Für Sie Recherchiert 3/2023
Anazor F.C., Uthraraj N., Relwani J.
[Article in Press] Haemophilia 2023 :
Go to publisher for the full text
Abstract
INTRODUCTION: Total elbow replacement (TER) is a surgical treatment option for haemophilic elbow arthropathy. AIM: To review the outcomes of TER in haemophilic elbow arthropathy. The primary outcome measures were perioperative blood loss, postoperative complications, revision rates and length of hospital stay (LOS). Secondary outcomes were elbow range of motion (ROM), functional outcome scores and the visual analogue pain scale (VAS). MATERIALS AND METHODS: PubMed, Medline, Embase and the Cochrane register were searched conforming to the PRISMA guidelines. Only studies with a minimum postoperative follow-up of 1 year were included. Quality appraisal was performed utilizing the MINORS criteria. RESULTS: One hundred and thirty-eight articles were identified. Following article screening, only seven studies met the inclusion criteria. A total of 51 TERs in 38 patients were performed, with the Coonrad-Morrey prosthesis utilized in 51% of cases. The pooled postoperative complication and revision rates were 49% and 29%, respectively. Surgery-related postoperative mortality was 3.9%. The mean preoperative Mayo elbow performance score (MEPS) was 43 ± 20 whereas the mean postoperative MEPS was 89 ± 6. Mean preoperative VAS was 7.2 ± 1.9 while the mean postoperative VAS was 2.0 ± 1.4. Mean preoperative and postoperative elbow flexion arcs were 54 ± 15 and 91 ± 10 degrees, respectively. Mean preoperative and postoperative forearm rotation arcs were 86 ± 40 and 135 ± 19 degrees, respectively. CONCLUSION: TER for haemophilic elbow arthropathy provides good to excellent improvements in pain and elbow ROM postoperatively. However, the overall complication and revision rates are relatively high, when compared to TER performed for other indications.
Activation of the Acute-phase Response in Hemophilia
Knowles L.M., Wolter C., Menger M.D., Laschke M.W., Beyer L., Gruen U., Eichler H., Pilch J.
[Article in Press] Thromb Haemost 2023 :
Go to publisher for the full text
Abstract
To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP) and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) > 30. Subgroup analysis of the remaining non-obese hemophilia patients (BMI 18-29.9) revealed a significant spike of IL-6, CRP and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients that did not experience recent bleeding had IL-6, CRP and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a 4-fold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia.
Kloosterman F.R., Zwagemaker A.-F., Bay-Jensen A.C., Cnossen M.H., Kruip M.J.H.A., Leebeek F.W.G., Hemke R., Maas M., Fijnvandraat K., Gouw S.C., Coppens M.
[Article in Press] J Thromb Haemost 2023 :
Go to publisher for the full text
Abstract
BACKGROUND: Persons with non-severe hemophilia A (NSHA) experience less frequent joint bleeding than persons with severe hemophilia A but may still develop joint damage. Biomarkers of cartilage and synovial remodelling can reflect ongoing pathological processes that may precede or coincide with damage on joint imaging. If so, biomarkers may be an important diagnostic tool for joint damage in NSHA. OBJECTIVE: To assess the correlation between biomarkers and MRI-detected joint damage in persons with NSHA. PATIENTS/METHODS: In a cross-sectional study, males with NSHA (FVIII 2-35 IU/dL) were included. Participants underwent MR imaging of elbows, knees and ankles and blood and urine sampling for biomarker analysis on a single visit. The following biomarker(s) were analyzed in urine: CTX-II or serum: COMP, CS-846, VCAM-1, osteopontin, C2M, PRO-C2, C4M and PRO-C4. Spearman's rank correlations were calculated between these biomarkers and the total IPSG score, soft-tissue sub-score and osteochondral sub-score. RESULTS: In total, 48 persons with NSHA were included. Median age was 43 years (range 24-55) and median FVIII was 10 IU/dl (IQR 4-16). The median IPSG score was 4 (IQR 2-9). Median IPSG soft-tissue subscores were 3 (IQR 2-4) and osteochondral subscores were 0 (IQR 0-4). No strong correlations were found between the studied biomarkers, total IPSG score, subsequent soft-tissue and osteochondral sub-scores. CONCLUSIONS: In this study, selected biomarkers indicative of different aspects of hemophilic arthropathy showed no consistent correlation with IPSG scores. This suggests that systemically measured biomarkers are currently not suitable to identify milder joint damage in NSHA as observed on MRI.
Duminuco A., Calagna M., Markovic U., Esposito B., Grasso S., Riccobene C., Di Raimondo F., Giuffrida G.
