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A Case of Thrombotic Microangiopathy Associated With Antiphospholipid Antibody Syndrome Successfully Treated With Eculizumab
... In the absence of previous aHUS, Chua et al. (52) showed activation of the classical and terminal complement in several transplant-associated conditions: in donors after brain death (DBD) or donors after circulatory death (DCD) (53)(54)(55), or associated with ischemia reperfusion injury (56), immunosuppressive drugs (mainly CNI or mTORi) (41,42,(57)(58)(59)(60)(61), ABMR (62-68), viral and fungal infection (69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82), and recurrence of antiphospholipid syndrome (APS) (83)(84)(85). The laboratory tests needed to evaluate causes of PT-TMA are described in Table 3. De novo aHUS has also been described in patients with C3 glomerulopathy in the native kidneys (86,87) and in 1 patient with TTP (88). ...
... APS can cause ESRD due to large and small kidney vessel thrombosis and TMA. These symptoms can recur after transplantation, and eculizumab has shown a beneficial effect in patients with this disease, preventing and treating the recurrence of APS (83)(84)(85). ...
Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy. De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.
... CAPS [223][224][225][226][227][228]. CAPS recurrence in renal transplant [229,230]. Prophylactic anticoagulation and eculizumab to enable renal transplantation in 3 patients [231]. ...
... There is observational data in humans suggesting that complement is activated [219][220][221]. Case reports and series describe the successful use of eculizumab for CAPS in native kidneys [223][224][225][226][227][228] and transplant kidneys [229][230][231]. There are no RCTs of complement-inhibiting therapy but the evidence supports the rationale, and a prospective, single-arm trial of eculizumab to enable renal transplantation in CAPS is ongoing (NCT01029587). ...
Thrombotic microangiopathy (TMA), characterized by organ injury occurring consequent to severe endothelial damage, can manifest in a diverse range of diseases. In complement-mediated atypical haemolytic uraemic syndrome (aHUS) a primary defect in complement, such as a mutation or autoantibody leading to over activation of the alternative pathway, predisposes to the development of disease, usually following exposure to an environmental trigger. The elucidation of the pathogenesis of aHUS resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. In other TMAs, although complement activation may be seen, its role in the pathogenesis remains to be confirmed by an interventional trial. Although many case reports in TMAs other than complement-mediated aHUS hint at efficacy, publication bias, concurrent therapies and in some cases the self-limiting nature of disease make broader interpretation difficult. In this article, we will review the evidence for the role of complement inhibition in complement-mediated aHUS and other TMAs.
... El uso de terapias que bloqueen el complemento puede ser una opción terapéutica, especialmente en pacientes refractarios al tratamiento habitual 20 . En la literatura 8 casos de SAFC, 4 trasplantados y 4 no trasplantados, han sido tratados exitosamente con eculizumab (tablas 2 y 3) [19][20][21][22][23][24][25][26][27] . ...
... Pese a ello, el riesgo de pérdida de injerto continúa siendo del 20-42% 74,77,78 . Dada la implicación del sistema del complemento en la MAT postrasplante y su mal pronóstico, en casos refractarios a terapia habitual se ha utilizado terapia anticomplemento en diferentes órganos (tabla 3) 24,25,27,75,[101][102][103][104][105] . En una revisión retrospectiva, Dhakal describe una tasa de recuperación hematológica y mejoría de la función renal en el 90% de 26 casos con MAT-TPH y TOS tratados con eculizumab. ...
Understanding the role of the complement system in the pathogenesis of atypical haemolytic uraemic syndrome and other thrombotic microangiopathies (TMA) has led to the use of anti-complement therapy with eculizumab in these diseases, in addition to its original use in patients with paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Scientific evidence shows that both primary and secondary TMAs with underlying complement activation are closely related. For this reasons, control over the complement system is a therapeutic target. There are 2 scenarios in which eculizumab is used in patients with TMA: primary or secondary TMA that is difficult to differentiate (including incomplete clinical presentations) and complement-mediated damage in various processes in which eculizumab proves to be efficacious. This review summarises the evidence on the role of the complement activation in the pathophysiology of secondary TMAs and the efficacy of anti-complement therapy in TMAs secondary to pregnancy, drugs, transplant, humoral rejection, systemic diseases and glomerulonephritis. Although experience is scarce, a good response to eculizumab has been reported in patients with severe secondary TMAs refractory to conventional treatment. Thus, the role of the anti-complement therapy as a new treatment option in these patients should be investigated.
