Abstract Introduction There is growing evidence that subclinical joint bleeding early in life may lead to subtle changes in joint function, gait, and muscle development in young children with ...haemophilia. The early identification of such changes provides an opportunity for clinicians to intervene before irreversible structural changes occur. Materials and methods We have undertaken motion analysis of the knee in 273 children (mean age 9.8 years) with haemophilia A, haemophilia B, or von Willebrand disease and compared the results with those from 200 healthy age- and sex-matched controls (mean age 10.3 years). We have also completed detailed orthopaedic assessments and evaluated overall fitness in most of these children. Results There was a clear correlation between total motion score and age: r2 = 0.47 for the healthy children and r2 = 0.69 for the haemophilic children. The differences were most striking in children aged 3–4 years. Significant between-group differences were also observed in the comparison of knee bends, gait scores, and rhythmicity. Orthopaedic examinations revealed previously clinically silent pressure pains in the ligaments of the knee joints of 38% of children and in the ligaments and capsule of the ankle joints of 60% of children. The five-item fitness check showed significant deficits relative to controls in overall fitness, endurance, coordination, and flexibility. Conclusions Children and adolescents with haemophilia show significant functional impairments relative to normal controls. Early comprehensive assessments of the musculoskeletal system should be made so that individualized physical, physiotherapy, and sports therapy programmes can be developed.
Background
The worldwide pandemic spread of SARS‐CoV‐2 can lead to either respiratory infection or containment‐associated isolation with possible higher impact on chronic diseases such as inherited ...bleeding disorders (IBD). The aim of the study was to evaluate the impact of COVID‐19 on patients and caregivers of IBD patients regarding their concerns and worries related to own health, access to treatment and availability of factor concentrates and their experiences related to medical care.
Methods
Multicentre, cross‐sectional study evaluating the impact of COVID‐19 on mental health of IBD patients. An ad hoc questionnaire was developed and sent to 586 patients/caregivers with haemophilia A, haemophilia B and VWD type III. The survey included information on demographic and clinical data, needs, concerns and experiences regarding medical care during COVID‐19 pandemic.
Results
In total, 355 of the IBD‐Group (200 patients, 155 caregivers) completed the survey (61.7% response rate). Most patients suffered from haemophilia A (73.8%) and were severely affected (64.7%). Eleven patients were in quarantine due to suspected COVID‐19; none had symptoms. One quarter worried (very) strongly about getting the coronavirus, 71.3% asked themselves what will happen to them when they will get COVID‐19, 40.1% felt unchanged, and 18.9% worried about delivery difficulties of their IBD treatment product. In 52.8%, medical appointments were postponed. Significant differences between caregivers and patients were found in most aspects.
Discussion
The IBD patients affected by a chronic disorder have particular thoughts and worries regarding COVID‐19. Haemophilia specialists should be committed to address these concerns and guarantee treatment despite containment strategies.
Three pediatric patients with different illnesses leading to knee arthritis and large Baker cysts and additional calf swelling are reported. Calf swelling was due to true popliteal venous thrombosis ...and not to the much more common cause of pseudothrombophlebitis. Careful ultrasound examination can differentiate these two causes of calf swelling. Even though all our patients had risk factors for thrombophilia, we do not recommend routine thrombophilia work-up for all arthritis patients in the absence of thrombosis.
Chronic diseases, such as inherited bleeding disorders (IBD) are often associated with high costs of medical care. COVID-19 containment measures, including isolation and triage, led to restrictions ...in the health care of chronically ill patients. The aim of the present study was to investigate the effects of the COVID-19 pandemic on the health care of IBD patients.
In this multicentre cross-sectional study to evaluate the effects of COVID-19 on the mental health and quality of care of patients with inherited bleeding disorder, an ad hoc questionnaire was sent to 586 patients/parents of children with haemophilia A, B or von Willebrand syndrome type 3. In addition to demographic and clinical data, patients/parents of patients with inherited bleeding disorders were asked about their thoughts, concerns and experiences regarding their medical care during the COVID-19 pandemic. Differences between clinical subgroups were calculated.
Significant differences were found between subgroups (severity, type of therapy, product class, comorbidities) with regard to the transmission of COVID-19 through plasma products, the effects of COVID-19 positive test results, fear of getting COVID-19, delayed drug supply and physiotherapy treatment.
