Muscle Hemorrhage Research Articles

Implementation and assessment of a self- and community-based rehabilitation programme in patients with haemophilia from Côte d'Ivoire.

In resource-constrained countries, few patients with haemophilia (PWH) have access to clotting factor concentrates (CFC), with increased musculoskeletal (MSK) complications. Physiotherapy actively contributes to preventing MSK complications, minimizing joint damage and reducing pain. To assess the impact of a 20-week self- and community-based rehabilitation (CBR) programme in Ivorian PWH. Fifty participants underwent a clinical and functional baseline assessment with identification of joints' functional defects and initiation of an individualized exercise programme comprising exercises to improve strength, joint mobility and proprioception. Hemophilia Joint Health Score (HJHS), 2-minute walking test (2MWT), Timed Up and Go (TUG), goniometry and maximal isometric voluntary contractions using the MicroFET2 were performed at baseline (T1) and at Week 20 (T2). At T2, there was a significant improvement in both the 2MWT and TUG tests. The HJHS total score decreased significantly from 23.6±14.2 at T1 to 20.4±13 at T2. A significant improvement in joint health was found in the left elbow, right knee and right ankle, with elements correlating with joint function responsible for these improvements. A strong programme adherence was observed, with 94% of participants reporting regular exercise performance and a high degree of satisfaction. The programme with its encouraging results is meant to be the first step towards a more ambitious project. Self-based and CBR programmes are inexpensive and efficient treatment options designed to minimize the detrimental effects of joint and muscle bleedings, and to increase the functional independence and quality of life of PWH with limited access to CFC and physiotherapy.

PF377 ACALABRUTINIB WITH OBINUTUZUMAB IN TREATMENT‐NAIVE AND RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA: 3‐YEAR FOLLOW‐UP

Background:Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor.Aims:This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody obinutuzumab in patients with treatment‐naive or relapsed/refractory chronic lymphocytic leukemia (CLL).Methods:Patients with treatment‐naive or relapsed/refractory (≥1 prior therapy) CLL were eligible. In 28‐day cycles, acalabrutinib was given orally at 100 mg twice daily or 200 mg once daily (n = 15; all switched to 100 mg twice daily) until progressive disease; obinutuzumab was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10–4).Results:Nineteen treatment‐naive and 26 relapsed/refractory patients were treated. The median age of all patients was 61 years (range, 42 to 76). Patient characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%), and dizziness (47%). Common Grade 3/4 adverse events were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Grade 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Grade 3 atrial fibrillation event.Summary/Conclusion:Acalabrutinib plus obinutuzumab was well tolerated and yielded high response rates that were durable and deepened over time in treatment‐naive and relapsed/refractory patients with CLL.image

Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Three-year follow-up.

7500 Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor. This Phase 1b/2 trial evaluated acalabrutinib with the CD20 antibody Ob in TN and R/R CLL. Methods: Patient (pts) with TN and R/R (≥1 prior therapy) CLL were eligible. In 28-day cycles, acalabrutinib was given at 100 mg BID or 200 mg QD PO (n=15; all switched to 100 mg BID) until progressive disease (PD); Ob was given in standard fashion for 6 cycles starting with Cycle 2. The primary endpoints were overall response rate (ORR) and safety. Minimal residual disease (MRD) was assessed using flow cytometry (sensitivity 10-4). Results: 19 TN and 26 R/R pts were treated; median age of all pts was 61 y (range 42-76). Pt characteristics, disposition, efficacy and MRD are in the Table. Common adverse events (AEs; any grade) were upper respiratory tract infection (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%) and dizziness (47%). Common Gr 3/4 AEs were decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight and cellulitis (9% each). There were 2 (4%) Gr 3 bleeding events (hematuria, muscle hemorrhage) and 1 (2%) Gr 3 atrial fibrillation event. Conclusions: Acalabrutinib plus Ob was well tolerated and yielded high response rates that were durable and deepened over time in TN and R/R CLL patients. Clinical trial information: NCT02296918. [Table: see text]

