Publications by authors named "Mariëtte H Driessens"

14 Publications

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A qualitative study on the experiences of haemophilia carriers before, during and after pregnancy.

Haemophilia 2021 Aug 20. Epub 2021 Aug 20.

Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Haemophilia carriers (HCs) face considerable haemostatic and psychological challenges during reproduction.

Aim: To explore the perspectives of HCs on healthcare in the current standard of haemophilia treatment during all reproductive phases: preconception, pregnancy, childbirth and the postpartum period. In addition, we examined the psychological impact of haemophilia during these phases.

Material And Methods: Focus group discussions (FGDs) and semi-structured interviews were conducted with HCs in January/February 2020 until data saturation was reached. All sessions were recorded, transcribed verbatim and analysed by two independent researchers through thematic content analysis using MAXQDA® software. The results were then discussed within the research team until consensus was reached. The constructed themes were shared with and reviewed by the HCs.

Results: Fifteen HCs were included in three FGDs and four interviews. Five central themes were constructed: (1) communication by healthcare professionals, (2) lack of knowledge, (3) feeling insecure, (4) autonomy and (5) family experiences with haemophilia. Desired improvements in care mainly concerned counselling during preconception and pregnancy. This included timely access to comprehensive information during each consecutive phase, acceptance of HCs' choices by healthcare providers and healthcare tailored to the HC's family experience with haemophilia.

Conclusions: In recent years, haemophilia treatment has seen major advances, which could impact general and reproductive care for HCs. HCs indicated that reproductive care would benefit from a more personal and informative approach. Healthcare professionals could use these insights to adapt their consultations to meet the needs of these women when they are preparing for having children.
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http://dx.doi.org/10.1111/hae.14396DOI Listing
August 2021

Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands.

J Thromb Haemost 2021 Jul 10. Epub 2021 Jul 10.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Background: The Patient-Reported Outcomes Measurement Information System (PROMIS) Profile-29 questionnaire is widely used worldwide, but it has not yet been validated in the Netherlands, nor in persons with hemophilia.

Objective: To validate the Dutch-Flemish version of the PROMIS-29 Profile v2.01 in adults with hemophilia.

Methods: Dutch males with hemophilia (all severities) completed questionnaires that contained sociodemographic and clinical characteristics, the PROMIS-29, RAND-36, and the Hemophilia Activities List (HAL). Structural validity of each subscale was assessed with confirmatory factor analysis (CFA). Internal consistency was calculated for each subscale with sufficient model fit in CFA. Construct validity was assessed by testing hypotheses about (1) correlations of each PROMIS-29 subscale with corresponding scales of RAND-36 and domains of HAL, and (2) mean differences in T-scores between subgroups with different hemophilia severities, self-reported joint impairment, and HIV infection status. We considered ≥75% of data in accordance with the hypotheses evidence for construct validity.

Results: In total, 770 persons with hemophilia participated in this cross-sectional study. CFA revealed sufficient structural validity for five subscales: Physical Function, Depression, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Internal consistency was high and Cronbach's alpha ranged from 0.79 for Sleep Disturbance to 0.96 for Pain Interference. Differences between clinical subgroups were in the expected direction. Construct validity was confirmed for Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Intensity.

Conclusion: This study revealed sufficient evidence for structural validity, internal consistency, and construct validity for most PROMIS Profile-29 subscales among people with hemophilia in the Netherlands.
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http://dx.doi.org/10.1111/jth.15454DOI Listing
July 2021

Similar sports participation as the general population in Dutch persons with haemophilia; results from a nationwide study.

Haemophilia 2021 Sep 19;27(5):876-885. Epub 2021 Jun 19.

Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.

Introduction: Although sports participation is advocated in people with haemophilia (PWH), detailed data concerning sports participation in Dutch PWH is lacking.

Aim: to assess sports participation in Dutch PWH (6-65 years) compared to the Dutch general population (GP).

Methods: Data from a nationwide, cross-sectional study in PWH were analysed. Sports participation (type, duration, frequency) was assessed by the Modifiable Activities Questionnaire (MAQ), limitations in activities using the (Paediatric) Haemophilia Activities List ((Ped)HAL). Sports in the two highest categories according to the National Hemophilia Foundation classification were considered high-risk sports. Groups were compared using Chi-square testing.