... El uso de terapias que bloqueen el complemento puede ser una opción terapéutica, especialmente en pacientes refractarios al tratamiento habitual 20 . En la literatura 8 casos de SAFC, 4 trasplantados y 4 no trasplantados, han sido tratados exitosamente con eculizumab (tablas 2 y 3) [19][20][21][22][23][24][25][26][27] . ...
... Pese a ello, el riesgo de pérdida de injerto continúa siendo del 20-42% 74,77,78 . Dada la implicación del sistema del complemento en la MAT postrasplante y su mal pronóstico, en casos refractarios a terapia habitual se ha utilizado terapia anticomplemento en diferentes órganos (tabla 3) 24,25,27,75,[101][102][103][104][105] . En una revisión retrospectiva, Dhakal describe una tasa de recuperación hematológica y mejoría de la función renal en el 90% de 26 casos con MAT-TPH y TOS tratados con eculizumab. ...
El conocimiento del papel del complemento en la patogenia del síndrome hemolítico urémico atípico y otras microangiopatías trombóticas (MAT) ha fomentado el desarrollo de la terapia anticomplemento con eculizumab más allá de su indicación original en la hemoglobinuria paroxística nocturna y en el síndrome hemolítico urémico atípico. La evidencia científica demuestra un estrecho límite entre MAT primarias y secundarias con activación del complemento subyacente en ambas. Por ello, el control del complemento se convierte en una diana terapéutica. El uso de eculizumab en MAT secundarias contempla 2 escenarios: diagnóstico diferencial difícil entre MAT primaria y secundaria (incluidos cuadros clínicos incompletos) o daño por complemento en procesos distintos, donde se demuestra la eficacia del tratamiento. Esta revisión es una síntesis de la evidencia científica sobre el papel de la activación del complemento en la fisiopatología de las MAT secundarias y la eficacia de la terapia anticomplemento en MAT asociadas a embarazo, fármacos, trasplante, rechazo humoral, enfermedades sistémicas y glomerulonefritis. La experiencia es aún limitada, pero la respuesta a eculizumab en pacientes con MAT secundarias graves y refractarias al tratamiento convencional abre una puerta a la investigación de la terapia anticomplemento como nueva opción terapéutica.
... Several cases of diverse etiologies that result in endothelial damage, which progressed to a clinically apparent TMA, have also been reported. One associated syndrome that has been infrequently linked to TMA is antiphospholipid antibody (APL ab) syndrome, including the catastrophic APL ab syndrome variant (CAPS) (13)(14)(15)(16)(17)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). In this condition, antiphospholipid antibodies result in thrombotic complications and are found circulating in serum, and typically can be removed with plasmapheresis/TPE (2,9,11,(13)(14)(15)(16)(17)20). ...
... It is also important to note that most of the cases mentioned report the use of eculizumab in the peritransplant setting. Our case is interesting in the use of eculizumab to treat APL ab syndrome with TMA, and in the use of a skin biopsy rather than a renal biopsy as a diagnostic aid in the confirmation of the presence of a TMA (13)(14)(15)(16)(17)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31); however, this has been reported before (13,35). The postulated mechanism of eculizumab in treating APL ab syndrome involves the prevention of complement activation and fixation by APL antibodies, which possibly would also trigger additional endothelial injury and complement dysregulation (17). ...
Thrombotic microangiopathies (TMA) can be caused by diverse clinical entities of various etiologies. Thrombotic thrombocytopenic purpura (TTP) is caused by a lack of von Willebrand-factor-cleaving metalloproteinase, ADAMTS13, which is the protein whose deficiency is etiologic in TTP. Shiga-toxin-induced hemolytic uremic syndrome (HUS) differs from atypical HUS (aHUS) due to the presence of the Shiga toxin and enteritis. aHUS is generally seen in younger patients and is linked to genetic and/or acquired complement system dysfunction. In addition to genetic links to the complement system, TMA, TTP, and aHUS have been known to be associated with many acquired triggers, such as malignancy, autoimmune disorders, infections, and pro-thrombotic states. We present the case of an unusual cause of TMA due to catastrophic antiphospholipid antibody syndrome (CAPS).
... A recent systematic review of the efficacy of eculizumab in treatment of TMA confirmed that it resulted in 100% hematological response and 85% kidney recovery (106). In patients with CAPS, eculizumab has resulted in prevention of recurrent APS and rescuing renal allografts after kidney transplantation (96,98,(107)(108)(109)(110)(111). Interestingly, eculizumab may prevent TMA associated with CAPS caused by COVID-19 infection (112). ...
