Traumatic bleeding and mortality in mice are intensified by iron deficiency anemia and can be rescued with tranexamic acid.

Background: Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes. Objectives: To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality. Methods: C57BL/6J mice received an iron-deficient diet (8 weeks; ±1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [F]II, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2-antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days. Results: Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with nonanemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice. Conclusion: These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA.

Prepartum Anemia and Risk of Postpartum Hemorrhage: A Meta-Analysis and Brief Review.

Postpartum hemorrhage (PPH) is responsible for 30% to 50% of maternal deaths. There is conflicting evidence if prepartum anemia facilitates PPH. A comprehensive analysis of studies describing their relation is missing. An extensive database search was conducted applying the terms "anemia" OR "hemoglobin" AND "postpartum hemorrhage." We used a random-effects meta-analysis model to estimate an overall odds ratio (OR) for PPH and prepartum anemia, separating studies that were conformant and non-conformant with the World Health Organization (WHO) definitions for anemia. The search yielded 2519 studies, and 46 were appropriate for analysis. The meta-analyses of WHO-conformant (n = 22) and non-conformant (n = 24) studies showed that the risk of PPH was increased when anemia was present. The ORs were 1.45 (CL: 1.23-1.71) for WHO-conformant studies, 2.88 (CL: 1.38-6.02) for studies applying lower thresholds for anemia, and 3.28 (CL: 2.08-5.19) for undefined anemia thresholds. PPH risk appeared to increase with lower anemia thresholds. Prepartum anemia is associated with an increased risk of PPH, an observation that is important regarding improved anemia correction strategies such as iron supplementation.

Consistency of serial ultrasonographic joint tissue measurements by the Joint tissueActivity and Damage Exam (JADE) protocol in relation to hemophilic joint health parameters.

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.

Diabetes, hepatitis C and human immunodeficiency virus influence hypertension risk differently in cohorts of haemophilia patients, veterans and the general population.

INTRODUCTION: The reasons for the high prevalence of hypertension in persons with haemophilia (PWH) are poorly understood. AIM: To examine the roles of diabetes, Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) in the etiology of hypertension for PWH. METHODS: Retrospective cross-sectional design. Adult PWH (n = 691) were divided into two groups: (A) free of diabetes, HCV and HIV; (B) with diabetes and/or HCV positivity and/or HIV positivity. Each group was matched by race and age with random samples from the general population of the US (National Health and Nutrition Examination Surveys, NHANES) and outpatients at the Veterans Affairs Medical Center (VAMC) in San Diego. Generalized additive models (GAMs) were fitted for graphical analysis of hypertension risk over the lifespan. RESULTS: In Group A, PWH had the highest prevalence of hypertension compared to NHANES and VAMC, especially in young adults. In Group B, diabetes increased the risk of hypertension for all three cohorts (PWH, NHANES and VAMC), especially for PWH. In PWH, hypertension risk was also increased by HIV, in NHANES by HCV, and in VAMC by HCV and HIV. CONCLUSION: Diabetes conferred the greatest risk of hypertension for all three cohorts. However, curves of hypertension in relation to age revealed that diabetes, HCV and HIV modulated hypertension risk differently in PWH. PWH experienced a disproportionally high risk increase with diabetes. Therefore, haemophilia care should include screening for hypertension and diabetes at a young age.

Patient-derived assessment tool using musculoskeletal ultrasound for validation of haemarthrosis.