Muscular hemorrhages around the scapula resulting from excessive upper extremity motion in cases of fatal drowning: autopsy findings for insights on manner of death

Muscular hemorrhages around the scapula are frequently found in fatal drowning cases without injuries in the upper back at time of autopsy. The present study investigated the frequency of muscular hemorrhages around the scapula and determined the mechanism responsible for this phenomenon. Muscular hemorrhages around the scapula were found in 104 of 164 (63.4%) bodies assessed. Hemorrhage in the infraspinatus muscle was most common, followed by the supraspinatus muscle. These muscular hemorrhages were not associated with upper extremity injuries and were most frequently found in accidental drowning cases (78.7%), followed by cases of suicide (56.0%), and in natural disease prior to drowning (19.0%). We examined muscular hemorrhage around the scapula and cervical injuries that restricted the active motion of upper extremities in drowning cases. The vertebral level of cervical injuries were related to muscular hemorrhages around the scapula. These results suggested that muscular hemorrhages around the scapula were not a result of agonal convulsions but were caused by consciously active excessive motion of the upper extremities while drowning. Investigations of the muscular hemorrhages around the scapula can provide insights towards the manner of fatal drowning.

Zastosowanie laseroterapii i rVIIa w leczeniu krwawienia do tkanek miękkich w trombastenii Glanzmanna

Glanzmann’s thrombasthenia (GT) is a rare thrombocytopathy. It is an autosomal recessive disorder. This disease is caused by the quantitative or qualitative defect of the αIIbβ3 membrane integrin, which is the receptor binding the adhesion proteins to the platelet surface in the initial stage of the coagulation process. Abnormal platelet aggregation associated with the αIIbβ3 mutation is the cause of serious and challenging bleeding. The first-line treatment for severe bleeding is transfusion of platelet concentrate or recombinant factor VIIa (rFVIIa) in case of refractoriness to transfusion. The primary objective of this study was to describe clinical effects observed in laser treatment of muscle bleeding in patients with coagulation disorders. We present the case of a 13-year-old boy with TG who was admitted to the hospital with quadriceps muscle hematoma after falling from the bicycle. Due to the lack of response to a platlet concentrate we used rFVIIa with a good effect. Due to the presence of a large painful muscle hematoma, we started laser therapy. Significant pain reduction and rapid hematoma regression were observed.

Imaging features of atypical bleeds in young patients with hemophilia.

Hemarthroses and muscle bleeds are well-known and well-documented complications in pediatric and young adult hemophilia patients. In contrast, deep bleeds in atypical locations can be a diagnostic challenge, since clinicians and radiologists are often unfamiliar with their clinical and radiological features. Some atypical bleeds, however, can be life-threatening or severely disabling, highlighting the need for prompt, accurate diagnosis. Rare bleeds include central nervous system bleeds (including intracranial and spinal hematomas), urogenital bleeds, intra-abdominal bleeds (mesenteric and gastrointestinal wall hematomas) and pseudo tumors in unusual locations like the sinonasal cavities. Because clinical assessment can be difficult, clinicians and radiologists should be aware of the possibility of these rare complications in their hemophilia patients, so that they can avoid unnecessary invasive diagnostic and surgical procedures and institute prompt, appropriate treatment. The purpose of this review is to illustrate the imaging features of bleeds that occur in rare locations in young (i.e., children and young adults) patients with hemophilia to make the reader more familiar with these conditions.

Characteristics of Bleed-Free Patients on Every-5-Day Dosing in the Protect VIII (BAY 94-9027) Study

