Patients with paroxysmal nocturnal hemoglobinuria demonstrate a prothrombotic clotting phenotype which is improved by complement inhibition with eculizumab

Macrae, Fraser L.; Peacock-Young, Barnaby; Bowman, Polly; Baker, Stephen R.; Quested, Sam; Linton, Emma; Hillmen, Peter; Griffin, Morag; Munir, Tahla; Payne, Daniel; McKinley, Claire; Clarke, Deborah; Newton, Darren J.; Hill, Anita; Ariëns, Robert A. S.

doi:10.1002/ajh.25841

Cited by 4 publications

(4 citation statements)

References 45 publications

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“…Fibrin fiber counts as a measure of fibrin clot density was determined using laser scanning confocal microscopy as previously described 25 . Plasma dilution and clotting initiation were done as for the turbidity assay but spiked with 50 μg/mL AlexaFluor488-labeled fibrinogen (Thermo Fisher Scientific).…”

Section: Confocal Microscopymentioning

confidence: 99%

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT

Iding,

Alkarithi,

Cate

et al. 2024

Blood Advances

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Ultrasound-accelerated catheter-directed thrombolysis (UA-CDT) to improve patency after deep vein thrombosis (DVT) has not conclusively been shown to prevent post-thrombotic syndrome (PTS) but might benefit patients who are unlikely to obtain patency with standard treatment. We hypothesized that these patients could be selected based on their fibrin clot properties. To study this, patients with acute iliofemoral DVT from the CAVA trial had blood samples taken at inclusion. Fibrin clot properties in plasma were determined by turbidimetric clotting (lag time and maximal turbidity) and lysis assays (time to 50% lysis and lysis rate), permeation assay (Ks), and confocal microscopy (fiber density), as well as levels of fibrin clot modifiers fibrinogen and C-reactive protein (CRP). Patency was defined as > 90% iliofemoral vein compressibility at 12-month ultrasound. PTS was defined as ≥ 5 Villalta score at 6 or 12 months. In total 91 of 152 patients were included, namely 43 with additional UA-CDT and 48 with standard treatment. Patients with additional UA-CDT more often obtained patency (55.8 vs. 27.1%; p = 0.005) Patients who obtained patency had longer lag times and lower maximal turbidity, fibrinogen, and CRP; only maximal turbidity and fibrinogen remained associated when adjusting for treatment, thrombus load, and body-mass index. Fibrinogen levels had an optimal cut-off at 4.85 g/L. Low fibrinogen levels best predicted patency (OR 5.59 [2.00-15.62]). Additional UA-CDT decreased the risk of PTS only in patients with high fibrinogen (OR 4.67 [1.14-19.07]). Therefore, additional UA-CDT might prevent PTS in selected patients based on routinely measured fibrinogen levels. The study was registered at ClinicalTrials.gov (nr. NCT00970619).

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Section: Confocal Microscopymentioning

confidence: 99%

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT

Iding,

Alkarithi,

Cate

et al. 2024

Blood Advances

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“…It was the first complement disease to be approved for routine clinical therapy, and during the last 15 years, innumerable patients have been efficiently treated with very good effects and with minor adverse effects (Kelly et al, 2011;Hillmen et al, 2013;Loschi et al, 2016;Ninomiya et al, 2016). Importantly, patients with PHN suffer thrombosis as one of the main complications and reasons for morbidity and mortality and when treated with the complement inhibitor eculizumab do not suffer from these serious thromboses (Macrae et al, 2020). In some cases, there is residual lysis despite C5 inhibition, and it has been proposed that the C3 opsonization might be the reason for extravascular lysis, and that inhibition of C3 is an alternative to prevent this lysis (Risitano et al, 2019).…”

Section: Therapeutic Complement Inhibitionmentioning

confidence: 99%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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The complement system was discovered at the end of the 19th century as a heat-labile plasma component that “complemented” the antibodies in killing microbes, hence the name “complement.” Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. Significance Statement The complement system is the host’s defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host’s enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

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“…37 Untreated patients with PNH have higher fibrino gen and throm bin gen er a tion lev els, lead ing to faster-forming fibrin clots that are harder to break down; these abnor mal i ties are improved by eculizumab. 51 Primary anticoagulation pro phylaxis has been pro posed for patients with more than 50% PNH granulocytes who have no con tra in di ca tions to anticoagulation. 38 However, pri mary anticoagulation pro phy laxis in PNH remains con tro ver sial.…”

Section: Clinical Case 3 (Classical Pnh)mentioning

confidence: 99%

When does a PNH clone have clinical significance?

Babushok

2021

Hematology

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease caused by somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene required to produce glycophosphatidyl inositol (GPI) anchors. Although PNH cells are readily identified by flow cytometry due to their deficiency of GPI-anchored proteins, the assessment of the clinical significance of a PNH clone is more nuanced. The interpretation of results requires an understanding of PNH pathogenesis and its relationship to immune-mediated bone marrow failure. Only about one-third of patients with PNH clones have classical PNH disease with overt hemolysis, its associated symptoms, and the highly prothrombotic state characteristic of PNH. Patients with classical PNH benefit the most from complement inhibitors. In contrast, two-thirds of PNH clones occur in patients whose clinical presentation is that of bone marrow failure with few, if any, PNH-related symptoms. The clinical presentations are closely associated with PNH clone size. Although exceptions occur, bone marrow failure patients usually have smaller, subclinical PNH clones. This review addresses the common scenarios that arise in evaluating the clinical significance of PNH clones and provides practical guidelines for approaching a patient with a positive PNH result.

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Patients with paroxysmal nocturnal hemoglobinuria demonstrate a prothrombotic clotting phenotype which is improved by complement inhibition with eculizumab

Cited by 4 publications

References 45 publications

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT

Fibrinogen levels and clot properties identify patients who benefit from catheter-directed thrombolysis after DVT

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

When does a PNH clone have clinical significance?

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