Results: A total of 524 Adult PWH (median age: 45 (IQR: 30-55); 37% severe) and 126 paediatric PWH (median age: 11 (IQR: 8-14); 52% severe) were included. Sports participation was higher in adults (70%) than the GP (58%) and similar to the GP in children (PWH: 68%, GP: 72%). High-risk sports participation decreased with age in PWH: from 65% (6-12 years) to 17% (50-65 years), which was also observed in the GP. Sports participation in children was independent of severity (non-severe: 67% vs. severe: 65%; P = 0.97), but not in adults (non-severe: 75%, severe: 62%; P < 0.01). Non-severe PWH played more high-risk sports than severe PWH: children at 65% vs. 48% (P = 0.05), adults at 25% vs. 15% (P = 0.07).

Discussion: These results suggest that sports participation in PWH was comparable to the GP. Sports participation was dependent of haemophilia severity in adults. Children were more involved in high-risk sports than adults. More studies on sports-related injury-risk are needed for adequate counselling.
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http://dx.doi.org/10.1111/hae.14366DOI Listing
September 2021

Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972-2019.

J Thromb Haemost 2021 Jun 12. Epub 2021 Jun 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Introduction: We conducted six cross-sectional nationwide questionnaire studies among all patients with hemophilia in the Netherlands from 1972 until 2019 to assess how health outcomes have changed, with a special focus on patients >50 years of age.

Methods: Data were collected on patient characteristics, treatment, (joint) bleeding, joint impairment, hospitalizations, human immunodeficiency virus and hepatitis C infections, and general health status (RAND-36).

Results: In 2019, 1009 patients participated, of whom 48% had mild, 15% moderate, and 37% severe hemophilia. From 1972 to 2019, the use of prophylaxis among patients with severe hemophilia increased from 30% to 89%. Their median annual bleeding rate decreased from 25 to 2 bleeds. Patients with severe hemophilia aged <16 years reported joint impairment less often over time, but in those aged >40 years joint status did not improve. In 2019, 5% of all 1009 patients were positive for the human immunodeficiency virus. The proportion of patients with an active hepatitis C infection drastically decreased from 45% in 2001 to 2% in 2019 due to new anti-hepatitis C treatment options. Twenty-five percent had significant liver fibrosis even after successful therapy. Compared to the general male population, patients aged >50 years reported much lower scores on the RAND-36, especially on physical functioning.

Discussion/conclusion: Our study shows that increased use of prophylactic treatment and effective hepatitis C treatment have improved joint health and nearly eradicated hepatitis C infection in patients with hemophilia in the Netherlands. However, patients still suffer from hemophilia-related complications, especially patients aged >50 years.
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http://dx.doi.org/10.1111/jth.15424DOI Listing
June 2021

A tailored intervention for illness acceptance improves adherence and quality of life in adults with haemophilia using prophylaxis.

Haemophilia 2021 Jul 7;27(4):e434-e440. Epub 2021 May 7.

Institute for Nursing Studies, Utrecht University of Applied Sciences, Utrecht, The Netherlands.

Introduction: Adherence to prophylactic treatment (prophylaxis) in persons with haemophilia is challenging and has been reported at only ±50%. Acceptance problems are one of the main reasons for non-adherence in haemophilia. An evidence-based intervention was developed based on an acceptance and commitment therapy (ACT) approach.

Aim: To evaluate a tailored intervention focused on illness acceptance in adults with haemophilia who were prescribed prophylaxis.

Methods: A pre-post study was executed in adults with haemophilia who were prescribed prophylaxis. A series of 8 2-hour group trainings were held, including 3-8 participants/series. Adherence (VERITAS-Pro, optimum 0), health-related quality of life (HRQoL, SF-36, optimum 100) and illness perception (BIPQ, optimum 0) were measured at start, after six months and 12 months and analysed using Wilcoxon signed-rank test.

Results: Twenty-four patients (median age 47 years, range 27-74) were included. After 12 months, adherence improved in 68% of patients, quality of life in 48% and illness perception in 31%. Adherence (total score) improved from 35 to 25 (P<0.01). HRQoL showed clinically relevant improvement in domains of social-functioning (P = 0.04), role-emotional, physical-functioning, role-physical and bodily pain. Illness perception improved statistically significant on domains of affect (P = 0.01), concern (P = 0.01) and understanding (P = 0.04). Patients evaluated the training useful, an eye-opener, a personal enrichment and insightful.

Conclusion: The tailored group intervention resulted in significant improvement of adherence, quality of life and illness perception. Based on our current experience, we have implemented it in clinical practice and collaborate with the patient association to make it available for all Dutch people with haemophilia.
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http://dx.doi.org/10.1111/hae.14320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360197PMC
July 2021

Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients.

Br J Clin Pharmacol 2021 Apr 22. Epub 2021 Apr 22.

Department of Pediatric Hematology, Erasmus University Medical Center, Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands.