Background: BAY 94‐9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 x 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial, in which patients could receive prophylaxis every 7 days (E7D), every 5 days (E5D), or twice-weekly (2×W). Patients in the E5D arm had a low median annualized bleeding rate (ABR) of 1.9. This post hoc analysis was conducted to identify clinical predictors for ‘best responders’ (patients with ABR = 0) during E5D prophylaxis with BAY 94-9027 in PROTECT VIII.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days. Prophylaxis patients received BAY 94-9027 25 IU/kg 2×W for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45‒60 IU/kg E5D or 60 IU/kg E7D for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg 2×W. All patients randomized to the E5D arm (n = 43) remained on this dose-frequency throughout the main study. This post hoc analysis presents a description of baseline characteristics of best responders to E5D dosing, defined as patients with ABR = 0 during the main study period; the study was not powered to support a formal statistical comparison.Results: Of 43 patients randomized to E5D dosing, 24 (55.8%) had ABR ≥ 1 and 19 (44.2%) had ABR = 0, meeting the criterion for best responders. The median (95% CI) age was slightly higher for best responders, 38 years [30.0; 47.0] versus 31.5 [24.0; 41.0]), than patients with ABR ≥ 1. In the 12 months prior to the study, best responders had lower median (95% CI) bleeds (2.0 [0.0; 5.0] versus 10.0 [3.0; 21.0]) and joint bleeds (0.0 [0.0; 2.0] versus 8.0 [2.0; 12.0]) compared with patients with ABR ≥ 1. Most patients in both groups had previously received prophylaxis prior to study (84.2% and 70.8%, respectively). Fewer best responders had target joints (57.9%, versus 70.8% of patients with ABR ≥ 1); and those who did have target joints only 36.4% had ≥ 1 target joint, versus 47.1% of patients with ABR ≥ 1.Conclusions: Overall, the 43 patients receiving BAY 94-9027 E5D prophylaxis had a low median ABR of 1.9. The 19 of these patients who had an ABR of 0 (best responders) had numerically fewer bleeds in the 12 months prior to treatment initiation, particularly joint bleeds, and numerically fewer target joints, vs patients with ABR ≥ 1. Though requiring validation in a powered study, taken together, these results suggest the applicability of E5D BAY 94-9027 dosing across patient profiles, and that patients with a similar bleed and joint profile to those analyzed here may be able to achieve ABR of 0 with E5D BAY 94-9027. DisclosuresSantagostino:Bayer, Shire, CSL Behring, Pfizer, Novo Nordisk, Grifols, Kedrion, Sobi, Bioverativ, Octapharma, Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tian:Bayer: Employment. Ducore:CSL Behring: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Shire: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator.

Decrease in Overall and Joint Bleeding Rates with Extended-Interval Dosing: > 4 Years of Bay 94-9027 Prophylaxis in the Protect VIII Extension

Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of bleeds and joint bleeds with BAY 94-9027 prophylaxis during the PROTECT VIII trial and its extension of more than 4 years.Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 previous exposure days (ED). Prophylaxis patients received 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on any regimen used in the main study. Prophylaxis patients who switched regimen after 7 days of the extension were analyzed together in a variable frequency group. Overall and joint annualized bleeding rates (ABRs) were calculated based on documentation in electronic patient diaries. Here, we present data for patients receiving prophylaxis.Results: The intent-to-treat population in the PROTECT VIII extension study included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 patients previously included in the main study (13 did not continue into the extension). At data cut-off (31 January 2018), patients had spent a median time of 3.9 years in the study since enrolment. Patients in the prophylaxis arms had spent a median (range) of 1163 (449; 1579) days in the extension study (approx. 3.2 years), with a median of 211 (96; 318) ED. Most (71) patients had completed 3 years of treatment, 53 had completed 4 years and 33 had completed 5 years of treatment with BAY 94-9027. During the extension, most patients in the 2×W, E5D, or E7D groups did not change regimen (96%, 78% and 65%, respectively). Eleven patients (E5D, 7; E7D, 4) switched to 2×W treatment. Median ABR was 1.6 in prophylaxis patients in the extension, while median joint ABR was 0.9. These values were lower than ABRs during the 6-month main study, of 2.1 and 1.9 for ABR and joint ABR, respectively. In the extension, ABR remained low across all prophylaxis regimens (Table). These values were lower than ABRs for the corresponding treatment groups in the main study (Table). Joint ABR also remained low across extension study patient groups receiving different BAY 94-9027 prophylaxis regimens, and again this was lower than joint ABR in the main study for each group (Table).Conclusions: In the PROTECT VIII extension study, the majority (79/107, 74%) of prophylaxis patients remained on the same dose-frequency of BAY 94-9027during total time in the extension study. Median ABR and joint ABR were lower over the 3-5 years of extension study than in the main study for prophylaxis patients; this was true for the combined prophylaxis cohort and for the 2×W, E5D and E7D BAY 94-9027 prophylaxis groups. Bleed rates were lowest for patients who stayed in the E7D group. Taken together, these results demonstrate that the 2×W, E5D and E7D dose-frequency options for BAY 94-9027 prophylaxis allow patients a decreasingly low rate of bleeds and joint bleeds once treated with a suitable individual regimen. [Display omitted] DisclosuresReding:Genentech: Other: Advisory Board. Pabinger:Bayer, Baxalta/Shire, Novo, Pfizer, Biotest, CSL Behring: Honoraria; CSL Behring and Novo.: Research Funding. Maas Enriquez:Bayer: Employment. Ducore:HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; CSL Behring: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; Shire: Consultancy, Other: travel support, investigator; Bayer Healthcare: Consultancy, Other: travel support, investigator.

