Inherited Disorders of the Fibrinolytic Pathway: Pathogenic Phenotypes and Diagnostic Considerations of Extremely Rare Disorders.

Fibrinolysis is initiated by the activation of plasminogen to plasmin via tissue-plasminogen activator (tPA) and urokinase-plasminogen activator (uPA); plasmin then converts fibrin to fibrin degradation products (FDPs). The antifibrinolytics counterbalancing this system include plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, α-2 antiplasmin (α2AP), which inhibits plasmin, and thrombin activatable fibrinolysis inhibitor, which inhibits the conversion of fibrin to FDP. Inherited disorders of the fibrinolytic pathway are rare and primarily have hemorrhagic phenotypes in humans: PAI-1 deficiency, α2AP deficiency, and Quebec platelet disorder. Patients with these disorders are usually treated for bleeds or receive prophylaxis to prevent bleeds in the surgical setting, with pharmacological antifibrinolytics such as aminocaproic acid and tranexamic acid. Disorders of the fibrinolytic pathway with fibrin deposition are extremely rare, mostly noted in patients with plasminogen deficiency, who have more recently benefited from advances in human plasma-derived plasminogen concentrates administered intravenously or locally. These disorders can be very difficult to diagnose using conventional or even specialized coagulation testing, as testing can be nonspecific or have low sensitivity. Testing of the corresponding protein's activity and antigen (where applicable) can be obtained in specialized centres, and routine laboratory measures are not diagnostic. Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway.

Primary thromboprophylaxis to prevent thrombotic events in pediatric oncology patients with a malignant mediastinal mass.

Children with malignant mediastinal masses have increased thrombotic events (TE). Eligible subjects with malignant mediastinal masses between January 2000 and December 2017 were evaluated for TE, with 19 among 76 subjects receiving enoxaparin thromboprophylaxis. There were 13 TEs among 76 subjects for an incidence of 17.1%. Mediastinal compression directly led to TE in 9.2% of subjects who also had statistically significant superior vena cava compression at diagnosis. Primary thromboprophylaxis did not significantly affect TE occurrence; however, larger studies are warranted to consider strategic thromboprophylaxis guided by radiological monitoring of dynamic vascular compression to improve TE outcomes.

Are children with SARS-CoV-2 infection at high risk for thrombosis? Viscoelastic testing and coagulation profiles in a case series of pediatric patients.

The coagulopathy of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented in adults, with increases in D-dimer and prothrombin time found to be strong predictors of mortality, and anticoagulation shown to decrease this mortality. Viscoelastic parameters such as elevations in maximum clot firmness (MCF) on rotational thromboelastometry (ROTEM) have correlated with a hypercoagulable state in adults with SARS-CoV-2. We report our experience in children infected with SARS-CoV-2, with noted elevations in D-dimer and MCF on ROTEM (indicating hypercoagulability). Exploration of viscoelastic testing to provide additional laboratory-based evidence for pediatric-specific risk assessment for thromboprophylaxis in SARS-CoV-2 is warranted.

Inherited disorders of the fibrinolytic pathway.

Deficiencies or excessive activation of the fibrinolytic system can result in severe, lifelong bleeding disorders. The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin. Another bleeding disorder due to a defect in the fibrinolytic pathway results from Plasminogen activator inhibitor-1 (PAI-1) deficiency causing enhanced fibrinolysis due to the decreased inhibition of plasminogen activators resulting in increased conversion of plasminogen to plasmin. Both these disorders are rare and have an autosomal recessive pattern of inheritance. They can remain undetected as routine coagulation and platelet function tests are normal. A unique gain-of-function defect in fibrinolysis causes the Quebec platelet disorder (QPD) which is characterized by profibrinolytic platelets containing increased urokinase-type plasminogen activator (uPA) in the α-granules. A high index of suspicion based on clinical phenotype along with the availability of specialized hemostasis testing is required for timely and accurate diagnosis. Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot. The purpose of this review is to summarize the pathogenesis, clinical phenotype, approaches to diagnosis and treatment for these three major disorders of fibrinolysis.

Management of rare coagulation disorders in 2018.