Transfus. Apheresis Sci. 2023 62:2
Go to publisher for the full text
Abstract
Acquired hemophilia A (AHA) is a rare coagulopathy characterized by hemorrhagic manifestations. It has been linked to various conditions, including autoimmune disorders, drugs, tumors, lymphoproliferative disorders, and infections. We present a case of AHA in a 71-year-old male patient with cutaneous hematoma occurring 8 days after vaccination for COVID-19. This report aims to highlight the risk of FVIII inhibitor development following an immune stimulus, thus improving our knowledge regarding possible vaccination-related adverse events. Furthermore, we underline how the potential risk of not recognizing disease manifestations promptly, together with specific coagulation alterations, could significantly affect the patient's outcome. Adequate management plans and the diffusion of shared guidelines are of fundamental importance in order to prevent the development of life-threatening complications and initiate appropriate treatment as soon as possible. Data Availability: All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Psychological complications among patients with congenital bleeding disorders
Asad F., Jahangarad S., Dorgalaleh A.
Blood Coagul Fibrinolysis 2023 34:3 (138-143)
Go to publisher for the full text
Abstract
Congenital bleeding disorders (CBDs), including inherited platelet function disorders and rare and common bleeding disorders, are a heterogeneous group of bleeding disorders with a wide range of clinical presentations, including psychological complications. Due to the chronic nature of CBDs, psychological complications are relatively common in these patients, which can affect treatment adherence, quality of life, and even the frequency of bleeding episodes. Chronic pain causes many psychological problems in CBDs, disrupting their social interactions, affecting all aspects of their lives, including their emotional functioning and behavior, and eventually leading to social exclusion. About one-third of patients with severe hemophilia A suffer from anxiety, 64% from depression, and 60% from other minor psychological complications such as withdrawal/depression, anxiety/depression, attention problems, and emotional problems. Anxiety, depression, and uncontrolled pain interfere with treatment adherence. For this reason, psychological interventions are needed in people with CBDs. Psychological interventions increase quality of life and treatment adherence. Therefore, early recognition of psychological complications in CBD patients may increase treatment adherence, leading to a reduction in bleeding episodes and thus an improvement in quality of life.
Humanistic burden of problem joints for children and adults with haemophilia
Burke T., Rodriguez-Santana I., Chowdary P., Curtis R., Khair K., Laffan M., Mclaughlin P., Noone D., O'Mahony B., Pasi J., Skinner M., O'Hara J.
Haemophilia 2023 29:2 (608-618)
Go to publisher for the full text
Abstract
Introduction: The “problem joint” (PJ) concept was developed to address patient-centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). Aim: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. Methods: Multivariable regression models evaluated the relationship between PJs and health-related quality of life (HRQoL, EQ-5D-5L) and overall work productivity loss (WPL) using data from the ‘Cost of HaEmophilia: a Socioeconomic Survey’ population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS-Paeds). Covariates included were haemophilia severity, age, comorbidities and education. Results: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS-Paeds included 198 PwH aged 4–17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p <.001). Few CHESS-Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p <.05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p <.05). Conclusion: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health.
van Leeuwen F.H.P., Timmer M.A., de Jong P.A., Fischer K., Foppen W.
Haemophilia 2023 29:2 (445-455)
Go to publisher for the full text
Abstract
Introduction: Ultrasound is increasingly used as addition to physical examination for detection of subclinical joint changes in haemophilia. However, the added value of ultrasound to physical examination for detecting synovial proliferation is not fully established. Aim: To determine the diagnostic accuracy of swelling at physical examination for ultrasound-detected synovial proliferation in haemophilia. Methods: PubMed and EMBASE were searched up to 2 August 2022. Studies reporting original data on occurrence of swelling at physical examination and synovial proliferation on ultrasound of index joints in persons with haemophilia were included. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Diagnostic accuracy parameters of swelling at physical examination for ultrasound-detected synovial proliferation were determined. Summary sensitivity and specificity were calculated using a bivariate random-effects model. Results: Fifteen studies reporting on swelling at physical examination and synovial proliferation on ultrasound in 2890 joints of 627 patients were included. Prevalence of subclinical synovial proliferation ranged between 0% and 55%. Sensitivity of swelling was low [summary estimate.34; 95% confidence interval (CI).24-.46], while specificity was high (summary estimate.97; CI.92-.99). Predictive values varied widely due to inter-study differences in prevalence of synovial proliferation. Conclusion: Joint swelling has low sensitivity for presence of ultrasound-detected synovial proliferation in haemophilia, suggesting underestimation of synovial proliferation by physical examination alone. Consequently, ultrasound screening may generate important information on synovial changes which would otherwise remain undetected.
Sarmiento Doncel S., Díaz Mosquera G.A., Cortes J.M., Agudelo Rico C., Meza Cadavid F.J., Peláez R.G.
Hematol. Rep. 2023 15:1 (130-150)
Go to publisher for the full text
Abstract
The purpose of this narrative review was to provide an overview that allows readers to improve their understanding of hemophilia A, which is considered a genetic disease with a high impact on the quality of life of people who suffer from it is considered one of the diseases with the highest cost for health systems (In Colombia it is part of the five diseases with the greatest economic impact). After this exhaustive review, we can see that the treatment of hemophilia is on the way to precision medicine, which involves genetic variables specific to each race and ethnicity, pharmacokinetics (PK), as well as environmental factors and lifestyle. Knowing the impact of each of these variables and their relationship with the efficacy of treatment (prophylaxis: regular infusion of the missing clotting factor VIII in order to prevent spontaneous bleeding) will allow for individualizing the medical behavior in a cost-effective way. For this is required to build more strong scientific evidence with statistical power that allows us to infer.
