TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

Wyseure, Tine; Yang, Ting; Zhou, Jiang; Cooke, Esther J; Wanko, Bettina; Olmer, Merissa; Agashe, Ruchi; Morodomi, Yosuke; Behrendt, Niels; Lotz, Martin; Morser, John; Drygalski, Annette von; Mosnier, Laurent O.

doi:10.1172/jci.insight.128379

Cited by 12 publications

(9 citation statements)

References 76 publications

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“…In other words, abnormal synovial perfusion and thinner vessel walls (with less αSMA expression) were associated with higher levels of vascular basement membrane turnover products. These findings imply decreased turnover of vascular wall constituents once vessel walls thicken and become more established after the initial formation of thin walled, permeable vessels 9,41,42 . This correlation establishes a link between vascular stabilization and measurable basement membrane turnover dynamics in plasma.…”

Section: Discussionmentioning

confidence: 60%

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Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

Gopal

Barnes

Cooke

et al. 2021

Journal of Thrombosis and Haemostasis

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Introduction: Interstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood.Methods: Thirty-one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during painfree intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII−/− mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers.Results: Ninety-one patient visits were compiled. Twenty-five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO-C4 and C4M), and a type VIII collagen synthesis marker (PRO-C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII-deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels. Conclusions:Our findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.

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Section: Discussionmentioning

confidence: 60%

“…These findings imply decreased turnover of vascular wall constituents once vessel walls thicken and become more established after the initial formation of thin walled, permeable vessels. 9,41,42 This correlation establishes a link between vascular stabilization and measurable basement membrane turnover dynamics in plasma.…”

Section: Discussionmentioning

confidence: 66%

Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

Gopal

Barnes

Cooke

et al. 2021

Journal of Thrombosis and Haemostasis

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“…The two strains of C57Bl/6J Cpb2 À/À mice had been previously directly compared in a study on joint vascularity with aging and both displayed a comparable increase in vascularity and arthritis. 10 All animal procedures were reviewed and approved by the Animal Ethics Committee of the University of Amsterdam under the institutional license to secure full compliance to the Dutch Experiments on Animals Act (WOD) and the European Directive for the use of animals for scientific purposes, or the Veterans Affairs Palo Alto Health Care System Institutional Animal Care and Use Committee in accordance with National Institutes of Health guidelines.…”

Section: Animal Modelsmentioning

confidence: 99%

“…[5][6][7][8] Without challenge, young Cpb2 À/À mice have no directly observable phenotype, 9 but arthritis becomes detectable as the mice age. 10 However, once challenged the animals display a variety of changes that confirmed activity of CPB2 toward its substrates. 9 For example, Cpb2 À/À mice have exacerbated polymicrobial sepsis, but are protected against Escherichia coli challenge.…”

Section: Introductionmentioning

confidence: 97%

Brain Expression of CPB2 and Effects of Cpb2 Deficiency in Mouse Models of Behavior

Harst¹,

Marx

Sahbaie

et al. 2023

Thromb Haemost

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Background Procarboxypeptidase B2 (proCPB2 or TAFI) is a zymogen that after activation cleaves C-terminal basic residues from peptides or proteins with many identified targets. A splice variant of CPB2 has been found in the brain lacking essential residues for its carboxypeptidase function. The aim was to determine CPB2 expression in the brain and effects of CPB2 deficiency (Cpb2 −/−) on behavior. Materials and Methods Behavioral effects were tested by comparing Cpb2 −/− mice in short-term (open field and elevated zero maze tests) and long-term (Phenotyper) observations with wild-type (WT) controls. Results Long-term observation compared day 1 (acclimatizing to novel environment) to day 4 (fully acclimatized) with the inactive (day) and active (night) periods analyzed separately. Brain expression of CPB2 mRNA and protein was interrogated in publicly available databases. Long-term observation demonstrated differences between WT and Cpb2 −/− mice in several parameters. For example, Cpb2 −/− mice moved more frequently on both days 1 and 4, especially in the normally inactive periods. Cpb2 −/− mice spent more time on the shelter and less time in it. Differences were more pronounced on day 4 after the mice had fully acclimatized. In short-term observations, no differences were observed between Cpb2 −/− mice and WT mice. Brain expression of CBP2 was not detectable in the human protein atlas. Databases of single-cell RNAseq did not show expression of CPB2 mRNA in either human or mouse brain. Conclusion Continuous observation of home-cage behavior suggests that Cpb2 −/− mice are more active than WT mice, show different day–night activity levels, and might have a different way of processing information.

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“…Furthermore, TAFI deficient mice demonstrated a decrease in thrombus size in FeCl 3 -induced vascular injury models and enhanced fibrinolysis in a thromboembolism model [87,88]. More recently, it was reported that functional TAFI deficiency in haemophilia promotes maladaptive vascular remodelling in the joints after bleeding [89], suggesting a more diverse role for this protein.…”

Section: Effects Of Tafi Deficiencymentioning

confidence: 99%

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics

Pechlivani

Kearney

Ajjan

2021

IJMS

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Thrombus formation remains a major cause of morbidity and mortality worldwide. Current antiplatelet and anticoagulant therapies have been effective at reducing vascular events, but at the expense of increased bleeding risk. Targeting proteins that interact with fibrinogen and which are involved in hypofibrinolysis represents a more specific approach for the development of effective and safe therapeutic agents. The antifibrinolytic proteins alpha-2 antiplasmin (α2AP), thrombin activatable fibrinolysis inhibitor (TAFI), complement C3 and plasminogen activator inhibitor-2 (PAI-2), can be incorporated into the fibrin clot by FXIIIa and affect fibrinolysis by different mechanisms. Therefore, these antifibrinolytic proteins are attractive targets for the development of novel therapeutics, both for the modulation of thrombosis risk, but also for potentially improving clot instability in bleeding disorders. This review summarises the main properties of fibrinogen-bound antifibrinolytic proteins, their effect on clot lysis and association with thrombotic or bleeding conditions. The role of these proteins in therapeutic strategies targeting the fibrinolytic system for thrombotic diseases or bleeding disorders is also discussed.

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TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

Cited by 12 publications

References 76 publications

Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

Brain Expression of CPB2 and Effects of Cpb2 Deficiency in Mouse Models of Behavior

Fibrinogen and Antifibrinolytic Proteins: Interactions and Future Therapeutics

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