated activation of FXI, and attenuates ferric chloride-induced arterial thrombosis in mice. Therefore, HRG downregulates the contact pathway in vitro and in vivo. OBJECTIVE: To identify the domains on HRG responsible for contact pathway inhibition. METHODS: Recombinant HRG domain constructs (N-terminal [N1, N2, and N1N2], proline-rich regions, histidine-rich region [HRR], and C-terminal) were expressed and purified. The affinities of plasma-derived HRG, HRG domain constructs, and synthetic HRR peptides for FXII, FXIIa, ß-FXIIa, and polyphosphate (polyP) were determined using surface plasmon resonance, and their effects on polyP-induced FXII autoactivation, FXIIa-mediated activation of FXI and prekallikrein, the activated partial thromboplastin time (APTT), and thrombin generation were examined. RESULTS: HRG and HRG domain constructs bind FXIIa, but not FXII or ß-FXII. HRR, N1, and N1N2 bind FXIIa with affinities comparable with that of HRG, whereas the remaining domains bind with lower affinity. Synthetic HRR peptides bind FXIIa and polyP with high affinity. HRG and HRR significantly inhibit FXII autoactivation and prolong the APTT. Like HRG, synthetic HRR peptides inhibit FXII autoactivation, attenuate FXIIa-mediated activation of prekallikrein and FXI, prolong the APTT, and attenuate thrombin generation. CONCLUSION: The interaction of HRG with FXIIa and polyP is predominantly mediated by the HRR domain. Like intact HRG, HRR downregulates the contact pathway and contributes to HRG-mediated down regulation of coagulation.
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Precalicreína , Trombina , Animales , Factor XII/metabolismo , Factor XIIa/metabolismo , Humanos , Ratones , Péptidos/farmacología , Polifosfatos , Precalicreína/metabolismo , Proteínas , Trombina/metabolismoRESUMEN
Histidine-rich glycoprotein (HRG) is an abundant plasma protein that binds factor XIIa (FXIIa) and inhibits factor XII (FXII) autoactivation and FXIIa-mediated activation of FXI. Polyphosphate (polyP), a potent procoagulant released from activated platelets, may serve as a physiological activator of the contact system. Previously, we showed that HRG binds DNA and neutralizes its procoagulant activity. Consequently, our goal was to determine whether the capacity of HRG to bind polyanions enables it to regulate polyP-induced thrombosis. In a plate-based assay, immobilized polyP bound HRG, FXII, and FXIIa in a zinc-dependent manner. Basal and polyP-induced thrombin generation was greater in plasma from HRG-deficient mice than in plasma from wild-type mice. Intraperitoneal injection of polyP shortened the activated partial thromboplastin time, enhanced thrombin generation, increased thrombin-antithrombin levels, reduced lung perfusion, and promoted pulmonary fibrin deposition to a greater extent in HRG-deficient mice than in wild-type mice, effects that were abrogated with FXII knockdown. HRG thus attenuates the procoagulant and prothrombotic effects of polyP in an FXII-dependent manner by modulating the contact system.
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Factor XII , Trombosis , Animales , Coagulación Sanguínea , Factor XII/genética , Ratones , Polifosfatos , Proteínas , Trombosis/inducido químicamenteRESUMEN
Despite advances in anticoagulant therapy, thrombosis remains the leading cause of morbidity and mortality worldwide. Heparin and vitamin K antagonists (VKAs), the first anticoagulants to be used successfully for the prevention and treatment of thrombosis, are associated with a risk of bleeding. These agents target multiple coagulation factors. Thus, by activating antithrombin, heparin mainly inhibits factor Xa and thrombin, whereas VKAs lower the levels of the vitamin K-dependent clotting factors. Direct oral anticoagulants, which have replaced VKAs for many indications, inhibit only factor Xa or thrombin. Although the direct oral anticoagulants are associated with less bleeding than VKAs, bleeding remains their major side effect. Epidemiological and animal studies have identified factor XI as a target for potentially safer anticoagulant drugs because factor XI deficiency or inhibition protects against thrombosis and is associated with little or no bleeding. Several factor XI-directed strategies are currently under investigation. This article (1) reviews the rationale for the development of factor XI inhibitors, (2) identifies the agents in most advanced stages of development, (3) describes the results of completed clinical trials and provides a summary of those underway, and (4) highlights the opportunities and challenges for this next generation of anticoagulants.