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Although anticoagulation is the primary treatment for APS, it fails in approximately 20-30% of obstetric APS cases and more than 30% of thrombotic APS cases. Therefore, there is a need for new, targeted treatments beyond anticoagulants. Biologics, such as rituximab and eculizumab, have been recommended for refractory catastrophic APS. This review focuses on the recent advancements in the pathogenesis of APS and explores the potential of targeted treatments, including eculizumab, rituximab, belimumab, daratumumab, obinutuzumab, and anti-TNF-α antibodies, for APS management.
... Indeed, renal transplantation in patients with aPL has been proven historically challenging due to increased risk of thrombosis and allograft failure [101], especially due to the development of thrombotic microangiopathy (TMA), which is often refractory to conventional treatment modalities such as aggressive anticoagulation and plasmapheresis [143]. Eculizumab therapy has been reported to be effective in obtaining the remission of the plasmapheresis-resistant form of TMA related to antiphospholipid syndrome nephropathy (APSN) in patients with SAPS [144,145]. ...
The antiphospholipid syndrome (APS) is characterized by the development of venous and/or arterial thrombosis and pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of APS occurring in about 1% of cases. Lifelong anticoagulation with vitamin K antagonists remains the cornerstone of the therapy for thrombotic APS, but frequently the use of anticoagulation may be problematic due to the increased risk of bleeding, drug interactions, or comorbidities. Immunosuppressant drugs are widely used to treat several autoimmune conditions, in which their safety and effectiveness have been largely demonstrated. Similar evidence in the treatment of primary APS is limited to case reports or case series, and studies on a large scale lack. Immunomodulatory drugs may be an emerging tool in managing such particular situations, like refractory obstetrical complications, CAPS, or so-called APS non-criteria manifestations. In addition, immunomodulatory drugs may be useful in patients experiencing recurrent thromboembolic events despite optimized anticoagulant therapy. We did a comprehensive review of literature analyzing the possible role of immunomodulation in primary APS to provide a broad overview of potentially safe and effective target treatments for managing this devastating disease.
... Eculizumab, a monoclonal anti-C5 drug, has been utilised as salvage therapy in refractory CAPS in case reports. [150][151][152][153][154][155][156][157] A recent study showed that CAPS patients experience a higher frequency of rare germline mutations of complement regulatory proteins, that might make them more susceptible to thrombosis. 158 There is a substantial body of literature endorsing the use of eculizumab for preventing aPL-related nephropathy recurrence following renal transplantation. ...
Antiphospholipid syndrome (APS), an acquired autoimmune thrombophilia, is characterised by thrombosis and/or pregnancy morbidity in association with persistent antiphospholipid antibodies. The 16th International Congress on Antiphospholipid Antibodies Task Force on APS Treatment Trends reviewed the current status with regard to existing and novel treatment trends for APS, which is the focus of this Task Force report. The report addresses current treatments and developments since the last report, on the use of direct oral anticoagulants in patients with APS, antiplatelet agents, adjunctive therapies (hydroxychloroquine, statins and vitamin D), targeted treatment including rituximab, belimumab, and anti-TNF agents, complement inhibition and drugs based on peptides of beta-2-glycoprotein I. In addition, the report summarises potential new players, including coenzyme Q10, adenosine receptor agonists and adenosine potentiation. In each case, the report provides recommendations for clinicians, based on the current state of the art, and suggests a clinical research agenda. The initiation and development of appropriate clinical studies requires a focus on devising suitable outcome measures, including a disease activity index, an optimal damage index, and a specific quality of life index.
... Eculizumab is a monoclonal antibody directed against the C5 fraction of complement approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. To date a series of case reports have been published regarding its use in APS, specifically in the setting of CAPS and post-transplantation renal thrombotic microangiopathy, with encouraging results (161)(162)(163)(164)(165)(166)(167)(168)(169)(170). ...
