Evolving evidence in the treatment of primary and recurrent posterior cruciate ligament injuries, part 1: anatomy, biomechanics and diagnostics.

The posterior cruciate ligament (PCL) represents an intra-articular structure composed of two distinct bundles. Considering the anterior and posterior meniscofemoral ligaments, a total of four ligamentous fibre bundles of the posterior knee complex act synergistically to restrain posterior and rotatory tibial loads. Injury mechanisms associated with high-energy trauma and accompanying injury patterns may complicate the diagnostic evaluation and accuracy. Therefore, a thorough and systematic diagnostic workup is necessary to assess the severity of the PCL injury and to initiate an appropriate treatment approach. Since structural damage to the PCL occurs in more than one third of trauma patients experiencing acute knee injury with hemarthrosis, background knowledge for management of PCL injuries is important. In Part 1 of the evidence-based update on management of primary and recurrent PCL injuries, the anatomical, biomechanical, and diagnostic principles are presented. This paper aims to convey the anatomical and biomechanical knowledge needed for accurate diagnosis to facilitate subsequent decision-making in the treatment of PCL injuries.Level of evidence V.

Assessments of pain, functional impairment, anxiety, and depression in US adults with hemophilia across patient-reported outcome instruments in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study.

INTRODUCTION: Pain, functional impairment, anxiety, and depression associated with joint disease may affect health-related quality of life (HRQoL) in people with hemophilia. OBJECTIVE: To report detailed patient-reported outcomes (PRO) assessments related to HRQoL in participants in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. METHODS: Pain and HRQoL were assessed via PRO instruments in US adult males with hemophilia A or B and a history of joint pain or bleeding. PRO instruments included EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form, SF-36v2, and Hemophilia Activities List. Instrument domain and item responses were described. RESULTS: Responses were collected from 381 adult males with a median age of 34 years. Pain was observed across instruments and affected daily activities and quality of life. Respondents reported functional impairment that limited the kind of work and activities they participated in, with activities involving the lower extremities being most affected. A high prevalence of mental health disorders was identified across instruments. CONCLUSIONS: Pain and HRQoL were evaluated using multiple PRO instruments, which vary in timescales of assessment and levels of detail. More consistent clinical assessments and patient dialog regarding pain and aspects of HRQoL may help drive improved outcomes.

What can we learn from using formal patient-reported outcome instruments to assess pain, functional impairment, anxiety, and depression in US adults with hemophilia?

People with hemophilia frequently suffer from arthropathy that leads to pain and functional impairment, ultimately resulting in reduced quality of life. The impact of pain and functional impairment on the lives of people with hemophilia was explored in the Pain, Functional Impairment, and Quality of Life (P-FiQ) study. Various patient-reported outcome (PRO) instruments were employed to assess the effect of pain and functional impairment on multiple aspects of health in people with hemophilia. The results presented in this supplement include detailed observations from PRO instruments regarding pain, functional impairment, anxiety, and depression, an analysis of the differences in health-related quality of life across subgroups of patients defined by demographic and treatment-related characteristics, and results of a modeling analysis to identify patient factors which influence perceptions of pain and functional impairment, independent of joint status. These data provide insights into how the results from PRO assessments may be used to evaluate outcomes for people with hemophilia in the clinical and research settings.

Prevalence and severity by age and other clinical correlates of haemophilic arthropathy of the elbow, knee and ankle among Taiwanese patients with haemophilia.

INTRODUCTION & AIMS: Haemophilic arthropathy (HA) is a major complication in patients with haemophilia (PWH), but the study of age-specific prevalence and severity of HA is very limited in Asian countries. MATERIALS & METHODS: This study retrospectively reviewed 146 severe- and moderate-type Taiwanese PWH aged 4-73 years, with roentgenograms of elbows, knees and ankles and calculated Pettersson scores. RESULTS: The prevalence of HA, mean number of HAs per patient and mean Pettersson scores of all the joints were 42.8%, 1.3 and 1.9 points in PWH aged 4-10 years; 64.3%, 1.4 and 4.1 points in PWH aged 11-19 years; 97.1%, 2.9 and 15.6 points in PWH aged 20-29 years; 93.1%, 4.4 and 33.1 points in PWH aged 30-39 years; 100%, 5.1 and 46.1 points in PWH aged 40-49 years and 100%, 5 and 49.6 points in PWH aged ≥50 years, respectively. There was a high prevalence of HA for PWH aged ≥20 years. Among PWH aged <20 years, prevalence of HA was low and mild ankle arthropathy was the most common. Besides, in the four age groups aged <40 years, the prevalence of ankle arthropathy was the highest, followed by elbow arthropathy and then knee arthropathy. CONCLUSIONS: Although severe arthropathy of the six major joints was rare in PWH aged <30 years, it increased rapidly in PWH after 30 years. Analysis of clinical correlates suggested that age, severity of haemophilia, absence of prophylaxis and presence of HCV infection correlated positively with Pettersson scores.