Efficacy and Safety of Bay 94-9027 Is Sustained for 5 Years: Outcomes in 33 Patients in the Protect VIII Extension Study

IntroductionBAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial and its extension. We present an analysis of efficacy and safety outcomes in patients from PROTECT VIII who had completed at least 5 years of treatment as of 31 January 2018.MethodsPROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous, joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice-weekly (2×W). Twenty patients received BAY 94-9027 on demand as they had been prior to study. Following completion of the main PROTECT VIII study, patients could enter an extension, continuing BAY 94-9027 on any regimen used in the main study; 121 patients entered the extension, of whom 107 were on the prophylactic arm. Prophylaxis patients who switched regimen after the first 7 days of being in the extension were analyzed in a combined variable frequency (VAR) group. Annualized bleeding rate (ABR) and joint ABR were analyzed, along with safety outcomes.ResultsAt the cut-off date, 33 patients had completed 5 years of treatment with BAY 94-9027 (2×W, n = 3; E5D, n = 10; E7D, n = 6; VAR, n = 14). Median number of infusions (range) was 363 (272-546), and median (range) annual factor consumption was 3385 (2732-5053) IU/kg. Median (range) ABR was 2 (0-15) in the full 5-year period, and 1 (0-12) for the final year. Corresponding joint ABRs were 1 (0-7) and 0 (0-7). Over the 5-year period, study drug-related adverse events (AE)s occurred in 6 patients (18.2%); no patients had a study drug-related serious AE. There were no discontinuations for AEs. No patients had confirmed FVIII inhibitors (titre ≥0.6 Bethesda units).ConclusionsThirty-three patients have received BAY 94-9027 prophylaxis for 5 years. The previously demonstrated efficacy of BAY 94-9027 was maintained across this period; in the last year of the extension median ABR was 1 and a third of patients were entirely free from bleeds. Consistent with the established safety profile of FVIII and with prior analyses of PROTECT VIII, there were few study drug-related AE and no evidence of any long-term toxicity of PEGylated product exposure. Taken together, these data support the use of BAY 94-9027 as a long-term treatment option for patients with hemophilia A. DisclosuresReding:Genentech: Other: Advisory Board. Hvitfeldt Poulsen:Primary investigator and national coordinator on clinical trials from Bayer Health Care: Other: Primary Investigator and national coordinator; Chaired an educational haemophilia symposium for nurses: Other: Chair; Nordic advisory boards (Bayer Health Care, Roche): Membership on an entity's Board of Directors or advisory committees; Lecturer on Nordic meeting on EHL FVIII (SOBI): Other: Lecturer . Tian:Bayer: Employment. Holme:Bayer, Biogen Idec, CSL Behring, Novo Nordisk, Pfizer, Shire and Sobi: Consultancy; Bayer, Octapharma, Pfizer and Shire: Research Funding.

