Ultrasound in addition to clinical assessment of acute musculoskeletal complaints in bleeding disorders: impact on patient management.

Background: Ultrasound is increasingly used for musculoskeletal assessment in hemophilia care. Objectives: To evaluate the impact of point-of-care ultrasound added to clinical assessment for diagnosis and treatment of acute musculoskeletal episodes in a heterogeneous cohort of children and adults with hemophilia and von Willebrand disease (VWD). Methods: This prospective cross-sectional study consecutively included children and adults with hemophilia or VWD who visited the outpatient clinic with acute musculoskeletal complaints between March 2020 and May 2023. For all episodes, initial diagnosis and treatment determined by clinical assessment were recorded on a case report form. Subsequently, a physiotherapist (M.A.T. and J.B.) with knowledge of the clinical diagnosis performed point-of-care ultrasound. After ultrasound, updated diagnosis and treatment were recorded. Diagnosis and treatment before and after ultrasound were compared, and proportions of change with 95% CIs were determined. Results: We evaluated 77 episodes in 67 patients (median age, 24 years; IQR, 13-42 years). Before ultrasound, 37 joint bleeds, 13 muscle bleeds, and 27 other diagnoses were diagnosed. After ultrasound, 33 joint bleeds, 11 muscle bleeds, and 33 other diagnoses were confirmed. The diagnosis changed in 28 of 77 episodes (36%; 95% CI, 26%-48%). Nine joint bleeds and 2 muscle bleeds were missed by clinical assessment. Ultrasound findings changed treatment strategy in 30 of 77 episodes (39%; 95% CI, 28%-51%). Conclusion: Ultrasound in addition to clinical assessment of acute musculoskeletal complaints in people with hemophilia and VWD has an impact on diagnosis (36%) and treatment (39%), which supports the use of ultrasound in acute musculoskeletal complaints in hemophilia and VWD.

Evaluation of the procoagulant state in chronic immune thrombocytopenia before and after eltrombopag treatment-a prospective cohort study.

BACKGROUND: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. OBJECTIVES: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. METHODS: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. RESULTS: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. ß-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. CONCLUSION: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.

Possible Targets to Reduce Fatigue in Chronic Immune Thrombocytopenia Patients - An Explorative Study.

Background Fatigue in immune thrombocytopenia (ITP) is frequent and burdensome, but we lack the knowledge to help these patients. Aim The aim of the study is to explore the role of disease activity and other potentially modifiable factors in fatigue. Method This cross-sectional study included adult chronic ITP patients ( n = 59). Univariable linear regression (corrected for confounders) was used to determine the relationship between disease activity (platelet count <30 × 10 9 /L or treatment), disease-specific factors (bleeding symptoms, ferritin), and transdiagnostic factors (FACT-G physical/functional/emotional/social well-being subscales, physical activity level, and vitamin D) and fatigue (Checklist Individual Strength fatigue subscale). Several multivariable models with clustered sets of variables were used to compare the proportion of explained variance of fatigue (adjusted R 2 ). Results Significant relations with moderate effect sizes (>0.50) were found for physical and functional well-being and fatigue, and physical activity and fatigue. Other significant relations with fatigue (effect size 0.30-0.47) included skin and organ bleeding, emotional and social well-being, vitamin D, and disease activity. Notably, the models with disease activity and disease-specific factors explained <20% of the variance in fatigue, while the models with transdiagnostic factors (functioning and physical activity) explained >50%. Vitamin D alone explained 12% of the variance in fatigue. Conclusion Transdiagnostic (non-disease-specific) rather than disease-specific factors explained a large part of the variance in ITP-related fatigue. Many factors related to fatigue are potentially modifiable and should be investigated as targets for interventions.

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 *109 /l. An LNG-IUD seemed to reduce blood loss significantly.

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.

Platelet count and indices as postpartum hemorrhage risk factors: a retrospective cohort study.