Aims: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively.

Methods: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation.

Results: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h  68 kg , 2930 mL 68 kg , 1810 mL 68 kg , and 172 mL h  68 kg , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL .

Conclusions: This study emphasizes the importance of external validation of population PK models using real-life data.
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http://dx.doi.org/10.1111/bcp.14864DOI Listing
April 2021

Informed consent for neonatal trials: practical points to consider and a check list.

BMJ Paediatr Open 2020 29;4(1):e000847. Epub 2020 Dec 29.

Department of Paediatric Clinical Phramcology and Pharmacogenetics, Robert Debré Hospital, APHP, 48 Boulevard Sérurier, Paris, France.

Obtaining informed consent from parents of critically ill neonates can be challenging. The parental decision-making process is influenced by the severity of the child's condition, the benefit-risk balance, their emotional state and the quality of the relationship with the clinical team. Independent of local legislation, parents may prefer that consent is sought from both. Misconceptions about the absence of risks or unrealistic expectations about benefits should be openly addressed to avoid misunderstandings which may harm the relationship with the clinical team. Continuous consent can be sought where it is unclear whether the free choice of parental consent has been compromised. Obtaining informed consent is a dynamic process building on trusting relationships. It should include open and honest discussions about benefits and risks. Investigators may benefit from training in effective communication. Finally, involving parents in neonatal research including the development of the informed consent form and the process of obtaining consent should be considered standard practice.
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http://dx.doi.org/10.1136/bmjpo-2020-000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778778PMC
December 2020

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

J Thromb Haemost 2021 03 18;19(3):645-653. Epub 2020 Dec 18.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands.

Objective: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward.

Patients/methods: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018.

Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time.

Conclusions: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.
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http://dx.doi.org/10.1111/jth.15182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986360PMC
March 2021

The experiences and attitudes of hemophilia carriers around pregnancy: A qualitative systematic review.

J Thromb Haemost 2020 07 12;18(7):1626-1636. Epub 2020 May 12.

Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Background: Hemophilia carriers (HCs) face specific psychosocial challenges related to pregnancy, caused by their inherited bleeding disorder. Optimal support from healthcare providers can only be realized by exploring medical and psychological healthcare requirements.

Objective: To review all published evidence on the experiences and attitudes of HCs regarding reproductive decision-making, prenatal diagnosis, pregnancy, childbirth, and puerperium to provide an accessible overview of this information for health care providers.

Study Selection: Cochrane library, PubMed/MEDLINE, EMBASE, CINAHL, and PsycINFO were searched for original qualitative data. Two authors performed study selection, risk-of-bias assessment, data extraction, and data analysis through meta-summary. The extracted themes were discussed within the research team.

Findings: Fifteen studies with an overall moderate quality were included. The following findings were identified: (a) Quality of life of family members with hemophilia influences reproductive decision-making; (b) Genetic counselling is generally considered useful; (c) The development of a specialized carrier clinic is considered valuable; (d) HCs describe prenatal diagnosis as beneficial yet psychosocially challenging; and (e) noninvasive prenatal diagnosis and preimplantation genetic diagnosis are predominantly considered beneficial. These findings are limited by the overall moderate quality of included studies and the possibly partly outdated results in the current era of hemophilia treatment.

Conclusions: Available qualitative literature on HCs around pregnancy focuses on genetic counselling and prenatal diagnosis. Future studies are needed on the experiences and needs of HCs through pregnancy and puerperium as well as in light of emerging hemophilia diagnosis and treatment options.
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http://dx.doi.org/10.1111/jth.14825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383726PMC
July 2020

Patient Perspectives on Novel Treatments in Haemophilia: A Qualitative Study.

Patient 2020 04;13(2):201-210

Department of Clinical Epidemiology, Leiden University Medical Center, Postzone C7-P, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.

Background And Objective: New treatments for haemophilia are under development or entering the market, including extended half-life products, designer drugs and gene therapy, thereby increasing treatment options for haemophilia. It is currently unknown how people with haemophilia decide whether to switch to a new treatment. Therefore, the objective of this study was to explore what factors may play a role when Dutch patients and parents of boys with moderate or severe haemophilia make decisions about whether to switch to a different treatment, and how disease and treatment characteristics may affect these decisions. This may aid clinical teams in tailored information provision and shared decision making.

Methods: We conducted interviews among adults with moderately severe or severe haemophilia and parents of young boys with severe haemophilia. We aimed to include participants from a variety of backgrounds in terms of involvement in the haemophilia community, age, treatment centre and treatments. Participants were recruited through the Netherlands Haemophilia Society and a haemophilia treatment centre. Semi-structured interviews were recorded and transcribed verbatim. Thematic content analysis was used to analyse the data.