Pain Management in Hemophilia Α: Analysis of a Large US Insurance Claims Database

Introduction: Persons with hemophilia A (PwHA) can develop pain resulting from joint and/or muscle bleeding over time, which can be debilitating and decrease quality of life. Hemophilia A guidelines recommend medications and other interventions to manage pain, however, little is known about how PwHA in the US use different interventions to manage pain. This study aims to describe interventions for pain management in PwHA in the US.Methods: This retrospective cross-sectional analysis identified PwHA between 2006-2015 using data from Truven Health Analytics MarketScan® Commercial Database. PwHA were identified using a previously validated claims-based algorithm with high sensitivity and specificity (Lyons et al. Value Health 2018). PwHA with pain were identified if they had at least one medical claim for pain as identified by the International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 & ICD-10). Pharmacologic treatment alternatives, including prescription opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and adjuvant therapies(including antirheumatics, anticonvulsants, muscle relaxants, topical pain products, and corticosteroids), were identified using national drug codes from pharmacy claims and/or J-codes from medical claims. Non-pharmacologic physical therapy services, regardless of the reason for the procedure, were included and identified using common procedural terminology codes in medical claims. Data on over-the-counter pain medications were not available in the database and were not included in the study. Demographic and clinical characteristics of PwHA with evidence of pain were examined. Descriptive rates were reported for pharmacologic and non-pharmacologic pain interventions in PwHA with any pain and joint pain. Patterns of pain management by age subgroups were also described.Results: We identified 2295 PwHA; of those, 1258 (54.8%) had evidence of any pain. The mean (standard deviation [SD]) age of PwHA was 21.9 (±15.3) years, with 99.7% males, mean (SD) Charlson Comorbidity Index (CCI) score of 0.27 (± 0.9); 44.9% had evidence of arthropathy, 8.9% of fracture, and 3.5% of joint replacement surgery. PwHA with evidence of pain were numerically older (23.4 ± 16.0 years), had higher mean CCI (0.32 ± 1.0) and a higher proportion of arthropathy (81.5%), fractures (14.5%), and joint replacement surgery (6.3%). Of the PwHA with evidence of any pain, 43.8% had at least one claim for physical therapy, 20.1% for prescription opioids, and 17.1% for NSAIDs. Similarly, physical therapy was the most common treatment recorded among patients with evidence of joint pain (46.1%), followed by prescription opioids (20.5%) and NSAIDs (19.0%). Approximately 39% of PwHA with evidence of any pain and joint pain received adjuvant therapies; however, the use of these agents cannot be completely attributed to pain management (Table 1). About a fifth of pediatric patients (<12 years) with any pain or joint pain had evidence of receiving prescription opioids (18.7% and 19.3%) and NSAIDs (6.9% and 8.2%), respectively, and these proportions increased with age. Among adults with evidence of any pain or joint pain, 25.1% and 26.1% of those in the age group of 45-64 years had received prescription opioids, and 26.8% and 28.8% had received NSAIDs, respectively.Conclusions: Over half of the PwHA had evidence of any pain. Nearly half of PwHA with pain received physical therapy services for any reason, while approximately a fifth of PwHA with pain received prescription opioids and NSAIDs. These findings suggest a high prevalence of pain and pain management interventions in hemophilia A. [Display omitted] DisclosuresRaimundo:Genentech Inc: Employment, Other: Ownership interests PLC. Patel:Genentech Inc: Employment. Ko:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment.

Acquired hemophilia A presenting as progressive intra-abdominal hemorrhage, muscle hemorrhage and hemothorax postpartum: A case report and literature review.

