Outcome measures in Haemophilia: Beyond ABR (Annualized Bleeding Rate) Manco‐Johnson, Marilyn J.; Warren, Beth Boulden; Buckner, Tyler W. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
February 2021, 2021-Feb, 2021-02-00, 20210201, Letnik:
27, Številka:
S3
Journal Article
Recenzirano
Odprti dostop
Options for management of haemophilia are increasing rapidly with completely novel therapeutic approaches that cannot be compared using traditional factor assays. In addition, as prophylaxis regimens ...have improved, bleeding rates have decreased, and consequently, it is difficult to show an impact of novel therapies on rates of spontaneous bleeding. There is currently an urgent need for a panel of outcome measures to compare therapies that are dissimilar in many essential ways. Conventional objective outcome measures including joint physical examination and joint imaging continue to hold a central importance. Factor assays are essential for evaluation of products derived from native factor genes, but are not applicable to some extended half‐life factors or non‐factor bypassing agents. Global assays including thrombin generation and chromogenic assays of factor X activation are under investigation for their usefulness in haemophilia assessment. Bleeding rate is a conventional subjective patient‐reported outcome that, while decreasing in frequency, is indispensable as an outcome given that the primary manifestation of haemophilia is bleeding. Other patient‐reported outcomes such as pain intensity and interference, health‐related quality of life and activities and participation are increasingly important to distinguish superior outcomes in comparative trials. This review of outcome measures for haemophilia presents examples of existing outcome measures with an emphasis on their strengths and limitations.
This analysis of the US Hemophilia Treatment Center Network and the Centers for Disease Control and Prevention surveillance registry assessed trends in prophylaxis use and its impact on key ...indicators of arthropathy across the life-span among participants with severe hemophilia A. Data on demographics, clinical characteristics, and outcomes were collected prospectively between 1999 and 2010 at annual clinical visits to 134 hemophilia treatment centers. Trends in treatment and outcomes were evaluated using cross-sectional and longitudinal analyses. Data analyzed included 26 614 visits for 6196 males; mean age at first registry visit was 17.7 years; and median was 14 (range, 2 to 69). During this time, prophylaxis use increased from 31% to 59% overall, and by 2010, 75% of children and youths <20 years were on prophylaxis. On cross-sectional analysis, bleeding rates decreased dramatically for the entire population (P < .001) in parallel with increased prophylaxis usage, possibly because frequent bleeders adopted prophylaxis. Joint bleeding decreased proportionately with prophylaxis (22%) and nonprophylaxis (23%), and target joints decreased more with prophylaxis (80% vs 61%). Joint, total, and target joint bleeding on prophylaxis were 33%, 41%, and 27%, respectively, compared with nonprophylaxis. On longitudinal analysis of individuals over time, prophylaxis predicted decreased bleeding at any age (P < .001), but only prophylaxis initiation prior to age 4 years and nonobesity predicted preservation of joint motion (P < .001 for each). Using a national registry, care providers in a specialized health care network for a rare disorder were able to detect and track trends in outcomes over time.
•Bleeding in US hemophilia patients has decreased dramatically in parallel with increased use of prophylaxis.•Only prophylaxis started before age 4 years preserves normal joint function.
Background
The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown.
Objective
To use a ...previously validated mathematical model of flow‐mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency.
Methods
We performed a global sensitivity analysis (GSA) on our mathematical model to identify potential modifiers of thrombin generation. Candidates from the GSA were confirmed by calibrated automated thrombography (CAT) and flow assays on collagen‐tissue factor (TF) surfaces at a shear rate of 100 per second.
Results
Simulations identified low‐normal factor V (FV) (50%) as the strongest modifier, with additional thrombin enhancement when combined with high‐normal prothrombin (150%). Low‐normal FV levels or partial FV inhibition (60% activity) augmented thrombin generation in FVIII‐inhibited or FVIII‐deficient plasma in CAT. Partial FV inhibition (60%) boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies. These effects were amplified by high‐normal prothrombin levels in both experimental models.
