Publications by authors named "Dirk Hendriks"

Carboxypeptidase U (CPU, TAFIa, CPB2) is a potent attenuator of fibrinolysis that is mainly synthesized by the liver as its inactive precursor proCPU. Aside from its antifibrinolytic properties, evidence exists that CPU can modulate inflammation, thereby regulating communication between coagulation and inflammation. Monocytes and macrophages play a central role in inflammation and interact with coagulation mechanisms resulting in thrombus formation.

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  • Statins not only lower cholesterol but also impact the CPU system, showing increased proCPU levels in hyperlipidemic patients and reduced levels with atorvastatin treatment.
  • A larger study involving 141 statin-treated individuals confirmed previous findings of high proCPU in hyperlipidemic individuals, emphasizing the drug's effectiveness in improving fibrinolysis.
  • Results indicate a significant correlation between atorvastatin dosage and decreased proCPU levels, highlighting the potential of statins to normalize elevated proCPU in hyperlipidemic patients.
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  • COVID-19 is caused by the SARS-CoV-2 virus and can lead to serious respiratory and thromboembolic complications due to a disturbed balance in blood clotting.
  • A study analyzed blood samples from 56 hospitalized COVID-19 patients and 32 healthy controls, finding that COVID-19 patients had lower levels of procarboxypeptidase U (proCPU) and higher levels of total active and inactivated CPU (CPU+CPUi) during initial hospitalization.
  • The changes in proCPU and CPU+CPUi antigen levels were linked to disease severity and hospitalization duration, suggesting that monitoring these levels could help predict patient outcomes and thrombotic risks in COVID-19 cases.
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Background: COVID-19 patients experience several features of dysregulated immune system observed in sepsis. We previously showed a dysregulation of several proline-selective peptidases such as dipeptidyl peptidase 4 (DPP4), fibroblast activation protein alpha (FAP), prolyl oligopeptidase (PREP) and prolylcarboxypeptidase (PRCP) in sepsis. In this study, we investigated whether these peptidases are similarly dysregulated in hospitalized COVID-19 patients.

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  • The study investigates the role of carboxypeptidase U (CPU), an antifibrinolytic enzyme, as a potential therapeutic target for acute ischemic stroke (AIS) treatment.
  • CPU activity was observed to increase rapidly during thrombolysis with rtPA and showed variability across patients, with levels peaking at the end of the treatment.
  • Findings indicate that a CPU inhibitor might be beneficial when administered during and after rtPA infusion, although not all patients may respond effectively due to differences in CPU generation.
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Statins (hydroxymethyl-glutaryl-CoA-reductase inhibitors) lower procarboxypeptidase U (proCPU, TAFI, proCPB2). However, it is challenging to prove whether this is a lipid or non-lipid-related pleiotropic effect, since statin treatment decreases cholesterol levels in humans. In apolipoprotein E-deficient mice with a heterozygous mutation in the fibrillin-1 gene (ApoEFbn1), a model of advanced atherosclerosis, statins do not lower cholesterol.

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  • Statins, commonly used to lower cholesterol and reduce cardiovascular risk, also have effects beyond cholesterol management, specifically on procarboxypeptidase U (proCPU) levels, as explored in this pilot study.
  • Blood samples from 16 hyperlipidemic patients before and after 3 months of statin therapy showed significant decreases in proCPU levels, bringing them in line with those of control subjects, and improved clot lysis times were observed.
  • The study suggests that patients with higher proCPU levels may benefit the most from statin treatment, indicating a need for further research with larger participant groups to confirm these findings.
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  • Procarboxypeptidase U (proCPU) is a zymogen that converts into an active enzyme (CPU) which inhibits fibrinolysis and links the coagulation and fibrinolysis processes.
  • Research indicates that targeting CPU with inhibitors could enhance natural fibrinolysis and improve thrombolytic treatments for thromboembolic diseases.
  • The paper reviews methods for measuring different forms of CPU and discusses their potential as diagnostic markers and their association with thrombotic risks.
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Background: Carboxypeptidase U (CPU, CPB2, TAFIa) is a potent attenuator of fibrinolysis. The inhibition of CPU is thus an interesting strategy for improving thrombolysis.

Objectives: The time course of CPU generation and proCPU consumption were assessed in an experimental rat model of acute ischemic stroke (AIS).

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  • TM-AC is a rare bleeding disorder linked to a specific variant in the thrombomodulin gene, leading to high plasma thrombomodulin levels that slow down thrombin generation and delay fibrinolysis.
  • Researchers reported a family with a novel variant causing TM-AC and the co-inherited deficiency of a protein known as TAFI, identifying abnormal bleeding and increased plasma TM levels among affected members.
  • This study adds to the understanding of TM-AC genetics and suggests that the delayed fibrinolysis in this condition is associated with increased TAFI activation, offering a unique model to explore the interplay between thrombin, thrombomodulin, and TAFI regulation.
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  • Hemolysis significantly inhibits the activity of (pro)carboxypeptidase U ((pro)CPU) in coagulation testing, especially affecting clot lysis assays.
  • The study showed that higher concentrations of oxyhemoglobin from hemolysis led to a marked decrease in CPU activity and proCPU levels, with quantified cutoff values for acceptable bias.
  • The findings suggest that hemolysis can artificially enhance fibrinolysis results, emphasizing the importance of considering hemolysis in coagulation evaluations.
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Carboxypeptidase U (CPU, CPB2, TAFIa) is a basic carboxypeptidase that is able to attenuate fibrinolysis. The inactive precursor procarboxypeptidase U is converted to its active form by thrombin, the thrombin-thrombomodulin complex or plasmin. The aim of this study was to investigate and characterise the time course of CPU generation in healthy individuals.

