Materiały źródłowe

• #1 The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8950029/

  The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti–2-glycoprotein 1, and/or anticardiolipin antibodies. […] In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. […] In obstetrical APS, a failure in the spiral artery remodeling by the extravillous trophoblast induces a reduction or interruption of the maternal blood supply to the placenta generating either hypoxic/ ischemic damage or inadequate nutrient influx to the fetus and/or an increased flux that may cause placental damage.

• #1 Pathophysiology of Antiphospholipid Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9391091/

  The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. […] A distinguishing feature of the antiphospholipid syndrome is the lupus anticoagulant. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of 2 -glycoprotein I and/or prothrombin bound to an anionic phospholipid. […] Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity.

• #1 Antiphospholipid syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Antiphospholipid_syndrome

  Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease. […] Antiphospholipid syndrome is an autoimmune disease, in which „antiphospholipid antibodies” react against proteins that bind to anionic phospholipids on plasma membranes. Anticardiolipin antibodies, 2glycoprotein 1, and lupus anticoagulant are antiphospholipid antibodies that are thought to clinically cause disease. These antibodies lead to blood clots and vascular disease in the presence (secondary APS) or absence (primary APS) of other diseases.

• #1 The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8950029/

  Because 2GP1 is constitutively expressed on the surface of all subpopulations of the placental trophoblast and maternal endothelial cells, it is likely to hypothesize that this protein is the target for -2GP1 and other aPLs. […] The presence of LA is strongly associated with a higher risk of venous and arterial thrombosis as compared with the risk imposed by aCL and -2GP1. […] Several mechanisms explain the thrombotic events in APS patients. […] APS patients have elevated levels of cell-free DNA and NETs which correlate with the -2GP1 titers and that these titers are more increased in LA positive patients and even more in triple-positive patients (aCL+, -2GPI+, LA+). […] The effects of aPLs on hemostasis and fibrinolysis range from inhibition of tPA activity and inhibition of FXII-mediated fibrinolysis to inhibition of FXI inactivation by antithrombin as well as increased FXIII synthesis. […] The complement system has a pivotal role in the pathophysiology of APS as demonstrated in a mouse model of surgical induced thrombosis where administration of aPLs did not induce thrombosis in C3 and C5 deficient mice or anti-C5 treated normal mice.

• #1 The Pathophysiology of Antiphospholipid Syndrome

  https://openurologyandnephrologyjournal.com/VOLUME/8/PAGE/2/FULLTEXT/

  Advances in our knowledge of the pathogenic mechanisms of antiphospholipid syndrome have been achieved in the past few years. […] The pathophysiology of APS is incompletely understood. Although a prothrombotic basis is presumed, the thrombotic mechanisms are not well established in arterial and venous thrombosis. […] A concept called the two-hit theory is used to explain the pathophysiology of some diseases. In the case of APS it implies that two triggers are needed to achieve the prothrombotic state. The first hit in the case of APS is likely to be the presence of aPL which have inflammatory and prothrombotic properties in endothelial, dendritic and mastocytic cells. The second would be an acute precipitating event such as surgery, infection, immobilization, pregnancy or oral contraceptives.

• #1 Antiphospholipid Syndrome: Insights into Molecular Mechanisms and Clinical Manifestations

  https://www.mdpi.com/2077-0383/13/14/4191

  Injecting aPLs into mice, rats, or hamsters does not induce spontaneous thrombotic complications. However, in accordance with the ‘multi-hit’ hypothesis of thrombosis, the thrombotic reaction following a priming event, like a minor vascular injury, is notably intensified when aPLs are present compared to the infusion of a control antibody. […] An activated complement system has been linked to a prothrombotic state through the membrane attack complex or anaphylatoxins, especially C5a.

• #1 Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

  https://www.mdpi.com/2077-0383/12/3/891

  The pathological features of antiphospholipid syndrome (APS) are related to the activity of circulating antiphospholipid antibodies (aPLs) associated with vascular thrombosis and obstetric complications. […] aPLs are not only disease markers, but also play a determining pathogenetic role in APS and exert their effects through the activation of cells and coagulation factors and inflammatory mediators for the materialization of the thromboinflammatory pathogenetic mechanism. […] Cellular activation in APS necessarily involves the interaction of aPLs with target receptors on the cell membrane, capable of triggering the signal transduction pathway(s). […] In this review, we describe the pathogenic mechanisms of APS through the key role of lipid rafts as signaling platforms, suggesting this pathogenetic step as a strategic target of new therapies.

• #1 Antiphospholipid Syndrome: Insights into Molecular Mechanisms and Clinical Manifestations

  https://www.mdpi.com/2077-0383/13/14/4191

  Antiphospholipid syndrome (APS) is a complex systemic autoimmune disorder characterized by a hypercoagulable state, leading to severe vascular thrombosis and obstetric complications. […] This article delves into the intricate pathogenesis of APS, explores the latest classification criteria, and evaluates cutting-edge diagnostic tools and therapeutic strategies. […] In APS, aPL can directly target endothelial cells, leading to endothelial dysfunction and activation. Mechanistically, aPL engages surface receptors on endothelial cells, triggering signaling pathways associated with inflammation and thrombosis. […] However, in APS, the normally quiescent endothelium undergoes activation, shedding its antithrombotic profile and assuming a proinflammatory phenotype. […] Understanding the intricate interplay between aPL and endothelial cells is essential for elucidating the pathophysiology of APS and developing targeted therapeutic strategies.

• #1 Antiphospholipid syndrome: pathophysiology, diagnosis and treatment – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/antiphospholipid-syndrome-pathophysiology-diagnosis-and-treatment

  Antiphospholipid syndrome (APS, also known as Hughes syndrome) is an autoimmune condition in which patients are in a hypercoagulable state, which means that they are at increased risk of developing thromboses in the venous, arterial or microvascular system. […] Several cellular pathways and events are associated with APS pathogenesis. For a detailed summary of the proposed mechanism of aPL-mediated thrombosis, see Figure 1. A group of aPL that bind to phospholipid binding proteins (most commonly β-2 glycoprotein 1, but also prothrombin, tissue plasminogen activator, annexin A2 and thrombin) may be associated with the activation of endothelial cells, monocytes and platelets. This activation results in the following mechanisms: Endothelial cells increase the expression of adhesion molecules (e.g. intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and upregulation of production of tissue factor); Monocytes upregulate the production of tissue factors; Platelets increase the expression of glycoprotein IIb-IIIa receptors and the synthesis of thromboxane A2.