The impact of joint range of motion limitations on health-related quality of life in patients with haemophilia A: a prospective study.

In patients with haemophilia A, repeated occurrences of haemarthrosis and synovitis lead to limitations in range of motion (ROM) of major joints. However, the effect of limitations in joint ROM on health-related quality of life (HRQOL) in these patients has not been studied previously. The aim of this study was to assess the impact of ROM limitations of 10 major joints (bilateral shoulders, elbows, hips, knees and ankles), combined with other possibly influential factors, on HRQOL in patients with haemophilia A. The ROM limitations in 13 movements and pain intensity of the 10 major joints were measured. The socio-demographic and clinical data were recorded. Short-Form 36 was used as the HRQOL measurement. Eighteen patients (mean age: 36.9 years) were included. Hip ROM limitations, knee ROM limitations and hip pain intensity predicted physical functioning scale (P < 0.001; adjusted R2 = 0.553). Shoulder ROM limitations and age predicted role limitation were due to emotional problems scale (P < 0.001; adjusted R2 = 0.373). Elbow ROM limitations and haemophilia severity predicted mental health scale (P = 0.001; adjusted R2 = 0.320). Hip ROM limitations predicted social functioning scale (P = 0.041; adjusted R2 = 0.091). Educational level and elbow ROM limitations predicted vitality scale (P < 0.001; adjusted R2 = 0.416). The ROM limitations of hip, knee, shoulder and elbow could be predictors for HRQOL in patients with haemophilia A. Improving ROM of major joints could be an appropriate treatment strategy to enhance HRQOL in these patients.

Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study.

BACKGROUND: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. OBJECTIVES: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. METHODS: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. RESULTS: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB. CONCLUSION: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage.

Magnetic resonance imaging features of hip disorders in an Egyptian pediatric population.

Hip disorders in a pediatric population are a diagnostic challenge. The aim of the study is to assess the role of magnetic resonance imaging (MRI) in the evaluation of non-traumatic hip disorders in a series of Egyptian patients and to review the literature on the most common hip conditions. Seventy two consecutive patients [40 males (55.6%) and 32 females (44.4)] with acute onset of hip complaints unrelated to trauma or falls were recruited. All patients underwent an initial full clinical assessment and blood tests as well as contrast enhanced MRI of both hips. The most common diagnosis in this group of Egyptian patients was transient synovitis in 29 (40.3%) cases, followed by seronegative enthesopathy and arthropathy syndrome in 8 (11.1%), septic arthritis in 10 (13.9%), tuberculous arthritis in 4 (5.6%), sickle-cell disease in 7 (9.7%), complicated with septic arthritis in 3 (4.2%), transient bone marrow edema (BME) in 3 (4.2%), osteomyelitis in 2 (2.8%), osteosarcoma in 2 (2.8%), sciatic nerve injury in 1 (1.4%), leukemia with BME in 1 (1.4%), coxa vara of both hips and L5/S1 facet joint ankylosis in 1 (1.4%), and a benign bone cyst in 1 (1.4%). MRI studies showed hip effusion in a total of 51 patients (70.8%), joint space narrowing in 9 (12.5%), and BME in 15(20.8%). MRI is a sensitive tool for assessing hip disorders in a pediatric population and can play an important role in both diagnosis and management of different hip disorders, irrespective of the underlying pathology.

Secondary prophylaxis vs. on-demand treatment to improve quality of life in severe adult haemophilia A patients: a prospective study in a single centre.