Antiphospholipid syndrome (APS) is an autoimmune antibody-mediated condition characterized by thrombotic events and/or pregnancy morbidity in association with persistent positivity to antiphospholipid antibodies (aPL). The nervous system is frequently affected, as intracranial vessels are the most frequent site of arterial pathology. Over the course of years, many other neurological conditions not included in the diagnostic criteria, have been associated with APS. The pathogenic mechanisms behind the syndrome are complex and not fully elucidated. aPL enhance thrombosis, interfering with different pathways. Nevertheless, ischemic injury is not always sufficient to explain clinical features of the syndrome and immune-mediated damage has been advocated. This may be particularly relevant in the context of neurological complications. The reason why only a subgroup of patients develop non-criteria nervous system disorders and what determines the clinical phenotype are questions that remain open. The double nature, thrombotic and immunologic, of APS is also reflected by therapeutic strategies. In this review we summarize known neurological manifestations of APS, revisiting pathogenesis and current treatment options.
... Eculizumab: Because the complement system seems to be involved in the pathogenesis of both thrombotic and pregnancy complications in APS, eculizumab -a humanized monoclonal antibody that binds the C5 complement fraction -has been applied to refractory cases of APS and CAPS [77,78]. In addition, eculizumab has been employed with success for the prevention and management of APSrelated thrombotic microangiopathy following renal transplantation [98][99][100]. ...
Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called “thrombotic APS”) and pregnancy complications (“obstetric APS”). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option.
Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication
... Methimazole (MMI)-induced pauci-immune crescentic glomerulonephritis has been reported rarely in the past [7,8]; however, co-occurrence of catastrophic anti-phospholipid syndrome (APS) is a potentially life-threatening adverse effect that has never been reported with MMI. Understanding the possibility of MMI-induced PCIGN with APS is of utmost importance, as early withdrawal of MMI and administration of steroids with or without immunosuppressant improve prognosis and survival [2,4,9]. In this article, we present a case of biopsy-proven MMI-induced PICGN which also had features of APS. ...
While methimazole (MMI) is the first line treatment for hyperthyroidism, this medication is not devoid of adverse effects. In this article, we present a 70-year-old male who admitted the hospital with right lower extremity pain and rash. The patient was recently treated with MMI for hyperthyroidism. Imaging studies revealed bilateral renal and splenic infarcts along with thrombosis of popliteal artery. Laboratory data revealed hematuria and proteinuria with positive (MPO), anti-proteinase-3 (PR3) and anti-cardiolipin IgG antibodies. Renal biopsy revealed pauci-immune glomerulonephritis and features with anti-phospholipid antibody syndrome (APS). MMI was discontinued and the patient was treated successfully with steroid therapy and anti-coagulation with resolution of proteinuria, hematuria and normalization of laboratory parameters. While MMI-induced pauci-immune glomerulonephritis has been previously reported, its association with APS has never been described before. Our case demonstrates that this rare diagnosis can be treated by early withdrawal of MMI and initiation of steroids along with anticoagulation.
... These observations have been known for decades. In addition, recent basic research and clinical reports of patients with APS and catastrophic APS (CAPS) lend further support to the role of complement activation and direct endothelial damage (as opposed to cell membrane injury caused by the MAC) in the pathogenesis of TMA when present in these disorders [90][91][92][93][94][95][96][97]. These case reports illustrate the potential efficacy of eculizimab when plasmapheresis and other immunosuppressive therapies are not effective. ...
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) originally understood to be limited to renal and hematopoietic involvement. Whereas aberrations in complement regulatory proteins (CRPs), C3 or complement factor B (CFB) are detected in ∼60% of patients, a complement-derived pathogenesis that reflects dysregulation of the alternative pathway (AP) of complement activation is present in ∼90% of patients. aHUS remains a diagnosis of exclusion. The discovery of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) and its utility in the diagnosis of thrombotic thrombocytopenic purpura (TTP) has resulted in the appreciation that cases of aHUS have been inappropriately diagnosed as TTP. Thus there has been an evolving appreciation of clinical manifestations of aHUS that renders the appellation aHUS misleading. This article will review the pathogenesis and the evolving clinical presentations of aHUS, present a hypothesis that there can be a phenotypic expression of aHUS due to a complement storm in a disorder where direct endothelial damage occurs and discuss future areas of research to more clearly define the clinical spectrum and management of aHUS.
... The efficacy of eculizumab has been shown in patients presenting aHUS [12]. More recently, case reports have been published regarding the action of eculizumab in patients with both SLE and APS presenting with thrombotic microangiopathy [8,9,[13][14][15][16][17][18][19][20][21][22][23][24][25]. ...