• #1 The Pathophysiology of Antiphospholipid Syndrome

  https://openurologyandnephrologyjournal.com/VOLUME/8/PAGE/2/FULLTEXT/

  Although many antibodies have been involved in the pathogenesis of APS (including those binding to 2-GPI, prothrombin, annexin A5, protein S, protein C, factor X1, and factor XII), 2-glycoprotein seems to be the most relevant target. […] After the formation of the antigen-antibody immunocomplex, the open linear configuration, also known as the fishhook remains open. The complex can activate cellular elements (monocytes, endothelial cells and platelets), inhibit the fibrinolytic system, activate the coagulation cascade, and the complement system. […] A possible mechanism of thrombosis is aPL-induced damage to the endothelial nitric oxide (eNO) synthesis pathway. APS patients have low plasma levels of eNO compared with controls. […] Another target under scrutiny is tissue factor (TF). This factor is the key initiator of blood coagulation.

• #1 Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-021-00240-8

  Anti-2GPI antibodies are known to be one of the major responsible causes of thrombotic events in APS. […] It has been demonstrated that anti-2GPI antibodies potentiate thrombosis by binding to 2GPI on cell surfaces activating endothelial cells, monocytes, platelets, neutrophils, fibroblasts, and trophoblasts. […] Recent studies suggest that APS is more related to endothelial cell activation rather than antibody-mediated coagulation. […] Endothelial cell activation through Toll-like receptor (TLR) family as a result of anti-2GPI antibodies and endothelial cell interaction was first described in 2003. […] A recently discovered pathway shows that anti-2GPI antibodies may cause endothelial cell activation by releasing endothelial cell-derived extracellular vesicles through TLR7 and that these endothelial vesicles may contribute to the activation of unstimulated neighboring endothelial cells by paracrine signaling.

• #1 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  Significant in vitro and in vivo studies confirm that aPL are pathogenic. The exact mechanism by which these antibodies participate in the prothrombotic tendency of APS, remain to be clearly defined. However, it has been illustrated that the heterogeneity of antibodies is associated with multiple mechanisms of action. These include briefly: the activation of cellular components (endothelial cells, platelets and monocytes), activation of the coagulation cascade, inhibition of the fibrinolytic system, inhibition of natural anticoagulant pathways and activation of the complement system. […] The interaction of aPL with endothelial cells has until now been in frequent disputes and misunderstandings. […] In vitro studies have shown that 2GPI binds to immobilized endothelial cells, and allows the anti-2GPI antibodies to bind to cells and induce a proinflammatory and procoagulant phenotype. […] A clinical demonstration of endothelial dysfunction in APS patients is the increased level of circulating endothelial microparticles and endothelial cells in peripheral blood. […] Animal models suggest that human polyclonal and monoclonal aPL activate endothelium and enhance clot formation in vivo. […] The study of the endothelium clearly indicates the potentially beneficial effect of statins in the therapeutic approach of patients. […] The role of anti-endothelial antibodies, especially of anti-HSP60, in the mechanism of thrombosis was studied in LA positive patients with secondary APS. […] The exact nature of aPL- receptors on the surface of endothelial cells remains obscure and is a key subject of current research. […] The study of signal transduction in aPL-mediated endothelial activation continues to be an important area of research.

• #1 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  The thrombophilic tendency in combination with the observation that thrombocytopenia is a frequent manifestation in APS, led early on the assumption that platelet activation is an important factor in the pathogenesis of the disease. […] Several studies demonstrate platelet activation and aggregation by aPL, both in vitro and in vivo. […] It has been demonstrated that aPL cannot bind to the surface of „intact” platelets, while they have the ability to bind to platelets with exposed negatively charged phospholipids in their membranes. […] A second indication of impaired platelet function in APS, is the observation that approximately 40% of patients show prolonged bleeding time, without accompanying bleeding tendency. […] Strong evidence of aPL-induced platelet activation is the enhanced expression of platelet membrane glycoproteins, particularly GPIIb-IIIa (fibrinogen receptor, critical in platelet aggregation) and GPIIIa. […] The activation of platelets by aPL, in vivo, has been supported by several groups.

• #1 Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-021-00240-8

  It has been recently demonstrated that aPLs activate AKT/ mammalian target of rapamycin (mTOR) pathway in the endothelial cells and cause proliferation of endothelial and vascular smooth muscle actin cells. […] Platelet activation also has an important effect on thrombus formation in ALP. […] Other studies demonstrate that neutrophils may also contribute to pathologic clotting, especially venous thrombosis in APS. […] Neutrophils release neutrophil extracellular traps (NETs), which consist of nucleus originated DNA and histones, as well as cytoplasm derived granule proteins, such as neutrophil elastase and myeloperoxidase. […] In addition, APS neutrophils show proinflammatory signature expression related to interferon (IFN)-mediated signaling pathway, cellular defense and intercellular adhesion.

• #1 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  Activation of monocytes by aPL has been extensively studied. The main findings include an increase of TF expression and activity as well as the increased production of proinflammatory cytokines. […] It is assumed that although aPL cause delayed clotting times in vitro, these antibodies exert procoagulant effects in vivo, with accelerated thrombin formation. […] The exact pathogenic involvement of aPL in the coagulation cascade remains obscure. […] It has been supported by several studies that although anti-PT antibodies are involved in the activity of LA, these antibodies by themselves are not associated with thrombosis. […] Research data suggest that impaired fibrinolysis may contribute to the thrombophilic tendency in APS. […] 2GPI has also been suggested to have a direct role in fibrinolysis, through direct interaction with components of plasminogen activation. […] The role of annexin A2 in the mechanism of fibrinolysis is also interesting.

• #1 What Rheumatologists Need to Know About Antiphospholipid Syndrome – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-rheumatologists-need-to-know-about-antiphospholipid-syndrome/

  One recent advancement in our understanding of APS has spotlighted the involvement of neutrophils and their inflammatory byproducts, known as neutrophil extracellular traps (NETs). Neutrophils are, of course, instrumental to the body’s innate defense against pathogens. In pursuit of containing pathogens, neutrophils release NETs, spider web-like structures built of nucleus-derived chromatin that becomes decorated with various antimicrobial enzymes. NETs are triggered not only by infections, but also by sterile stimuli, such as immune complexes and other inflammatory cues, and it is from this sterile perspective that they appear to contribute to the coagulopathy and inflammation inherent to APS. […] Several decades ago, it was shown that aPL can activate neutrophils to release damaging reactive oxygen species and to express tissue factor on the cells surface. Elegant work between 2000 and 2010 found that neutrophils play an instrumental role in driving the dysfunctional placentation that is unfortunately common in pregnant individuals with APS. Most recently, it has been revealed that at least some aPL also triggers NET release, with these prothrombotic structures then able to engage with, and activate, clotting factors, endothelial cells, platelets and the complement system.