Rare bleeding disorders (RBDs) comprise inherited deficiencies of factors I (fibrinogen), II (prothrombin), V, VII, X, XI, and XIII as well as combined factor V + VIII and vitamin K-dependent factors. They represent 3-5% of all congenital bleeding disorders and are usually transmitted as autosomal recessive traits. These disorders often manifest during childhood and have varied clinical presentations from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Bleeding manifestations generally vary within the same RBD and may also vary from 1 RBD to the other. Laboratory diagnosis is based on coagulation screening tests and specific factor assays, with molecular techniques providing diagnostic accuracy and enabling prenatal counseling. The approach to treatment of bleeding episodes and invasive procedures needs to be individualized and depends on the severity, frequency and procedure-related risk of bleeding. The first line of treatment of RBDs is replacement of the deficient factor, using specific plasma-derived or recombinant products and using fresh frozen plasma or cryoprecipitate when specific products are not available or in resource-limited countries. Prophylaxis may be considered in individuals with recurrent serious bleeding and especially after life-threatening bleeding episodes. Novel no-replacement strategies promoting hemostasis by through different mechanisms need to be studied in RBDs as alternative therapeutic options.

Exploration of rotational thromboelastometry (ROTEM) to characterize the coagulation profiles of newly diagnosed pediatric leukemia patients.

BACKGROUND: Viscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. OBJECTIVES: Analyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT's and Rotational Thromboelastometry (ROTEM). METHODS: Pediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. RESULTS: Sixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/µL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). CONCLUSION: Fibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement.

Neoangiogenesis contributes to the development of hemophilic synovitis.

Joint arthropathy secondary to recurrent hemarthroses remains a debilitating complication of hemophilia despite the use of prophylactic factor concentrates. Increased vascularity and neoangiogenesis have been implicated in the progression of musculoskeletal disorders and tumor growth. We hypothesized that de novo blood vessel formation could play a major role in the pathogenesis of hemophilic joint disease (HJD). We observed a 4-fold elevation in proangiogenic factors (vascular endothelial growth factor-A [VEGF-A], stromal cell-derived factor-1, and matrix metalloprotease-9) and proangiogenic macrophage/monocyte cells (VEGF(+)/CD68(+) and VEGFR1(+)/CD11b(+)) in the synovium and peripheral blood of HJD subjects along with significantly increased numbers of VEGFR2(+)/AC133(+) endothelial progenitor cells and CD34(+)/VEGFR1(+) hematopoietic progenitor cells. Sera from HJD subjects induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF, whereas peripheral blood mononuclear cells from HJD subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells, when incubated with HJD sera, could elicit up-regulation of HIF-1α mRNA with HIF-1α expression in the synovium of HJD subjects, implicating hypoxia in the neoangiogenesis process. Our results provide evidence of local and systemic angiogenic response in hemophilic subjects with recurrent hemarthroses suggesting a potential to develop surrogate biologic markers to identify the onset and progression of hemophilic synovitis.

Prolonged prothrombin time does not correlate with clinical bleeding symptoms in newly diagnosed paediatric leukaemia patients.

Prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) are frequently seen in newly diagnosed paediatric leukaemia patients (NDPLP), which can lead to delayed diagnostic and therapeutic procedures due to concern for bleeding. A single-centre retrospective chart review of NDPLP between 2015 and 2018 aged 1-21 years. We analysed 93 NDPLP of whom 33.3% had bleeding symptoms within 30 days of presentation, predominantly mucosal bleeding (80.6%) and petechiae (64.5%). Median laboratory values: white blood cell count 15.7, haemoglobin 8.1, platelets 64, PT 13.2 and a PTT 31. Red blood cells were administered in 41.2%, platelets in 52.9%, fresh frozen plasma in 7.8% and vitamin K in 21.6% of patients. Prolonged PT was found in 54.8% of patients, while aPTT was prolonged in 5.4%. Anaemia and thrombocytopenia did not correlate with prolonged PT ( P  = 0.73 and P  = 0.18, respectively), or prolonged aPTT ( P  = 0.52 and 0.42). Leukocytosis showed significant correlation with elevated PT ( P  < 0.001), but not aPTT ( P  = 0.3). Bleeding symptoms upon presentation did not correlate with prolonged PT ( P  = 0.83), prolonged aPTT ( P  = 1) or anaemia ( P  = 0.06) but had a significant correlation with thrombocytopenia ( P  ≤ 0.0001). Therefore, a prolonged PT in NDPLP may not necessitate the reflexive use of blood product replacement, in the absence of significant bleeding, which is likely related to leukocytosis than to a true coagulopathy.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders.