Acquired hemophilia A (AHA) is a rare antibody-mediated condition in which autoantibodies form against a coagulation factor, most commonly factor VIII (FVIII), causing severe coagulopathy. Here the present report presents a case of AHA in a 35-year-old postpartum woman with continuous polyserous bloody effusions who was admitted to the First Affiliated Hospital of Zhejiang Chinese Medical University (Hangzhou, China) in October 2017 without a history of trauma, anticoagulation treatment or coagulopathy. At presentation, the patient's hemoglobin level was low (70 g/l; normal range: 115–150 g/l) g/l, blood pressure was 89/58 mmHg (normal range, 90–140/60–90 mmHg), and activated partial thromboplastin time was 68.4 sec (normal range: 25.0–36.0 sec), with a normal international normalized ratio (0.94; normal range, 0.8–1.2). The reaction time in thrombography was prolonged (35.8 min; normal range: 5–10 min), coagulation FVIII had markedly decreased activity (12.6%; normal range, 60–150%), and FVIII inhibitor had a high titer [7.4 Bethesda units (BU)/ml; normal range, 0–0.6 BU/ml]. Notably, the patient's autoantibody level was markedly higher than normal (1:320; normal range: <1:100). The patient was successfully treated with bleeding control, eradication of FVIII inhibitor, and treatment of the underlying disease. To the best of our knowledge, this is the first case of AHA with polyserous bloody effusions in a patient with an autoimmune disorder during the postpartum period. Reports of such rare cases will aid the characterization of disease pathogenesis, which may in turn lead to the recognition and timely treatment of this rare disorder.

Ranges and drivers of risk associated with sports and recreational activities in people with haemophilia: results of the Activity-Intensity-Risk Consensus Survey of US physical therapists.

Limited evidence describes physical activity-associated bleeding risks for people with haemophilia, and risks are usually described only generically. To assess activity-specific ranges of risk for joint, soft tissue and head bleeds by identifying inherent and modifiable risk factors associated with each activity, based on opinions of expert physical therapists (PTs). Physical therapists from US haemophilia treatment centres (HTCs) participated in a survey of 101 physical activities. For each activity, PTs provided minimum/maximum risk scores (low=1; high=5), and indicated specific bleeding risks in six joints and three injury types (bruising, muscle bleeding, head injury). Risk drivers were identified from free-text comments and explored at a consensus meeting, where they were categorized as inherent or modifiable and activity-driven or patient-driven. Of 32 invited PTs, 17 participated; median experience was 24years as a PT and 16years at an HTC. Only a few activities had a wide range of risk assessments encompassing both lower and upper ends of the response range. Joint injury risks were consistent with position and physical requirements, and head and muscle bleed risks were associated with physical contact. Eight PTs participated in the consensus meeting; key risk drivers identified included progression from seasonal to year-round participation, overtraining and improper body mechanics. Inherent risks included impact with surface/ball/equipment and field/surface condition; modifiable risks included safety equipment and tricks/stunts. These data provide a framework for discussion with patients/families, recognizing how certain activities may be modified to decrease risk, and identifying activities with nonmodifiable inherent risks.

Bleeding events and safety outcomes in persons with haemophilia A with inhibitors: A prospective, multi‐centre, non‐interventional study

Prospectively collected, real-world data on bleeds, haemophilic treatment and safety outcomes in persons with haemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. A prospective, global, multi-centre, non-interventional study (NIS; NCT02476942) collected detailed real-world data in PwHA treated per local routine clinical practice. To characterize bleeding rates, haemophilic treatment practices, prophylaxis adherence and adverse events (AEs) in adult/adolescent PwHA with inhibitors in the NIS. Participants aged ≥12years with congenital haemophilia A/documented high-titre FVIII inhibitor history were enrolled. Participants remained on their usual treatment; no interventions were applied. Overall, 103 PwHA with inhibitors enrolled, (median [range] age 31 [12-75] years) and were monitored for median (range) 26.0 (4.1-69.6) weeks. In the episodic (n=75) and prophylactic (n=28) treatment groups, respectively, 1244 and 325 bleeds were reported, and 528 (42.4%) and 104 (32.0%) were not treated; annualized bleeding rates (ABRs; 95% confidence interval) were 18.6 (15.2-22.8) and 14.9 (10.5-21.2) for treated bleeds, and 32.7 (27.3-39.1) and 25.0 (18.4-34.0) for all bleeds. Coagulation products used included activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII. Among participants prescribed aPCC prophylaxis, 35.0% adhered to both prescribed frequency of aPCC administration and prescribed dose. Serious AEs of haemarthrosis and muscle haemorrhage were reported; most common AEs were arthralgia, viral upper respiratory tract infection and pyrexia. ABRs (treated bleeds and all bleeds) remain high on standard treatment; this prospective NIS demonstrates the need for more effective treatments for PwHA with inhibitors to reduce/prevent bleeds, with potential to improve prophylaxis adherence and further improve outcomes.

