Thromboembolic events as a complication of antineutrophil cytoplasmic antibody–associated vasculitis

Weidner, Sven; Hafezi‐Rachti, Syrus; Rupprecht, Harald

doi:10.1002/art.21704

Cited by 94 publications

(79 citation statements)

References 13 publications

(11 reference statements)

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“…One study reported 13 of 105 ANCA vasculitis patients developed a VTE. 24 Ten of these patients were PR3-ANCA positive and three were MPO-ANCA positive, a percentage quite similar to our findings. A second study showed that 29 of 180 patients in a clinical trial of Wegener's granulomatosis developed a VTE.…”

Section: Discussionsupporting

confidence: 90%

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

Bautz¹,

Preston²,

Lionaki³

et al. 2008

Journal of the American Society of Nephrology

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Patients with inflammatory vascular disease caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) can harbor antibodies not only to the autoantigen proteinase 3 (PR3) but also to complementary PR3 (cPR3 ), a recombinant protein translated from the antisense strand of PR3 cDNA. The purpose of this study was to identify potential endogenous targets of anti-cPR3 antibodies. Patients' plasmapheresis material was tested for the presence of antigens reactive with affinity-purified rabbit and chicken anti-cPR3105-201 polyclonal antibodies. Antigen-containing fractions were tested with patients' anti-cPR3105-201 affinity-purified IgG, and putative protein targets were sequenced by mass spectrometry. Unexpectedly, plasminogen was identified as a target of anti-cPR3 . Reactivity of affinitypurified antibodies from two patients was lost when plasminogen was converted to plasmin, indicating restricted specificity. Antiplasminogen antibodies from five patients bound plasminogen at a surfaceexposed loop structure within the protease domain. This loop contains an amino acid motif that is also found in a portion of recombinant cPR3 ; site-directed mutagenesis of this sequence decreased antibody reactivity by 30%. Functionally, antiplasminogen antibodies delayed the conversion of plasminogen to plasmin and increased the dissolution time of fibrin clots. Serologically, antiplasminogen antibody levels were higher in PR3-ANCA patients (n ϭ 72) than healthy control subjects (n ϭ 63), myeloperoxidase-ANCA patients (n ϭ 34), and patients with idiopathic thrombosis (n ϭ 57; P ϭ 0.001). Of the patients with PR3-ANCA, nine had documented deep venous thrombosis events, five of whom were positive for antiplasminogen antibodies. In summary, capitalizing on interactions with complementary proteins, specifically complementary PR3, this study identified plasminogen as a previously undescribed autoantigen in PR3-ANCA vasculitis.

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Section: Discussionsupporting

confidence: 90%

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

Bautz¹,

Preston²,

Lionaki³

et al. 2008

Journal of the American Society of Nephrology

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“…(9) In conclusion, we demonstrated a high prevalence of microvascular thrombosis among our patients with WG, as well as a significant association between pulmonary arterial thrombosis and WG. Consequently, it would be interesting to add these findings to the existing data regarding the pathophysiological pathway of this type of vasculitis.…”

Section: Resultssupporting

confidence: 56%

“…Recently, thromboembolic events have also emerged as a novel clinical conundrum in WG. (6,8,9) However, there have been few histopathological descriptions of thrombi in the pulmonary microcirculation of ANCA-associated vasculitis, probably due to a lack of awareness of this histopathological finding, considering that the question of thromboembolic events in WG was not raised until 2005. (8,(10)(11)(12) Therefore, we conducted this confocal laser scanning microscopy-based study in order to determine the presence of fibrin thrombi and to quantify them in small and medium-sized pulmonary arteries.…”

