RESUMO
Placenta-mediated pregnancy complications are a major challenge in the management of maternal-fetal health. Maternal thrombophilia is a suspected risk factor, but the role of thrombotic processes in these complications has remained unclear. Endothelial protein C receptor (EPCR) is an anticoagulant protein highly expressed in the placenta. EPCR autoantibodies and gene variants are associated with poor pregnancy outcomes. In mice, fetal EPCR deficiency results in placental failure and in utero death. We show that inhibition of molecules involved in thrombin generation or in the activation of maternal platelets allows placental development and embryonic survival. Nonetheless, placentae exhibit venous thrombosis in uteroplacental circulation associated with neonatal death. In contrast, maternal EPCR deficiency results in clinical and histological features of placental abruption and is ameliorated with concomitant Par4 deficiency. Our findings unveil a causal link between maternal thrombophilia, uterine hemorrhage, and placental abruption and identify Par4 as a potential target of therapeutic intervention.
Assuntos
Descolamento Prematuro da Placenta , Receptor de Proteína C Endotelial , Trombofilia , Trombose , Descolamento Prematuro da Placenta/etiologia , Descolamento Prematuro da Placenta/patologia , Animais , Receptor de Proteína C Endotelial/fisiologia , Feminino , Camundongos , Placenta/patologia , Gravidez , Trombofilia/complicações , Trombofilia/patologia , Trombose/patologiaRESUMO
Tissue factor pathway inhibitor (TFPI) is a serine protease with multiple anticoagulant activities. The Kunitz1 (K1) domain of TFPI binds the active site of factor VIIa and is required for inhibition of tissue factor (TF)/factor VIIa catalytic activity. Mice lacking TFPI K1 domain die in utero. TFPI is highly expressed on trophoblast cells of the placenta. We used genetic strategies to selectively ablate exon 4 encoding TFPI K1 domain in the embryo, while maintaining expression in trophoblast cells. This approach resulted in expected Mendelian frequency of TFPI K1 domain-deficient mice. Real-time polymerase chain reaction confirmed 95% to 99% genetic deletion and a similar reduction in transcript expression. Western blotting confirmed the presence of a truncated protein instead of full-length TFPI. Mice with severe TFPI K1 deficiency exhibited elevated thrombin-antithrombin (TAT) levels, frequent fibrin deposition in renal medulla, and increased susceptibility to TF-induced pulmonary embolism. They were fertile, and most lived normal life spans without any overt thrombotic events. Of 43 mice observed, 2 displayed extensive brain ischemia and infarction. We conclude that in contrast to complete absence of TFPI K1 domain, severe deficiency is compatible with in utero development, adult survival, and reproductive functions in mice. Inhibition of TFPI activity is being evaluated as a means of boosting thrombin generation in hemophilia patients. Our results show that in mice severe reduction of TFPI K1 activity is associated with a prothrombotic state without overt developmental outcomes. We note fibrin deposits in the kidney and rare cases of brain ischemia.
Assuntos
Lipoproteínas/deficiência , Trombina/metabolismo , Animais , CamundongosRESUMO
The interaction of platelet glycoprotein Ibα (GPIbα) with von Willebrand factor (VWF) initiates hemostasis after vascular injury and also contributes to pathological thrombosis. GPIbα binding to the VWF A1 domain (VWFA1) is a target for antithrombotic intervention, but attempts to develop pharmacologic inhibitors have been hindered by the lack of animal models because of the species specificity of the interaction. To address this problem, we generated a knockin mouse with Vwf exon 28-encoding domains A1 and A2 replaced by the human homolog (VWFh28). VWFh28 mice (M1HA) were crossbred with a transgenic mouse strain expressing human GPIbα on platelets (mGPIbαnull;hGPIbαTg; H1MA) to generate a new strain (H1HA) with humanized GPIbα-VWFA1 binding. Plasma VWF levels in the latter 3 strains were similar to those of wild-type mice (M1MA). Compared with the strains that had homospecific GPIbα-VWF pairing (M1MA and H1HA), M1HA mice of those with heterospecific pairing had a markedly greater prolongation of tail bleeding time and attenuation of thrombogenesis after injury to the carotid artery than H1MA mice. Measurements of GPIbα-VWFA1 binding affinity by surface plasmon resonance agreed with the extent of observed functional defects. Ristocetin-induced platelet aggregation was similar in H1HA mouse and human platelet-rich plasma, and it was comparably inhibited by monoclonal antibody NMC-4, which is known to block human GPIbα-VWFA1 binding, which also inhibited FeCl3-induced mouse carotid artery thrombosis. Thus, the H1HA mouse strain is a fully humanized model of platelet GPIbα-VWFA1 binding that provides mechanistic and pharmacologic information relevant to human hemostatic and thrombotic disorders.
