Littérature scientifique sur le sujet « APS, Complement System, Coagulation Cascade »

Introduction: Catastrophic antiphospholipid syndrome (CAPS) is characterized by multiple intravascular thrombotic events occurring over a short time period in the presence of persistently detectable antiphospholipid antibodies (APLA). Despite its clinical significance with mortality rate of 40-50%, the underlying pathophysiology remains somewhat enigmatic. More recent focus on the complement system as it interacts with the coagulation cascade has led to off-label use of eculizumab, a humanized monoclonal antibody against C5, in the treatment of CAPS. Consequently, monitoring of disease status with complement levels is an area of interest. We report complement levels in four patients with CAPS who had various clinical outcomes. Methods: Four patients admitted to SUNY Upstate Medical University with CAPS between February and May 2019 were included in this case series. All patients had APS with prior history of refractory CAPS (persistent disease despite standard therapy with steroids, rituximab, and therapeutic plasma exchange [TPEX]). Antiphospholipid antibodies (APLA) and complement (C3 and C4) levels were monitored during admission until discharge or death. Results: Patient characteristics are summarized in Table 1. Patient 1 was a 42-year-old female with antiphospholipid syndrome (APS) on warfarin, ischemic stroke, and aortic valve replacement admitted on March 2019 with shortness of breath, hemoptysis and menorrhagia. She was found to have elevated APLA, thrombocytopenia, and acute renal failure with renal biopsy confirming APS nephropathy. Despite therapy with ongoing anticoagulation, steroids, rituximab, IVIG, and TPEX her clinical course continued to deteriorate. Hypocomplementemia was present (both low C3 and C4), with lowest C3 level on admission at 31 (Graph 1A). Decision was made to pursue eculizumab on 4/16/19 with continued clinical decline and no improvement in complement levels. She ultimately died on 4/24/19. Patient 2 was a 35-year-old male with systemic lupus erythematosus (SLE), APS, end-stage renal disease, and Libman-Sacks endocarditis status post bioprosthetic aortic valve replacement admitted in February 2019 for worsening digital ischemia. Workup showed presence of lupus anticoagulant, thrombocytopenia, low C3 levels (Graph 1B), normal C4 levels, and arterial thrombi in the upper and lower extremities. Prior to initiation of treatment, respiratory status declined due to massive pulmonary embolus. He died after PEA arrest shortly thereafter. Patient 3 is a 63-year-old male with chronic ITP and APS on warfarin, maintenance rituximab and intermittent apheresis admitted with worsening renal dysfunction in April 2019. Workup demonstrated acute on chronic thrombocytopenia, elevated APLA, and normal C3 and C4 levels (Graph 1C). Renal replacement therapy was commenced and he was discharged to receive ongoing outpatient therapy. Patient 4 is a 35-year-old male with history of SLE and APS admitted in April 2019 with renal failure, anemia and thrombocytopenia. Workup showed presence of APLA. Despite therapy with steroids, IVIG, rituximab and TPEX he became anuric with renal biopsy showing thrombotic microangiopathy. He was also bacteremic with a mitral valve vegetation for which he underwent valve replacement. Hospital course was complicated by need respiratory failure necessitating intubation and ECMO. C3 levels were consistently low, but varied throughout his long admission (Graph 1D) and were not necessarily related to his clinical course (sepsis, ECMO, etc.). C4 levels were normal. Conclusions: Complement levels were variable among the patients in this case series. Three out of four patient had low C3, while only one patient had low C4. Further, complement levels did not improve in one patient after administration of eculizumab. Routine laboratory testing for C3 and C4 may not be optimal assays for monitoring disease status in CAPS. More specialized complement testing, such a C5 a/b, may be more appropriate especially in the setting of eculizumab use. While eculizumab is typically used in refractory disease, it may be pertinent to move this therapy into early line treatment to achieve better outcomes in certain clinical scenarios. Identification of a more specific biomarker to recognize cases in need of early therapy is warranted. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Eculizumab, a humanized monoclonal IgG antibody that binds to complement protein C5, is discussed for its off-label use in the treatment of catastrophic antiphospholipid antibody syndrome.

Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI.

Complement and coagulation are both key systems that defend the body from harm. They share multiple features and are similarly activated. They each play individual roles in the systemic circulation in physiology and pathophysiology, with significant crosstalk between them. Components from both systems are mapped to important structures in the central nervous system (CNS) and peripheral nervous system (PNS). Complement and coagulation participate in critical functions in neuronal development and synaptic plasticity. During pathophysiological states, complement and coagulation factors are upregulated and can modulate synaptic transmission and neuronal conduction. This review summarizes the current evidence regarding the roles of the complement system and the coagulation cascade in the CNS and PNS. Possible crosstalk between the two systems regarding neuroinflammatory-related effects on synaptic transmission and neuronal conduction is explored. Novel treatment based on the modulation of crosstalk between complement and coagulation may perhaps help to alleviate neuroinflammatory effects in diseased states of the CNS and PNS.

AbstractTransplant-associated thrombotic microangiopathy (TA-TMA) is a severe and life-threatening complication of hematopoietic cell transplantation (HCT) that often coincides with graft-versus-host-disease (GVHD). Although endothelial damage seems to be the common denominator for both disorders, the role of complement system, neutrophils, and coagulation has not been clarified. In an effort to distinguish the pathogenesis of TA-TMA from GVHD, we evaluated markers of complement activation, neutrophil extracellular trap (NET) release, endothelial damage, and activation of coagulation cascade in the circulation of patients with these two disorders, as well as control HCT recipients without TA-TMA or GVHD. We observed that the terminal complement product C5b-9 levels, the levels of markers of NET formation, and thrombin–antithrombin complex levels were significantly increased in the TA-TMA group compared with patients without complications, whereas there was no significant difference between the GVHD and the control group. On the other hand, the levels of circulating thrombomodulin, an endothelial damage marker, were significantly increased in both TA-TMA and GVHD patients. These findings propose a role for the interplay between complement system, neutrophil activation through NET release, and activation of the coagulation cascade in TA-TMA.

SummaryThe antiphospholipid syndrome (APS) is defined as the association of antiphospholipid antibodies (aPL) with thrombosis, fetal loss or thrombocytopenia. Some aPL can be detected via coagulation assays where they present as an aspecific inhibitor termed the lupus anticoagulant (LA). Others can be measured via direct binding to cardiolipin and are termed anticardiolipin antibodies. aPL found in APS patients bind to a variety of PL-binding proteins such as beta-2-glycoprotein I (β2GPI) and prothrombin bound to PL surfaces. LA retard coagulation reactions in vitro by forming stable bivalent immune complexes on coagulation active phospholipids. These complexes have increased affinity for PL and compete with coagulation factors for the same catalytic surface. Animal experimental work has provided evidence that aPL are pathogenic. Based on similarities with heparin induced thrombocytopenia, another thrombotic syndrome, the following mechanism might be proposed. As a consequence of an initial activation, anionic PL exposed on bloodcells, endothelium or trophoblasts may promote the formation of bivalent complexes of aPL and PL-binding proteins. In this way, aPL concentrate on the cell surface, activate cellular FcγRII receptors or the complement system and induce thrombosis.

Overactivation of the complement system has been characterized in severe COVID-19 cases. Complement components are known to trigger NETosis via the coagulation cascade and have also been reported in human tracheobronchial epithelial cells. In this longitudinal study, we investigated systemic and local complement activation and NETosis in COVID-19 patients that underwent mechanical ventilation. Results confirmed significantly higher baseline levels of serum C5a (24.5 ± 39.0 ng/mL) and TCC (11.03 ± 8.52 µg/mL) in patients compared to healthy controls (p < 0.01 and p < 0.0001, respectively). Furthermore, systemic NETosis was significantly augmented in patients (5.87 (±3.71) × 106 neutrophils/mL) compared to healthy controls (0.82 (±0.74) × 106 neutrophils/mL) (p < 0.0001). In tracheal fluid, baseline TCC levels but not C5a and NETosis, were significantly higher in patients. Kinetic studies of systemic complement activation revealed markedly higher levels of TCC and CRP in nonsurvivors compared to survivors. In contrast, kinetic studies showed decreased local NETosis in tracheal fluid but comparable local complement activation in nonsurvivors compared to survivors. Systemic TCC and NETosis were significantly correlated with inflammation and coagulation markers. We propose that a ratio comprising systemic inflammation, complement activation, and chest X-ray score could be rendered as a predictive parameter of patient outcome in severe SARS-CoV-2 infections.

