Practice and the dynamics of handwriting performance: Evidence for a shift of motor programming load

ABSTRACT. Sixteen adult subjects served in an experiment in which the writing of six unfamiliar graphemes was practiced. To investigate the learning process, we analyzed the absolute and relative changes of movement time of the first three consecutive segments as a function of practice. The results showed that movement time of all three segments decreased. This decrease was significantly less in the first segment than it was in the second and third segment, however. We interpret these effects of practice, from an information-processing viewpoint, as follows: (a) Initially separate response segments become integrated in more comprehensive response chunks, and (b) the preparation of later segments of the grapheme is realized more and more during the real-time execution of the initial segment. The results further revealed that these learning effects were more pronounced in graphemes composed of familiar segments than in graphemes that contained unfamiliar segments. Finally, it turned out that similarity between initial and final segments hindered the writing speed of the first segment; the effect of similarity was independent of the above-mentioned effects of practice. The latter effect is interpreted as confirming evidence for the view that the preparation of later segments of a grapheme is reflected by changes of movement time of the first segments of a grapheme

ADAMTS-13 and bleeding phenotype in von Willebrand disease

Background: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD. Objectives: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD. Methods: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score. Results: ADAMTS-13 activity was similar in individuals with VWD (109% +/- 20.6%) and controls (110% +/- 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, -0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, -2.1% to 4.9%). Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD

Von Willebrand Factor Multimer Densitometric Analysis:Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease

Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], P < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], P < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], P < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: beta = -7.6 (-13.0 to -2.1), P = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients

Dentoalveolar Procedures in Immune Thrombocytopenia; Systematic Review and an Institutional Guideline

Background  Dentoalveolar procedures in immune thrombocytopenia (ITP) pose a risk of bleeding due to thrombocytopenia and infection due to immunosuppressive treatments. We aimed to systematically review the safety and management of dentoalveolar procedures in ITP patients to create practical recommendations. Methods  PubMed, Embase, Cochrane, and Cinahl were searched for original studies on dentoalveolar procedures in primary ITP patients. We recorded bleeding- and infection-related outcomes and therapeutic strategies. Clinically relevant bleeding was defined as needing medical attention. Results  Seventeen articles were included, of which 12 case reports/series. Overall, the quality of the available evidence was poor. Outcomes and administered therapies (including hemostatic therapies and prophylactic antibiotics) were not systematically reported. At least 73 dentoalveolar procedures in 49 ITP patients were described. The range of the preoperative platelet count was 2 to 412 × 10 9 /L. Two clinically relevant bleedings (2%) were reported in the same patient of which one was life-threatening. Strategies used to minimize the risk of bleeding were heterogeneous and included therapies to increase platelet count, antifibrinolytics, local measures, and minimally invasive techniques. Reports on the occurrence of bleedings due to anesthetics or infection were lacking. Conclusion  Based on alarmingly limited data, clinically relevant bleedings and infections after dentoalveolar procedures in ITP patients seem rare. Awaiting prospective and controlled studies to further evaluate these risks and the efficacy of therapeutic interventions, we provided our institutional guideline to guide the management of dentoalveolar procedures in ITP patients

Social participation is reduced in type 3 Von Willebrand disease patients and in patients with a severe bleeding phenotype

Introduction The negative impact of haemophilia on social participation is well established in previous studies, however, the impact of Von Willebrand disease (VWD) on social participation has not been studied. Aim To compare the social participation of a large cohort of VWD patients in the Netherlands with the general Dutch population. In addition, to identify factors associated with social participation in VWD. Methods Patients participating in the "Willebrand in the Netherlands" study completed an extensive questionnaire on educational level, absenteeism from school or work, and occupational disabilities. Results Seven-hundred and eighty-eight VWD patients were included (mean age 38.9 years, 59.5% females), of whom 136 children = 16 years the days lost from school and/or work in the year prior to study inclusion differed significantly between the VWD types (p = .011). Using negative binomial regression analysis, the occurrence of bleeding episodes requiring treatment in the year preceding study inclusion was significantly associated with the number of days lost from school and/or work among patients aged >= 16 years. Multivariable logistic regression analysis showed that a higher total bleeding score, older age and presence of at least one comorbidity were significantly associated with occupational disability in patients aged >= 16 years. Conclusion Our study shows that social participation was lower in type 3 VWD and VWD patients with a more severe bleeding phenotype

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management

Menstrual problems in chronic immune thrombocytopenia: A monthly challenge - a cohort study and review