Kennedy M., Roche S., McGowan M., Singleton E., Elsheikh E., O'Donovan M., Ryan K., O'Connell N.M., O'Mahony B., Lavin M., O'Donnell J.S., Turecek P.L., Gormley J.
Haemophilia 2023 29:1 (72-83)
Go to publisher for the full text
Abstract
Aim: This study aimed to examine physical activity (PA), physical fitness and cardiometabolic risk amongst people with moderate and severe haemophilia (PwMSH). Methods: The following domains were examined: PA (accelerometry); functional aerobic capacity (6-Minute Walk Test); grip strength (dynamometry); balance (One Leg Stand Test); body composition (anthropometry and bioimpedance analysis); blood pressure; arterial stiffness; and cardiometabolic disorders. Results: A total of 53 PwMSH (44 years) and 33 controls (43 years; p =.679) were recruited. Compared to controls, PwMSH were significantly less active in moderate and vigorous PA parameters (all p <.05), and less physically fit indicated by 6-Minute Walk distance (p <.0005), grip strength (p =.040) and balance (p <.0005). PwMSH had higher rates of abdominal adiposity compared to controls measured by waist circumference indices (all p <.05). Resting blood pressure and arterial stiffness were not significantly different (p =.797 and.818, respectively). With respect to overall PA, World Health Organisation recommended targets for adults were achieved by the majority of both groups (haemophilia: 72.9% vs. controls: 90.0%; p =.069). Importantly, the number of PwMSH who achieved guideline recommended PA via longer, sustained bouts of moderate–vigorous PA was significantly lower compared to controls (18.8% vs. 56.7%; p =.001). Lastly, clinically diagnosed hypertension, insulin resistance and hyperlipidaemia were more prevalent amongst PwMSH compared to controls. Conclusion: Low levels of PA and physical fitness, and significant rates of abdominal adiposity and hypertension may collectively influence the risk and severity of various cardiometabolic and/or musculoskeletal health issues amongst ageing PwMSH. Personalised multi-disciplinary health interventions involving PA, dietary and health psychology input for PwMSH warrant future investigation.
Functional decline in persons with haemophilia and factors associated with deterioration
Blokzijl J., Pisters M.F., Veenhof C., Schutgens R.E.G., Timmer M.A.
[Article in Press] Haemophilia 2023 :
Go to publisher for the full text
Abstract
Introduction: The World Haemophilia Federation advises regular musculoskeletal assessment covering all International Classification of Functioning and Health (ICF) domains, including limitations in activities and participation in persons with haemophilia (PWH). This enables clinicians to detect changes early and enable adjustments in personalized healthcare when needed. However, data on the course of physical functioning and occurrence of decline is lacking. The aim of this study is to describe changes in perceived limitations in activities of PWH and to identify factors associated with a change. Methods: Data were collected from medical health records of regular check-up visits of adults with moderate and severe haemophilia in two time periods. Perceived limitations in activities was measured with the Haemophilia Activities List (HAL). Association between variables (e.g., age, body mass index, bleeding rate and synovitis) and change in perceived limitations was assessed using a generalized linear model. Results: A total of 104 PWH were included. At T0, the median HAL sum score was 79.5 (IQR 62.1–93.6) and at T1 the median HAL sum score was 74.2 (IQR 57.5–88.3). A functional decline was found in 35.6% of PWH, 55.8% remained stable and 8.7% improved. Among other variables, a BMI > 30 kg/m2 appeared to be an important factor that negatively influenced the change in perceived functioning in adult PWH. With the included factors we could only explain a small part of this decline (R2adj:.12). Conclusion: The majority of PWH remained stable in their perceived functional ability over mid-long term (median 3.5 years). However, about a third showed a clinical relevant decline in their functional ability.
Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width
van Bergen E.D.P., Mastbergen S.C., Lafeber F.P.J.G., Bay-Jensen A.-C., Madsen S.F., Port H., Foppen W., Schutgens R.E.G., Jansen M.P., van Vulpen L.F.D.
[Article in Press] Haemophilia 2023 :
Go to publisher for the full text
Abstract
Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult.
Tat A.M., Özkan S., Tat N.M., Karaman K., Öner A.F.