Assuntos
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Fator de von Willebrand/metabolismo , Animais , Biomarcadores , Plaquetas/metabolismo , Cruzamentos Genéticos , Éxons , Hemostasia , Humanos , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Agregados Proteicos , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Trombose/etiologia , Trombose/metabolismo , Fator de von Willebrand/química , Fator de von Willebrand/genéticaRESUMO
Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd-/-) mice to term. Half of the Thbd-/- offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd-/- animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd-/- mice. However, Thbd-/- females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy.
RESUMO
BACKGROUND: Serological safety is an integral part of overall safety for blood banks. Emphasis is on the use of routinue Red Blood Cell (RBC) antibody screen test, at set time intervals, to reduce risks related to alloantibodies. Also emphasis is on importance of issuing antigen negative blood to alloantibody positive patients. Effect of using leucodepleted blood on the rate of alloimmunization is highlighted. The concept of provision of phenotypically matched blood is suggested. MATERIALS AND METHODS: Antibody screen test is important to select appropriate blood for transfusion. Repeat antibody screen testing, except if time interval between the earlier and subsequent transfusion was less than 72 hours, followed by antibody identification, if required, was performed in patients being treated with repeat multiple blood transfusions. Between February 2008 and June 2009, repeat samples of 306 multi-transfused patients were analyzed. Search for irregular antibodies and reading of results was conducted using RBC panels (three-cell panel of Column Agglutination Technology (CAT) and two cell panel of the Solid Phase Red Cell Adherence Technology (SPRCAT). Specificities of antibodies were investigated using appropriate panels, 11 cell panel of CAT and 16 cell panel of SPRCA. These technologies, detecting agglutination in columns and reactions in solid phase, evaluate the attachment of irregular incomplete antibody to antigen in the first phase of immunological reaction more directly and hence improve the reading of agglutination. Three to four log leuco reduced red blood cells were transfused to patients in the study using blood collection bags with integral filters. RESULTS: Alloimmunization rate of 4.24% was detected from 306 multiply transfused patients tested and followed up. The Transfusion therapy may become significantly complicated. CONCLUSION: Red cell antibody screening and identification and subsequent issue of antigen negative blood have a significant role in improving blood safety. Centers that have incorporated antibody screen test and identification have ensured safe transfusion. Identified patients should be flagged in a database and information shared. Such patients can be given carry-on cards and educated about the names of the identified antibodies. Full red cell phenotyping of individuals, patients and donors, can be feasibility.
RESUMO
Low molecular weight heparin (LMWH) is being tested as an experimental drug for improving pregnancy outcome in women with inherited thrombophilia and placenta-mediated pregnancy complications, such as recurrent pregnancy loss. The role of thrombotic processes in these disorders remains unproven, and the issue of antithrombotic prophylaxis is intensely debated. Using a murine model of factor V Leiden-associated placental failure, we show that treatment of the mother with LMWH allows placental development to proceed and affords significant protection from fetal loss. Nonetheless, the therapeutic effect of LMWH is not replicated by anticoagulation; fondaparinux and a direct Xa inhibitor, C921-78, achieve anticoagulation similar to LMWH but produce little or no improvement in pregnancy outcome. Genetic attenuation of maternal platelet aggregation is similarly ineffective. In contrast, even a partial loss of thrombin sensitivity of maternal platelets protects pregnancies. Neonates born from these pregnancies are growth retarded, suggesting that placental function is only partially restored. The placentae are smaller but do not reveal any evidence of thrombosis. Our data demonstrate an anticoagulation-independent role of LMWH in protecting pregnancies and provide evidence against the involvement of thrombotic processes in thrombophilia-associated placental failure. Importantly, thrombin-mediated maternal platelet activation remains central in the mechanism of placental failure.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fator V/fisiologia , Heparina/uso terapêutico , Camundongos Knockout , Doenças Placentárias/tratamento farmacológico , Doenças Placentárias/etiologia , Gravidez de Alto Risco , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/genética , Embrião de Mamíferos , Fator V/genética , Feminino , Heparina/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doenças Placentárias/genética , Gravidez , Complicações Hematológicas na Gravidez/tratamento farmacológico , Complicações Hematológicas na Gravidez/etiologia , Complicações Hematológicas na Gravidez/genética , Gravidez de Alto Risco/sangueRESUMO
Inherited thrombophilia is recognized as one of the causes of recurrent fetal loss. Yet, the risk of fetal loss in women with thrombophilia is far from absolute. Other risk modifiers are clearly involved, but remain to be identified. The mechanism that translates maternal thrombophilia into pregnancy disorder is also not understood. Genetically engineered mice have led to the development of new insights into the etiology and pathogenesis of thrombophilia-associated fetal loss. These insights are the focus of this review.