Immune thrombocytopenia (ITP) may cause menstrual problems. This cross-sectional study assessed menstrual problems in premenopausal chronic ITP women by several questionnaires, including the pictorial bleeding assessment calendar (PBAC; score ≥100 indicates heavy menstrual bleeding [HMB]), and the menorrhagia multiattribute scale (MMAS). Spearman was used for assessing correlations. A literature review was performed in Pubmed. The cohort comprised 37 women (mean age 31 ± 9). A total of 29/37 (78%) had experienced clinical menstrual problems in the present or past. Of the 33 patients who returned the PBAC, 13 (39%) had a score of ≥100. The median MMAS score was 79 (IQR 60-95). The PBAC scores correlated with the MMAS. Both questionnaires were unrelated to the platelet count. Patients with a levonorgestrel intrauterine device (LNG-IUD) had lower PBAC scores than patients with other or no hormonal therapy. MMAS scores were correlated with fatigue. The review identified 14 papers. HMB occurred in 6%-55% at ITP diagnosis and 17%-79% during disease. Menstrual symptoms influenced the quality of life, particularly in patients with a low platelet count. This explorative study suggested that HMB is frequent in women with chronic ITP despite management and platelet counts >50 *10 9 /l. An LNG-IUD seemed to reduce blood loss significantly

Navigating the challenges: a case report on managing a complicated postpartum course in type 3 von Willebrand disease with alloantibodies

BACKGROUND: Von Willebrand disease (VWD) type 3 is characterized by a complete deficiency of von Willebrand factor (VWF), resulting in a severe bleeding phenotype. Treatment often requires administration of VWF concentrates/factor (F)VIII. However, the development of alloantibodies is a rare complication, resulting in ineffective recovery and allergic reactions. Emicizumab, a bispecific antibody mimicking FVIII function, has emerged as a potential alternative, with promising results reported in several case reports. KEY CLINICAL QUESTION: Description of multiple approaches to control highly severe postpartum hemorrhage in type 3 VWD with alloantibodies, including off-label use of emicizumab. CLINICAL APPROACH: Here we present a 28-year-old patient with type 3 VWD and alloantibodies, known to have arthropathy of the right elbow. Previous immune tolerance induction was unsuccessful. Despite receiving negative pregnancy advice during preconception counseling, the patient became pregnant. Delivery was induced at 38 4/7 weeks with prostaglandin, and recombinant FVIIa (rFVIIa) was administered every 2 hours. Despite administration of rFVIIa, bleeding persisted, requiring manual placental removal and insertion of a Bakri balloon. Since bleeding persisted, plasma-derived VWF was administered with an initial excellent recovery and successful embolization of the uterine artery. Twelve days postpartum, she developed endometritis and recurrent vaginal bleeding treated with antibiotics, rFVIIa every 2 hours, and multiple erythrocyte transfusions. Plasma-derived VWF was administered but was complicated by anaphylaxis and no recovery. Due to persistent vaginal bleeding, reembolization of uterine arteries was performed and off-label emicizumab was initiated. Twenty-nine days postpartum, she developed septic shock requiring an abdominal hysterectomy, again complicated by severe bleeding necessitating direct intraabdominal packing after rFVIIa. A computed tomography scan 9 days postsurgery revealed thrombosis in the left iliac vein and asymptomatic pulmonary embolisms. rFVIIa was stopped and prophylactic low-molecular-weight heparin was started. The patient was discharged 2 months after delivery on low-dose low-molecular-weight heparin, emicizumab, and antibiotics for an intra-abdominal abscess. During 2.5 years of emicizumab prophylaxis, she has had no rebleeding in her arthropathic right elbow. CONCLUSION: The current case emphasizes the postpartum clinical challenges of patients with type 3 VWD and alloantibodies. It underscores the potential role of emicizumab in maintaining hemostatic control

Bleeding phenotype and diagnostic characterization of patients with congenital platelet defects

Phenotypic characterization of congenital platelet defects (CPDs) could help physicians recognize CPD subtypes and can inform on prognostic implications. We report the analyses of the bleeding phenotype and diagnostic characteristics of a large cohort of adult patients with a confirmed CPD. A total of 96 patients were analyzed and they were classified as Glanzmann thrombasthenia, Bernard-Soulier syndrome, dense granule deficiency, defects in the ADP or thromboxane A2 (TxA2) pathway, isolated thrombocytopenia or complex abnormalities. The median ISTH-BAT bleeding score was nine (IQR 5-13). Heavy menstrual bleeding (HMB) (80%), post-partum hemorrhage (74%), post-operative bleeds (64%) and post-dental extraction bleeds (57%) occurred most frequently. Rare bleeding symptoms were bleeds from the urinary tract (4%) and central nervous system (CNS) bleeds (2%). Domains with a large proportion of severe bleeds were CNS bleeding, HMB and post-dental extraction bleeding. Glanzmann thrombasthenia and female sex were associated with a more severe bleeding phenotype