East. J. Med. 2023 28:1 (51-58)
Go to publisher for the full text
Abstract
Hemophilic arthropathy (HA) of the elbow joint should be examined separately from the knee and ankle because of the anatomical and biomechanical differences of the elbow. The aim is to investigate possible correlations between age, range of motion (ROM), muscle strength, upper extremity functions, joint health and radiological findings. Twenty-seven joints of 20 patients aged 11-30 years with findings of HA in elbow were evaluated. International Prophylaxis Study Group Magnetic Resonance Imaging (IPSG MRI) score was used in the radiological evaluation. In physical evaluations, ROM and muscle strength were measured by goniometer and digital dynamometer, respectively. Joint health was evaluated with Hemophilia Joint Health Score-Elbow Point (HJHS-EP) and upper extremity functionality with Quick-Disability of Arm Shoulder and Hand (Q-DASH). The age was strongly correlated with HJHS-EP, loss of extension and pronation ROM and moderately correlated with IPSG MRI score. HJHS-EP showed strong correlation with loss of extension. There were a moderate correlation between Q-DASH and muscle strength of the elbow. The IPSG MRI scores were not significantly correlated with physical examinations. The elbow joint should be evaluated both radiographically and physically and these assessments cannot be alternatives to each other. Even goniometric assessment of elbow extension alone may provide important information about joint health. Functionality can be improved by increasing muscle strength. Since the deterioration in physical and radiographic examinations with age, it is recommended to conservatively or surgically treat of the elbow joint with physiotherapy at early ages.
Perioperative Outcomes of Patients with Bleeding Disorders Undergoing Major Surgery at an Academic Hemophilia Treatment Center
Rhoades R., French Z., Yang A., Walsh K., Drelich D.A., McKenzie S.E.
Clin Appl Thromb Hemost 2023 29: (10760296231165056)
Go to publisher for the full text
Abstract
Persons with bleeding disorders (PwBD) are at high risk for bleeding with invasive procedures. However, the risk of bleeding in PwBD undergoing major surgery and outcomes of patients managed perioperatively at a hemophilia treatment center (HTC) are not well described. We performed a retrospective review of surgical outcomes among PwBD undergoing major surgery between January 1st, 2017 and December 31st, 2019 at the Cardeza Foundation Hemophilia and Thrombosis Center in Philadelphia, PA. The primary outcome was postoperative bleeding, assessed according to the ISTH-SSC's 2010 definition. Secondary outcomes included use of unplanned postoperative hemostatic therapy, LOS, and 30-day readmission rate. Results were compared to non-PwBD population from a surgical database, matched for surgery, age, and sex. During the study period, 50 PwBD underwent 63 major surgeries. The most common diagnoses were VWD (64%) and hemophilia A (20.0%). The most common surgical procedure category was orthopedic (33.3%), predominantly arthroplasties. Postoperatively,4.8% of procedures were complicated by major bleeding and 1.6% by non-major bleeding. The mean LOS was 1.65 days, and 30-day readmission rate was 1.6%. In comparison to matched, non-PwBD patients in a national surgical database undergoing the same procedures, study patients had a similar rate of bleeding complications per procedure (5.0% vs 1.04% P = .071, Fisher's exact test). PwBD undergoing major surgeries have low rates of major bleeding when receiving comprehensive care at an HTC. Bleeding and hospital readmission rates were similar to non-PwBD baseline in a large database.
Consistency of serial ultrasonographic joint tissue measurements by the Joint tissueActivity and Damage Exam (JADE) protocol in relation to hemophilic joint health parameters
Barnes R.F.W., Aguero P., Hanacek C., Flores A., Steiner B., Bailey C., Quon D.V., Kruse-Jarres R., von Drygalski A.
BMC Musculoskeletal Disorders 2023 24:1 Article Number 299
Go to publisher for the full text
Abstract
Objectives: The Joint tissueActivity and Damage Exam (JADE) is a point-of-care (POC) musculoskeletal ultrasound (MSKUS) protocol for non-radiologists to evaluate hemophilic arthopathy. Our aim was to determine the consistency of cross-sectional analyses of direct tissue measurements (JADE protocol) and clinical Hemophilia Joint Health Score [HJHS] and functional joint assessments (arc) at three clinic visits. Methods: We prospectively studied adults (n = 44) with hemophilia (A or B) of any severity and arthropathy at 3 North American sites. We assessed HJHS, total arc, and JADE parameters (bilateral elbows, ankles, and knees) at study entry, at ≈12–18 months, and at ≈24–36 months, and used MSKUS to evaluate painful episodes between study visits. JADE measurements included osteochondral alterations, cartilage thickness, and soft tissue expansion at sentinel positions. Associations between joint HJHS and total arc with each JADE variable were examined with random intercept models. Results: At each visit increasing HJHS and decreasing total arc were associated in the expected direction with increasing length of OAs and soft tissue expansion in all joints, and decreasing cartilage thickness in the knee. However, HJHS associations with cartilage thickness were U-shaped for elbow and ankle (i.e. cartilage thinning and thickening). Associations between total arc and cartilage thickness followed a similar curve. (Near) normal levels of both joint parameters (HJHS and total arc) were associated with normal ranges of cartilage thickness. JADE views were also helpful to detect hemarthrosis in association with joint pains. Conclusions: POC MSKUS applying direct tissue measurements using the JADE protocol provided reproducible cross-sectional associations with joint health outcomes on three visits. These findings advance protocol validation and enable iterative adaptations resulting in JADE protocol version 2.