Platelets are small anuclear cells that play a central role in haemostasis. Platelets become activated in response to various stimuli triggering release of their granular contents into the surrounding milieu. One of these types of granules, termed dense granules, have been found to contain polyphosphate (polyP) in addition to other inorganic biomolecules, such as serotonin, ADP, ATP, PPi. Individuals deficient in dense granules exhibit bleeding tendencies, emphasizing their importance in haemostasis. Platelet polyP is of a relatively defined size, approximately 60–100 phosphate monomers in length. These linear polymers act at various points in the coagulation and fibrinolytic systems thereby modulating the haemostatic response. Due to its highly anionic nature, polyP lends itself to being a natural activator of the contact system. The contact system functions in multiple pathways including coagulation, fibrinolysis, inflammation and complement. Activation of the contact system accelerates thrombin generation, the terminal enzyme in the coagulation cascade. PolyP also modulates factors further downstream in the coagulation cascade to augment thrombin generation. The net effect is increased fibrin formation and platelet activation resulting in faster clot formation. PolyP is incorporated into the forming clot thereby modifying the structure of the resulting fibrin network and its susceptibility to degradation by certain plasminogen activators. In conclusion, release of platelet polyP at the site of injury may facilitate clot formation and augment clot stability thereby promoting wound healing.

Background In a recent experimental study, we showed that low molecular weight heparin improved ultrafiltration and blocked complement activation and coagulation in a single peritoneal dialysis (PD) dwell. Objective The aim of the present study was to evaluate the possible contribution of the complement factor C5a and the potential interactions between C5a, the coagulation system, and cytokines of the interleukin (IL)-8 family (cytokine-induced neutrophil chemoattractant; CINC-1). Methods Nonuremic rats were exposed through an indwelling catheter to a single dose of 20 mL glucose- (2.5%) based filter-sterilized PD fluid, with or without the addition of anti-rat C5 antibody. The dwell fluid was analyzed 2 and 4 hours later concerning activation of the coagulation cascades, neutrophil recruitment, ultrafiltration volume; CINC-1, glucose, urea, and histamine concentrations; and ex vivo intraperitoneal chemotactic activity. Results The numbers of neutrophils and levels of thrombin–antithrombin complex (TAT) and CINC-1 increased significantly during the PD dwell. C5 blockade significantly reduced the levels of TAT and increased the ultrafiltration volumes at 2 hours. Glucose concentrations were significantly positively correlated to ultrafiltration volumes. Conclusions Blockade of C5 leads to an increase in ultra-filtration, probably by a mechanism that involves a reduction in glucose transport. This effect may form a basis for improving PD efficiency in situations where high glucose transport limits ultrafiltration. Mechanisms connected to complement activation during PD may involve coagulation. Further studies of the intraperitoneal cascade systems under conditions of PD are indicated.