INTRODUCTION: Haemophilia patients experience painful joint episodes which may or may not be associated with haemarthrosis. We sought to validate a questionnaire developed by the Canadian Haemophilia Society using point-of-care musculoskeletal ultrasound (POC MSKUS) to confirm haemarthrosis. METHODS: The questionnaire comprised of 20 questions (10 each associated with haemarthrosis and arthritis pain) and was administered to adult haemophilia patients reporting to the Haemophilia Treatment Centre (University of California San Diego). We confirmed the presence (or absence) of haemarthrosis using POC MSKUS [Joint Activity and Damage Exam (JADE)]. We fitted univariate and multivariate generalized estimating equations to identify symptoms associated with haemarthrosis. RESULTS: We evaluated 79 painful episodes in 32 patients [median age = 38 years (range 21-74)]. POC MSKUS detected haemarthrosis in 36 (46%) episodes. The strongest predictor for haemarthrosis pain was 'like a balloon swelling with water' (odds ratio [OR] 2.88 [CI .68;12.10]); 'no feeling of sponginess with movement' (OR .24[CI .07;.76]) was the strongest for arthritic pain. We identified four questions with the strongest OR for differentiating haemarthrosis pain from arthritic pain to develop an algorithm for haemarthrosis prediction. Answering these questions in "yes/no" fashion yielded estimates of the probability of haemarthrosis CONCLUSION: Objective diagnosis of haemarthrosis by MSKUS facilitated the development of a symptom-based prediction tool for diagnosis of haemarthrosis. The tool requires further validation and will be particularly helpful in situations where MSKUS is not readily available.

Blood pressure in persons with haemophilia with a focus on haemophilia-specific risk factors.

INTRODUCTION: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown. AIM: We investigated the relationship between hypertension/blood pressure and inhibitors in PWH. Additional goals were to determine the relationships with haemophilia type, race, and viral status. METHODS: Records were extracted retrospectively for PWH (age ≥18 years) between 2003 and 2014 from four Hemophilia Treatment Centers in North America and included demographics, weight, height, haemophilia type/severity, HCV and HIV infection status, hypertension, use of anti-hypertensive medications, and inhibitor status. We fitted semiparametric generalized additive models (GAMs) to describe adjusted curves of blood pressure (BP) against age. RESULTS: Among 691 PWH, 534 had haemophilia A and 157 had haemophilia B, with a median age of 39 years (range 18 to 79). Forty-four PWH (6.5%) had a history of inhibitors, without evidence for a higher prevalence of hypertension or higher BP. A higher prevalence of hypertension and higher BP were noted for haemophilia A (vs. haemophilia B), coinfection with HCV/HIV (vs. uninfected), or moderate haemophilia (vs. severe haemophilia). CONCLUSION: While there was no signal to suggest that a history of inhibitors is associated with hypertension, differences based on haemophilia type, severity, and viral infection status were identified, encouraging prospective investigations to better delineate haemophilia-specific risk factors for hypertension.

Risk of diabetes in haemophilia patients compared to clinic and non-clinic control cohorts.

INTRODUCTION: Ageing patients with haemophilia (PWH) develop cardiovascular risk factors impacting care. Little is known about the prevalence of diabetes in PWH and its relation to other comorbidities. AIM: To examine the risk of diabetes for adult PWH compared to men from the general United States population (National Health and Nutrition Examination Surveys [NHANES]) and outpatients attending a Veterans Affairs Medical Center (VAMC) clinic. METHODS: Retrospective cross-sectional design. PWH from four haemophilia centres (n = 690) were matched with random samples from NHANES and VAMC. Diabetes (yes/no) was the outcome, while age, body mass index (BMI), race and Hepatitis C (HCV; by serology) and human immunodeficiency virus (HIV) positivity were covariates. We fitted semiparametric generalized additive models (GAMs) in order to compare diabetes risk between cohorts. RESULTS: Younger PWH were at lower risk of diabetes than NHANES or VAMC subjects irrespective of BMI. However, the risk of diabetes rose in older PWH and was closely associated with HCV. For HCV-negative subjects, the risk of diabetes was considerably lower for PWH than NHANES and VAMC subjects. The difference persisted after controlling for BMI and age, indicating that the low risk of diabetes in PWH cannot be explained by lean body mass alone. CONCLUSION: Since many ageing PWH are HCV positive and therefore at heightened risk for diabetes, it is important to incorporate diabetes screening into care algorithms in Haemophilia Treatment Centers, especially since PWH are not always followed in primary care clinics.

Quantitative measurements of haemophilic joint tissues by point-of-care musculoskeletal ultrasound: Associations with clinical and functional joint outcome parameters.