Paul H., Berg V., Gangadharan B., Bowen J., LeBeau P., Blatný J., Male C., Radulescu V.C., Diaz R., Mancuso M.E., Brown D.L., Reipert B.M.
[In Process] Blood Advances 2023 7:9 (1831-1848)
Go to publisher for the full text
Abstract
Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.
Kempers E.K., van Kwawegen C.B., de Meris J., Spaander M.C.W., Schols S.E.M., Ypma P.F., Heubel-Moenen F.C.J.I., van Vulpen L.F.D., Coppens M., van der Bom J.G., Fijnvandraat K., Meijer K., Eikenboom J., Gouw S.C., Leebeek F.W.G., Kruip M.J.H.A.
Journal of Thrombosis and Haemostasis 2023 21:5 (1177-1188)
Go to publisher for the full text
Abstract
Background: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. Objectives: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia. Methods: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands. Results: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02). Conclusion: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population.
Monitoring recovery of joints after bleeding: Physical examination and ultrasound are complementary
van Leeuwen F.H.P., Fischer K., Foppen W., van Vulpen L.F.D., Timmer M.A.
[In Process] Haemophilia 2023 29:3 (883-891)
Go to publisher for the full text
Abstract
Aim: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound. Methods: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines. Results: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred. Conclusion: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care.
Elsheikh E., Lavin M., Heck L.A., Larkin N., Mullaney B., Doherty D., Kennedy M., Keenan C., Guest T., O'Mahony B., Fazavana J., Fallon P.G., Preston R.J.S., Gormley J., Ryan K., O'Connell N.M., Singleton E., Byrne M., McGowan M., Roche S., Doyle M., Crowley M.P., O'Shea S.I., Reipert B.M., Johnsen J.M., Pipe S.W., Di Paola J., Turecek P.L., O'Donnell J.S.
Journal of Thrombosis and Haemostasis 2023 21:5 (1123-1134)
Go to publisher for the full text
Abstract
Background: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. Objectives: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. Methods: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. Results: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p =.0035) increased in patients with an FVIII half-life of <12 hours. Conclusion: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.
Villalón-González M., Fernández de Luco-Santamaría Í., Cuesta-Barriuso R., López-Pina J.A., Pérez-Llanes R.
[In Process] Journal of Clinical Medicine 2023 12:9 Article Number 3275
Go to publisher for the full text
Abstract
Background: Hemophilia is characterized by recurrent hemarthrosis leading to degenerative arthropathy. The aim was to evaluate the differences in muscle strength and activity and the pressure pain threshold between patients with knee arthropathy and their healthy peers; (2) Methods: A case-control study in which 23 adult patients with knee arthropathy and 24 healthy peers matched in terms of characteristics were recruited. The study variables were quadriceps muscle strength, muscle activation and the pressure pain threshold; (3) Results: There were significant differences between the two groups in quadriceps strength on the dominant (CI95%: 64.69, 129.2) and non-dominant (CI95%: 29.95, 93.55) sides and in the pressure pain threshold on the dominant (CI95%: 3.30, 43.54) and non-dominant (CI95%: 3.09, 45.25) sides. There were differences in neuromuscular fatigue on the non-dominant side in the vastus medialis (CI95%: 8.72, 21.51), vastus lateralis (CI95%: 4.84, 21.66) and rectus femoris (CI95%: 6.48, 24.95) muscles; (4) Conclusions: Muscle strength and the pressure pain threshold are lower in patients with hemophilia. Quadriceps muscle activation in patients with hemophilic knee arthropathy does not in any way differ from activation in healthy subjects. However, muscle fatigue is greater in patients with knee arthropathy. Strength training in patients with hemophilia should focus on the activation of the vastus medialis and lateralis muscles.
Recombinant FVIII: the milestone of modern hemophilia treatment
Mannucci P.M.
Haematologica 2023 108:5 (1201-1202)
Go to publisher for the full text
Acquired haemophilia A diagnosed during pregnancy
Ejaz A., O’Doherty C., Sharpley F.A., Curry N., Shapiro S., Desborough M.J.R.
Obstetric Medicine 2023 16:1 (56-58)
Go to publisher for the full text
Abstract
Pregnancy-associated haemophilia A is an uncommon, acquired bleeding disorder which usually presents post-partum; very rarely it may present during pregnancy. No consensus guidelines exist on the management of this condition in pregnancy and very few cases have been reported in the literature. Here we describe the case of a woman presenting with acquired haemophilia A during pregnancy and outline the management of her bleeding disorder. We contrast her case with that of two other women, presenting to the same tertiary referral centre, with acquired haemophilia A presenting post-partum. These cases highlight the heterogeneous management of this condition and how it may be successfully managed in pregnancy.
Reding M.T., Pabinger I., Holme P.A., Maas Enriquez M., Mancuso M.E., Lalezari S., Miesbach W., Di Minno G., Klamroth R., Hermans C.