The medical care of patients with inherited bleeding disorders, who need a continuous supply of essential drugs, is a particular challenge in times of pandemics. Therefore, worries and fears of IBD patients should be taken seriously and innovative communication channels established to maintain therapy standards and quality of care.
Zusammenfassung
Fragestellung
Chronische Erkrankungen, wie z. B. angeborene
Blutungsneigungen (IBD: Inherited Bleeding Disorders), gehen häufig
mit einem erhöhten Versorgungsaufwand einher. Maßnahmen ...zur
Eindämmung der COVID-19 Pandemie, inklusive Isolation und
Triageierung, haben zu Einschränkungen in der Krankenversorgung von
chronisch kranken Patienten geführt. Ziel der vorliegenden Arbeit
ist es, die Auswirkungen der COVID-19 Pandemie auf die Krankenversorgung von
IBD-Patienten zu untersuchen.
Methodik
In dieser multizentrischen Querschnittsstudie zur Bewertung
der Auswirkungen von COVID-19 auf die psychische Gesundheit und
Versorgungsqualität von Patienten mit angeborener Blutungsneigung
wurde ein ad-hoc Fragebogen an 586 Patienten/Eltern von Kindern mit
Hämophilie A, B oder von Willebrand Syndrom Typ 3 verschickt. Neben
demografischen und klinischen Daten wurden IBD Patienten zu ihren Gedanken,
Sorgen und Erfahrungen in Bezug auf ihre medizinische Versorgung
während der COVID-19 Pandemie befragt. Unterschiede zwischen
klinischen Subgruppen wurden berechnet.
Ergebnisse
Signifikante Unterschiede zeigten sich zwischen Subgruppen
(Schweregrad, Art der Therapie, Produktklasse, Komorbiditäten)
bezüglich Übertragung von COVID-19 durch Plasmaprodukte,
Auswirkungen COVID-19 positiver Testergebnisse, Angst COVID-19 zu bekommen,
verzögerter Medikamentenversorgung und Physiotherapiebehandlung.
Diskussion
Die medizinische Versorgung von IBD-Patienten, die eine
kontinuierliche Versorgung mit lebensnotwendigen Medikamenten
benötigen, stellt in Pandemiezeiten eine besondere Herausforderung
dar. Daher sollten Sorgen und Ängste von IBD-Patienten ernst
genommen und innovative Kommunikationswege zur Aufrechterhaltung von
Therapiestandards und Versorgungsqualität etabliert werden.
Abstract
Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and ...Emicizumab, the ‘Ständige Kommission Hämophilie’ of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the ‘Ständige Kommission Hämophilie’ and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.
Summary
Background:
The endothelial cell protein C receptor (EPCR) enhances protein C activation by the thrombin-thrombomodulin complex. As evidence is accumulating that EPCR is an important ...component of the protein C anticoagulant pathway, polymorphisms in the EPCR gene might be candidate risk factors predisposing to venous thromboembolism (VTE). Recently, a 23bp insertion in exon 3 of the EPCR gene has been identified, which duplicates the preceding 23 bases and results in a STOP codon downstream from the insertion point. However, the clinical significance of this mutation in VTE remains to be clarified.
Methods and Results:
In this study we evaluated the EPCR 23bp insertion in 889 patients with documented VTE and in 500 healthy controls. The prevalence of the EPCR insertion among patients was 0.1%, which was not significantly different compared to controls (0.6%, p = 0.1).
Conclusions:
Our findings showed that the EPCR 23bp insertion is very rare in both patients with VTE and the general population and failed to support an association between the EPCR 23bp insertion and an increased risk of VTE.
We characterized a consanguineous Turkish family suffering from von Willebrand disease (VWD) with significant mucocutaneous and joint bleeding. The relative reduction of large plasma von Willebrand ...factor (VWF) multimers and the absent VWF triplet structure was consistent with type 2A (phenotype IIC) VWD. Surprisingly, platelet VWF was completely deficient of multimers beyond the VWF protomer, suggesting defective α-granular storage of larger multimers. Patients were nearly unresponsive to desmopressin acetate, consistent with a lack of regulated VWF release from endothelial cell Weibel-Palade bodies, suggesting defective storage also in endothelial cells. We identified an N528S homozygous mutation in the VWF propeptide D2 domain, predicting the introduction of an additional N-glycosylation site at amino acid 526 in close vicinity to a “CGLC” disulphide isomerase consensus sequence. Expression studies in mammalian cells demonstrated that N528S-VWF was neither normally multimerized nor trafficked to storage granules. However, propeptide containing the N528S mutation trafficked normally to storage granules. Our data indicate that the patients' phenotype is the result of defective multimerization, storage, and secretion. In addition, we have identified a potentially novel pathogenic mechanism of VWD, namely a transportation and storage defect of mature VWF due to defective interaction with its transporter, the mutant propeptide.