BACKGROUND: Painful arthropathy is a long-term complication in patients with hemophilia (PWH), affecting mobility and quality of life. A major barrier for the appraisal of joint health is the absence of point-of-care (POC) imaging modalities to promptly identify and manage arthropathic changes. Accordingly, we developed the Joint tissue Activity and Damage Exam (JADE) POC musculoskeletal ultrasound (MSKUS) protocol. JADE is validated for haemophilic joint tissue recognition with high intra/inter-rater and inter-operator reliability. AIMS: Evaluate associations of JADE with clinical (Hemophilia Joint Health Score, [HJHS]) and functional (total arc [combined flexion and extension range of motion [ROM]]) parameters. METHODOLOGY: In this multi-centre prospective study, we recruited PWH A or B with at least one arthropathic joint. We evaluated joint health (both elbows, knees, and ankles) by comparing JADE measurements (soft tissue and cartilage thickness, and osteochondral alterations) with HJHS and total arc. RESULTS: Of 44 PWH, most had hemophilia A (35/44), were severe (36/44) and had a median age of 36 years. Increasing HJHSs and declining total arc, indicating worsening arthropathy, were associated with JADE measurements in the expected direction, including (1) increasing length of osteochondral alterations, (2) diminished cartilage thickness, and (3) greater soft tissue expansion. The ankles had the highest proportion of joints without measurable (missing) cartilage. In multivariable models MSKUS measurements explained 68% and 71% of the variation in HJHS and total arc respectively for the elbow, 55% and 29% respectively for the knee, and 50% and 73% for the ankle. CONCLUSIONS: This study highlights the associations of direct intra-articular ultrasonography measurements using the JADE protocol with clinical and functional parameters. Our findings underscore the clinical value of POC MSKUS using the JADE protocol as a complementary instrument for the diagnosis and management of haemophilic arthropathy.

Pulmonary Embolism Does Not Have an Unusually High Incidence Among Hospitalized COVID19 Patients.

INTRODUCTION: Acute respiratory illnesses from COVID19 infection are increasing globally. Reports from earlier in the pandemic suggested that patients hospitalized for COVID19 are at particularly high risk for pulmonary embolism (PE). To estimate the incidences of PE during hospitalization for COVID19, we performed a rigorous systematic review of published literature. METHODS: We searched for case series, cohort studies and clinical trials from December 1, 2019 to July 13, 2020 that reported the incidence of PE among consecutive patients who were hospitalized for COVID19 in ICUs and in non-ICU hospital wards. To reflect the general population of hospitalized COVID19 patients, we excluded studies in which subject enrollment was linked to the clinical suspicion for venous thromboembolism (VTE). RESULTS: Fifty-seven studies were included in the analysis. The combined random effects estimate of PE incidence among all hospitalized COVID19 patients was 7.1% (95% CI: 5.2%, 9.1%). Studies with larger sample sizes reported significantly lower PE incidences than smaller studies (r2 = 0.161, p = 0.036). The PE incidence among studies that included 400 or more patients was 3.0% (95% CI: 1.7%, 4.6%). Among COVID19 patients admitted to ICUs, the combined estimated PE incidence was 13.7% (95% CI: 8.0%, 20.6%). The incidence of ICU-related PE also decreased as the study sample sizes increased. The single largest COVID19 ICU study (n = 2215) disclosed a PE incidence of 2.3% (95% CI: 1.7%, 3.0%). CONCLUSION: PE incidences among hospitalized COVID19 patients are much lower than has been previously postulated based on smaller, often biased study reports. The incidence of "microthrombosis," leading to occlusion of microscopic blood vessels, remains unknown.

Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia.

INTRODUCTION: Interstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood. METHODS: Thirty-one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during pain-free intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII-/- mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers. RESULTS: Ninety-one patient visits were compiled. Twenty-five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO-C4 and C4M), and a type VIII collagen synthesis marker (PRO-C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII-deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels. CONCLUSIONS: Our findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.

Recent Partner Violence, Sexual Relationship Power, and STIs among Women Who Use Methamphetamine: Does Type of Sexual Partner Matter?