Wednesday, September 26, 2018 1:00 PM – 2:00 PM What's New in MIS: 40. Clinical and radiological outcomes of unilateral biportal endoscopic decompression by 30° endoscopy in lumbar spinal stenosis: minimum 2-years follow-up

BACKGROUND CONTEXT Open laminectomy or open laminectomy and lumbar spinal fusion has been regarded as the standard surgical method to date in degenerative spinal stenosis. The conventional method has been associated with complications such as paraspinal muscle damage, bleeding and infection. Several surgical techniques including microendoscopic decompression have been introduced to solve these problems. PURPOSE The aim of this study is to introduce a new spinal surgical technique using a 30° endoscopy through unilateral biportal endoscopic decompression technique and to report the results of patients who have been on follow-up for more than 2 years. STUDY DESIGN/SETTING Retrospective study. PATIENT SAMPLE Fifty-five patients who were suffering from neurologic symptoms by degenerative lumbar spinal stenosis were included even after preoperative conservative treatment. Patients with foraminal stenosis requiring an extraforaminal approach were excluded from the study. OUTCOME MEASURES Clinical outcomes were analyzed in view of modified-Macnab criteria, Oswestry Disability Index (ODI), Visual Analog Scale (VAS), and postoperative complications were analyzed. Plain X-ray studies before and after surgery were compared to confirm disc height reduction and progression of spondylolithesis. METHODS Two or three portals were used for each level. One portal was used for viewing, the others, for working of certain instruments. Unilateral laminotomy was followed by bilateral decompression under 30° endoscopy. RESULTS Eighty-one percent of the patients improved over a level based on the Macnab criteria. There were not any case of infection. The interverbral angle was significantly reduced from 6.26±3.54° to 5.58±3.23° at 2 years postoperatively, the dynamic intervertebral angle was slightly decreased by 6.54±3.71° at 6.76±3.59°, but was not statistically significant. No significant change in percentage slip was observed (3.76±5.01% preoperatively vs. 3.81±5.28% at the last follow-up). The dynamic percentage slip (gap in percentage slip between flexion and extension X-ray exams) did not change significantly from 2.65±3.37 to 2.76±3.71%. However, at 2 years postoperatively, intervertebral distance was significantly reduced from 10.43±2.23 mm to 10.0±2.24 mm. CONCLUSIONS Full endoscopic decompression using 30° endoscopy demonstrated a satisfactory clinical outcome after surgery. This technique was able to reduce infection, and was a good procedure without postoperative segmental instability. It could be alternative method of microscopic decompression. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Inactivation of Venom PLA₂ Alleviates Myonecrosis and Facilitates Muscle Regeneration in Envenomed Mice: A Time Course Observation.

Snake venom is a complex cocktail of toxins which induces a series of clinical and pathophysiological manifestations in victims, including severe local tissue damage and systemic alterations. Deinagkistrodon acutus (D. acutus) ranks among the “big four” life-threatening venomous species in China, whose venom possesses strong myotoxicity and hematotoxicity that often lead to permanent disability or muscle atrophy. Varespladib, an inhibitor of mammalian phospholipase A2 (PLA2), has been recently reproposed as an effective antidote against snakebite envenomation. The present study aimed at evaluating the protective role of varespladib on muscle regeneration in envenomed mice. Mice were grouped and subjected to inoculation with D. acutus venom or a mixture of venom and varespladib or control vehicle in the gastrocnemius muscle. Local injuries including hemorrhage, myonecrosis, ulceration, and systemic damages including general dysfunction, visceral failure, and inflammatory responses were observed at 1, 3, 7, 14, and 21 days. The results indicated that most of the muscle myonecrosis and hemorrhage were alleviated by varespladib. Besides, the pretreated mice recovered rapidly with lesser atrophy and muscle fibrosis. In conclusion, the findings of the present study suggested that varespladib is an effective antidote that could neutralize D. acutus venom and allow for earlier and improved rehabilitation outcome.