The association of thrombotic microangiopathy (TMA) with systemic lupus erythematosus (SLE) has been described in 0.5 to 10% of cases, and patients present worse outcome. TMA is described as the association of microangiopathic hemolytic anemia, thrombocytopenia, and an organ injury, frequently the kidney. This study describes a successful case of use of eculizumab in a patient with SLE and TMA refractory to standard therapy, and provides a literature review. Case description and search in PubMed and MEDLINE using systemic lupus erythemathous and/or antiphospholipid syndrome (APS) and eculizumab retrieved 15 case reports. Eighteen-year-old female presented acute renal failure and TMA and was diagnosed with SLE. Steroids and IV cyclophosphamide were started together with plasma exchange. After 55 days, she still persisted with microangiopathic anemia, thrombocytopenia, and anuria, and eculizumab was introduced. She had rapid improvement in hematological parameters, and dialysis was discontinued 25 days after the first dose. Genetic analysis showed large heterozygous deletion encompassing the entire CFHR1 and CFHR3, a finding previously associated with patients presenting atypical hemolytic-uremic syndrome (aHUS). Twenty patients who received eculizumab with SLE and/or APS have been published to date: 11 were female and mean age at presentation was 31 years. Seven out of the 20 patients presented only SLE, 5 patients only APS and 8 patients both SLE and APS. Eighteen patients underwent plasma exchange, with a mean of 20 (4–120) sessions per patient. Thirteen patients received rituximab. Hematological response was evident in 100% and kidney recovery in 85% of patients. The terminal complement blockade with eculizumab is an optional treatment for patients with SLE and/or APS presenting TMA and refractory to current immunosuppression therapies. Genetic testing may help recognize patients with aHUS and SLE/APS and therefore help to determine length of treatment with eculizumab.
... Но повышение С3а не коррелировано с развитием тромбозов [24]. В связи с важной ролью системы комплемента в патогенезе осложнений АФС в клинической практике у пациентов, рефрактерных к стандартной терапии АФС, стали успешно применять анти-С5а моноклональные антитела [10,44,62] . Успехи терапии данными препаратами способствовали разработке новых препаратов, влияющих на систему комплемента, например, антагониста С5аR, находящегося сейчас на этапе доклинических испытаний. ...
Antiphospholipid antibodies by disrupting trophoblast invasion and endometrial angiogenesis might contribute to a defective placentation and, in turn, affect the successful beginning of pregnancy. It is well known and proven that these processes begin with the founding of the utero-placental blood flow. Given the ability of aPLs to affect implantation and placentation, authors have recently suggested the possibility that aPLs may be responsible also for recurrent implantation failure, early pregnancy loss and unexplained sterility. Possible pathogenic mechanisms: the ability of aPLs to exert a direct negative effect on uterine endothelium and preimplantation embryos, increased activity of NK-cells, increased prothrombotic mechanisms and disruption of the processes of fibrinolysis and fibrin formation.
... 65 Few cases of eculizumab effi cacy in catastrophic APS (possible bias in reporting). [66][67][68] Systemic sclerosis Vessel wall intimal proliferation and lumen obstruction. Might be precipitated by steroids. ...
Haemolytic uraemic syndrome is a form of thrombotic microangiopathy affecting predominantly the kidney and characterised by a triad of thrombocytopenia, mechanical haemolytic anaemia, and acute kidney injury. The term encompasses several disorders: shiga toxin-induced and pneumococcus-induced haemolytic uraemic syndrome, haemolytic uraemic syndrome associated with complement dysregulation or mutation of diacylglycerol kinase ɛ, haemolytic uraemic syndrome related to cobalamin C defect, and haemolytic uraemic syndrome secondary to a heterogeneous group of causes (infections, drugs, cancer, and systemic diseases). In the past two decades, experimental, genetic, and clinical studies have helped to decipher the pathophysiology of these various forms of haemolytic uraemic syndrome and undoubtedly improved diagnostic approaches. Moreover, a specific mechanism-based treatment has been made available for patients affected by atypical haemolytic uraemic syndrome due to complement dysregulation. Such treatment is, however, still absent for several other disease types, including shiga toxin-induced haemolytic uraemic syndrome.
... 15 Its successful use has subsequently been reported in a case of APS development 3 years post-transplant with TMA and acute graft dysfunction in a patient with previous lupus nephritis. 16 ...
Thrombotic microangiopathy (TMA) is a well‐recognised complication following transplantation, often due to an underlying genetic predisposition, medications or rejection. The use of eculizumab in these settings has been previously described, but its role still remains to be clarified.