Assuntos
Morte Fetal/etiologia , Complicações Hematológicas na Gravidez/genética , Trombofilia/complicações , Trombofilia/genética , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Fator V/genética , Feminino , Morte Fetal/sangue , Morte Fetal/genética , Humanos , Camundongos , Camundongos Knockout , Gravidez , Complicações Hematológicas na Gravidez/sangue , Trombofilia/sangueRESUMO
In mice lacking the blood coagulation regulator thrombomodulin, fibrinolytic degradation products (FDP) of fibrin induce apoptotic cell death of a specialized cell type in the placenta, polyploid trophoblast giant cells. Here, we document that this bioactivity of FDP is conserved in human FDP, is not limited to trophoblast cells, and is associated with an Aalpha-chain segment of fibrin fragment E (FnE). The majority of proapoptotic activity is arginine-glycine-aspartic acid (RGD)-independent and requires caveolin-1-dependent cellular internalization of FnE. Internalization through caveoli is mediated by an epitope contained within Aalpha52-81 that is necessary and sufficient for cellular uptake of FnE. Aalpha52-81 does not cause apoptosis itself, and competitively inhibits FnE internalization and apoptosis induction. Apoptotic activity per se resides within Aalpha17-37 and requires the N-terminal neoepitope generated by release of fibrinopeptide A. Cellular internalization of FnE elicits depression of mitochondrial function and consequent apoptosis that is strictly dependent on the activity of caspases 9 and 3. These findings describe the molecular details of a novel mechanism linking fibrin degradation to cell death in the placenta, which may also contribute to pathologic alterations in nonplacental vascular beds that are associated with fibrinolysis.
Assuntos
Apoptose , Caveolina 1/fisiologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Animais , Aorta/citologia , Aorta/metabolismo , Caspase 3/metabolismo , Células Cultivadas , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Glutationa Transferase/genética , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Fragmentos de Peptídeos/metabolismo , Gravidez , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Trofoblastos/citologia , Trofoblastos/metabolismo , Veias Umbilicais/citologia , Veias Umbilicais/metabolismo , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologiaRESUMO
Absence of the blood coagulation inhibitor thrombomodulin (Thbd) from trophoblast cells of the mouse placenta causes a fatal arrest of placental morphogenesis. The pathogenesis of placental failure requires tissue factor, yet is not associated with increased thrombosis and persists in the absence of fibrinogen. Here, we examine the role of alternative targets of coagulation that might contribute to the placental failure and death of Thbd(-/-) embryos. We demonstrate that genetic deficiency of the protease-activated receptors, Par1 or Par2, in the embryo and trophoblast cells does not prevent the death of Thbd(-/-) embryos. Similarly, genetic ablation of the complement pathway or of maternal immune cell function does not decrease fetal loss. In contrast, Par4 deficiency of the mother, or the absence of maternal platelets, restores normal development in one-third of Thbd-null embryos. This finding generates new evidence implicating increased procoagulant activity and thrombin generation in the demise of thrombomodulin-null embryos, and suggests that platelets play a more prominent role in placental malfunction associated with the absence of thrombomodulin than fibrin formation. Our findings demonstrate that fetal prothrombotic mutations can cause localized activation of maternal platelets at the feto-maternal interface in a mother with normal hemostatic function.
Assuntos
Plaquetas/fisiologia , Doenças Placentárias/etiologia , Receptores Ativados por Proteinase/fisiologia , Trombomodulina/deficiência , Animais , Coagulação Sanguínea , Embrião de Mamíferos , Feminino , Troca Materno-Fetal , Camundongos , Camundongos Knockout , Mães , Gravidez , Receptores Ativados por Proteinase/deficiência , TrombofiliaRESUMO
Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but <10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.