Therapeutic Advances in Hematology 2023 14
Go to publisher for the full text
Abstract
Background: Advances in treatment have enabled patients with haemophilia A to live longer and therefore may be subjected to comorbidities associated with ageing, in addition to disease-associated morbidities. There have been few reports to date on efficacy and safety of treatment specifically in patients with severe haemophilia A and comorbidities. Objective: To explore the efficacy and safety of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A aged ⩾40 years with comorbidities of interest. Design: A post hoc analysis of data from the phase 2/3 PROTECT VIII study and its extension. Methods: Bleeding and safety outcomes were analysed in a subgroup of patients aged ⩾40 years with ⩾1 comorbidity receiving damoctocog alfa pegol (BAY 94-9027; Jivi®) prophylaxis. Results: Thirty-four patients with severe haemophilia A were included in this analysis, with a mean age of 49.4 years at time of enrolment. The most prevalent comorbidities were hepatitis C (n = 33; chronic, n = 23), hepatitis B (n = 8) and hypertension (n = 11). Four patients had human immunodeficiency virus. All received damoctocog alfa pegol prophylaxis for the entire study [median (range) time in study = 3.9 (1.0–6.9) years]. During the main study and extension, median total annualised bleeding rates (ABRs) (Q1; Q3) were 2.1 (0.0; 5.8) and 2.2 (0.6; 6.0), respectively; median joint ABRs were 1.9 (0.0; 4.4) and 1.6 (0.0; 4.0), respectively. Mean adherence with prophylaxis schedule was greater than 95% throughout the study. No deaths or thrombotic events were reported. Conclusion: Efficacy, safety and adherence of damoctocog alfa pegol were confirmed in patients aged ⩾40 years with haemophilia A and one or more comorbidities, with data for up to 7 years supporting its use as a long-term treatment option in this group. Plain language summary: Advances in treatment mean that people with haemophilia A are now living longer and, as a result, may have additional medical conditions that occur with ageing. We aimed to investigate the efficacy and safety of the long-acting replacement factor VIII damoctocog alfa pegol in people with severe haemophilia A who had additional medical conditions. To do this, we investigated the recorded information about patients aged 40 years of age or older who had been treated with damoctocog alfa pegol in a previously completed clinical trial. We found that the treatment was well-tolerated; no deaths or thrombotic events (undesirable clotting events) were reported. Treatment was efficacious in reducing bleeding in this group of patients. The findings support the use of damoctocog alfa pegol as a long-term treatment for older patients with haemophilia A and coexisting conditions.
Clotting factor activity levels and bleeding risk in people with haemophilia playing sports
Versloot O., Kemler E., Blokzijl J., Timmer M., Schuuring M., van Galen K.P.M., Kremer Hovinga I.C.L., van der Valk P.R., van Vulpen L.F.D., Schutgens R.E.G., van Koppenhagen C.F., van der Net J., Fischer K.
[Article in Press] [In Process] Haemophilia 2023
Go to publisher for the full text
Abstract
Background: Improved treatment options for people with haemophilia (PWH) have increased the possibilities for sports participation, but the risk of sports-induced bleeding (SIB) is still considered considerable by many. Aim: To assess sports associated injury- and bleeding risk in PWH and to assess clotting levels associated with safe sports participation. Methods: Sports injuries and SIBs were prospectively collected for 12 months in PWH aged 6–49 without inhibitors playing sports at least once weekly. Injuries were compared according to factor levels, severity, joint health, sports risk category and sports intensity. Factor activity at the time of injury was estimated using a pharmacokinetic model. Results: 125 participants aged 6–49 (41 children, 90% haemophilia A; 48% severe, 95% severe on prophylaxis) were included. Sports injuries were reported by 51 participants (41%). Most participants (62%) reported no bleeds at all and only 16% reported SIBs. SIBs were associated with factor levels at time of injury (OR: 0.93/%factor level (CI 0.88–0.99); p =.02), but not with haemophilia severity (OR: 0.62 (CI 0.20–1.89); p =.40), joint health, sports risk category or sports intensity. PWH with factor levels <10% during sports injury had a bleeding risk of 41% versus 20% in those with higher (>10%) factor levels. Conclusion: The results of this study emphasize the importance of clotting factor levels in prevention of bleeds. This information is vital for patient counselling and tailoring prophylactic treatment with clotting factors and non-replacement therapy.
NEW GRAPHICAL METHOD TO QUANTIFY INHIBITORS IN HEMOPHILIA
Martínez De La Puente Molina E., Jiménez Ventura I., Bóveda Uribe O., Peña Pérez I., Rubio Ollo I., Conde Rubio P.