A 45‐year‐old man, with a history of type 1 diabetes mellitus and subsequent end‐stage kidney failure, presented for a simultaneous pancreas‐kidney transplant. Immunologically, he was well matched with the donor, and he received standard induction immunosuppression including tacrolimus. His early transplant course was complicated by Haemophilus parainfluenzae paronychia and a Pseudomonas aeruginosa catheter‐associated urinary tract infection. Within 1 week, he developed thrombotic microangiopathy with significant renal dysfunction and eventual dialysis dependence, without evidence of transplant rejection on biopsy. He was also noted to have antiphospholipid antibodies in moderate titres. The TMA did not resolve despite cessation of tacrolimus, and he was subsequently commenced on eculizumab. The patient achieved a partial remission from TMA, with ongoing biochemical evidence of haemolysis, although now with stable graft function, despite significant damage. His transplanted pancreas remained seemingly unaffected by TMA, and continues to function well.
This case describes an unusual presentation of TMA post‐transplantation and is the only described case of eculizumab use following pancreas‐kidney transplant. It remains unclear in this case what the likely precipitant for TMA was, although it seems to be, at least in part, controlled by ongoing use of eculizumab, presumably by terminal complement inhibition.
... As the complement plays a central role in the aPL-associated thrombosis, eculizumab, a monoclonal antibody binding the C5 complement fraction, has been used for the management of APSrelated thrombotic microangiopathy following renal transplantation, and it has been demonstrated to be useful in preventing acute thrombotic microangiopathy in renal transplant recipients [127,128]. Eculizumab has also been shown to give a long lasting remission in patients with recurrent CAPS [129,130]. ...
The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis and pregnancy morbidity in the presence of pathogenic autoantibodies known as antiphospholipid antibodies (aPL). APS may be associated with other diseases, mainly systemic lupus erythematosus (SLE). The presence or absence of SLE might modify the clinical or serological expression of APS. Apart from the classical manifestations, APS patients with associated SLE more frequently display a clinical profile with arthralgias, arthritis, autoimmune hemolytic anemia, livedo reticularis, epilepsy, glomerular thrombosis, and myocardial infarction.
The management of patients with SLE and APS/aPL should include an accurate stratification of vascular risk factors. Low dose aspirin and hydroxychloroquine should be considered as primary prophylaxis. In high risk situations, such as surgery, prolonged immobilization, and puerperium, the prophylaxis should be potentiated with low molecular weight heparin. The challenge of treating patients with a previous vascular event (secondary prophylaxis) is the choice of treatment (anti-platelet agents, anticoagulation with vitamin K antagonists or combined therapy) and its duration, based on individual risk stratification and the site of vascular presentation. The role of novel anticoagulants in APS patients is still to be clearly defined. Novel approaches are needed since the prognosis of SLE patients with APS/aPL is still worse than that of SLE patients with negative aPL. The goal for the future is to improve the outcome of these patients by means of early recognition and optimal preventative treatment.
... In 2014, several case reports or series described the outcomes of eculizumab-treated aPL-positive patients: 1) Bakhtar et al. described a lupus and APS patient who developed biopsy-proven TMA, thrombocytopenia, and hemolysis 3 years after livingrelated kidney transplantation; after 7 months of eculizumab, there was no evidence of TMA on biopsy and both hemoglobin and platelets were normal [52]; 2) Lonze et al. reported 3 APS patients (2 with catastrophic APS, and including the follow-up information of the first eculizumab-receiving patient reported in 2010) who were treated with anticoagulation and eculizumab prior to and following live donor renal transplantation (2 also received plasmapheresis); after a follow-up ranging from 4 months to 4 years, all patients had functioning renal allografts [53]; 3) Strakhan et al. reported another catastrophic APS patient (multiple strokes, non-ST elevation myocardial infarction, endstage renal disease due to TMA, intraretinal hemorrhage, and thrombocytopenia) who had no response to corticosteroids and plasma exchange (no heparin during the acute period); the patient's condition stabilized after eculizumab [54]; 4) Zapantis et al. reported 3 APS patients with recurrent thrombosis and thrombocytopenia unresponsive to conventional therapy with significant improvement of thrombocytopenia after eculizumab administration (personal communication) [55]. ...