Conclusions
These results show that low‐normal FV levels can enhance thrombin generation in hemophilia A. Further explorations with the mathematical model suggest a potential mechanism: lowering FV reduces competition between FV and FVIII for factor Xa (FXa) on activated platelet surfaces (APS), which enhances FVIII activation and rescues thrombin generation in FVIII‐deficient blood.
Objective
Repeated hemarthrosis in hemophilia causes arthropathy with pain and dysfunction. The Hemophilia Joint Health Score (HJHS) was developed to be more sensitive for detecting arthropathy than ...the World Federation of Hemophilia (WFH) physical examination scale, especially for children and those using factor prophylaxis. The HJHS has been shown to be highly reliable. We compared its validity and sensitivity to the WFH scale.
Methods
We studied 226 boys with mild, moderate, and severe hemophilia at 5 centers. The HJHS was scored by trained physiotherapists. Study physicians at each site blindly determined individual and total joint scores using a series of visual analog scales.
Results
The mean age was 10.8 years. Sixty‐eight percent were severe (93% of whom were treated with prophylaxis), 15% were moderate (24% treated with prophylaxis), and 17% were mild (3% treated with prophylaxis). The HJHS correlated moderately with the physician total joint score (rs = 0.42, P < 0.0001) and with overall arthropathy impact (rs = 0.42, P < 0.0001). The HJHS was 97% more efficient than the WFH at differentiating severe from mild and moderate hemophilia. The HJHS was 74% more efficient than the WFH at differentiating subjects treated with prophylaxis from those treated on demand. We identified items on the HJHS that may be redundant or rarely endorsed and could be removed from future versions.
Conclusion
Both the HJHS and WFH showed evidence of strong construct validity. The HJHS is somewhat more sensitive for mild arthropathy; its use should be considered for studies of children receiving prophylaxis.
The hemostasis system is composed of procoagulant, anticoagulant, and fibrinolytic proteins that interact with endothelial and blood cells and with each other in a complex system of checks and ...balances to maintain blood flow while preventing both hemorrhage and thrombosis. Pregnancy is a unique physiological state in which biological alterations predispose both mother and fetus to both bleeding and clotting. The placenta is a vascular interface for maternal and fetal blood exchange which predisposes the mother to hemorrhage. Maternal hemostasis presents a compensatory hypercoagulability including elevated factor VIII, von Willebrand factor, fibrinogen and thrombin generation, decreased thrombin regulation with resistance to activated protein C and decreased free protein S, and decreased fibrinolysis with increased plasminogen activator inhibitors. The placental vascular surface is of fetal trophoblastic origin that derives many characteristics of endothelium but differs in that tissue factor is constitutively expressed. Ontogeny of fetal hemostasis is characteristic. Platelets, von Willebrand factor, factor VIII, and fibrinogen are expressed and mature early in gestation, while vitamin K-dependent and contact factors exhibit delayed development. The fetal hemostatic system has a decreased capacity to generate or regulate thrombin, resulting in a fragile balance with little capacity to compensate under stress conditions, particularly in the infant born prematurely. Dysfunction of the maternal/placental/fetal unit gives rise to gestational disorders including preeclampsia, fetal growth restriction, placental abruption, and premature delivery. Knowledge of normal hemostasis levels and function are critical to evaluate bleeding or clotting syndromes in the pregnant woman and her fetus or newborn infant.
Background
The Colorado Adult Joint Assessment Scale (CAJAS) is designed to assess joint health in adults with hemophilia. The CAJAS comprises nine items (swelling, muscle atrophy, axial deformity, ...crepitus, range of motion, contracture, instability, strength, gait) and assesses six joints.
Objective
To assess CAJAS content validity and psychometric properties.
Patients/Methods
Data were obtained from the Trial to Evaluate the Effect of Secondary Prophylaxis With rFVIII Therapy in Severe Hemophilia A Adult and/or Adolescent Subjects Compared to That of Episodic Treatment (SPINART) study and a separate CAJAS validation study. CAJAS assessments in SPINART were performed by physical therapists (PTs) from the United States, Romania, Bulgaria, and Argentina. In the validation study, content validity was assessed from interviews with six PTs at three US hemophilia centers; cultural equivalence was assessed with seven non‐US PTs from SPINART. Reliability data were collected from 30 subjects at four US centers. Test‐retest reliability was evaluated by having the same PT perform CAJAS examinations at two visits, 7‐10 days apart. Inter‐rater reliability was assessed by comparing CAJAS scores of two different PTs performing separate examinations of the same patient several hours apart at the same visit. Psychometric properties were assessed using SPINART and validation study data.