• #1 Antiphospholipid syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Antiphospholipid_syndrome

  While the exact functions of the antibodies are not known, the activation of the coagulation system is evident. […] Anti-ApoH and a subset of anti-cardiolipin antibodies bind to ApoH. ApoH inhibits protein C, a glycoprotein with important regulatory function of coagulation (inactivates Factor Va and Factor VIIIa). Lupus anticoagulant antibodies bind to prothrombin, thus increasing its cleavage to thrombin, its active form. […] Other antibodies associated with APS include antibodies against protein S and annexin A5. Protein S is a co-factor of protein C, which is one of the body’s own anti-clotting factors. Annexin A5 forms a shield around negatively charged phospholipid molecules, which reduces the membrane’s ability to participate in clotting. Thus, antibodies against protein S and anti-annexin A5 decrease protein C efficiency and increase phospholipid-dependent coagulation steps respectively, which leads to increased clotting potential.

• #1 Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

  https://www.mdpi.com/2077-0383/12/3/891

  Several studies have shown that aPLs exert their effects through activation of various cells (endothelial cells, monocytes, platelets, endometrial and decidual cells), as well as a complement system, coagulation factors and inflammatory mediators. […] These pathogenetic mechanisms underlying clinical manifestations of APS can be exploited as targets of immunomodulatory therapeutic strategies to be used in APS patients. […] In addition, the thrombogenic effect of aPLs may involve the activation of the complement system, through both the alternative and the classical pathway. […] Many studies have described the direct activity of aPLs in association with pregnancy complications as part of the pathogenesis of OAPS. […] The first indication derived from the observation of Sorice et al. is that the anti-β2-GPI target antigen was found within lipid rafts which are specialized portions of the cell plasma membrane implied in signal transduction pathways, as revealed by the sucrose gradient analysis and coimmunoprecipitation experiments. […] These findings indicated that lipid rafts play a key role in the signal transduction pathway induced by anti-β2-GPI antibodies, and that raft-dependent anti-β2-GPI antibody triggering resulted in the release of either TNF-α and TF, which may contribute to the pathogenesis of thrombosis in APS.

• #1 Pathophysiology of Antiphospholipid Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9391091/

  The endothelium releases a variety of factors that retard thrombosis, but its antithrombotic activity is severely compromised by APA. […] The net effect of APA is to enhance platelet adhesion and diminish the clot-inhibitory properties of the endothelium. […] Accelerated (premature) atherosclerosis is another feature of APS. […] The consequence is vascular occlusion, tissue infarction, and fetal loss. […] Antibodies to PT were reported in 31 of 42 (74%) patients with LAC. […] They prolong in vitro clotting tests by out-competing factor Xa for phospholipid-binding sites, but in vivo the increased affinity of LACPT complexes for phospholipid surfaces augments thrombin production and might contribute to the enhanced risk of thrombosis in patients with SLE. […] Complement activation, recognized by bioassay and detection of C5b-9 deposition on cell surfaces, is present in about a third of APS samples, occurs mainly in conjunction with triple positivity (positive tests for LAC, ACA, and anti- 2 -GPI), and is associated with thrombotic events.

• #1 Pathogenesis of antiphospholipid syndrome: understanding the antibodies | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.52

  Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). […] Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit’, frequently related to innate inflammatory immune responses. […] 2 glycoprotein I (2GPI)-dependent aPL, the most important subset of these antibodies, mediate several not necessarily alternative thrombogenic mechanisms, mainly on the basis of their reactivity with 2GPI expressed on the membrane of cells that participate in the coagulation cascade. […] Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. […] 2GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation.

• #1 Antiphospholipid syndrome in pregnancy: a comprehensive literature review | BMC Pregnancy and Childbirth | Full Text

  https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-025-07471-w

  The two-hit model in APS pathogenesis indicates that antiphospholipid antibodies lead to endothelial dysfunction, necessitating a secondary environmental trigger to manifest clinical symptoms. […] Following this two-hit pattern, aPLs lead to placental insufficiency by inducing a pro-inflammatory state in the vascular wall of the trophoblastic tissues which leads to a prothrombotic state. […] The pro-inflammatory state mediated by antiphospholipid antibodies is facilitated by inflammatory factors such as the deposition of IgG and complement, neutrophilic infiltration, but also a local secretion of TNF-alpha. […] Emerging evidence points to complement activation and endothelial dysfunction as critical mechanisms in APS pathophysiology. […] In APS pregnancies, complement activation, driven by antiphospholipid antibodies, disrupts placental function, causing inflammation, thrombosis, and impaired blood flow, leading to fetal growth restriction, preeclampsia, and pregnancy loss.

• #1 Antiphospholipid syndrome: pathophysiology, diagnosis and treatment – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/antiphospholipid-syndrome-pathophysiology-diagnosis-and-treatment

  These three pathways induce a thrombogenic state by increasing the synthesis of tissue factor and thromboxane A2, which may lead to activation of the coagulation system and subsequent development of thrombosis. However, the mechanisms causing thrombosis are not currently fully understood. Other suggested mechanisms for its development include interference in the protein C anticoagulant pathway, inhibition of fibrinolysis and inhibition of annex V binding to phospholipids. […] Complications in pregnancy can develop as a result of APS. This is commonly through the inhibition of trophoblastic function (the outer layer of cells that provide nutrients to the embryo), which can lead to miscarriage. Although other mechanisms may include a local inflammatory response (as a result of activation of the complement system) or, in later stages of pregnancy, the formation of thrombosis in the placental bed. However, it should be noted that other contributing factors can increase the risk of foetal death, (e.g. underlying hypertension, SLE or renal disease).

• #1 Pathogenesis of antiphospholipid syndrome: understanding the antibodies | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.52

  Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question. […] Whereas evidence shows that a second hit (usually an inflammatory event) is required for thrombus formation in APS, this requirement is less clear for fetal loss. […] In addition to placental thrombosis, other mechanisms for direct effects of aPL on placental tissues have been proposed. […] 2 glycoprotein I (2GPI)-dependent autoantibodies seem to be the main pathogenic subpopulation of aPL. […] More information about the epitope specificity of anti-2GPI aPL, as well as about the tissue expression of the target molecule, might help to better understand the pathogenesis of APS.

• #1 Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

  https://www.mdpi.com/2077-0383/12/3/891

  At the end, the heterogeneity of the mechanisms underlying APS may be related to the different signal transduction pathways triggered by aPLs. Recently, increasing evidence suggests that they are driven by specific microdomains on the cell plasma membrane termed lipid rafts. […] Evidence of the thrombogenic activity of aPLs has been provided by both in vitro and in vivo studies; however, despite the presence of aPLs in the circulation, thrombotic manifestation is not always observed in the patients. […] These considerations suggest the “two-hit hypothesis” concept to better clarify the pathogenetic role of aPLs in the mechanisms underlying the development of thrombosis in APS patients. […] Thrombus formation is the most studied aspect of APS pathophysiology, and the procoagulant phenotype observed in the disease has been described as a result of the synergistic activation of many elements, where inflammation represents a central pathogenetic factor that acts as a mediator between the coagulation dysfunction and thrombotic manifestations.