Clinical Chemistry and Laboratory Medicine 2023 61 Supplement 1 (S215)
Go to publisher for the full text
Abstract
BACKGROUND-AIM Clotting factor inhibitors represent a significant management challenge for people with hemophilia. It is possible to find them as a consequence of treatment or in acquired hemophilia. Typically, they are antibodies against VIII factor (FVIII) or rarely against IX factor (FIX). METHODS Inhibitors are detected and quantified in the laboratory by the functional Bethesda assay, introduced in 1975, which relies on titration to measure them. In this assay, pooled normal plasma (PN), as the source of FVIII or FIX, is added to an equal amount of patient plasma (PP), which may contain the inhibitor. Serial dilutions of the PP (1/2, 1/4, 1/8.) are incubated at 37°C for 2 hours along with PN, control and a blank. One Bethesda Unit (BU) is defined as the amount of inhibitor that neutralizes 50% of the FVIII or FIX activity in the PN sample after incubation. RESULTS We propose a new graphical method to assess the inhibitor concentration by plotting two lines: 1. We represent the residual factor (%) in the Y axis and dilutions of PP in the X axis according to this formula: -log2(1/x) 2. We also represent the 50% of the factor activity in the PN as a horizontal line. We have created an Excel template for this matter. CONCLUSIONS The interpretation of the plot is the following: -If there is no inhibitor present in the sample, both lines should never cross. -If there is an inhibitor, the lines would cross. The intersection point shows the concentration of inhibitor that neutralizes 50% of the FVIII or IX factor. This representation may improve the selection of the point nearer to the 50% of inhibition, required for the calculation of the BU, in a more visual way. Besides, in our plot it is possible to extrapolate the cross point more accurately. This new graphical method has also helped us evaluate the presence of rare inhibitors with unusual kinetic and has been helpful for detection of strong inhibitors with high titration point.
Schutgens R.E.G., Jimenez-Yuste V., Escobar M., Falanga A., Gigante B., Klamroth R., Lassila R., Leebeek F.W.G., Makris M., Owaidah T., Sholzberg M., Tiede A., Werring D.J., Van Der Worp H.B., Windyga J., Castaman G.
[In Process] HemaSphere 2023 7:6 (E900)
Go to publisher for the full text
Abstract
Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.
Haemophilia and Fragility Fractures: From Pathogenesis to Multidisciplinary Approach
Alito A., Bellone F., Portaro S., Leonardi G., Cannavò V., Coppini F., Leonetti D., Catalano A., Squadrito G., Fenga D.
[In Process] International Journal of Molecular Sciences 2023 24:11 Article Number 9395
Go to publisher for the full text
Abstract
Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.
Arvanitakis A., Holme P.A., Berntorp E., Astermark J.
[Article in Press] Haemophilia 2023
Go to publisher for the full text
Abstract
Introduction: The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). Aim: To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). Methods: Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. Results: The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p <.001), EQ-5D-5L index (0.9647 vs. 0.904, p =.022), EQ VAS (87 vs. 75, p =.01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p =.02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS. Conclusion: Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.
[Article in Press] Expert Review of Hematology 2023
Go to publisher for the full text
Cuesta-Barriuso R., Pérez-Llanes R., Donoso-Úbeda E., Ucero-Lozano R.
Haemophilia 2022 28:5 (857-864)
Go to publisher for the full text
Abstract
Background: Prophylactic treatment is the gold standard in the treatment of patients with haemophilia. Prophylaxis with extended half-life (EHL) treatment has shown long-term safety and efficacy in patients with haemophilia. Aim: To evaluate the efficacy of prophylaxis with EHL treatment in the frequency of haemarthrosis and musculoskeletal health in adult patients with severe haemophilia A. Methods: Prospective cohort study. Forty-six patients with severe haemophilia A were recruited. The frequency of haemarthrosis (self-reports), joint condition (Haemophilia Joint Health Score), pain intensity (visual analogue scale), range of motion (goniometry), and strength (dynamometry) and muscle activation (surface electromyography) were evaluated. Three assessments were carried out: at baseline (T0), at 6 months (T1) and at 12 months following treatment (T2). Results: There were significant changes in the within-subject effect in the frequency of haemarthrosis in elbow (F(1.05;96.20) = 3.95; P <.001) and knee (F(1.73;157.99) = 9.96; P <.001). Significant within-subject effect in elbow pain intensity (F(2;182) = 63.51; P <.001) was found. The mean values of the frequency haemarthrosis in elbow (from.66±1.01 to.04±.20) and knees (from.55±.68 to.33±.53) decrease after the period study. The intensity of elbow pain and (from 3.08±1.69 to 2.67±1.73), decrease after the 12-month follow-up period. Conclusions: Prophylaxis with extended half-life treatment reduces the frequency of haemarthrosis in elbow and knee in adult patients with haemophilia. EHL treatment reduces the intensity of elbow pain in patients with haemophilic arthropathy.
The bleeding phenotype in people with nonsevere hemophilia
Kloosterman F.R., Zwagemaker A.-F., Bagot C.N., Beckers E.A.M., Castaman G., Cnossen M.H., Collins P.W., Hay C., Hof M., Gorkom B.L.-V., Leebeek F.W.G., Male C., Meijer K., Pabinger I., Shapiro S., Coppens M., Fijnvandraat K., Gouw S.C., Fijnvandraat K., Coppens M., Gouw S.C., Leebeek F.W.G., Kruip M., Cnossen M.H., Meijer K., Eikenboom J., Smiers F.J.W., Beckers E.A.M., Nieuwenhuizen L., Brons P., Gorkom B.L.-V., Collins P., Bagot C.N., Hay C., Shapiro S., Boyce S., Male C., Pabinger I., Jackson S.