Obiettivo. Durante l'ultimo decennio è stato dibattuto il ruolo dell’attivazione del sistema del complemento nella patogenesi della Sindrome da anticorpi Anti Fosfolipidi (APS), tuttavia ad oggi non è stata ancora trovata una correlazione evidente con il fenotipo pro-infiammatorio e pro-coagulante tipico di questa malattia. È stato condotto uno studio retrospettivo su soggetti affetti da APS per valutare l'espressione di molecole solubili e locali del sistema del complemento e della cascata coagulativa ritenute coinvolte nella promozione di eventi trombotici e di complicanze cliniche legate alla gravidanza.Metodi. I livelli plasmatici delle molecole del sistema del complemento C5a e del complesso C5b-9, del Tissue Factor (TF) e del Tissue Factor Pathway Inhibitor (TFPI) di pazienti con APS e di donne sane sono stati analizzati mediante test ELISA. Campioni di placenta di pazienti con APS e controlli sani sono stati sottoposti ad analisi di western immunoblot con anticorpi specifici per il Recettore della componente 5a del complemento (C5aR), CD46 (MCP, Proteina Cofattore di Membrana), CD55 (DAF, Fattore di Accelerazione di Decadimento), CD59, p-selectina, TF e TFPI. È stata inoltre eseguita l’analisi delle mutazioni e dei polimorfismi nei geni regolatori del complemento.Risultati. Nei pazienti con APS, sia in condizioni di gravidanza che non, sono stati riscontrati livelli plasmatici di C5a, C5b-9 e TF maggiori rispetto ai soggetti sani. Nelle placente di donne con APS, i livelli di C5aR, C5b-9 e di p-selectina sono risultati maggiori rispetto ai controlli; al contrario, i livelli di CD46, CD55 e CD59 sono risultati inferiori rispetto ai soggetti sani. Dal momento che la gestione clinica della gravidanza in APS richiede una terapia anticoagulante (eparina), i livelli plasmatici e placentari di TF e TFPI hanno risentito di questo trattamento. Nei donatori di placenta affetti da APS non sono state riscontrate mutazioni o varianza allelica nei geni CD46, CD55 e CD59.Conclusioni. I nostri dati suggeriscono l’attivazione del complemento nei pazienti con APS, sia in condizioni di gravidanza che non, come supportato dall'incremento delle molecole chiave del sistema del complemento. In questo studio, gli elevati livelli di molecole del complemento attivato riscontrati nei soggetti con APS sono stati associati ad uno stato pro-infiammatorio e pro-coagulante. Una diminuzione della concentrazione di CD46, CD55 e CD59 a livello placentare può comprometterne la protezione locale, favorendo l’iperattivazione del complemento e causando infiammazione, trombosi, danni tissutali e la possibile morte fetale. Tuttavia sono necessari ulteriori studi per comprendere meglio i meccanismi coinvolti nella disregolazione del complemento nella APS.
Objective. During the last decade, the role of complement system activation in the pathogenesis of antiphospholipid syndrome (APS) has been debated but an evident correlation with the proinflammatory and procoagulant phenotype in this disease has never been found. We carried out a retrospective study on APS women to evaluate the expression of some soluble and local complement and coagulation molecules supposed to be involved in promoting thrombotic events and pregnancy-related clinical complications.Methods. Complement C5a and C5b-9 complex, Tissue Factor (TF) and Tissue Factor Pathway Inhibitor (TFPI) plasma levels of APS patients and matched healthy women were analyzed by ELISA assays. Placenta samples of APS patients and controls were subjected to immunoblotting analysis with specific antibodies for complement component 5a Receptor (C5aR), CD46 (MCP, Membrane Cofactor Protein), CD55 (DAF, Decay Accelerating Factor), CD59, p-selectin, TF and TFPI. Mutations and polymorphisms analysis in the complement regulator genes were also performed. Results. In APS patients, both in pregnant and non-pregnant conditions, we found higher plasma levels of C5a, C5b-9 and TF compared to healthy subjects. In APS placenta, C5aR, C5b-9 and p-selectin levels were higher than in controls, conversely, CD46, CD55 and CD59 levels were lower compared to healthy subjects. Since clinical management of pregnancy in APS requires anticoagulant therapy (heparin), plasma and placenta content of TF and TFPI were affected by this treatment. In APS placenta donors, we did not find mutations or allele variances in the CD46, CD55 and CD59 genes.Conclusions. Our data suggest complement activation both in pregnant and non-pregnant APS patients as supported by the increase in key molecules from complement system. In this study, higher levels of activated complement molecules were associated to a proinflammatory and procoagulant state in APS subjects. The lower placental CD46, CD55 and CD59 expression may impair local protection, favoring local complement hyperactivation and leading to inflammation, thrombosis, tissue damage and possible fetal death, but further studies are necessary to better understand the mechanisms involved in complement dysregulation in APS syndrome.