Inhibitors in Hemophilia B.

Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication.

Efficacy, safety and pharmacokinetics of a new high‐purity factor X concentrate in women and girls with hereditary factor X deficiency

Background A high-purity, plasma-derived factor X concentrate (pdFX) has been approved for the treatment of hereditary FX deficiency, an autosomal recessive disorder. Objective To perform post hoc assessments of pdFX pharmacokinetics, safety and efficacy in women and girls with hereditary FX deficiency. Patients/Methods Subjects aged ≥ 12 years with moderate/severe FX deficiency (plasma FX activity of < 5 IU dL-1 ) received on-demand or preventive pdFX (25 IU kg-1 ) for ≤ 2 years. Results Of 16 enrolled subjects, 10 women and girls (aged 14-58 years [median, 25.5 years]) received 267 pdFX infusions. Mean monthly infusions per subject were higher among women and girls (2.48) than among men and boys (1.62). In women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeds, 47 joint bleeds, 15 muscle bleeds, and nine other bleeds) were treated with pdFX, with a 98% treatment success rate versus 100% in men and boys. Mean pdFX incremental recovery was similar in the two groups (2.05 IU dL-1 versus 1.91 IU dL-1 per IU kg-1 ), as was the mean half-life (29.3 h versus 29.5 h). Of 142 adverse events in women and girls, headache was the most common (12 events in six subjects). Six events (two infusion-site erythema, two fatigue, one back pain, one infusion-site pain) in two subjects were considered to be possibly pdFX-related. Following the trial, pdFX was used to successfully maintain hemostasis in two subjects undergoing obstetric delivery. Conclusions pdFX was well tolerated and effective in women and girls with FX deficiency. Although women and girls had different bleeding symptoms and sites than men and boys, their pdFX pharmacokinetic profile was comparable.

Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise.

Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. In this international multicentre study, haemophilia B patients with FIX<0.05 IUmL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79kg). Sixty percent of FIX levels within 24hours of surgery were below target with a median difference of 0.22 IUmL-1 [IQR 0.12-0.36]; while >6days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IUmL-1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment.

Safety of fascial therapy in adult patients with hemophilic arthropathy of ankle. A cohort study

BackgroundHemophilic arthropathy is characterized by loss of function and chronic pain. Fascial therapy mobilizes the connective tissue, intervening in the state of the injured fascial complex and the surrounding tissues. ObjectivesThe aim of this study is to evaluate the safety of a physiotherapy program through fascial therapy in adult patients with hemophilic ankle arthropathy. DesignProspective cohort study. MethodsTwenty-three adult patients with hemophilia from 26 to 65 years of age were recruited. The intervention consisted of three sessions of 45-minute fascial therapy for three consecutive weeks. An evaluation was carried out before as well as after treatment. The study variables were joint status (assessed with Hemophilia Joint Health Score), joint pain (using visual analogue scale), ankle range of motion (with a universal goniometer) and bleeding frequency (administering self-registration of bleeding). The mean difference was calculated using the Student's t-test for paired samples and using the Cohen formula we calculated the effect size of the dependent variables. ResultsNone of the patients developed muscular or articular bleeding during the treatment period. After treatment, significant improvements (p < 0.05) in plantar flexion, ankle pain under load and joint condition were observed in both ankles. Similarly, we found improvement in left ankle dorsiflexion. ConclusionsThe application of physiotherapy through fascial therapy does not appear to produce muscle or joint hemorrhages. A treatment through three sessions of fascial therapy may improve joint pain, mobility and joint ankle condition in patients with hemophilic arthropathy.

Manual therapy in the treatment of patients with hemophilia B and inhibitor

BackgroundThe main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor.Case presentationA 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality.ConclusionsUntil now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.