• #1 The well-defined antiphospholipid syndrome induced by COVID-19: a rare case report and review of the literature | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-024-00669-6

  Therefore, we propose that SARS-CoV-2 infection may induce antiphospholipid syndrome characterized by sustained elevation in antiphospholipid antibody levels. […] The possible pathogenesis of APS in patients with COVID-19 is as follows: I) the anti-2GPI-2GPI complex disrupts the antithrombotic barrier between endothelial cells and annexin A5; II) the anti-2GPI-2GPI complex increases signal transduction; III) the anti-2GPI-2GPI complex interferes with fibrinolysis and endogenous antithrombotic formation; and IV) the anti-2GPI-2GPI complex triggers platelet activation. […] The pathogenesis of antiphospholipid syndrome. The possible pathogenesis of APS: 1. The anti-2GPI-2GPI complex binds to anionic coagulation-promoting surfaces, such as heparan acetylates, via the V-region cation of 2GPI upon damage to the endothelial surface; 2. The anti-2GPI-2 GPI complex triggers the activation of annexin A2, ApoE2, TLR4, and other receptors on endothelial cells, thereby promoting downstream signalling pathways involving protein kinase (p38MAPK) and nuclear B factor (NF-B). This leads to increases in the levels of tissue factor (TF), adhesion molecule (AM), and proinflammatory coagulation; 3. The anti-2GPI-2GPI complex hinders fibrinolysis and anticoagulation by suppressing the activity of fibrinolytic enzymes, the anticoagulant annexin A5, and the protein C (Prot C) pathway. 4. The anti-2GPI-2GPI complex directly binds to activated platelets and facilitates platelet aggregation.

• #1 Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome

  https://www.wjgnet.com/2220-3214/full/v5/i2/59.htm

  Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the pathological action of antiphospholipid antibodies (aPL), that leads to recurrent pregnancy loss and thrombosis. […] Despite limited evidence, it is clear that there are both inherited and acquired components of the ontogeny of these antibodies. […] Various pathogenetic processes have been proposed based on the available evidence and what seems clear is that both inherited and acquired factors play roles in the initial induction of pathogenic aPL in APS patients. […] One of these key environmental factors seems to be infectious agents and indeed, most of the work done to elucidate the effect of environmental factors on aPL production has centered on viral and bacterial infectious agents. […] It is therefore very likely that only a select group of environmental agents, most likely infectious agents and even then only a select few viral or bacterial entities, are important in disease development.

• #1 Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome

  https://www.wjgnet.com/2220-3214/full/v5/i2/59.htm

  The first direct evidence of certain MHC II alleles being involved in the induction of pathogenic aPL and development of APS clinical manifestations came from Papalardo et al. […] The underlying problem is the difficulty in defining disease phenotypes appropriately due to variable clinical expression, the coexistence of clinical entities and variability in the progression of disease. […] However, we discuss below the HLA genes which are associated with an increased susceptibility to the development of APS and the production of aPL antibodies. […] The break in tolerance in APS patients is also likely to involve regulatory T-cell (Treg) function based on recent evidence. […] The majority of circulating 2GPI exists in a reduced form containing unpaired cysteines (free thiols), which are involved in the interaction with platelets and endothelial cells.

• #1 Catastrophic Antiphospholipid Syndrome | HSS Rheumatology

  https://www.hss.edu/conditions_catastrophic-antiphospholipid-syndrome.asp

  Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which the patients immune system makes antibodies (antiphospholipid antibodies [aPL]) that increase the risk of blood clots (thickened blood) and pregnancy complications. […] Catastrophic APS generally happens when certain triggers, like infections, surgery and trauma, cancer, pregnancy complications like HELLP syndrome (which involves breaking down red blood cells, liver problems, and low platelets) and placental infarction, estrogen use, drugs, or SLE flares, cause the immune system to overreact. This overreaction makes the blood clot too easily, blocking blood vessels in multiple organs and leading to organ failure. […] Some patients with CAPS have underlying complement regulatory gene (a gene that controls immune system activity) variants that increase complement activity (immune protein system), predisposing them to widespread thrombosis (blood clotting) and multiorgan failure. These genetic changes affecting immune proteins can result in a severe clinical form of CAPS.

• #1 Put Hughes Syndrome on Your Radar – The Rheumatologist

  https://www.the-rheumatologist.org/article/put-hughes-syndrome-on-your-radar/

  Since its clinical description in 1983, antiphospholipid syndrome (APS or Hughes Syndrome) has become the domain not only of rheumatologists and obstetricians, but of neurologists, cardiologists, psychiatrists, otolaryngologists, and orthopedists. […] APS is an autoimmune disease in which antibodies directed against phospholipid-protein complexes appear to lead directly to thrombosis. […] Like all autoimmune diseases APS has a genetic component, and cases of thyroid disease, Sjgrens syndrome, and lupus are frequently seen in families with APS. […] While arterial and venous thromboses are the hallmarks of the syndrome, there are other clinical clues. […] The most feared complication of APS is stroke, with up to 20% of strokes in people under 45 possibly having this etiology.

• #1 Antiphospholipid Syndrome and Its Management

  https://www.uspharmacist.com/article/antiphospholipid-syndrome-and-its-management

  Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis or pregnancy morbidity coupled with persistent antiphospholipid antibodies. […] It is thought that the initiating events for induction of antibodies to phospholipid-binding proteins are infections, oxidative stress, and major physical stresses (e.g., surgery, trauma). These contributors seem to induce increased apoptosis of the vessel endothelial cells and subsequent exposure of phospholipids. The binding of phospholipids to serum proteins (e.g., B2GPI, prothrombin) leads to neoantigen formation and triggers the induction of antiphospholipids. The binding of antiphospholipids to the disrupted endothelial cells results in the initiation of intravascular coagulation and thrombus formation. Other proposed mechanisms for thrombotic events and APS-related obstetric complications include complement neutrophil activation and an imbalance between type I and III interferons.5

• #1 Update on the Diagnosis and Treatment of the Antiphospholipid Syndrome

  https://www.emjreviews.com/rheumatology/article/update-on-the-diagnosis-and-anticoagulant-treatment-of-the-antiphospholipid-syndrome/

  APS carries significant morbidity and mortality. […] Antibody profile is the major risk stratification tool. Patients with a single isolated positivity are at low risk of clinical manifestations of APS, whereas patients with triple positivity showed the strongest association with thrombotic or obstetric events. […] In APS patients presenting with VTE, the standard initial treatment involves unfractionated heparin (UFH) or LMWH, followed by VKA with INR target range 2.0-3.0. […] Monitoring VKA can be difficult in APS patients. Since certain commercial thromboplastins used to measure the prothrombin time are more sensitive to LAC than others and can cause artifactual prolongation of the INR, and thus subtherapeutic VKA dose, lupus insensitive reagents should ideally be used. […] Recurrent thrombosis during VKA treatment at therapeutic INR (warfarin failure) is a known complication of APS and can lead to different management strategies, such as increasing the INR target range, shifting to LMWH, or adding low-dose aspirin. […] There are two published RCT evaluating the use of rivaroxaban compared to warfarin in APS patients. […] In women with obstetrical APS, the combination of prophylactic-dose LMWH (or prophylactic/intermediate-dose UFH) and low-dose aspirin is usually prescribed to prevent pregnancy complications, based on the evidence that this association may halve the risk of pregnancy loss.