Assuntos
Endotoxemia/metabolismo , Endotoxemia/patologia , Proteína C/metabolismo , Engenharia de Proteínas , Sepse/metabolismo , Sepse/patologia , Animais , Apoptose , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Endotoxemia/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína C/genética , Sepse/tratamento farmacológico , Transdução de Sinais , Taxa de SobrevidaRESUMO
We describe a mouse model of fetal loss in factor V Leiden (FvL) mothers in which fetal loss is triggered when the maternal prothrombotic state coincides with fetal gene defects that reduce activation of the protein C anticoagulant pathway within the placenta. Fetal loss is caused by disruption of placental morphogenesis at the stage of labyrinth layer formation and occurs in the absence of overt placental thrombosis, infarction, or perfusion defects. Platelet depletion or elimination of protease-activated receptor 4 (Par4) from the mother allows normal placentation and prevents fetal loss. These findings establish a cause-effect relationship for the observed epidemiologic association between maternal FvL status and fetal loss and identify fetal gene defects as risk modifiers of pregnancy failure in prothrombotic mothers. Pregnancy failure is mediated by Par4-dependent activation of maternal platelets at the fetomaternal interface and likely involves a pathogenic pathway independent of occlusive thrombosis. Our results further demonstrate that the interaction of two given thrombosis risk factors produces markedly disparate consequences on disease manifestation (i.e., thrombosis or pregnancy loss), depending on the vascular bed in which this interaction occurs.
Assuntos
Resistência à Proteína C Ativada/complicações , Plaquetas/metabolismo , Modelos Animais de Doenças , Fator V/genética , Morte Fetal/etiologia , Doenças Fetais/genética , Placenta/patologia , Resistência à Proteína C Ativada/genética , Animais , Feminino , Morte Fetal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Placenta/irrigação sanguínea , Mutação Puntual/genética , Gravidez , Resultado da Gravidez/genética , Receptores de Trombina/metabolismo , Fatores de Risco , Trombomodulina/genéticaRESUMO
Humans and rodents exhibit a peculiar type of placentation in which zygote-derived trophoblast cells, rather than endothelial cells, line the terminal maternal vascular space. This peculiar aspect of the placental vasculature raises important questions about the relative contribution of fetal and maternal factors in the local control of hemostasis in the placenta and how these might determine the phenotypic expression of thrombophilia-associated complications of pregnancy. Using genomewide expression analysis, we identify a panel of genes that determine the ability of fetal trophoblast cells to regulate hemostasis at the fetomaternal interface. We show that spontaneous differentiation of trophoblast stem cells is associated with the acquisition of an endothelial cell-like thromboregulatory gene expression program. This program is developmentally regulated and conserved between mice and humans. We further show that trophoblast cells sense, via the expression of protease activated receptors, the presence of activated coagulation factors. Engagement of these receptors results in cell-type specific changes in gene expression. Our observations define candidate fetal genes that are potential risk modifiers of maternal thrombophilia-associated pregnancy complications and provide evidence that coagulation activation at the fetomaternal interface can affect trophoblast physiology altering placental function in the absence of frank thrombosis.
Assuntos
Coagulação Sanguínea/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hemostasia/fisiologia , Troca Materno-Fetal/fisiologia , Gravidez/fisiologia , Trofoblastos/fisiologia , Animais , Fatores de Coagulação Sanguínea/metabolismo , Diferenciação Celular/fisiologia , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Complicações Hematológicas na Gravidez/genética , Complicações Hematológicas na Gravidez/metabolismo , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Células-Tronco/citologia , Células-Tronco/fisiologia , Trombofilia/genética , Trombofilia/metabolismo , Trombose/genética , Trombose/metabolismo , Trofoblastos/citologia , Zigoto/citologia , Zigoto/fisiologiaRESUMO
Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration (1) elicits augmented fibrin deposition in specific organs, (2) interacts with an independent modifier of hemostatic activity to regulate fibrin turnover/deposition, (3) exacerbates neointimal hyperplasia in an experimental model of stasis-induced vascular remodeling, yet (4) may suppress thrombin generation in response to a procoagulant challenge. These findings provide direct experimental evidence that hyperfibrinogenemia is more than a by-product of cardiovascular disease and may function independently or interactively to modulate the severity and/or progression of vascular disease.