Results: Twelve people with haemophilia and two mothers of boys with haemophilia were included. In general, participants reported to be satisfied with their current treatment. However, they considered ease of use of the medication (fewer injections, easier handling, alternative administration) an added value of new treatments. Participants were aware of the high cost of coagulation factor products and some expressed their concern about the Netherlands Haemophilia Society's long-term willingness to pay for current and novel treatments, especially for increased usage due to high-risk activities. Participants also expressed their concerns about the short- and long-term safety of new treatments and believed the effects of gene therapy were not yet fully understood. Participants expected their treatment team to inform them when a particular new treatment would be suitable for them.

Conclusions: With the number of treatment options set to increase, it is important for healthcare providers to be aware of how patient experiences shape patients' decisions about new therapies.
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http://dx.doi.org/10.1007/s40271-019-00395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075838PMC
April 2020

Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study.

BMJ Open 2019 04 23;9(4):e022719. Epub 2019 Apr 23.

Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Introduction: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption.

Methods And Analysis: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment.

Ethics And Dissemination: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences.

Trial Registration Number: NTR5383; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500101PMC
April 2019

The "OPTI-CLOT" trial. A randomised controlled trial on periOperative PharmacokineTIc-guided dosing of CLOTting factor concentrate in haemophilia A.

Thromb Haemost 2015 Aug 11;114(3):639-44. Epub 2015 Jun 11.

M. H. Cnossen, MD, PhD, Department of Paediatric Haematology, Erasmus University Medical Centre, Sophia Children's Hospital Rotterdam, P. O. Box 2040, 3000 CA Rotterdam, the Netherlands, E-mail:

Haemophilia A is an X-linked inherited, rare bleeding disorder, caused by a deficiency of coagulation factor VIII (FVIII). Previous studies in prophylactic dosing have demonstrated that FVIII consumption can be significantly reduced by individualising dosing based on combined analysis of individual pharmacokinetic (PK) profiling and population PK data (Bayesian analysis). So far, no studies have been performed that address perioperative concentrate consumption using iterative PK-guided dosing based on a PK population model. The "OPTI-CLOT" trial is an open-label, prospective, multicentre randomised controlled superiority trial (RCT), aiming to detect a 25 % difference in perioperative FVIII concentrate consumption with iterative Bayesian PK-guided dosing in comparison to the standard dosing procedure. Sixty haemophilia A patients ≥ 12 years of age, with FVIII plasma levels ≤ 0.05 IUml(-1) will be included requiring FVIII replacement therapy administered either by continuous or bolus infusion for an elective, low or medium risk surgical procedure. The proposed study aims to investigate a novel perioperative iterative PK-guided dosing strategy, based on a recently constructed perioperative PK population model. This model will potentially decrease underdosing and overdosing of clotting factor concentrate and is expected to overall reduce FVIII consumption by minimally 25 %. Moreover, participating hospitals will gain experience with PK-guided dosing, facilitating future implementation of this intervention which is expected to optimise current care and reduce costs of treatment.
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http://dx.doi.org/10.1160/TH14-11-0925DOI Listing
August 2015

Endoglin has a crucial role in blood cell-mediated vascular repair.

Circulation 2006 Nov 6;114(21):2288-97. Epub 2006 Nov 6.

Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

Background: Endoglin, an accessory receptor for transforming growth factor-beta in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity.

Methods And Results: In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng+/-) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng+/- mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients.

Conclusions: These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.106.639161DOI Listing
November 2006

B plexins activate Rho through PDZ-RhoGEF.

FEBS Lett 2002 Oct;529(2-3):168-72

Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Plexins are receptors for the repulsive axon guidance molecules semaphorins. Previously, we have shown that plexin-B1 binds activated Rac, but that clustering of plexin-B1 causes Rho activation, resulting in stress fiber formation. Using the yeast two-hybrid system, we found that the C-terminus of B plexins interacted directly with Rho-specific exchange factors, via their PDZ domain. Mutation of the carboxy-terminal amino acids of plexin-B1 or coexpression of a dominant negative PDZ-RhoGEF abrogated the ability of plexin-B1 to cause stress fiber formation. Our results demonstrate a role for PDZ-RhoGEF in B plexin-mediated activation of Rho/Rho kinase signaling, implicated in the regulation of axon guidance and cell migration.
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http://dx.doi.org/10.1016/s0014-5793(02)03323-9DOI Listing
October 2002
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