Blood Advances 2022 6:14 (4256-4265)
Go to publisher for the full text
Abstract
Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed.
The Bone Microarchitecture Deficit in Patients with Hemophilia Is Influenced by Arthropathy, Hepatitis C Infection, and Physical Activity
Holstein K., Witt L., Matysiak A., Schmidt C., Barvencik F., Amling M., Rolvien T., Langer F.
Thrombosis and Haemostasis 2022 122:5 (692-702)
Go to publisher for the full text
Abstract
Low bone mineral density (BMD) is common in patients with hemophilia (PWHs). The aim of the present study was to describe BMD and microarchitecture in PWHs in Northern Germany and to determine factors contributing to possible skeletal alterations. Demographic characteristics, BMD and microarchitecture, bone metabolism markers, and orthopaedic joint score (OJS) were assessed during routine check-ups. Areal BMD was assessed by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine. Volumetric BMD and microarchitecture were quantified by high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Eighty male PWHs (median age, 33 years; range, 18-77) were retrospectively analyzed, of whom 67 (84.0%) and 13 (16.0%) had hemophilia A and B, respectively. Fifty-four (68.0%), six (7.0%), and 20 (25.0%) patients had severe, moderate, or mild hemophilia, and 35 (44.0%) were hepatitis C virus (HCV) positive. DXA analysis revealed low BMD (Z-score ≤ - 2.0) in 27.5% of PWHs, and higher bone turnover values were associated with lower BMD. Bone microarchitecture was dominated by cortical deficits at the radius and trabecular deficits at the tibia. Cortical deficits at the radius were influenced by lower body mass index, low-grade inflammation, and treatment regimen (higher cortical thickness on primary prophylaxis). Trabecular alterations at the tibia were mainly associated with OJS and HCV status. A positive effect of self-reported sportive activity on BMD could be shown. In conclusion, our findings demonstrate that the site-specific microarchitectural deficit observed in PWHs is primarily negatively influenced by poor joint status, inflammation, HCV infection, and high bone turnover.
Optimizing factor VIII dosing in obese individuals with haemophilia A
Godby R.C., Raju D., Massicano F., Williams L.A., Black B., Dorn D., Marques M.B.
[In Process] Blood Coagulation and Fibrinolysis 2021 32:7 (528-530)
Go to publisher for the full text
Calatayud J., Ogrezeanu D.C., Carrasco J.J., Martinez-Valdes E., Pérez-Alenda S., Cruz-Montecinos C., Andersen L.L., Aagaard P., Suso-Martí L., Casaña J.
European Journal of Haematology 2023 111:1 (47-56)
Go to publisher for the full text
Abstract
Objective: To compare the safety, feasibility, and neuromuscular activity of acute low-load resistance exercise with/without blood flow restriction (BFR) in people with severe hemophilia (PwH). Methods: Eight PwH under prophylaxis (5 with resistance training experience) performed 6 randomly ordered conditions of 3 intensity-matched knee extensions: no external load and no BFR, no external load and light BFR (20% of arterial occlusion pressure [AOP]), no external load and moderate BFR (40% AOP), external low load and no BFR, external low load with light BFR, and external low load with moderate BFR. Rated perceived exertion, pain, exercise tolerability, and adverse effects were assessed. Normalized root-mean-square (nRMS), nRMS spatial distribution, and muscle fiber-conduction velocity (MFCV) were determined using high-density surface electromyography for the vastus medialis and lateralis. Results: Exercises were tolerated, without pain increases or adverse events. Externally resisted conditions with/without BFR provided greater nRMS than nonexternally resisted conditions (p < 0.05). Spatial distribution and MFCV did not vary between conditions. Conclusions: In these patients, knee extensions with low external resistance and BFR at 20% or 40% AOP appear safe, feasible and do not cause acute/delayed pain. However, BFR during three consecutive repetitions does not increase nRMS nor changes nRMS spatial distribution or MFCV.
Time to revisit the classification of hemophilia: if it ain't broke, don't fix it!
Young G., Makris M.
Journal of Thrombosis and Haemostasis 2023 21:7 (1755-1756)
Go to publisher for the full text
Hemophilia Gene Therapy: First, Do No Harm
Valentino L.A., Kaczmarek R., Pierce G.F., Noone D., O'Mahony B., Page D., Rotellini D., Skinner M.W.
[Article in Press] Journal of thrombosis and haemostasis : JTH 2023
Go to publisher for the full text
Abstract
The introduction of AAV-mediated, liver directed gene therapy into the hemophilia treatment landscape brings great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of the human immunodeficiency virus and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past five decades, considerable advances in hemophilia treatment have improved the survival, quality of life and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic and shared decision-making approach must be employed. Bias on the part of healthcare professionals and people with hemophilia must be addressed and minimized. Here, we review the data leading to the regulatory authorization in Europe of valoctocogene roxaparvovec, an adeno-associated virus (AAV)-5 gene therapy to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.