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Anticoagulantes/uso terapéutico , Factor XI/uso terapéutico , Trombosis/tratamiento farmacológico , Anticoagulantes/farmacología , Factor XI/farmacología , HumanosRESUMEN
Although anticoagulants have been in use for more than 80 years, heparin and vitamin K antagonists were the sole available options until recently. Although these agents revolutionized the prevention and treatment of thrombotic diseases, their use has been hampered by the necessity for coagulation monitoring and by bleeding complications resulting in part from their multiple sites of action. Owing to advances in basic science, animal models, and epidemiology, the arsenal of available anticoagulants has expanded in the past two decades. This evolution has yielded many novel compounds that target single coagulation enzymes. Initially, thrombin and factor Xa were targeted because of their critical roles in coagulation. However, attention has now shifted to compounds that target upstream reactions, particularly those catalyzed by factors XIIa and XIa, which are part of the contact system. This shift is predicated on epidemiological and experimental evidence suggesting that these factors are more important for thrombosis than for hemostasis. With the goal of developing a new class of anticoagulants associated with a lower risk of bleeding than currently available agents, dozens of drugs targeting the contact system are now in development. This article focuses on the rationale, development, and testing of these new agents with a concentration on those that have reached or completed phase 2 evaluation for at least one indication.
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Anticoagulantes , Trombosis , Animales , Anticoagulantes/efectos adversos , Coagulación Sanguínea , Fibrinolíticos/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Trombosis/tratamiento farmacológicoRESUMEN
BACKGROUND: Patients with mechanical heart valves (MHVs) require warfarin to prevent thromboembolism. Dabigatran was less effective than warfarin in patients with MHVs, which prompted a black box warning against the use of direct oral anticoagulants for this indication. However, rivaroxaban and apixaban, which inhibit factor Xa, have not been evaluated in patients with MHVs. To determine whether rivaroxaban and apixaban would be effective, we used MHV-induced thrombin generation assays to compare them with warfarin either alone or in combination with dabigatran. METHODS: Thrombin generation in the absence or presence of MHV leaflets or sewing ring segments (SRSs) was quantified. Studies were done in control plasma; plasma from patients on warfarin; plasma containing varying concentrations of rivaroxaban, apixaban, or dabigatran alone; or plasma containing rivaroxaban plus dabigatran. RESULTS: Mean endogenous thrombin potential (ETP) increased 1.2-fold, 1.5-fold, and 1.8-fold in the presence of leaflets, Teflon (Terumo Aortic (Sunrise, FL)) SRSs, or Dacron (Terumo Aortic (Sunrise, FL)) SRSs, respectively. Rivaroxaban and apixaban reduced ETP at concentrations above 50 ng/mL but were less effective than warfarin. When rivaroxaban and dabigatran were combined, they suppressed ETP in a more than additive manner. CONCLUSIONS: Whereas warfarin suppresses MHV-induced thrombin generation, MHVs induce the generation of factor Xa in concentrations that overwhelm clinically relevant concentrations of rivaroxaban or apixaban. When used in combination, rivaroxaban and dabigatran are more effective than either agent is alone, suggesting that concomitant inhibition of factor Xa and thrombin is better than inhibition of either clotting enzyme alone.
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Dabigatrán/uso terapéutico , Cardiopatías/prevención & control , Prótesis Valvulares Cardíacas/efectos adversos , Rivaroxabán/uso terapéutico , Trombina/antagonistas & inhibidores , Trombosis/prevención & control , Antitrombinas/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Cardiopatías/etiología , Humanos , Trombina/metabolismo , Trombosis/sangre , Trombosis/etiologíaRESUMEN
The fragment 2 domain (F2) of prothrombin and its interaction with factor (F) Va is known to contribute significantly to prothrombinase-catalyzed activation of prothrombin. The extent to which the F2-FVa interaction affects the overall thrombin generation, however, is uncertain. To study this interaction, nuclear magnetic resonance spectroscopy of recombinant F2 was used to identify seven residues within F2 that are significantly responsive to FVa binding. The functional role of this region in interacting with FVa during prothrombin activation was verified by the FVa-dependent inhibition of thrombin generation using peptides that mimic the same region of F2. Because six of the seven residues were within a 9-residue span, these were mutated to generate a prothrombin derivative (PT6). These mutations led to a decreased affinity for FVa as determined by surface plasmon resonance. When thrombin generation by an array of FXa containing prothrombinase components was monitored, a 54% decrease in thrombin generation was observed with PT6 compared with the wild-type, only when FVa was present. The functional significance of the specific low-affinity binding between F2 and FVa is discussed within the context of a dynamic model of molecular interactions between prothrombin and FVa engaging multiple contact sites.