Methamphetamine use, sexual relationship power (SRP), and partner violence (PV) are associated with increased risk of sexually transmitted infections (STIs) among women. The objective of our study was to examine the association of recent PV and SRP on STIs by partner type among HIV-negative, heterosexual women who use methamphetamine in San Diego, CA. Using baseline survey data from 209 women enrolled in FASTLANE II, an HIV behavioral intervention trial, we conducted logistic regression analyses to examine associations between PV, SRP, and self-reported lifetime STIs (e.g., chlamydia, gonorrhea). Models focused on PV perpetrated within the past 2 months by: (1) spouse, live-in, or steady sexual partners and (2) casual or anonymous sexual partners. Seventy-eight percent of women reported lifetime physical PV and 57% reported lifetime sexual PV. In the past 2 months, 19.6% reported physical and/or sexual violence by a spouse, live-in, or steady sexual partner, and 7.2% reported physical and/or sexual PV by a casual or anonymous partner. Median SRP score was 2.36 (interquartile range: 2.02-2.68). Twenty-six percent of women reported ever being diagnosed with ≥ 1 STI. While recent physical violence and sexual violence were not associated with STI history among women in steady relationships, women who reported recent sexual violence by casual/anonymous partners were approximately 8 times more likely to ever have an STI compared with those with no history of recent PV by casual/anonymous partners (AOR: 7.70; 95% CI: 1.32, 44.84). SRP was not associated with lifetime STIs among women who reported either partner type. Our findings support a relationship between recent sexual violence perpetrated by casual/anonymous partners and women's STI history. Women who use methamphetamine need help in navigating partner violence experiences. Risk reduction interventions to support this marginalized population are needed.

Maternal death and postpartum hemorrhage in sub-Saharan Africa - A pilot study in metropolitan Mozambique.

BACKGROUND: Maternal mortality in sub-Saharan Africa is approximately 500 to 1000 per 100 000 births (vs. approximately 5-20 in developed countries). Postpartum hemorrhage (PPH) is deemed responsible for 30% to 50% of the deaths. OBJECTIVE: To study PPH, risk factors, and mortality in metropolitan Mozambique to inform future studies and intervention strategies. MATERIALS/METHODS: Retrospective cross-sectional data extraction from all charts available to us (n = 495) recording deliveries between January and June 2018 at Maputo Central Hospital. Data included age, maternal survival, HIV status, parity, delivery mode, complications, vital signs, laboratory values, and maternal/fetal data. PPH was determined by charted diagnosis, interventions for hemorrhaging, placental abruption, transfusion, or blood loss. Autopsy reports from all deceased patients (n = 35) were examined. RESULTS: Median age was 29 years with 17% HIV prevalence. Risk factors for PPH (frequency, 12%) included parity (adjusted odds ratios (AORs) for 3+ versus nulliparity, 7.20 (95% confidence interval [CI], 2.46-21.10), gestation length (AOR, 0.86; CI, 0.81-0.92 per week), and body temperature (AOR, 1.10; CI, 1.04-1.16 per 0.1°C). Maternal mortality was strongly associated with PPH (AOR, 5.22; 95% CI, 2.26-12.08) and HIV (AOR, 11.66; 95% CI, 4.72-28.78). Laboratory values (n = 241) were available from mothers experiencing complications (approximately 50%). Anemia (prevalence 54%) was a strong predictor of PPH with an inverse relationship between hemoglobin levels on admission (AOR, 0.62; 95% CI, 0.50-0.77 per g/dL higher hemoglobin) and the probability of later suffering from PPH. Mothers who died following PPH had lower median hemoglobin (6.2 g/dL) than mothers who survived (9.2 g/dL). Protocols to estimate peripartum blood loss were not used; antifibrinolytics and/or cryoprecipitate were unavailable. CONCLUSION: Postpartum hemorrhage is a serious problem even in metropolitan areas of sub-Saharan Africa, and anemia influenced bleeding and death substantially. To address this problem, it is critical to raise awareness and region-specific prevention and intervention protocols.