Antiphospholipid syndrome (APS) is characterized by thrombosis (arterial, venous, small vessel) and/or pregnancy morbidity occurring in patients with persistently positive antiphospholipid antibodies (aPL). Catastrophic APS is the most severe form of the disease, characterized by multiple organ thromboses occurring in a short period and commonly associated with thrombotic microangiopathy (TMA). Similar to patients with complement regulatory gene mutations developing TMA, increased complement activation on endothelial cells plays a role in hypercoagulability in aPL-positive patients. In mouse models of APS, activation of the complement is required and interaction of complement (C) 5a with its receptor C5aR leads to aPL-induced inflammation, placental insufficiency, and thrombosis. Anti-C5 antibody and C5aR antagonist peptides prevent aPL-mediated pregnancy loss and thrombosis in these experimental models. Clinical studies of anti-C5 monoclonal antibody in aPL-positive patients are limited to a small number of case reports. Ongoing and future clinical studies of complement inhibitors will help determine the role of complement inhibition in the management of aPL-positive patients.
... In the last 4 years, successful treatment with eculizumab has been reported on few patients. All these case reports have shown that it was successful whether in treating refractory cases of CAPS or in preventing the recurrence of APS among renal transplant recipients [97][98][99][100][101][102][103][104]. ...
Antiphospholipid syndrome (APS) or "Hughes Syndrome" is a prothrombotic disease characterized by thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). More than three decades have passed and experts are still uncovering new pieces of this disease complex pathogenesis and management.
We searched literature using MEDLINE and PubMed databases focusing on the latest development on disease pathogenesis, risk assessment of thrombosis and treatment in APS.
The phosphatidylinositol 3-kinase (PI3K)-AKT-mTORC pathway was most recently identified to have a crucial role in activating inflammation among endothelial vessel wall causing vascular lesions in APS. Additionally, new variables are being implemented to assess risk of thrombosis in APS patients. Global APS Score (GAPSS) utilizes cardiovascular risk factors and new autoimmune antibodies as part of the score assessment and is the most valid so far. It can be a promising tool in the future for prediction of thrombosis. Anticoagulation remains the corner stone in APS, however, many new potential therapeutic agents are developing and currently under investigation.
The most recent advances in pathogenesis, risk stratification and treatment provide a platform for high yield studies with the ultimate goal of providing the optimal management to APS patients.
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APS is a hypercoagulability condition characterized by the development of thrombosis and pregnancy morbidity (recurrent early miscarriages, fetal deaths after the 10th week of gestation and/or premature births), that occur in patients with antiphospholipid antibodies, namely lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein-I antibodies. It is usually isolated but can occur in the setting of another autoimmune disease, mainly systemic lupus erythematosus. Moreover antiphospholipid antibodies can be found in individuals without the disease. Treatment of thrombosis is based on indefinite anticoagulation while low-dose aspirin and low molecular weight heparin are the cornerstone of pregnancy morbidity treatment. Catastrophic antiphospholipid syndrome is treated with anticoagulation, plasma-exchange, and corticosteroids. Standardization of serological assays, inclusion of other antibodies and manifestations in the classification criteria, treatment of non-criteria manifestations and refractory cases are areas of uncertainty.
Uncontrolled hypercoagulation and inflammation (“thromboinflammation”), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of “thromboinflammatory” pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of “critical” hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy.
Non-criteria manifestations of antiphospholipid syndrome (APS), such as skin ulcers, antiphospholipid antibody (aPL)-associated nephropathy, thrombocytopenia, and heart valve disease, represent a treatment challenge. Only few formal prospective studies address their pathogeneses and treatments. The management of some manifestations of APS remains empirical and with limited evidence-based data. In this chapter, together with a concise literature review, each situation is illustrated by a real clinical case followed by an expert discussion. Potential future treatment strategies for aPL-positive patients are also discussed.
SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity.
Purpose of review This article summarizes the recent developments in the recognition and management of antiphospholipid syndrome (APS). Recent findings Five Task Forces, created as part of the 14th International Congress on antiphospholipid antibodies (aPL), published their systematic reviews. 'For the recognition of APS': the assessment of aPL profile is crucial for risk stratification; lupus anticoagulant positivity, especially in the context of 'triple aPL positivity' displays the highest risk; a panel of criteria and noncriteria aPL tests may help better risk-stratify the aPL-positive in the future. 'For the management of APS': direct oral anticoagulants are not currently recommended; statins ameliorate the proinflammator/thrombotic markers, whereas hydroxychloroquine reduces the risk of thrombosis in experimental models and lupus patients, which justify their use as an adjunctive treatment in refractory cases; B-cell inhibition may have a role in difficult-to-treat patients with hematologic and microthrombotic/angiopathic manifestations; and complement and mammalian targets of rapamycin complex pathway inhibition are promising targets in APS. Summary Warfarin, heparin, and/or antiplatelet drugs are the standard of care for aPL-positive patients. Recent studies suggest novel approaches that target new coagulation and immunomodulatory pathways; mechanistic and/or controlled clinical studies are needed to determine the effectiveness of these novel approaches.