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  • Dipeptidyl peptidase IV (DPPIV) inhibition could be a beneficial treatment for acute stroke, as it may help extend the effects of neuroprotective substances.
  • A related enzyme, fibroblast activation protein (FAP), also affects these substances and should be studied as a potential stroke target.
  • In a study of 50 stroke patients, higher stroke severity was linked to increased DPPIV activity initially and a more significant drop in both DPPIV and FAP activity over the week, indicating worse outcomes for those with stronger fluctuations in enzyme levels.
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  • Prolyl carboxypeptidase (PRCP) is linked to cerebrovascular risk factors and the study investigates its relation to acute ischemic stroke outcomes.
  • The research measured serum PRCP activity in 50 stroke patients at multiple time points post-stroke, finding a significant decrease in PRCP levels within the first 24 hours.
  • Higher initial stroke severity and infarct volume were correlated with greater reduction in PRCP, indicating that lower levels of PRCP may predict worse short-term outcomes and increased likelihood of needing institutional care.
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This review covers carboxypeptidase M (CPM) research that appeared in the literature since 2009. The focus is on aspects that are new or interesting from a clinical perspective. Available research tools are discussed as well as their pitfalls and limitations.

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Although the kidney generally has been regarded as an excellent source of carboxypeptidase M (CPM), little is known about its renal-specific expression level and distribution. This study provides a detailed localization of CPM in healthy and diseased human kidneys. The results indicate a broad distribution of CPM along the renal tubular structures in the healthy kidney.

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  • Since its discovery over 20 years ago, significant insights into the biochemistry and physiological roles of carboxypeptidase U (CPU) have emerged.
  • Recent studies have focused on determining the crystal structure of proCPU and the reasons behind the instability of the active form, CPU.
  • New sensitive assays now allow for accurate measurement of CPU levels in circulation, and research into CPU inhibitors as potential treatments that enhance fibrinolysis has gained traction in both academic and pharmaceutical sectors.
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This article introduces a novel assay for the measurement of carboxypeptidase U (CPU) in plasma using the selective CPU substrate Bz-o-cyano-Phe-Arg (N-benzoyl-ortho-cyano-phenylalanyl-arginine), thereby limiting the interference of plasma carboxypeptidase N (CPN) as well as the intrinsic activity of procarboxypeptidase U (proCPU). A limit of detection of 0.05 U/L (10 pM) was reached.

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Although the maintenance of precise balance between coagulation and fibrinolysis is of utmost importance for normal haemostasis, until recently these two systems were considered as completely separate mechanisms involved in the process of formation and dissolution of blood clot. Thrombin activatable fibrinolysis inhibitor (TAFI) is a recently described attenuator of the fibrinolytic rate and is considered to be the molecular link between coagulation and fibrinolysis. TAFI circulates in plasma as an inactive precursor and its conversion in active enzyme (TAFIa) occurs by the action of thrombin or plasmin, but most efficiently by thrombin in the presence of its cofactor thrombomodulin.

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To date, several assays for procarboxypeptidase U (proCPU) determination exist, all having their own inherent disadvantages and advantages. A drawback of activity-based assays is the interference of the constitutively active carboxypeptidase N (CPN) in plasma. Recent screening of Bz-Xaa-Arg peptides with modified aromatic amino acids at the P1 position revealed a selective CPU substrate, N-benzoyl-ortho-cyano-phenylalanyl-arginine (Bz-o-cyano-Phe-Arg), which will allow straightforward determination of proCPU in plasma.

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Introduction: It is considered that high plasma levels of procarboxypeptidase U (proCPU or TAFI) can promote the development of thrombosis, but data comparing proCPU levels in thrombophilia carriers and healthy subjects are rather scarce. Moreover, the results of previous studies on the risk of thrombosis related to high proCPU concentration in this population were not consistent. Although the 325 polymorphism of proCPU has a significant effect on the CPU half-life, it's influence on the risk of thrombosis or spontaneous pregnancy loss in carriers of hereditary thrombophilia is not clear.

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  • Patients with hereditary mucocutaneous bleeding often fall into the "bleeders of unknown cause" (BUC) category, and the role of hyperfibrinolysis is not well understood, despite treatments available.
  • Researchers analyzed procarboxypeptidase U (proCPU) levels in 193 patients compared to 143 healthy controls to understand its role in bleeding tendencies.
  • Results showed that while proCPU levels were higher in patients than controls, the findings suggest the proCPU system does not significantly contribute to bleeding issues and may even help mitigate them.
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Introduction: Thrombolytic therapy improves clinical outcome in patients with acute ischemic stroke but is compromised by symptomatic intracranial hemorrhage and an unpredictable therapeutic response. In vitro and in vivo data suggest that activation of procarboxypeptidase U (proCPU) inhibits fibrinolysis.

Aims: To investigate whether the extent of proCPU activation is related to efficacy and safety of thrombolytic therapy in ischemic stroke patients.

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  • Carboxypeptidase M is an important enzyme that removes amino acids from the ends of proteins and peptides, playing key roles in processes like blood coagulation, inflammation, digestion, and neuropeptide processing.
  • Its active form is constitutively expressed on specialized cells and tissues, highlighting its significance in human physiology, although its exact functions are not entirely understood.
  • Recent research has provided new insights into CPM's roles, its distribution in various cell types and diseases, and its potential functions beyond protease activity, including participation in cell-surface interactions.
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