Joint Bleeding Tendencies in Adult Patients With Hemophilia: It's Not All Pharmacokinetics.

Hemophilic arthropathy from joint bleeding remains a complication with major morbidity in the increasingly aging patients with hemophilia. Prophylactic clotting factor infusions, based on pharmacokinetic dosing to reduce bleeding rates, are being explored more and more. However, there is little evidence on the benefits of pharmacokinetic dosing in direct association with bleeding events. Here, we prospectively followed a cohort of adult patients with hemophilia A and B (n = 26) and arthropathic joints on various clotting factor products over a period of 2 years with clinical and radiographic joint health assessments, frequent joint ultrasound, and pharmacokinetic studies. Joint bleeds and synovitis with synovial vascularity changes were objectively diagnosed by musculoskeletal ultrasound and power Doppler and analyzed in relation to pharmacokinetic, joint- and patient-specific parameters. Results revealed that, contrary to common beliefs, bleeding episodes were not readily explained by pharmacokinetic features, as they were not associated with more time spent below certain clotting factor thresholds. Joint bleeding was found to be associated with prominent vascularity changes, suggesting that vascular remodeling and leakiness may contribute to joint bleeding that cannot be prevented by clotting factor replacement alone.

Advanced magnetic resonance imaging of cartilage components in haemophilic joints reveals that cartilage hemosiderin correlates with joint deterioration.

INTRODUCTION: Evidence suggests that toxic iron is involved in haemophilic joint destruction. AIM: To determine whether joint iron deposition is linked to clinical and imaging outcomes in order to optimize management of haemophilic joint disease. METHODS: Adults with haemophilia A or haemophilia B (n = 23, ≥ age 21) of all severities were recruited prospectively to undergo assessment with Hemophilia Joint Health Scores (HJHS), pain scores (visual analogue scale [VAS]) and magnetic resonance imaging (MRI) at 3T using conventional MRI protocols and 4-echo 3D-UTE-Cones sequences for one affected arthropathic joint. MRI was scored blinded by two musculoskeletal radiologists using the International Prophylaxis Study Group (IPSG) MRI scale. Additionally, UTE-T2* values of cartilage were quantified. Correlations between parameters were performed using Spearman rank correlation. Two patients subsequently underwent knee arthroplasty, which permitted linking of histological findings (including Perl's reaction) with MRI results. RESULTS: MRI scores did not correlate with pain scores or HJHS. Sixteen joints had sufficient cartilage for UTE-T2* analysis. T2* values for cartilage correlated inversely with HJHS (rs  = -0.81, P < 0.001) and MRI scores (rs  = -0.52, P = 0.037). This was unexpected since UTE-T2* values decrease with better joint status in patients with osteoarthritis, suggesting that iron was present and responsible for the effects. Histological analysis of cartilage confirmed iron deposition within chondrocytes, associated with low UTE-T2* values. CONCLUSIONS: Iron accumulation can occur in cartilage (not only in synovium) and shows a clear association with joint health. Cartilage iron is a novel biomarker which, if quantifiable with innovative joint-specific MRI T2* sequences, may guide treatment optimization.

Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints.