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During pregnancy women have a four- to five-fold increased risk of thromboembolism (TE) compared to women who are not pregnant. Among the most important risk factors for TE in pregnancy is the ...presence of thrombophilia. Multiple reports have described an association between antithrombin (AT) deficiency and an increased rate of thromboembolic events especially during pregnancy. As the placental development depends on well-balanced pro- and anticoagulant mechanisms, thrombophilia, e.g. AT deficiency may be associated with poor pregnancy outcome. Despite anticoagulation with low molecular weight heparin (LMH) during pregnancy and the postpartum period alone, women with AT deficiency are still at a high risk to develop TE, especially perinatal and during puerperium because of withheld anticoagulation to prevent bleeding complications. Therefore, several guidelines recommend the administration of antithrombin concentrates during high risk situations as pregnancy. Here, we present the results of our study on the usage of AT concentrates in pregnant women with AT deficiency who either suffered from fetal loss or thromboembolism prior inclusion.
In total, 22 pregnancies in 19 patients (age: 31.9±4.7; 22-41) with AT deficiency were included in this open-label, single-center study. Ten patients (53%) had a history of fetal loss, 9/19 (47%) patients hat a history of thromboembolism. During all pregnancies AT concentrate (AT-C) was administered, in 18/22 (81.8%) pregnancies LMH was given in addition. Prior pregnancy losses (21/30, 70%) occurred in all trimester (t1: n=11, t2: n=5, and in t3: n=5). Historical live birth rate (LBR) was 30%. Blood samples were collected in all trimesters and postpartum to analyze AT activity and antigen, endogenous thrombin potential (ETP), thrombin-antithrombin-complex (TAT), Fragment 1+2 (F1+2) and c-reactive protein test (CRP). A total of 114 uneventful pregnancies of 113 healthy women served as controls. Furthermore, the mean doses of AT concentrates/kg BW and the mean total number of infusions were calculated.
In total, 21 pregnancies (95.5%) were successful. Mean total requirement of AT concentrate per pregnancy was 79.454 IU (range: 3.000-272.000 IU) during 27.8 treatment days per pregnancy (range: 1-88). Our data show an increase of F1+2 in the course of pregnancy. Mean levels of F1+2 at t1, t2 and t3 (t1= 255.9 ± 107.6, t2= 360.9 ± 117.4, t3= 545.3 ± 220.3 pmol/L) were significantly higher than in controls (t1= 82.2 ± 43, t2= 140 ± 100.2, t3= 183.5 ± 103.1, p<.001). Mean level of TAT was higher (3.1 ± 1.4 ng/mL) than in controls (1.7 ± 1.6 ng/mL, p=.001) in t1, whereas mean TAT in t2 and t3 was lower than in controls (3.8 ± 1.3 vs. 4.8 ± 1.9, p=.03; 5.0 ± 1.4 vs. 6.1 ± 3.0 ng/mL, n.s., resp.). No thromboembolic events occurred. In patients receiving AT-C, LBR increased from 30% to 95.5% (p<0.001) with a relative risk of 49.0 to develop pregnancy loss without anticoagulant treatment (5.7 – 421.8; 95% CI).
In patients with AT deficiency receiving AT concentrate and LMH we could demonstrate a significant increase of LBR from 30% to 95.5%. Furthermore, no thromboembolic events occurred, though almost half of the patients had a history of thromboembolism. There was no clear evidence of increased hypercoagulability. We conclude that combined AT concentrate and LMH are safe and efficacious for mother and child in preventing thromboembolism and pregnancy loss. Further studies to evaluate the exact mode of anticoagulation and benefit of combining AT concentrate and LMH are warranted.
No relevant conflicts of interest to declare.
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