BACKGROUND: Retrospective publications show a decrease in the bleeding frequency and an improvement in the quality of life (QoL) in severe adult haemophilia A (SAHA) after switching from the on-demand treatment (DT) to secondary prophylaxis (SP). But there are no prospective studies which demonstrate, using a haemophilia-specific questionnaire, an improvement in the QoL after such treatment change. The main objective of this study is to prospectively compare the QoL and the musculoskeletal assessment after switching from DT to SP in SAHA using the A36 Hemofilia-QoL(®) . As secondary objective, we compare the haemarthrosis frequency and factor VIII consumption in DT and SP during a similar period of time (12 months) after switching. MATERIALS AND METHODS: We have designed a prospective study including SAHA who have been under DT and were changed to a protocol, which combines SP (biweekly administration of factor VIII) with individualized physiotherapy programme. RESULTS: Twelve months after switching to SP, the QoL was significantly improved (P = 0·005). Musculoskeletal assessment of pathologic irreversible joints and joints with a reversible alteration was generally improved, although in only a few joints, this improvement was statistically significant. Haemarthrosis was strongly reduced (12·60-1·42, P < 0·001). CONCLUSIONS: This prospective study has demonstrated a statistically significant improvement in the QoL after 1 year from switching patients from DT to SP. The musculoskeletal assessment after 1 year was maintained similar or slightly improved. When we compared retrospective DT and prospective SP, haemarthrosis where strongly reduced requiring a slight increase in the consumption of factor VIII concentrates.

[Radiodiagnosis and knee joint replacement in hemophilic arthropathies in Kazakhstan residents].

AIM: To assess complex radiodiagnosis and highly specialized medical care as knee joint replacement (KJR) to patients with hemophilic arthropathies (HA) who live in the Republic of Kazakhstan. SUBJECTS AND METHODS: The results of examination and treatment were analyzed in 40 patients with knee HA who were treated at the specialized Polytrauma Unit, Republican Research Center for Emergency Health Care. All patients with hemophilia A underwent joint X-ray study, computed tomography and magnetic resonance imaging (MRI), X-ray densitometry and ultrasound osteometry on admission and after KJR. RESULTS: Joint X-ray studies and computed tomography revealed that all the patients had Grades II-III arthroses with severe dysfunction of joints, their multiple involvements of different grades, which depended on the rate of recurrent hemarthrosis. Ultrasound study (USS) is the only mini-invasive method to control surgical hemostasis in hemophiliac patients after KJR. Osteodensitometry revealed osteopenia and osteoporosis in all the patients with hemophilia, which was a basis for prescribing calcium preparations in the early postoperative period for the prevention of instability of endoprosthetic components. We elaborated an algorithm for combination treatment in HA patients, which involved knee joint replacement. CONCLUSION: Highly specialized medical care to hemophilic patients and active introduction of the early surgical rehabilitation of the affected joint in their combination treatment contributed to the increased number of positive results, by restoring the quality of life in the patients: excellent, good, and satisfactory anatomic and functional results were obtained in 26.7, 51.1, and 22.2%, respectively. USS and MRI could evaluate joint changes in HA in detail, which plays an important role in the estimation of the course time of the disease, in the planning of endoprosthetic replacement, and in the timely prevention of severe complications of HA. Osteodensitometry makes it possible to monitor bone mineral density around the prosthesis and to postoperatively prevent endoprosthetic instability.

The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia.

This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two-hundred and eighty-six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrollment, free of TJs at enrollment, developed at least one TJ after enrollment, and received either prophylaxis or episodic treatment continuously for two follow-up visits after TJ development. The outcomes of interest - percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0.01); there was no difference in the decrease in TJ ROM between the two groups (P = 0.9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development.

Is on-demand treatment effective in patients with severe haemophilia?

On-demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on-demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on-demand and short-term prophylaxis regimen; the rest was under on-demand treatment. One hundred and forty-five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy-one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty-three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty-six patients underwent orthopaedic surgery at least once. These data show that on-demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary.

Total knee arthroplasty in a patient with hemophilic arthropathy and high-titer inhibitors: a cost analysis.

A patient with hemophilia A, who developed factor VIII inhibitors and initially had funding for his total knee arthroplasty declined, is discussed. A total of £1 542 000 (US $2 474 603) was spent on medical treatment for recurrent hemarthroses over a 4-year period, while funding was sought. In comparison, the total cost for his knee arthroplasty was £542 858 (US $871 084) including perioperative recombinant clotting factors. Postoperatively, with 1-year follow-up, no further hemoarthroses have occurred; his analgesic requirement is significantly reduced; he has a much improved level of function; and treatment costs are significantly reduced, leading to a substantial overall saving. Our findings suggest that surgical treatment is beneficial and cost-effective for patients with hemophilia with inhibitors. Hospitals should not deny operative treatment based on cost alone.

Arthropathy in people with mild haemophilia: Exploring risk factors.