OBJECTIVES: Musculoskeletal ultrasound (US) is used increasingly to examine hemophilic arthropathy. However, quantitative algorithms to document findings are lacking. We developed and sought to validate a protocol quantifying hemophilic joint abnormalities. METHODS: Thirty-one patients with hemophilia were examined serially for 2 years with musculoskeletal US (≈600 joint examinations and ≈6000 images). Based on the spectrum of pathologies, a quantitative algorithm, named Joint Tissue Activity and Damage Examination (JADE), was developed for soft tissue and osteochondral measurements, including power Doppler, using nominal group techniques. To study intra- and inter-rater reliability, 8 musculoskeletal US-experienced hemophilia providers performed anatomic landmark recognition and tissue measurements on 86 images with arthropathic changes, with repetition 1 month later. Twenty-three musculoskeletal US-inexperienced providers performed similar assessments. Inter-operator reliability was established by 6 musculoskeletal US-experienced hemophilia providers, each acquiring images and JADE assessments of 3 hemophilic arthropathic joints. A radiologist and musculoskeletal sonographer functioned as adjudicators. The statistical analysis was performed with the intraclass correlation coefficient (ICC), Fleiss κ, and Cohen κ where appropriate. RESULTS: The musculoskeletal US-experienced providers showed excellent intra-and inter-rater reliability for tissue measurements (ICCs, 0.94-0.96). Agreement was good to excellent for landmark recognition (Fleiss κ, 0.87-0.94). Inter-operator reliability was excellent for measurements and landmark recognition (ICC, 0.90; Fleiss κ, 1.0). Agreement with adjudicators was mostly good to excellent. Musculoskeletal US-inexperienced providers showed excellent inter-rater reliability for measurements (ICC, 0.96) and moderate agreement for landmark recognition (Fleiss κ, 0.58). CONCLUSIONS: The JADE protocol appears feasible for quantifying hemophilic intra-articular abnormalities. Musculoskeletal US-trained hemophilia providers showed high intra-rater, inter-rater, and inter-operator reliability, supporting JADE as a protocol for clinical management and research.

Advanced Hemophilic Arthropathy: Sensitivity of Soft Tissue Discrimination With Musculoskeletal Ultrasound.

OBJECTIVES: Point-of-care musculoskeletal ultrasound (US) is increasingly used by hemophilia providers to guide management; however, pathologic tissue differentiation with US is uncertain. We sought to determine the extent to which point-of-care musculoskeletal US can identify and discriminate pathologic soft tissue changes in hemophilic arthropathy. METHODS: Thirty-six adult patients with hemophilia A/B were prospectively enrolled. Point-of-care musculoskeletal US examinations were performed on arthropathic joints (16 knees, 10 ankles, and 10 elbows) using standard views by a musculoskeletal US-trained and certified hematologist, who recorded abnormal intra-articular soft tissue accumulation. Within 3 days, magnetic resonance imaging was performed using conventional and multiecho ultrashort echo time sequences. Soft tissue identification (synovial proliferation with or without hemosiderin, fat, and/or blood products) was performed by a musculoskeletal radiologist. Findings obtained with both imaging modalities were compared and correlated in a blinded fashion. RESULTS: There was perfect agreement between the modalities on the presence of abnormal soft tissue (34 of 36 cases). However, musculoskeletal US was unable to discriminate between coagulated blood, synovium, intrasynovial or extrasynovial fat tissue, or hemosiderin deposits because of wide variations in echogenicity. CONCLUSIONS: Musculoskeletal US is valuable for point-of-care imaging to determine the presence of soft tissue accumulation in discrete areas. However, because of limitations of musculoskeletal US in discriminating the nature of pathologic soft tissues and detecting hemosiderin, magnetic resonance imaging will be required if such discrimination is clinically important.

The hypertension of hemophilia is associated with vascular remodeling in the joint.

OBJECTIVE: Hemophilic arthropathy is associated with pronounced vascular joint remodeling. Also, compared to the general population, PWH have a higher prevalence of hypertension not explained by usual risk factors. As vascular remodeling in various vascular beds is a hallmark of hypertension, we hypothesized that vascular joint remodeling is associated with elevated blood pressures and hypertension. METHODS: Elbows, knees, and ankles of 28 adult PWH were evaluated for vascular abnormalities with MSKUS/PD, as well as for radiographic and clinical status and pain. Logistic and linear regression models were fitted to examine associations between hypertension, blood pressure, and PD score. RESULTS: The extent of vascular abnormalities was associated with hypertension and blood pressures. Hypertensive patients had a higher PD score compared to nonhypertensive patients, and the risk of hypertension increased steeply with PD score. SBP was also strongly associated with PD score, while DBP was only weakly associated. CONCLUSIONS: Vascular remodeling in hemophilic joints is associated with hypertension and elevated blood pressures. As hypertension is a grave risk factor for intracranial hemorrhage, a prominent cause of mortality in hemophilia patients, future studies are needed to address the causal pathways between vascular joint remodeling and blood pressure.