• #1 Antiphospholipid syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Antiphospholipid_syndrome

  The lupus anticoagulant antibodies are those that show the closest association with thrombosis; those that target 2glycoprotein 1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to high titres (over 40 GPLU or MPLU). Patients with both lupus anticoagulant antibodies and moderate or high titre anticardiolipin antibodies show a greater risk of thrombosis than with one alone. […] The increased risks of recurrent miscarriage, intrauterine growth restriction and preterm birth by antiphospholipid antibodies, as supported by in vitro studies, include decreased trophoblast viability, syncytialization and invasion, deranged production of hormones and signalling molecules by trophoblasts, as well as activation of coagulation and complement pathways.

• #1 Update on the Diagnosis and Treatment of the Antiphospholipid Syndrome

  https://www.emjreviews.com/rheumatology/article/update-on-the-diagnosis-and-anticoagulant-treatment-of-the-antiphospholipid-syndrome/

  The recent development of integrated tests, which can perform screening and confirmation tests in parallel just by varying the concentration of phospholipid, has reduced the number of mixing tests. […] However, the role of the mixing test is still debated; while some authors acknowledge that it can introduce a dilution factor and generate false-negative results if the LAC is weak, others argue that the mixing test still has a role when the other test results are borderline or that skipping the mixing test might generate both false-negative and false-positive results. […] Several other autoantibodies not included in the laboratory criteria have been recently identified in APS patients. […] The practical relevance of these non-criteria antiphospholipid antibodies is currently debated. However, there is recent evidence that they could be involved in APS pathogenesis and explain some of the seronegative APS.

• #1 Microvascular Antiphospholipid Syndrome | HSS Rheumatology

  https://www.hss.edu/conditions_microvascular-antiphospholipid-syndrome.asp

  MAPS increases the risk of developing CAPS, which involves severe, multi-organ clots. Early treatment can prevent this progression. […] Given that APS is an autoimmune disease in which the immune system attacks the body’s own cells, immunosuppressive medications to control the immune response play a major role in the management of APS patients with microvascular disease. […] Some of the medications used in APS patients with microvascular involvement include corticosteroids, mycophenolate mofetil, rituximab, intravenous immunoglobulin, sirolimus, eculizumab, hydroxychloroquine, and statins.

• #1 Movement Disorders in Antiphospholipid Syndrome & Systemic Lupus Erythematosus

  https://practicalneurology.com/articles/2020-sept/movement-disorders-in-antiphospholipid-syndrome-systemic-lupus-erythematosus

  In thrombotic APS refractory to adequate anticoagulation, rituximab, IVIG, and plasmapheresis have been used. […] Although an autoimmune mechanism has been proposed, improvement of neurologic symptoms (including movement disorders) has also been reported with antiplatelets and anticoagulants. […] A variety of movement disorders have been recognized in the context of APS and SLE, although chorea is by far the most commonly reported. […] Most individuals see improvement in movement symptoms with a combination of symptomatic therapies, antiplatelets, anticoagulants, and immunosuppressants. […] More research is needed to better understand the underlying pathophysiology of these disorders and guide the development of effective treatments.

• #1 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  Complement activation appears to have a key role in the thrombophilic diathesis of APS. […] The involvement of complement was first suggested by the observation of increased activated complement components in plasma of patients with APS and history of thrombosis. […] It remains unclear why only some people with aPL develop clinical manifestations of disease. […] According to this model, aPL alone is insufficient to cause thrombosis and thus requires the concomitant triggering of innate immunity (e.g., a ligand for TLRs). […] Despite the clinical diversity (several manifestations with thrombotic or non-thrombotic etiology) and laboratory heterogeneity (autoantibodies recognizing many different proteins) of APS, it is accepted that only anti-2GPI antibodies are responsible for the clinical presentation of the syndrome. […] More specifically, a subpopulation of anti-2GPI antibody against a cryptic epitope (Arg39-Arg43) in domain I of 2GPI, which is highly correlated with clinical symptoms and prognosis of the syndrome, has been identified. […] The newest trend in the study of 2GPI, oriented to reveal conformational changes and / or post-translational modifications of the molecule, which are induced by specific conditions and appear to be associated with the pathogenesis of APS. […] An important indication about the biology of 2GPI and the mechanisms of action of anti-2GPI is the observation that the dimerization of the molecule on the surface of cell membranes is a critical step to initiate cellular activation. […] In summary, our study describes for the first time a new interaction between 2GPI and PF4. The main significance of this interaction is the stabilization of dimeric structures of 2GPI upon interaction with PF4, which facilitates the recognition by specific antibodies. The formation of anti-2GPI/2GPI/PF4 complexes induces platelet activation, mainly through the F(ab’)2 fragments of specific antibodies.

• #1

  https://link.springer.com/article/10.1007/s11926-020-00976-7

  Even neutrophils have been recently shown to be involved in the pathogenesis of aPL-associated pregnancy complications via the release of NET. […] The knowledge of the multifaceted nature of pediatric APS should be implemented to further reduce the risk of underdiagnosing or undertreating this condition. […] It is desirable that the recent insights into APS pathogenesis, in particular the elucidation of the physiologic role of 2GPI and the identification of novel cellular pathogenic players, will soon allow opening new windows of opportunity in the management of pediatric APS.

• #2 Antiphospholipid Syndrome: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/333221-overview

  Antiphospholipid syndrome (APS) is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, (predominantly beta-2 glycoprotein I [apolipoprotein H]); and/or evidence of a circulating anticoagulant. […] Although antiphospholipid (aPL) antibodies are clinically linked to APS, whether they are involved in the pathogenesis or are an epiphenomenon is unclear. […] In APS, the homeostatic regulation of blood coagulation is altered; however, the mechanisms of thrombosis are not well defined. One hypothesis postulates a defect in cellular apoptosis, which exposes membrane phospholipids to the binding of various plasma proteins, such as beta-2 glycoprotein I. Once bound, a phospholipid-protein complex is formed and a neoepitope is uncovered, which subsequently becomes the target of autoantibodies. Evidence suggests that oxidized beta-2 glycoprotein I is able to bind to and activate dendritic cells in a manner similar to activation triggered by Toll-like receptor 4 (TLR-4), which could amplify the production of autoantibodies.