Assuntos
Fibrinogênio/biossíntese , Fibrinogênio/fisiologia , Doenças Vasculares/etiologia , Doenças Vasculares/patologia , Animais , Artérias Carótidas/patologia , Cloretos , Reagentes de Ligações Cruzadas/farmacologia , Dimerização , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Compostos Férricos/farmacologia , Fibrinogênio/metabolismo , Camundongos , Camundongos Transgênicos , Ligação Proteica , Trombina/metabolismo , TromboseRESUMO
Sepsis is associated with systemic inflammation, coagulopathy, and disrupted protein C (PC) pathway function. The effect of prothrombotic polymorphism, factor V Leiden (Arg506Gln; FV Leiden), was examined in a large clinical trial (PROWESS) of severe sepsis and a mouse endotoxemia model. In PROWESS, 4.1% (n = 65) of patients were heterozygous FV Leiden (VL+/-) carriers. The 28-day mortality was lower in VL+/- (13.9%) than in non-FV Leiden (VL-/-; 27.9%) patients (P =.013). The mortality benefit of recombinant human activated PC (rhAPC) treatment was similar in VL+/- (placebo, 15.6%; rhAPC,12.1%) and VL-/- patients (placebo, 31.0%; rhAPC, 24.7%; interaction P =.981). VL+/- status did not appear to influence baseline biomarkers of coagulopathy and inflammation or disease severity, with the exception that vasopressor usage was less in VL+/- patients (46.2% versus 63.0%; P =.009). In a median lethal dose (40 mg/kg) endotoxin mouse model, VL+/- mice had lower mortality than wild-type mice (19% versus 57%; P =.008), whereas the mortality of homozygous (VL+/+) mice was almost identical to that of wild-type mice (65% versus 57%; P =.76). The findings suggest that FV Leiden constitutes a rare example of a balanced gene polymorphism that maintains the FV Leiden mutation in the general gene pool due to a survival advantage of VL+/- in severe sepsis.
Assuntos
Endotoxemia/genética , Fator V/fisiologia , Sepse/genética , Idoso , Animais , Biomarcadores/sangue , Coagulação Sanguínea , Endotoxemia/mortalidade , Feminino , Heterozigoto , Humanos , Inflamação , Masculino , Camundongos , Camundongos Mutantes , Pessoa de Meia-Idade , Mutação Puntual , Proteína C/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Sepse/tratamento farmacológico , Sepse/mortalidade , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Genetic or acquired thrombophilia of the pregnant mother has been associated with the occurrence of gestational vascular disease and recurrent fetal loss and may contribute to the aetiology of pre-eclampsia. This chapter reviews insights into this link between thrombophilia and pregnancy complications that were gained from the study of genetically altered mice. These studies strongly support the notion of a cause-effect relationship between altered function of the thrombomodulin-protein C pathway and adverse pregnancy outcome. Analysis of the mouse models highlights unique aspects of vascular structure and function at the feto-maternal interface, and exposes new biological functions of natural anticoagulant pathways in pregnancy. These roles are unrelated to the maintenance of vascular patency and may be mediated through specific signalling pathways activated by coagulation factors. Abnormal signalling by placental trophoblasts at the feto-maternal interface is suggested as a hitherto unrecognized mechanism that may underlie adverse pregnancy outcome associated with haemostatic disorders.
Assuntos
Fatores de Coagulação Sanguínea/genética , Desenvolvimento Embrionário e Fetal , Animais , Inibidores dos Fatores de Coagulação Sanguínea/deficiência , Inibidores dos Fatores de Coagulação Sanguínea/genética , Inibidores dos Fatores de Coagulação Sanguínea/fisiologia , Fatores de Coagulação Sanguínea/fisiologia , Desenvolvimento Embrionário e Fetal/genética , Feminino , Camundongos , Camundongos Knockout , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/etiologia , Trombofilia/complicaçõesRESUMO
Disruption of the mouse gene encoding the blood coagulation inhibitor thrombomodulin (Thbd) leads to embryonic lethality caused by an unknown defect in the placenta. We show that the abortion of thrombomodulin-deficient embryos is caused by tissue factor-initiated activation of the blood coagulation cascade at the feto-maternal interface. Activated coagulation factors induce cell death and growth inhibition of placental trophoblast cells by two distinct mechanisms. The death of giant trophoblast cells is caused by conversion of the thrombin substrate fibrinogen to fibrin and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of protease-activated receptors (PAR)-2 and PAR-4 by coagulation factors. These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.