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life. RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities. RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection. CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

Living with an ultra-rare inherited bleeding disorder is challenging. Patients can feel alone and unsure of where to find support because their disorder is so rare. In this paper, a group of ultra-rare bleeding disorder experts, including doctors, researchers, regulators, patient advocates, and patients, identify the research that could best improve the lives of people with these disorders. They propose a national network of specialists who can help doctors, who may never have seen these disorders before, to find the right diagnosis faster. A centralized laboratory specialized in ultra-rare bleeding disorders could also improve diagnosis and do research studies. This would help us learn, for example, how symptoms change throughout a patient's life, how effective different treatments are, and what it is like for patients to live with these disorders. A second research priority is to better understand each individual disorder so that the best treatments can be chosen or developed. A pathway showing doctors which treatment options to try, in which order, would help them help their patients. The third research priority is to make it easier to study new treatments for ultra-rare bleeding disorders. This requires designing studies with very small numbers of participants, identifying meaningful outcomes to measure, and convincing pharmaceutical companies to invest in these studies. International agreement on these requirements would allow more patients to participate and benefit from the research. These top-priority research goals should greatly improve knowledge about, and diagnosis and treatment of, ultra-rare inherited bleeding disorders.

Exploration of the pathogenesis of haemophilic joint arthropathy: understanding implications for optimal clinical management.

Haemophilia is an inherited disorder of clotting factor deficiencies resulting in musculoskeletal bleeding, including haemarthroses, leading to orthopaedic complications. The pathogenesis of haemophilic joint arthropathy continues to be explored and there is evidence to suggest that iron, cytokines, and neo angiogenesis can initiate synovial and early cartilage damage resulting in molecular changes and the perpetuation of a chronic inflammatory state. This joint arthropathy has long term consequences for bone health resulting in chronic pain and quality of life issues in the individual with haemophilia. Haemarthroses can be prevented by the administration of clotting factor concentrates (prophylaxis). However, high costs and the need for venous access devices in younger children continue to complicate recommendations for universal prophylaxis. In patients who fail or refuse prophylaxis, procedures, such as synovectomy and arthroplasty, can provide relief from repeated haemarthroses. The optimal timing of these, however, is not well defined. Prevention of joint arthropathy needs to focus on prevention of haemarthroses through prophylaxis, identifying early joint disease through the optimal use of cost effective imaging modalities and the validation of serological markers of joint arthropathy. Screening for effects on bone health and optimal management of pain to improve quality of life are, likewise, important issues.

Six Month Follow-up of Patients With Multi-System Inflammatory Syndrome in Children.

BACKGROUND AND OBJECTIVES: Myocardial dysfunction and coronary abnormalities are prominent features of multisystem inflammatory syndrome in children (MIS-C). In this study we aim to evaluate the early and midterm outcomes of MIS-C. METHODS: This is a longitudinal 6-month cohort study of all children admitted and treated for MIS-C from April 17 to June 20, 2020. Patients were followed ∼2 weeks, 8 weeks, and 6 months postadmission, with those with coronary aneurysms evaluated more frequently. RESULTS: Acutely, 31 (62%) patients required intensive care with vasoactive support, 26 (52%) had left ventricular (LV) systolic dysfunction, 16 (32%) had LV diastolic dysfunction, 8 (16%) had coronary aneurysms (z score ≥2.5), and 4 (8%) had coronary dilation (z score <2.5). A total of 48 patients (96%) received immunomodulatory treatment. At 2 weeks, there was persistent mild LV systolic dysfunction in 1 patient, coronary aneurysms in 2, and dilated coronary artery in 1. By 8 weeks through 6 months, all patients returned to functional baseline with normal LV systolic function and resolution of coronary abnormalities. Cardiac MRI performed during recovery in select patients revealed no myocardial edema or fibrosis. Some patients demonstrated persistent diastolic dysfunction at 2 weeks (5, 11%), 8 weeks (4, 9%), and 6 months (1, 4%). CONCLUSIONS: Children with MIS-C treated with immunomodulators have favorable early outcomes with no mortality, normalization of LV systolic function, recovery of coronary abnormalities, and no inflammation or scarring on cardiac MRI. Persistence of diastolic dysfunction is of uncertain significance and indicates need for larger studies to improve understanding of MIS-C. These findings may help guide clinical management, outpatient monitoring, and considerations for sports clearance.

Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia.

BACKGROUND AND AIMS: Congenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. METHODS: Eleven adult patients from a multinational, phase 1-2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. RESULTS: For the Clauss method, (mean [standard deviation]) baseline adjusted Cmax was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. CONCLUSIONS: The pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.

Multisystem inflammatory syndrome in children (MIS-C) and the prothrombotic state: Coagulation profiles and rotational thromboelastometry in a MIS-C cohort.

BACKGROUND: Adults infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have had high rates of thrombosis. A novel condition in children infected with SARS-CoV-2, multisystem inflammatory syndrome in children (MIS-C), has limited data on their prothrombotic state or need for thromboprophylaxis. OBJECTIVES: We aimed to analyze the prothrombotic state using coagulation profiles, rotational thromboelastometry (ROTEM) parameters and clinical outcomes, to determine if this could aid in risk stratification for thromboprophylaxis. METHODS: This analysis included patients (<21 years of age) with a diagnosis of MIS-C (n = 40) and controls (presenting with suspicion of MIS-C but later ruled out; n = 26). RESULTS: MIS-C patients had higher levels of inflammatory markers including D-dimer (p < .0001), compared with controls, along with evidence of hypercoagulability on ROTEM with elevated evaluation of fibrinogen activity (FIBTEM) maximum clot firmness (MCF) (p < .05). For MIS-C patients with D-dimers >1000 ng/ml, there was a significant correlation of FIBTEM MCF (p < .0001) with a mean value of 37.4 (standard deviation 5.1). D-dimer >2144 ng/ml was predictive of intensive care unit admission (area under the curve [AUC] 0.80; 95% confidence interval, 0.60-0.99; p < .01; sensitivity: 82%, specificity: 75%), and elevated FIBTEM MCF (AUC 1 for >2500 ng/ml). MIS-C patients (50%) received enoxaparin thromboprophylaxis (in addition to aspirin) with significant improvement in their inflammatory and ROTEM parameters upon outpatient follow-up; none developed symptomatic thrombosis. CONCLUSIONS: Despite an observed prothrombotic state, none of the MIS-C patients (on aspirin alone or in combination with enoxaparin) developed symptomatic thrombosis. ROTEM, in addition to coagulation profiles, may be helpful to tailor thromboprophylaxis in critically ill MIS-C patients.

Hemophilic joint disease - current perspective and potential future strategies.

Recurrent hemarthroses can lead to hemophilic joint disease (HJD), which is one of the most disabling complications of these X-linked recessive disorders characterized by a deficiency of clotting factors VIII/IX. The pathogenesis of HJD is not well understood and there is evidence to suggest that iron may play a central role in the pathogenetic process causing changes at the molecular level and through the release of cytokines and perpetuation of a chronic inflammatory state. Also, there may be a role for angiogenesis in accelerating the joint damage begun by recurrent hemarthroses. Hemophilic joint disease can be diagnosed by MRI which provides information about the pathology of the synovium, articular cartilage and bone. However, it is expensive, and maybe cumbersome in young children who require sedation. Newer, cost-effective imaging tools such as ultrasonography need to be explored to facilitate diagnosis and monitoring of joint disease. Repeated bleeds into the joint could be prevented by reducing the number of bleeds by the prophylactic infusion of factor concentrates on a bi-weekly to alternate day schedule depending on the activity level and bleeding phenotype. However, the dose, schedule and timing of prophylaxis still remain unresolved despite some multi-center clinical studies proving its benefit in preserving joint function. Prohibitive costs and the need for venous access devices in delivering factor concentrates in younger children continue to complicate universal recommendations of prophylaxis. In those patients who fail or refuse prophylaxis, procedures such as isotopic synovectomy can provide relief from repeated joint bleeds, again the timing of which is not well-defined. Newer strategies to identify early joint disease through the use of serological markers are needed. Also, cost-effective imaging modalities are needed so that treatment strategies such as prophylaxis and isotopic synovectomy can be appropriately timed to reap maximum benefits. A combination of serological and imaging evidence of early joint disease might ultimately impact on the optimal management of hemophilic joint disease.

Bleeding Disorders in Congenital Syndromes.