• #2 Pathophysiology of Antiphospholipid Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9391091/

  The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. […] A distinguishing feature of the antiphospholipid syndrome is the lupus anticoagulant. This is not a single entity but rather a family of antibodies directed against complex antigens consisting of 2 -glycoprotein I and/or prothrombin bound to an anionic phospholipid. […] Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity.

• #2 Pathophysiology of Antiphospholipid Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9391091/

  The endothelium releases a variety of factors that retard thrombosis, but its antithrombotic activity is severely compromised by APA. […] The net effect of APA is to enhance platelet adhesion and diminish the clot-inhibitory properties of the endothelium. […] Accelerated (premature) atherosclerosis is another feature of APS. […] The consequence is vascular occlusion, tissue infarction, and fetal loss. […] Antibodies to PT were reported in 31 of 42 (74%) patients with LAC. […] They prolong in vitro clotting tests by out-competing factor Xa for phospholipid-binding sites, but in vivo the increased affinity of LACPT complexes for phospholipid surfaces augments thrombin production and might contribute to the enhanced risk of thrombosis in patients with SLE. […] Complement activation, recognized by bioassay and detection of C5b-9 deposition on cell surfaces, is present in about a third of APS samples, occurs mainly in conjunction with triple positivity (positive tests for LAC, ACA, and anti- 2 -GPI), and is associated with thrombotic events.

• #2 Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

  https://www.mdpi.com/2077-0383/12/3/891

  At the end, the heterogeneity of the mechanisms underlying APS may be related to the different signal transduction pathways triggered by aPLs. Recently, increasing evidence suggests that they are driven by specific microdomains on the cell plasma membrane termed lipid rafts. […] Evidence of the thrombogenic activity of aPLs has been provided by both in vitro and in vivo studies; however, despite the presence of aPLs in the circulation, thrombotic manifestation is not always observed in the patients. […] These considerations suggest the “two-hit hypothesis” concept to better clarify the pathogenetic role of aPLs in the mechanisms underlying the development of thrombosis in APS patients. […] Thrombus formation is the most studied aspect of APS pathophysiology, and the procoagulant phenotype observed in the disease has been described as a result of the synergistic activation of many elements, where inflammation represents a central pathogenetic factor that acts as a mediator between the coagulation dysfunction and thrombotic manifestations.

• #2

  https://link.springer.com/article/10.1007/s00281-022-00916-w

  Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. […] Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.

• #2 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  Significant in vitro and in vivo studies confirm that aPL are pathogenic. The exact mechanism by which these antibodies participate in the prothrombotic tendency of APS, remain to be clearly defined. However, it has been illustrated that the heterogeneity of antibodies is associated with multiple mechanisms of action. These include briefly: the activation of cellular components (endothelial cells, platelets and monocytes), activation of the coagulation cascade, inhibition of the fibrinolytic system, inhibition of natural anticoagulant pathways and activation of the complement system. […] The interaction of aPL with endothelial cells has until now been in frequent disputes and misunderstandings. […] In vitro studies have shown that 2GPI binds to immobilized endothelial cells, and allows the anti-2GPI antibodies to bind to cells and induce a proinflammatory and procoagulant phenotype. […] A clinical demonstration of endothelial dysfunction in APS patients is the increased level of circulating endothelial microparticles and endothelial cells in peripheral blood. […] Animal models suggest that human polyclonal and monoclonal aPL activate endothelium and enhance clot formation in vivo. […] The study of the endothelium clearly indicates the potentially beneficial effect of statins in the therapeutic approach of patients. […] The role of anti-endothelial antibodies, especially of anti-HSP60, in the mechanism of thrombosis was studied in LA positive patients with secondary APS. […] The exact nature of aPL- receptors on the surface of endothelial cells remains obscure and is a key subject of current research. […] The study of signal transduction in aPL-mediated endothelial activation continues to be an important area of research.

• #2 Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts

  https://www.mdpi.com/2077-0383/12/3/891

  Several studies have shown that aPLs exert their effects through activation of various cells (endothelial cells, monocytes, platelets, endometrial and decidual cells), as well as a complement system, coagulation factors and inflammatory mediators. […] These pathogenetic mechanisms underlying clinical manifestations of APS can be exploited as targets of immunomodulatory therapeutic strategies to be used in APS patients. […] In addition, the thrombogenic effect of aPLs may involve the activation of the complement system, through both the alternative and the classical pathway. […] Many studies have described the direct activity of aPLs in association with pregnancy complications as part of the pathogenesis of OAPS. […] The first indication derived from the observation of Sorice et al. is that the anti-β2-GPI target antigen was found within lipid rafts which are specialized portions of the cell plasma membrane implied in signal transduction pathways, as revealed by the sucrose gradient analysis and coimmunoprecipitation experiments. […] These findings indicated that lipid rafts play a key role in the signal transduction pathway induced by anti-β2-GPI antibodies, and that raft-dependent anti-β2-GPI antibody triggering resulted in the release of either TNF-α and TF, which may contribute to the pathogenesis of thrombosis in APS.

• #2 Vitamin D and Anti-Phospholipid Antibody Syndrome: A Comprehensive Review

  https://www.openrheumatologyjournal.com/VOLUME/12/PAGE/248/FULLTEXT/

  It is widely accepted that anti-2GPI antibodies, in the presence of 2GPI, can induce endothelial cell perturbation. […] Although the precise mechanism of aPL-induced activation of endothelial cells remains to be determined, TLR4 has been demonstrated to play a central role. […] Vitamin D is able to suppress the expression of TLRs such as TLR4, which is responsible for the activation of nuclear factor B and the signaling cascade that ultimately induces a prothrombotic state in endothelial cells by aPL. […] Vitamin D can reduce TF expression induced by proinflammatory stimuli such as TNF- or LPS on monocytes. […] Vitamin D can inhibit TLR4 signaling in peripheral blood monocytes of pregnant women at risk for preeclampsia, thereby down-regulating inflammatory pathways and reducing the risk of endothelial cell damage.

• #2 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  The thrombophilic tendency in combination with the observation that thrombocytopenia is a frequent manifestation in APS, led early on the assumption that platelet activation is an important factor in the pathogenesis of the disease. […] Several studies demonstrate platelet activation and aggregation by aPL, both in vitro and in vivo. […] It has been demonstrated that aPL cannot bind to the surface of „intact” platelets, while they have the ability to bind to platelets with exposed negatively charged phospholipids in their membranes. […] A second indication of impaired platelet function in APS, is the observation that approximately 40% of patients show prolonged bleeding time, without accompanying bleeding tendency. […] Strong evidence of aPL-induced platelet activation is the enhanced expression of platelet membrane glycoproteins, particularly GPIIb-IIIa (fibrinogen receptor, critical in platelet aggregation) and GPIIIa. […] The activation of platelets by aPL, in vivo, has been supported by several groups.