The impact of antiphospholipid antibodies (APA) on clinical outcome and graft histology following renal transplantation remains poorly known and controversial. We retrospectively explored the functional and histological significance of APA, primarily lupus anticoagulant (LA), in kidney transplant recipients using a systematic evaluation of 3- and 12-month posttransplant screening biopsies and glomerular filtration rate measurements (mGFR). During the study period, 37 patients had APA (2.7%), primarily LA, and 12 fulfilled antiphospholipid syndrome (APS) diagnostic criteria (0.8%) at the time of transplantation. Early after transplantation, 4 of the 12 APS patients died. Early thrombosis of graft vessels and deep venous thrombosis occurred more frequently in APA+ patients than in controls (27% vs. 7%, p < 0.05 and 35% vs. 14%, p < 0.05, respectively). The survival rate was significantly lower in patients with APS. Strikingly, the hallmark lesions of APS-associated nephropathy (APSN) were found in most of screening graft biopsies in APA+ patients but not in the controls. Accordingly, APA+ patients had a dramatic increase in chronic vascular scores and a faster decline in mGFR at 1 year. In conclusion, renal transplantation may be life-threatening in APS patients, and the presence of LA at the time of transplantation is associated with a high rate of allograft APSN and poor transplantation outcomes.
Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor-specific antibodies. After follow-up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation.
Previous studies have documented the high frequency of thrombosis and fetal loss in patients with lupus nephritis and antiphospholipid (aPL) antibodies, but there is little information on the impact of aPL antibodies on the outcome of lupus nephritis. The aims of this study are to evaluate the prevalence of aPL antibodies in patients with lupus nephritis and assess their prognostic value for thrombosis and pregnancy morbidity and impact on long-term renal outcome.
One hundred eleven patients with lupus nephritis followed up for a mean of 173 +/- 100 months were tested regularly for immunoglobulin G (IgG) and IgM anticardiolipin antibodies and lupus anticoagulant.
The overall prevalence of aPL antibodies was 26%. In follow-up, 79% of aPL antibody-positive patients experienced thrombotic events and/or fetal losses, and aPL antibodies were associated significantly with arterial or venous thrombosis (P = 0.00001), pregnancy morbidity (P = 0.045), thrombocytopenia (P = 0.0015), and persistent arterial hypertension (P = 0.028). aPL antibodies were significantly more frequent in patients with biopsy-proven membranous lupus nephritis (P = 0.01). A strong association between aPL antibodies and the development of chronic renal insufficiency in the long-term outcome also was found (P = 0.01). With multivariate analysis, aPL antibody positivity (P = 0.02), high plasma creatinine level at presentation (P = 0.01), and chronicity index (P = 0.00004) were independent predictors of chronic renal function deterioration.
Detection of aPL antibodies in patients with lupus nephritis is useful not only to identify patients at risk for vascular and obstetric manifestations, but also for their potential deleterious impact on renal outcome.
Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL-induced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis.
To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used.
Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti-C5 monoclonal antibodies prevented thrombophilia induced by aPL.
These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.
Two forms of post-transplant thrombotic microangiopathy (TMA) may be recognized: recurrent TMA and de novo TMA. Recurrent TMA may occur in patients who developed a nondiarrhoeal form of haemolytic uraemic syndrome (HUS) being particularly frequent in patients with autosomal recessive or dominant HUS. The recurrence is almost the rule in patients with mutation in complement factor H gene. Most patients eventually lose the graft. Treatment with plasma infusions or plasmapheresis is often disappointing, but few cases may be rescued. Intravenous immunoglobulins and rituximab have also been successful in anedoctic cases. De novo TMA is rarer. A number of factors including viral infection may be responsible of de novo TMA, but in most cases TMA is triggered by calcineurin inhibitors or mTOR inhibitors. The clinical presentation of de novo TMA may be variable with some patients showing clinical and laboratory features of HUS while others showing only a progressive renal failure. The prognosis is less severe than with recurrent TMA. Complete withdrawal of the offending drug may lead to improvement in many cases. The addition of plasma exchange may result in graft salvage in about 80% of cases.