Section: Introductionmentioning

confidence: 99%

Trombose em artérias pulmonares pequenas e médias em granulomatose de Wegener: um estudo com microscopia confocal por varredura a laser

et al. 2010

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Objective: Wegener's granulomatosis (WG) can cause endothelial cell damage and thromboembolic events. Nevertheless, there have been few studies on the pulmonary microcirculation-small and medium-sized pulmonary arteries (SMSPA)-in patients with WG. The objective of this study was to quantify fibrin thrombi in the SMSPA of patients with WG. Methods: We analyzed 24 SMSPA samples collected from six patients with WG and 16 SMSPA samples collected from four patients without WG. In all samples, we used the endothelial cell marker CD34 and confocal laser scanning microscopy in order to detect intravascular fibrin thrombi. We calculated the total vessel area, the free lumen area, and the thrombotic area. Results: The mean total vessel area was similar in the WG and control groups (32,604 µm 2 vs. 32,970 µm 2 , p = 0.8793). Thrombi were present in 22 (91.67%) of the 24 WG group samples and in none of the control group samples (p < 0.0001; OR = 297; 95% CI: 13.34-6,612). The mean thrombotic area was greater in the WG group samples than in the control group samples (10,068 µm 2 vs. 0.000 µm 2 ; p < 0.0001). In contrast, the mean free lumen area was smaller in the WG group samples than in the control group samples (6,116 µm 2 vs. 24,707 µm 2 ; p < 0.0001). Conclusions: Confocal laser scanning microscopy revealed a significant association between pulmonary microvascular thrombosis and WG. This suggests a possible role of microvascular thrombosis in the pathophysiology of pulmonary WG, evoking the potential benefits of anticoagulation therapy in pulmonary WG. However, further studies are needed in order to confirm our findings, and randomized clinical trials should be conducted in order to test the role of anticoagulation therapy in the treatment of patients with pulmonary WG. Keywords:Vasculitis; Antibodies, antineutrophil cytoplasmic; Wegener granulomatosis; Thrombosis; Lung; Microscopy, confocal. ResumoObjetivo: A granulomatose de Wegener (GW) pode causar dano nas células endoteliais e fenômenos tromboembólicos. Entretanto, poucos estudos analisaram a microcirculação pulmonar -artérias pulmonares de pequeno/médio calibre (APPMC) -em pacientes com GW. O objetivo deste estudo foi quantificar trombos de fibrina em amostras de APPMC de pacientes com GW. Métodos: Analisamos 24 APPMC de seis pacientes com GW e 16 APPMC de quatro pacientes controles sem WG. Utilizamos CD34 para a marcação do endotélio em todas as amostras e microscopia confocal a laser para detectar trombos de fibrina intravasculares. Calculamos a área total do vaso, a área livre do lúmen e a área trombótica. Resultados: A média da área total do vaso foi similar no grupo GW e no grupo controle (32.604 µm 2 vs. 32.970 µm 2 , p = 0,8793). Trombos foram identificados em 22 das 24 APPMC (91,67%) no grupo GW, e em nenhuma do grupo controle (p < 0,0001; OR = 297 (IC95%: 13,. A média da área trombótica foi maior no grupo GW do que no grupo controle (10.068 µm 2 vs. 0.000 µm 2 , p < 0,0001). Em contraste, a média da área livre do lúmen foi menor no grupo GW que n...

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“…However, little information is available on their interaction with platelets. Of interest, thromboembolic events are common but relatively unappreciated complications of ANCA-associated vasculitis, and could be a direct consequence of the disease [3,91].…”

Section: The Cross-talk Between Activated Platelets and Circulating Lmentioning

confidence: 99%

Translational Mini-Review Series on Immunology of Vascular Disease: Mechanisms of vascular inflammation and remodelling in systemic vasculitis

Maugeri

Rovere‐Querini

Baldini

et al. 2009

Clinical and Experimental Immunology

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SummaryVessel walls are the primary inflammatory sites in systemic vasculitides. In most cases the initiating event is unknown, and a self-sustaining circuit attracts and activates inflammatory leucocytes in the wall of vessels of various size and anatomical characteristics. Recent studies have revealed homeostatic roles of vascular inflammation and have identified the action of humoral innate immunity, in particular injury-associated signals and acute phase proteins, on the activation of circulating leucocytes, platelets and endothelial cells. These advances have provided clues to the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury.

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Thromboembolic events as a complication of antineutrophil cytoplasmic antibody–associated vasculitis

Cited by 94 publications

References 13 publications

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis

Trombose em artérias pulmonares pequenas e médias em granulomatose de Wegener: um estudo com microscopia confocal por varredura a laser

Translational Mini-Review Series on Immunology of Vascular Disease: Mechanisms of vascular inflammation and remodelling in systemic vasculitis

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