• #2

  https://link.springer.com/article/10.1007/s11926-020-00976-7

  The contribution of neutrophils to aPL-mediated hypercoagulatory state has been unraveled only recently: in vitro treatment with anti-2GPI antibodies results in the release of higher levels of neutrophil extracellular traps (NET, which are networks of DNA complexed with histones and proteins) via Toll-like receptor (TLR) and adenosine A2A receptor activation. […] The complement system represents an emerging player in the pathogenesis of thrombotic APS, with 2GPI/anti-2GPI antibody complexes resulting in the activation of the classical pathway. […] Despite in vitro data on aPL pathogenicity, treatment with Ig fractions is not sufficient to trigger vascular occlusion in experimental animals, requiring a second hit such as pre-treatment with LPS, mechanical or photochemical trauma. […] The above-cited aPL pro-thrombotic mechanisms can be shifted to obstetric APS, where intravascular thrombosis might lead to occlusion of uterine spiral arteries.

• #2 What Rheumatologists Need to Know About Antiphospholipid Syndrome – The Rheumatologist

  https://www.the-rheumatologist.org/article/what-rheumatologists-need-to-know-about-antiphospholipid-syndrome/

  Beyond the increased production of NETs, serum isolated from some patients with APS does not effectively degrade prothrombotic NETs. This may result in a vicious cycle of thrombo-inflammation, including complement system activation. Potentially adding further fuel to the fire, multiple groups have now shown that the key APS autoantigen 2GPI interacts not only with phospholipids, but also with the DNA-based backbone of NETs. Disrupted regulation of NETs is most likely to be appreciated in subgroups of patients with high-risk antibody profiles, recurrent thrombotic events and/or microvascular disease, all groups for which more effective treatments are needed. […] This burgeoning knowledge highlights a complex interaction between innate immunity and coagulation in APS that will, hopefully, pave the way for novel research and, most importantly, more effective therapeutic strategies for those grappling with this multifaceted disease.

• #2 Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS) | IntechOpen

  https://www.intechopen.com/chapters/23222

  Activation of monocytes by aPL has been extensively studied. The main findings include an increase of TF expression and activity as well as the increased production of proinflammatory cytokines. […] It is assumed that although aPL cause delayed clotting times in vitro, these antibodies exert procoagulant effects in vivo, with accelerated thrombin formation. […] The exact pathogenic involvement of aPL in the coagulation cascade remains obscure. […] It has been supported by several studies that although anti-PT antibodies are involved in the activity of LA, these antibodies by themselves are not associated with thrombosis. […] Research data suggest that impaired fibrinolysis may contribute to the thrombophilic tendency in APS. […] 2GPI has also been suggested to have a direct role in fibrinolysis, through direct interaction with components of plasminogen activation. […] The role of annexin A2 in the mechanism of fibrinolysis is also interesting.

• #2 The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8950029/

  Because 2GP1 is constitutively expressed on the surface of all subpopulations of the placental trophoblast and maternal endothelial cells, it is likely to hypothesize that this protein is the target for -2GP1 and other aPLs. […] The presence of LA is strongly associated with a higher risk of venous and arterial thrombosis as compared with the risk imposed by aCL and -2GP1. […] Several mechanisms explain the thrombotic events in APS patients. […] APS patients have elevated levels of cell-free DNA and NETs which correlate with the -2GP1 titers and that these titers are more increased in LA positive patients and even more in triple-positive patients (aCL+, -2GPI+, LA+). […] The effects of aPLs on hemostasis and fibrinolysis range from inhibition of tPA activity and inhibition of FXII-mediated fibrinolysis to inhibition of FXI inactivation by antithrombin as well as increased FXIII synthesis. […] The complement system has a pivotal role in the pathophysiology of APS as demonstrated in a mouse model of surgical induced thrombosis where administration of aPLs did not induce thrombosis in C3 and C5 deficient mice or anti-C5 treated normal mice.

• #2 The Pathophysiology of Antiphospholipid Syndrome

  https://openurologyandnephrologyjournal.com/VOLUME/8/PAGE/2/FULLTEXT/

  As explained above, aPL can upregulate the expression of procoagulant and proadhesive cell-surface molecules such as TF. […] Factor X, is an enzyme of the final common pathway of the coagulation cascade which needs to be in its active form, FXa, to exert its procoagulant effect. […] APL appears to reduce annexin A5 levels and accelerate coagulation of plasma on cultured trophoblasts and endothelial cells. […] Complement activation by aPL has recently been shown in mice models to play an important role in thrombosis, pregnancy loss and fetal growth restriction.

• #2 Pathogenesis of antiphospholipid syndrome: understanding the antibodies | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2011.52

  Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question. […] Whereas evidence shows that a second hit (usually an inflammatory event) is required for thrombus formation in APS, this requirement is less clear for fetal loss. […] In addition to placental thrombosis, other mechanisms for direct effects of aPL on placental tissues have been proposed. […] 2 glycoprotein I (2GPI)-dependent autoantibodies seem to be the main pathogenic subpopulation of aPL. […] More information about the epitope specificity of anti-2GPI aPL, as well as about the tissue expression of the target molecule, might help to better understand the pathogenesis of APS.

• #2 Antiphospholipid syndrome in pregnancy: a comprehensive literature review | BMC Pregnancy and Childbirth | Full Text

  https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-025-07471-w

  The antiphospholipid antibodies may also have different negative effects on the pregnancy. […] Besides the contribution aPL has in the pathogenesis of antiphospholipid syndrome, pregnancy loss in APS may also be related to the maternal spiral arteries, which may be inadequately invaded by the extravillous cytotrophoblast, a situation that leads to early miscarriages and recurrent pregnancy loss. […] The syndrome presents in two primary forms: thrombotic APS, marked by blood clots in both venous and arterial vessels, and obstetric APS (OAPS).