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Factor Va/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Protrombina/química , Protrombina/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Humanos , Cinética , Unión Proteica , Mapas de Interacción de Proteínas , Estructura Secundaria de Proteína , Análisis de Secuencia de ProteínaRESUMEN
Rivaroxaban and apixaban are both small molecules that reversibly inhibit factor Xa. Compared with rivaroxaban, apixaban has minimal effects on the prothrombin time and activated partial thromboplastin time. To investigate this phenomenon, we used a factor Xa-directed substrate in a buffer system. Although rivaroxaban and apixaban inhibited factor Xa with similar K i values at equilibrium, kinetic measurements revealed that rivaroxaban inhibited factor Xa up to 4-fold faster than apixaban ( p < 0.001). Using a discontinuous chromogenic assay to monitor thrombin production by prothrombinase in a purified system, rivaroxaban was 4-fold more potent than apixaban (K i values of 0.7 ± 0.3 and 2.9 ± 0.5 nM, respectively; p = 0.02). Likewise, in thrombin generation assays in plasma, rivaroxaban prolonged the lag time and suppressed endogenous thrombin potential to a greater extent than apixaban. To characterize how the two inhibitors differ in recognizing factor Xa, inhibition of prothrombinase was monitored in real-time using a fluorescent probe for thrombin. The data were fit using a mixed-inhibition model and the individual association and dissociation rate constants were determined. The association rates for the binding of rivaroxaban to either free factor Xa or factor Xa incorporated into the prothrombinase complex were 10- and 1,193-fold faster than those for apixaban, respectively, whereas dissociation rates were about 3-fold faster. Collectively, these findings suggest that rivaroxaban and apixaban differ in their capacity to inhibit factor Xa and provide a plausible explanation for the observation that rivaroxaban has a greater effect on global tests of coagulation than apixaban.
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The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development.
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Anticoagulantes/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Diseño de Fármacos , Factor XI/antagonistas & inhibidores , Fibrinolíticos/uso terapéutico , Trombosis/tratamiento farmacológico , Anticoagulantes/efectos adversos , Factor XI/genética , Factor XI/metabolismo , Fibrinolíticos/efectos adversos , Hemorragia/inducido químicamente , Humanos , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/genéticaRESUMEN
D-dimer is a soluble fibrin degradation product that results from ordered breakdown of thrombi by the fibrinolytic system. Numerous studies have shown that D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis. Consequently, D-dimer has been extensively investigated for the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and as an aid in the identification of medical patients at high risk for VTE. Thus, quantification of D-dimer levels serves an important role in guiding therapy. This review: 1) describes how D-dimer is generated; 2) reviews the assays used for its detection; and 3) discusses the role of D-dimer determination in these various conditions.
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Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Tromboembolia Venosa/sangre , Tromboembolia Venosa/diagnóstico , Biomarcadores/sangre , Productos de Degradación de Fibrina-Fibrinógeno/química , HumanosRESUMEN
The direct oral anticoagulants (DOACs) have now supplanted vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE). The DOACs include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. The DOACs are as effective for the prevention of recurrence as conventional VTE treatment, consisting of a parenteral anticoagulant followed by a VKA, and are associated with less bleeding. Because of these properties and the convenience of fixed dosing without the need for routine coagulation monitoring, guidelines now recommend DOACs over VKAs for VTE treatment in patients without active cancer. This paper examines the increasing role of the DOACs for VTE treatment.
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The thrombin-thrombomodulin (TM) complex activates thrombin-activable fibrinolysis inhibitor (TAFI) more efficiently than thrombin alone. The exosite on TAFI required for its TM-dependent activation by thrombin has not been identified. Based on previous work by us and others, we generated TAFI variants with one or more of residues Lys 42, Lys 43, Lys 44 and Arg 12 within the activation peptide mutated to alanine. Mutation of one, two, or three Lys residues or the Arg residue alone decreased the catalytic efficiency of TAFI activation by thrombin-TM by 2.4-, 3.2-, 4.7-, and 15.0-fold, respectively, and increased the TAFI concentrations required for half-maximal prolongation of clot lysis times (K1/2) by 3-, 4,- 15-, and 24-fold, respectively. Mutation of all four residues decreased the catalytic efficiency of TAFI activation by 45.0-fold, increased the K1/2 by 130-fold, and abolished antifibrinolytic activity in a clot lysis assay at physiologic levels of TAFI. Similar trends in the antifibrinolytic activity of the TAFI variants were observed when plasma clots were formed using HUVECs as the source of TM. When thrombin was used as the activator, mutation of all four residues reduced the rate of activation by 1.1-fold compared with wild-type TAFI, suggesting that these mutations only impacted activation kinetics in the presence of TM. Surface plasmon resonance data suggest that mutation of the four residues abrogates TM binding with or without thrombin. Therefore, Lys 42, Lys 43, Lys 44 and Arg 12 are critical for the interaction of TAFI with the thrombin-TM complex, which modulates its antifibrinolytic potential.