Pediatricians provide a medical home for children with congenital syndromes who often need complex multidisciplinary care. There are some syndromes associated with thrombocytopenia, inherited platelet disorders, factor deficiencies, connective tissue disorders, and vascular abnormalities, which pose a real risk of bleeding in affected children associated with trauma or surgeries. The risk of bleeding is not often an obvious feature of the syndrome and not well documented in the literature. This makes it especially hard for pediatricians who may care for a handful of children with these rare congenital syndromes in their lifetime. This review provides an overview of the etiology of bleeding in the different congenital syndromes along with a concise review of the hematologic and nonhematologic clinical manifestations. It also highlights the need and timing of diagnostic evaluation to uncover the bleeding risk in these syndromes emphasizing a primary care approach.

Point-of-care ultrasonography (POCUS) in hemophilia A: a commentary on current status and its potential role for improving prophylaxis management in severe hemophilia A.

In patients with severe hemophilia A, recurrent bleeding into joints results in increased morbidity and reduced quality of life. Prophylaxis using replacement factor products, especially when initiated early, has established benefits in terms of reducing joint bleeds and preserving joint function. Poor adherence to prophylactic regimens is a common cause for breakthrough bleeds and resultant arthropathy. Improving prophylaxis management, especially in the transitional age group, is a challenge. Here, we discuss the current status of ultrasonography (US) in hemophilia A, challenges in its wider implementation, and the potential for use of point-of-care US (POCUS) as an adjunct in the routine management of patients with hemophilia following prophylaxis regimens. Using POCUS, in which US is performed by trained hematologists and nonphysician operators (rather than comprehensive US performed by imaging specialists), specific clinical questions can be addressed in a time-efficient, user-friendly manner to promote adherence to prophylaxis and guide or modify treatment approaches. This review also discusses barriers to acceptance of POCUS as a part of routine management of patients with hemophilia, including questions related to its diagnostic accuracy, dependence on trained operators, agreement on appropriate scoring systems, and potential usefulness in patient management.

Management of factor VIII inhibitors.

The development of inhibitory alloantibodies to factor VIII is arguably one of the most severe and important complications of clotting factor concentrate exposure in haemophilia A. The development of an inhibitor compromises the ability to effectively manage haemorrhage, resulting in a greater rate of disability, complications and costs of therapy. This chapter briefly reviews the epidemiology, immunobiology, and laboratory evaluation of inhibitors. It discusses the therapeutic approach and management of inhibitors in various clinical settings and also focuses on inhibitor eradication practices (immune tolerance) and newer experimental strategies with potential clinical application for inhibitor prevention.

Advances in hemophilia and the role of current and emerging prophylaxis.

The primary goal of hemophilia treatment and management is the prevention of painful, disabling, and costly joint arthropathy that results from its characteristic bleeding into joints and muscles. Prophylactic treatment with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the standard of care for hemophilia A and B. Data has demonstrated the clinical efficacy and overall benefits of prophylaxis in young children, adolescents, and adults. Early initiation with prima-ry prophylaxis is ideal, but secondary prophylaxis in adolescents and adults has also demonstrated significant success. Because the standard of care includes prophylaxis with factor-concentrate replacement in order to prevent joint damage in patients with hemophilia, prophylaxis is now more common and needs to be addressed in all clinical settings, including managed care. However, further research is needed to help clinicians develop individualized factor-replacement protocols and under-stand the impact of long-term use into adulthood. World Federation of Hemophilia guidelines do not have definitive recommendations on continuation of prophylaxis into adulthood. The optimal regimen for initiating prophylaxis, duration of treatment, and dosing regimens continue to be studied.

Orthopedic management of hemophilia.

Hemophilia is an X-linked inherited bleeding disorder characterized by a deficiency of clotting factor VIII or IX in the intrinsic pathway of the coagulation cascade. This disease can have a profound, debilitating effect on the musculoskeletal system through recurrent hemarthroses and intermuscular hematomas. Although medical management with replacement factor is often effective, patients with severe hemophilia may develop chronic synovitis and arthropathy best treated with more invasive means. Radioactive synovectomy performed at select hemophilia centers and arthroscopic or open synovectomy are helpful for chronic, active synovitis. Arthroplasty helps improve function and pain relief for most patients, but complication rates, particularly for infection, are higher than those for arthroplasty performed on patients without hemophilia.