Results
The CAJAS demonstrated good content validity. Test‐retest reliability was high (intraclass correlation coefficient, 0.98), as was inter‐rater reliability (intraclass correlation coefficient, 0.88). Internal consistency reliability was strong (α = .90). The CAJAS demonstrated good convergent/divergent validity, known‐groups validity, and ability to detect change.
Conclusions
The CAJAS is a valid and reliable measure of joint health in adults with moderate‐severe hemophilia and is appropriate for use in clinical practice.
This randomized trial involving young boys with severe hemophilia showed that prophylaxis with regular infusions of recombinant factor VIII was associated with clinically and statistically ...significant reductions in joint damage, as compared with episodic infusions at the time of a clinically evident hemarthrosis. Because of the high cost of recombinant factor VIII, its widespread use for prophylaxis may be impractical.
Prophylaxis with regular infusions of recombinant factor VIII was associated with clinically and statistically significant reductions in joint damage, as compared with episodic infusions.
Before the development of cryoprecipitate, a plasma fraction that contains concentrated factor VIII, boys with severe hemophilia A had a diminished life expectancy.
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These children are at risk for many types of hemorrhages, but the predominant source of chronic coexisting disease is crippling, painful arthritis due to hemarthrosis.
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Small trials were conducted in the 1960s to determine whether routine administration of factor VIII concentrate was effective as prophylaxis against hemophilic arthropathy.
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Clinically effective prophylactic schedules were developed empirically, without the benefit of data from controlled trials,
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and many clinicians began to recommend prophylaxis with factor VIII.
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In the . . .
Post-thrombotic syndrome is a manifestation of chronic venous insufficiency following deep venous thrombosis. This systematic review was conducted to critically evaluate pediatric evidence on ...frequency of occurrence, validity of outcome measures, and prognostic indicators of post-thrombotic syndrome.
A comprehensive literature search of original reports revealed 19 eligible studies, totaling 977 patients with upper/lower extremity deep venous thrombosis. Calculated weighted mean frequency of post-thrombotic syndrome was 26% (95% confidence interval: 23-28%) overall, and differed significantly by prospective/non-prospective analysis and use/non-use of a standardized outcome measure.
Standardized post-thrombotic syndrome outcome measures included an adaptation of the Villalta scale, the Clinical-Etiologic-Anatomic-Pathologic classification, and the Manco-Johnson instrument. Data on validity were reported only for the Manco-Johnson instrument. No publications on post-thrombotic syndrome-related quality of life outcomes were identified. Candidate prognostic factors for post-thrombotic syndrome in prospective studies included use/non-use of thrombolysis and plasma levels of factor VIII activity and D-dimer.
Given that affected children must endure chronic sequelae for many decades, it is imperative that future collaborative pediatric prospective cohort studies and trials assess as key objectives and outcomes the incidence, severity, prognostic indicators, and health impact of post-thrombotic syndrome, using validated measures.
The incidence of pediatric venous thromboembolic disease is increasing in hospitalized children. While the mainstay of treatment of pediatric thrombosis is anticoagulation, reports on the use of ...systemic thrombolysis, endovascular thrombolysis, and mechanical thrombectomy have steadily been increasing in this population. Thrombolysis is indicated in the setting of life- or limb-threatening thrombosis. Thrombolysis can rapidly improve venous patency thereby quickly ameliorating acute signs and symptoms of thrombosis and may improve long-term outcomes such as postthrombotic syndrome. Systemic and endovascular thrombolysis can result in an increase in minor bleeding in pediatric patients, compared with anticoagulation alone, and major bleeding events are a continued concern. Also, endovascular treatment is invasive and requires technical expertise by interventional radiology or vascular surgery, and such expertise may be lacking at many pediatric centers. The goal of this mini-review is to summarize the current state of knowledge of thrombolysis/thrombectomy techniques, benefits, and challenges in pediatric thrombosis.
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