BACKGROUND: Severe postpartum hemorrhage (SPPH) is the leading cause of maternal mortality and morbidity worldwide. Platelet anomalies frequently occur during pregnancy. However, their role in the etiology of SPPH is largely unknown. OBJECTIVE: To study the relation between platelet parameters and SPPH. METHODS: This retrospective single-center cohort included deliveries between 2009 and 2017. SPPH was defined as ≥1000 ml blood loss within 24 h after delivery. Platelet parameters were measured within 72 h before delivery. Multiple imputation was performed for missing data. Odds ratios were adjusted (aORs) for maternal age, multiple gestation, macrosomia, induction of labor, preeclampsia, and hemolysis, elevated liver enzymes, and low platelets syndrome. RESULTS: A total of 23 205 deliveries were included. Of the 2402 (10.4%) women with thrombocytopenia (<150 × 109 /L), 10.3% developed SPPH, compared with 7.6% of women with a normal platelet count (aOR: 1.34, 95% CI: 1.14-1.59). Women with a platelet count of <50 × 109 /L were most at risk (aOR of 2.24 [1.01-4.94]) compared with the reference group with normal platelet counts; the aOR was 1.22 (0.77-1.93) for the 50-99 × 109 /L platelet count group and 1.31 (1.10-1.56) for the 100-149 × 109 /L platelet count group. Plateletcrit was associated with SPPH (aOR 1.15 [1.08-1.21] per 0.05% decrease), and, although rarely present, a platelet distribution width (PDW) ≥23% (n = 22) also increased the odds of SPPH (aOR 6.05 [2.29-16.20]). CONCLUSION: Different degrees of thrombocytopenia were independently associated with the occurrence of SPPH. Despite their relation to SPPH, plateletcrit and a PDW of ≥23% have limited additional value in addition to platelet count.

Hemostatic changes by thrombopoietin-receptor agonists in immune thrombocytopenia patients.

Thrombopoietin receptor agonist (TPO-RA) treatment increases the thrombosis rate in immune thrombocytopenia (ITP). We hypothesize that TPO-RAs influence platelet function, global and secondary hemostasis and/or fibrinolysis. A systematic review was performed. If possible, data were compared between responders (relevant increase in platelet count), and non-responders. Twelve observational studies with 305 patients were included (responders (127/150 (85%))). There were indications that TPO-RA treatment enhanced platelet function, with respect to platelet-monocyte aggregates, soluble P-selectin, GPVI expression, and adhesion under flow. Studies addressing global and secondary hemostasis and fibrinolysis were scarce. Overall, no changes were found during TPO-RA treatment, apart from an accelerated clot formation and conflicting data on levels of plasminogen activator inhibitor (PAI)-1. The parameters that increased have previously been associated with thrombosis in other patient groups, and might contribute to the increased rate of thrombosis observed in TPO-RA-treated ITP patients.

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.

Persistent Hepatitis E Infection in a Patient with Tuberous Sclerosis Complex Treated with Everolimus: A Case Report.

INTRODUCTION: The incidence of hepatitis E (HEV) genotype 3 is rising in developed countries. HEV infections are usually self-limiting, but can become chronic in immunocompromised patients. This might lead to rapid fibrosis development even resulting in cirrhosis. Chronic HEV is mainly described in patients after solid-organ or hematological transplantations. We present the first case of HEV infection in a patient with tuberous sclerosis complex (TSC) treated with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. CASE: A 46-year-old male with TSC was referred to the infectious diseases department with an acute rise of liver enzymes during routine laboratory check-up. He was diagnosed with an acute HEV infection. His current treatment for TSC was everolimus. After awaiting a spontaneous clearance for 3 months, everolimus was discontinued. Hereafter, the infection was cleared within another 3 months. DISCUSSION: Due to a favorable side-effect profile, everolimus is gaining popularity as an immunosuppressive therapy. However, in vitro experiments suggest that inhibition of mTOR leads to a significant increase in HEV replication. Thus far, there have been no clinical reports of HEV infections in patients treated with everolimus. CONCLUSION: Due to higher dosing of everolimus in TSC patients, they are more vulnerable to the development of chronic HEV infection. Periodic assessment of transaminases in these patients is advised.