Knee Fat Pad Volumes in Patients with Hemophilia and Their Relationship with Osteoarthritis.

Hemophilic arthropathy is a progressive, disabling condition with poorly understood pathobiology. Since there is an emerging interest to study the role of intra-articular fat pad size and biology in arthritic conditions, we explored fat pad volume changes in hemophilic arthropathy and to what extent they differed from osteoarthritis. We matched a cohort of 13 adult patients with hemophilic arthropathy of the knee with age- and gender-matched cohorts without osteoarthritis ("control cohort") and with the same degree of radiographic osteoarthritis ("OA cohort") in 1 : 2 fashion. Infrapatellar fat pad (IPFP) and suprapatellar fat pad (SPFP) volumes were calculated based on magnetic resonance imaging and differences in fat pad volumes, demographics, height, weight, and osteoarthritis scores were evaluated. Fat pad volumes were positively associated with body size parameters in all three cohorts but were unaffected by the degree of osteoarthritis. While IPFP volumes did not differ between cohorts, SPFP volumes expanded disproportionally with weight in hemophilia patients. Our observations indicate that IPFPs and SPFPs behave biologically differently in response to different arthritic stimuli. The exaggerated expansion of the SPFP in hemophilia patients highlights the importance of further studying the implications of fat pad biology for progression of hemophilic arthropathy.

The Hypertension of Hemophilia Is Not Explained by the Usual Cardiovascular Risk Factors: Results of a Cohort Study.

Background. The etiology of the high prevalence of hypertension among patients with hemophilia (PWH) remains unknown. Methods. We compared 469 PWH in the United States with males from the National Health and Nutrition Examination Survey (NHANES) to determine whether differences in cardiovascular risk factors can account for the hypertension in hemophilia. Results. Median systolic and diastolic BP were higher in PWH than NHANES (P < 0.001) for subjects not taking antihypertensives. Those taking antihypertensives showed similar differences. Differences in both systolic and diastolic BP were especially marked among adults <30 years old. Differences between PWH and NHANES persisted after adjusting for age and risk factors (body mass index, renal function, cholesterol, smoking, diabetes, Hepatitis C, and race). Conclusions. Systolic and diastolic BP are higher in PWH than in the general male population and especially among PWH < 30 years old. The usual cardiovascular risk factors do not account for the etiology of the higher prevalence of hypertension in hemophilia. New investigations into the missing link between hemophilia and hypertension should include age of onset of hypertension and hemophilia-specific morbidities such as the role of inflammatory joint disease.

Multidrug-resistant tuberculosis among patients in Baja California, Mexico, and Hispanic patients in California.

OBJECTIVES: We sought to compare prevalence and determinants of multidrug-resistant tuberculosis (MDR-TB) between tuberculosis patients in Baja California, Mexico, and Hispanic patients in California. METHODS: Using data from Mexico's National TB Drug Resistance Survey (2008-2009) and California Department of Public Health TB case registry (2004-2009), we assessed differences in MDR-TB prevalence comparing (1) Mexicans in Baja California, (2) Mexico-born Hispanics in California, (3) US-born Hispanics in California, and (4) California Hispanics born elsewhere. RESULTS: MDR-TB prevalence was 2.1% in Baja California patients, 1.6% in Mexico-born California patients, 0.4% in US-born California patients, and 2.7% in Hispanic California patients born elsewhere. In multivariate analysis, previous antituberculosis treatment was associated with MDR-TB (odds ratio [OR] = 6.57; 95% confidence interval [CI] = 3.34, 12.96); Mexico-born TB patients in California (OR = 5.08; 95% CI = 1.19, 21.75) and those born elsewhere (OR = 7.69; 95% CI = 1.71, 34.67) had greater odds of MDR-TB compared with US-born patients (reference category). CONCLUSIONS: Hispanic patients born outside the US or Mexico were more likely to have MDR-TB than were those born within these countries. Possible explanations include different levels of exposure to resistant strains and inadequate treatment.