BACKGROUND: It is important to investigate which factors are associated with the development of arthropathy in people with mild haemophilia (PWMH), in order to prevent it and to limit its effect on function and quality of life. PURPOSE: To examine the risk factors associated with arthropathy and to predict its presence and degree of involvement in our PWMH population. METHODS: This was an observational, cross-sectional cohort study of 85 PWMH under follow-up in our centre. Patient variables (age, body mass index, haemophilia type, genetic mutations, baseline factor levels, age at diagnosis, history of inhibitor, level of physical activity and years of practice, history of haemarthrosis and muscle haematoma) were analysed and related to the presence or absence of arthropathy and the degree of arthropathy (measured with HJHS and HEAD-US). Multivariable models were performed. RESULTS: Some 36.5% of PWMH had arthropathy. The variables that showed an independent association with the presence of arthropathy were patient age (median 42 years) and clotting factor levels (median 10.5 IU/dL). The risk of developing arthropathy increased by 7.9% for each additional year of age and decreased by 7.7% for each 1 IU/dL increase in clotting factor. When arthropathy developed, its degree of involvement might have been influenced by the type of physical activity performed. CONCLUSIONS: Patient age and factor levels appear to be the most determinant risk factors associated with the development of arthropathy in mild haemophilia. Monitoring joint health is desirable in this patient population. In patients with arthropathy, physical activities with a low risk of bleeding are the most recommended.

Twelve-month prevalence of haemarthrosis and joint disease using the Haemophilia Joint Health score: evaluation of the UK National Haemophilia Database and Haemtrack patient reported data: an observational study.

OBJECTIVES: To report the 12-month prevalence of joint bleeds from the National Haemophilia Database (NHD) and Haemtrack, a patient-reported online treatment diary and concurrent joint disease status using the haemophilia joint health score (HJHS) at individual joint level, in children and adults with severe haemophilia A and B (HA/HB) without a current inhibitor. DESIGN: A 2018 retrospective database study of NHD from which 2238 cases were identified, 463 patients had fully itemised HJHS of whom 273 were compliant in recording treatment using Haemtrack. SETTING: England, Wales and Scotland, UK. PARTICIPANTS: Children (<18 years) and adults (≥18 years) with severe HA and HB (factor VIII/factor IX, <0.01 iu/mL) without a current inhibitor. PRIMARY AND SECONDARY OUTCOMES: Prevalence of joint haemarthrosis and concurrent joint health measured using the HJHS. RESULTS: The median (IQR) age of children was 10 (6-13) and adults 40 (29-50) years. Haemarthrosis prevalence in HA/HB children was 33% and 47%, respectively, and 60% and 42%, respectively, in adults. The most common site of haemarthrosis in children was the knee in HA and ankle in HB. In adults, the incidence of haemarthrosis at the ankles and elbows was equal. The median total HJHS in HA/HB children was 0 and in adults with HA/HB, were 18 and 11, respectively. In adults with HA/HB, the median ankle HJHS of 4.0 was higher than the median HJHS of 1.0 for both the knee and elbow. CONCLUSION: Despite therapeutic advances, only two-thirds of children and one-third of adults were bleed-free, even in a UK cohort selected for high compliance with prophylaxis. The median HJHS of zero in children suggests joint health is relatively unaffected during childhood. In adults, bleed rates were highest in ankles and elbows, but the ankles led to substantially worse joint health scores.

Joint status and related risk factors in patients with severe hemophilia A: a single-center cross-sectional study.

OBJECTIVES: Hemophilic arthropathy is the most common complication of severe hemophilia A. This study aims to investigated joint status and related risk factors in patients with severe hemophilia A (PWSHA). METHODS: This single-center study included 31 patients. Six index joints (both elbows, knees, and ankles) were evaluated using the Hemophilia Early Arthropathy Detection with UltraSound in China (HEAD-US-C) and Hemophilia Joint Health Score (HJHS). Treatment adherence was measured using the Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro). We analyzed the influence of age, treatment delay (the interval between diagnosis and the initiation of treatment), prophylaxis, and treatment adherence on joint outcomes. RESULTS: All patients were male (median age, 22 years). The median age at diagnosis was 1 year; that at initial treatment was 5 years. All patients experienced joint bleeding. HEAD-US-C and HJHS scores were positively correlated (R = 0.70, P < 0.0001). Median [range] HEAD-US-C and HJHS scores were 15 [0-36] and 32 [2-49], respectively. Age was positively correlated with both HEAD-US-C (P = 0.002) and HJHS scores (P < 0.0001). The difference of HEAD-US-C scores between groups with ≤1 year and >1 year treatment delay was close to significant (P = 0.055). HJHS scores were significantly different between these two groups (P = 0.03). Joint assessment scores were not significantly different between on-demand and low-dose prophylaxis groups. VERITAS-Pro scores were correlated with both HEAD-US-C and HJHS scores (P = 0.046 and P = 0.005, respectively). CONCLUSIONS: Hemophilic arthropathy was pervasive in PWSHA. Age and poor adherence were significantly correlated with joint damage. Prompt treatment and adherence improvement may reduce severity.