• #2 The well-defined antiphospholipid syndrome induced by COVID-19: a rare case report and review of the literature | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-024-00669-6

  Therefore, we propose that SARS-CoV-2 infection may induce antiphospholipid syndrome characterized by sustained elevation in antiphospholipid antibody levels. […] The possible pathogenesis of APS in patients with COVID-19 is as follows: I) the anti-2GPI-2GPI complex disrupts the antithrombotic barrier between endothelial cells and annexin A5; II) the anti-2GPI-2GPI complex increases signal transduction; III) the anti-2GPI-2GPI complex interferes with fibrinolysis and endogenous antithrombotic formation; and IV) the anti-2GPI-2GPI complex triggers platelet activation. […] The pathogenesis of antiphospholipid syndrome. The possible pathogenesis of APS: 1. The anti-2GPI-2GPI complex binds to anionic coagulation-promoting surfaces, such as heparan acetylates, via the V-region cation of 2GPI upon damage to the endothelial surface; 2. The anti-2GPI-2 GPI complex triggers the activation of annexin A2, ApoE2, TLR4, and other receptors on endothelial cells, thereby promoting downstream signalling pathways involving protein kinase (p38MAPK) and nuclear B factor (NF-B). This leads to increases in the levels of tissue factor (TF), adhesion molecule (AM), and proinflammatory coagulation; 3. The anti-2GPI-2GPI complex hinders fibrinolysis and anticoagulation by suppressing the activity of fibrinolytic enzymes, the anticoagulant annexin A5, and the protein C (Prot C) pathway. 4. The anti-2GPI-2GPI complex directly binds to activated platelets and facilitates platelet aggregation.

• #2 Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations | Journal of Ophthalmic Inflammation and Infection | Full Text

  https://joii-journal.springeropen.com/articles/10.1186/s12348-021-00240-8

  It has been recently demonstrated that aPLs activate AKT/ mammalian target of rapamycin (mTOR) pathway in the endothelial cells and cause proliferation of endothelial and vascular smooth muscle actin cells. […] Platelet activation also has an important effect on thrombus formation in ALP. […] Other studies demonstrate that neutrophils may also contribute to pathologic clotting, especially venous thrombosis in APS. […] Neutrophils release neutrophil extracellular traps (NETs), which consist of nucleus originated DNA and histones, as well as cytoplasm derived granule proteins, such as neutrophil elastase and myeloperoxidase. […] In addition, APS neutrophils show proinflammatory signature expression related to interferon (IFN)-mediated signaling pathway, cellular defense and intercellular adhesion.

• #2

  https://www.nhs.uk/conditions/antiphospholipid-syndrome/causes/

  Antiphospholipid syndrome (APS) is caused by the body’s immune system producing abnormal antibodies called antiphospholipid antibodies. […] In APS, the immune system produces abnormal antibodies that rather than attacking bacteria and viruses, mistakenly attack proteins found on the outside of cells in the blood and blood vessels. […] It’s not known how this causes the blood to clot more easily. […] This balance may be disrupted by abnormal antibodies in people with APS. […] Research into the genetics around APS is still at an early stage, but it seems the genes you inherit from your parents may play a role in the development of abnormal antiphospholipid antibodies. […] Studies have shown that some people with APS have a faulty gene that plays a role in other autoimmune conditions, such as lupus. […] It’s thought that one or more environmental triggers may be needed to start APS in some people. […] Another theory is that many people with abnormal antiphospholipid antibodies only go on to develop APS if they have a higher risk of developing blood clots.

• #2 Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome

  https://www.wjgnet.com/2220-3214/full/v5/i2/59.htm

  It is therefore possible that the generation of reactive oxidative and nitrosative species by certain infectious agents could allow for generation of an abundance of oxidized 2GPI and foster autoantibody production. […] The concept that apoptosis plays a role in the production of aPL was first proposed by Piroux et al. […] The relative degree to which inherited and acquired factors determine the risk for developing aPL and APS has not been fully elucidated.

• #2 Antiphospholipid Syndrome – APS | Choose the Right Test

  https://arupconsult.com/content/antiphospholipid-syndrome

  Antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome, is an autoimmune disorder in which autoantibodies are directed against phospholipid-protein complexes. APS is characterized by thromboses (arterial, venous, or small vessel) and/or pregnancy complications and persistently positive tests for antiphospholipid-protein (aPL) antibodies. […] An uncommon acute form of the syndrome, catastrophic APS, results in extensive microvascular thrombosis and multiorgan failure. […] Those at increased risk for APS include patients with systemic lupus erythematosus (SLE), infections, malignancy, and liver or vascular disease. […] Because antiphospholipid-protein (aPL) antibodies can occur transiently, persistent positivity on consecutive testing occasions is required for classification as antiphospholipid syndrome (APS). […] Positivity for LA alone, apart from the other aPLs, has a strong association with thrombotic events and adverse outcomes in pregnancy. […] However, LA testing in pregnant individuals may produce false-positive or false-negative results.

• #2 Antiphospholipid Syndrome (APS) – An Update on Clinical Features and Treatment Options

  https://openurologyandnephrologyjournal.com/VOLUME/8/PAGE/27/FULLTEXT/

  Direct immune interaction of the aPL antibodies with the neurons, is also thought to contribute to manifestations such as seizures, chorea and transverse myelitis. […] Recent progress in understanding the pathogenic mechanisms of APS has expanded the horizon for targeted therapies such as anti-inflammatory and immunosuppressive medications. […] Eculizumab is a recombinant humanized monoclonal antibody that binds to the terminal complement protein C5 and inhibits its cleavage. […] Increasing evidence linking the coagulation cascade and complement activation has caused complement inhibition to receive a lot of attention recently. […] The mechanism of action of IVIG remains unclear but appears to suppress inflammatory and immune mediated processes. […] The mechanism of action and its benefit in APS is unknown but it is thought to remove cytokines and complement components.

• #2

  https://link.springer.com/article/10.1007/s11926-020-00976-7

  Even neutrophils have been recently shown to be involved in the pathogenesis of aPL-associated pregnancy complications via the release of NET. […] The knowledge of the multifaceted nature of pediatric APS should be implemented to further reduce the risk of underdiagnosing or undertreating this condition. […] It is desirable that the recent insights into APS pathogenesis, in particular the elucidation of the physiologic role of 2GPI and the identification of novel cellular pathogenic players, will soon allow opening new windows of opportunity in the management of pediatric APS.

• #3 Antiphospholipid Syndrome and Stroke – European Stroke Organisation

  https://eso-stroke.org/antiphospholipid-syndrome-and-stroke/

  The first description of antiphospholipid syndrome (APS) is dated to 1983 following the discovery of lupus anticoagulant immunoglobulin and its relation to autoimmune disorders. APS represents an autoimmune condition characterized by a wide range of clinical manifestations. […] APS is accompanied by the presence of antiphospholipid antibodies (aPL), primarily lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta(2)-glycoprotein I (aB2GPI). The circulating antibodies induce endothelial dysfunction and interfere with the coagulation pathways by competing with coagulation factors. This leads to a procoagulant state, clot formation, and recurrent thromboembolic events. The pathophysiology is probably based on a two-hit hypothesis where the first hit represents the asymptomatic presence of aPL antibodies occurring in approx. 1-5% of the population. The second hit represents a stress condition (pregnancy, infection, etc.) triggering the pathologic state itself.

Zobacz więcej