Clinical severity of haemophilia A: does the classification of the 1950s still stand?

The classification of haemophilia originates from 1950s and has been adopted unchallengedly by the ISTH in 2001. The aim of this study was: does the current classification compare onset of bleeding and age at first treatment, as well as annual joint bleeding frequency according to baseline FVIII activity? Data on age and reason of diagnosis, onset of treatment, onset of bleeding and bleeding frequency from 411 patients with haemophilia A born after 1970 were collected. Data were analysed according to base-line FVIII activity levels. Age at diagnosis, onset of bleeding and start of treatment according to FVIII activity were compared with the current classification. Overall, the distinction between severe and non-severe haemophilia was clear. The distinction between mild and moderate haemophilia was more difficult, mostly due to the wide variability in the group of patients with moderate haemophilia. Patients with severe haemophilia experienced their milestones like diagnosis, first treatment and joint bleed earliest, mostly as infants aged 0-3 years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2-7 years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5-14 years. This study confirms the clinical distinction between severe and non-severe haemophilia A. However, the group of moderate haemophilia patients showed a wide variability, warranting close follow-up and individualized treatment.

Assessment of musculoskeletal function and mood in haemophilia A adolescents: a cross-sectional study.

Haemophilia A is characterized by the occurrence of frequent spontaneous intra-articular and intramuscular bleeding. If inadequately treated, it results in progressive damage to joints and muscles leading to crippling deformities and musculoskeletal dysfunction. These complications result in lifelong chronic pain and disability that may greatly affect the patients' mood. We aimed to evaluate the musculoskeletal function in our haemophilia A patients and its correlation to depressed mood in these patients and determine the impact of degree of factor VIII deficiency, different replacement therapy regimens and frequency of hemarthrosis, on both musculoskeletal function and mood. A cross-sectional study was carried out on 50 adolescent haemophilia A patients. Musculoskeletal function was assessed using Functional Independence Score for Hemophilia (FISH) and mood status was assessed using Beck Depression Inventory-Short Form (BDI-SF). The mean FISH score was 23.32 ± 4.69 (range 13-28) and the tasks that obtained lower scores were step climbing, squatting and walking. Of our 50 patients included, 16(32%) were not depressed, 18(36%) were with mild depression, 11(22%) were with moderate depression and 5(10%) were with severe depression. There was a highly significant negative correlation between mean FISH score and mean BDI-SF score (P < 0.001). The better the replacement therapy regimen, the better the musculoskeletal function that could be obtained in haemophilia A patients and the better the mood.

Prophylaxis therapy in haemophilia A: current situation in Spain.

The Spanish Epidemiological Study in Haemophilia carried out in 2006 enrolled 2400 patients [2081-86.7% with haemophilia A (HA) and 319-13.3% with haemophilia B]; 465 of them (19.4%) were on prophylaxis. These rates were higher in patients with severe haemophilia (45.4%) and severe paediatric cases (72.5%). On the basis of information recorded in this study, we analysed the current situation of prophylaxis therapy administered to patients with HA in Spain, as well as their orthopaedic status. Prophylaxis was used in 399 (19.2%) patients with HA; such prophylaxis was primary (PP) in 20.3% and secondary (SP) in 75.9% of cases. Among severe HA patients, 313 (45.9%) were on prophylaxis (22.3% on PP and 74.7% on SP). Taking into account the patients' age, 34.7% of severe HA adults were on prophylaxis (6% PP and 92.1% SP), whereas 71.5% of severe HA paediatric patients (40.5% PP and 55.4% SP) received this kind of treatment. Established haemophilic arthropathy (EHA) was detected in 142 from 313 severe HA patients (45.3%) on prophylaxis, but only in 2.9% of patients under PP vs. 59% of patients receiving SP. There was no EHA in adult severe HA patient on PP, whereas 70.4% on SP had joint damage (P < 0.00001). Among paediatric severe HA patients, EHA was detected in 3.3% under PP and 37.8% under SP (P < 0.00001). In conclusion, our data suggest that an early initiation of prophylaxis avoids EHA in the long-term in patients with severe HA. We should emphasize the early onset of prophylaxis regimens.

Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels.

Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self-reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77-0.86] of bleeding frequency with every IU dL(-1) increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01-0.06 IU mL(-1)). The best way to analyse low frequency bleeding data is using a negative binomial distribution.