The most important clinical strategy for management of patients with hemophilia is the avoidance of recurrent hemarthroses by means of continuous, intravenous hematological prophylaxis. When only intravenous on-demand hematological treatment is available, frequent evaluations are necessary for the early diagnosis and treatment of episodes of intra-articular bleeding. The natural history of the disease in patients with poorly controlled intra-articular bleeding is the development of chronic synovitis and, later, multi-articular hemophilic arthropathy. Once arthropathy develops, the functional prognosis is poor. Treatment of these patients should be conducted through a comprehensive program by a multidisciplinary hemophilia unit. Although continuous prophylaxis can avoid the development of the orthopedic complications of hemophilia still seen in the twenty-first century, such a goal has not, so far, been achieved even in developed countries. Therefore, many different surgical procedures such as arthrocentesis, radiosynoviorthesis (radiosynovectomy) (yttrium-90, rhenium-186), tendon lengthenings, alignment osteotomies, joint arthroplasties, removal of pseudotumours, and fixation of fractures are still frequently needed in the care of these patients.
hemophilia; orthopedic surgery; musculo-skeletal complications
Individuals with severe factor VIII deficiency experience recurrent hemorrhages and develop progressive joint damage. Large retrospective, nonrandomized studies of patient cohorts followed over decades show that factor prophylaxis initiated at an early age before the onset of recurrent bleeding reduces the incidence of hemophilic arthropathy. Two recent prospective, multicenter, randomized trials conducted in Europe (the ESPRIT study) and the USA (the Joint Outcome Study) confirm the efficacy of prophylaxis in the prevention of hemarthroses and arthropathy. Regular prophylaxis initiated in early childhood enhances the quality of life for patients with severe hemophilia and reduces the risk of inhibitor development. The substantial costs of such preventative therapy may be offset by the reduced expenditures that the care of degenerative joint disease in adult hemophilia patients would otherwise require.
hemophilia; factor VIII; prophylaxis; arthropathy; bleeding
The major morbidity of hemophilia is bleeding induced hemophilic arthropathy (HA) which once established may not be interrupted completely even by prophylactic clotting factor replacement. Specific therapies to oppose inflammatory cytokines, including Interleukin 6 (IL-6) receptor antagonists, have become important in the management of inflammatory arthritides.
We investigated combining therapy using MR16-1, a rat IgG antibody directed against mouse IL-6 receptor (anti-IL-6R), with factor VIII (FVIII) replacement to protect against bleeding induced arthropathy in hemophilia A mice.
Three recurrent hemarthroses were induced in the knee joint capsule of factor VIII knockout mice. Treatment at the time of each hemorrhage included either: No treatment; FVIII replacement given at the time of hemorrhage; FVIII replacement at hemorrhage plus anti-IL-6R as four weekly injections; FVIII replacement with non-specific control antibody (rat IgG); anti-IL-6R alone without FVIII replacement. Six weeks following the first hemarthosis joints were harvested and histopathology was scored for synovitis, for cartilage integrity and for macrophage infiltration.
Animals that received anti-IL-6R as an adjunct to FVIII replacement demonstrated the best survival and the least acute joint swelling and pathology on histologic examination of synovium and cartilage (P<0.05 for each parameter). All histopathologic parameters in the mice receiving FVIII+anti-IL-6R were limited and were comparable to findings in injured hemostatically normal mice. The major benefits of adjunctive anti-IL-6R were decreasing synovial hyperplasia, hemosiderin deposition and macrophage infiltration.
Short-course specific inhibition of inflammatory cytokines as an adjunct to replacement hemostasis may be an approach to minimize hemophilic joint degeneration.
IL-6; anti-IL-6; anti-cytokine; hemophilia; hemarthrosis; hemophilic arthropathy; MR16-1
Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries.
bleeding; comprehensive care; clotting factor concentrates; hemophilia; inhibitors; prophylaxis; treatment
Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). In hemophilia B patients the severity of the bleeding phenotype is related to the degree of the FIX defect. Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients’ quality of life. The purpose of this narrative review is to summarize the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX products either clinically used or in development. There is only one rFIX product that is licensed to treat hemophilia B patients; from the analysis of the literature data presented in this review, the authors conclude that this rFIX product has demonstrated an excellent safety profile and excellent clinical efficacy for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy and to improve patients’ quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage. Further clinical studies are needed to better assess the safety and efficacy (ie, the incidence of adverse reactions and inhibitor development) of newer rFIX products.
recombinant FIX products; plasma-derived FIX concentrate; bleeding; blood clotting disorder; on-demand treatment; prophylaxis treatment
A study was made of the clotting defect and the course of the malady in a group of male dogs with an inherited, sex-linked bleeding disease. The clotting defect is characterized by a prolonged clotting time and a delayed prothrombin utilization, and is corrected by the addition either of thromboplastin or of normal plasma. A plasma protein fraction, fraction I, also corrects the defect. The defect appears to be due to a deficiency of a plasma factor, which normally, in the presence of platelets, makes thromboplastin available in shed blood. The clotting anomaly appears to be identical with that found in human hemophilia. The hemostatic defect is characterized by repeated hemorrhages, usually without obvious relationship to trauma. Hemarthroses occur frequently and may result in permanent joint deformity. The animals usually die early in life from massive hemorrhage. Transfusions with normal blood or plasma correct the clotting defect and readily control the hemorrhagic phenomena. By the use of transfusions, these dogs have been reared to maturity.
Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding episodes and rarely developed significant joint deterioration (haemophilic arthropathy), and the pioneer experience in Sweden, prophylaxis (i. e. the regular and long-term administration of clotting factor concentrate in order to prevent bleeding) has been practiced for more than forty years in severe haemophilia and is currently recommended as the first choice of treatment by the World Health Organisation and World Federation of Hemophilia and by many national medical/scientific organizations. Observational studies clearly established the superiority of prophylaxis over on-demand treatment in reducing the risk of arthropathy, also showing that starting prophylaxis earlier in life and after very few joint bleeds was associated with better joint outcomes, and led to the current definitions of primary (started before the age of 2 yrs and after no more than one joint bleed) and secondary prophylaxis. More recently, evidences from randomized trials, which were previously lacking in this setting, were also provided.
This review summarizes available data from which current clinical practice of primary (and early secondary) prophylaxis in children with severe haemophilia was drawn. Open issues concerning optimal regimens and barriers to the implementation of prophylaxis are also discussed.
bleeding; children; haemophilia; prophylaxis; treatment
Hemophilia is a rare genetic bleeding disorder that, if not adequately controlled, is associated with life-threatening bleeding events and serious and costly complications, primarily from joint damage. The advent of effective clotting factor replacement therapy for patients with hemophilia is considered one of the foremost medical advances of the 20th century. The last 3 decades of experience in hemophilia care have witnessed the effectiveness of the care of patients with hemophilia within specialized comprehensive care centers, advances in factor replacement therapies, the benefits of prophylaxis over on-demand replacement therapy, and the role of aggressive management of joint disease to prevent dysfunction. Ongoing challenges, including the management of inhibitors to factor therapies and the consequences of thousands of patients with hemophilia becoming infected with human immunodeficiency virus and hepatitis C virus in the 1980s from contaminated plasma-derived factor concentrates, have highlighted the need for vigilance with respect to clotting factor product safety, access to care, and a full complement of choice of factor replacement therapies. Advate® (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM]) is the first recombinant factor VIII therapy manufactured without human or animal protein additives to eliminate the risk of pathogen transmission that could be carried by these additives. Preclinical studies established bioequivalence with recombinant antihemophilic factor (Recombinate®), a product with 16 years of clinical experience. Currently licensed in 44 countries worldwide, rAHF-PFM has over 7 years of clinical research within 5 global studies supporting its safety and efficacy in the treatment of patients with hemophilia A.
factor VIII; hemophilia A; recombinant proteins; clinical trials
Progressive arthropathy of large joints of the limbs (knees, ankles, elbows), resulting from recurrent joint bleeds and subsequent long-term degenerative phenomena, is one of the main causes of morbidity and of deterioration of quality of life in adult severe hemophiliacs. While primary prophylaxis (i.e. the regular continuous long-term infusion of factor concentrates started before the age of two years and/or after no more than one joint bleed) is nowadays considered the gold standard for preserving joint function in patients with severe haemophilia, the benefits of secondary prophylaxis (i.e., all the long-term regular treatments not fulfilling the criteria of primary prophylaxis) are still controversial.
In this review we present the literature data on secondary prophylaxis, focusing on adolescent and adults haemophiliacs along with clinical experience in Italy.
On the whole, the more recently published studies suggest the effectiveness of early and delayed secondary prophylaxis. However, a number of questions are still unanswered, including the optimal dose, dosing interval and duration of secondary prophylaxis. Only large, prospective, long-term, possibly randomized studies will help to definitively assess the clinical impact of this strategy in adolescent and adult hemophiliacs.
secondary prophylaxis; haemophilia; adolescent-adult; cost; effectiveness; quality of life
Individuals with severe hemophilia A have reduced blood levels of clotting factor VIII (FVIII) leading to recurrent bleeding into joints and muscles. Primary prophylaxis with clotting factor concentrates started early in childhood prevents joint bleeds, thus avoiding joint damage and improving people’s quality of life. There remain significant differences in the implementation of primary prophylaxis worldwide mainly due to the cost of prophylaxis compared with treatment on demand.
To evaluate the cost-effectiveness of primary prophylaxis with FVIII concentrates versus secondary prophylaxis, versus treatment on demand, and versus a “hybrid” (primary prophylaxis followed by on-demand treatment in adults) in individuals with severe hemophilia A.
A Markov model was developed and run using different sources of clinical, cost, and utility data. The model was populated with a hypothetical cohort of 100 individuals with severe hemophilia A. The perspective of the Italian National Health System was used.
The baseline results showed that primary and secondary prophylaxis is cost-effective compared both with treatment on demand and with a hybrid strategy. The incremental costs per quality-adjusted life-year gained for individuals with hemophilia A receiving primary and secondary prophylaxis were €40,229 to €40,236 versus an on-demand strategy. However, the sensitivity analyses performed showed that the results were sensitive to the unit cost of clotting FVIII, bleeding frequency, and the discount rate.
Although primary prophylaxis is a costly treatment, our results show that it is cost-effective compared with treatment on demand.
hemophilia; cost-utility; factor VIII; prophylaxis; treatment on demand; quality of life
We recently re-established a line of sheep that accurately mimics the clinical symptoms and genetics of severe hemophilia A (HA). Herein, we tested a novel, non-ablative transplant therapy in 2 pediatric HA animals. Paternal mesenchymal stem cells (MSC) were transduced with a porcine FVIII-encoding lentivector, and transplanted via the intraperitoneal route, without preconditioning. At the time of transplantation, these animals had received multiple hFVIII treatments for various spontaneous bleeds, and had developed debilitating hemarthroses which produced severe defects in posture and gait. Transplantation of transduced MSC resolved all existent hemarthroses, and spontaneous bleeds ceased. Damaged joints recovered fully; the animals regained normal posture and gait and resumed normal activity. Despite achieving factor-independence, a sharp rise in pre-existent Bethesda titers occurred following transplantation, decreasing the effectiveness and duration of therapy. Post-mortem examination revealed widespread engraftment, with MSC present within the lung, liver, intestine, and thymus, but particularly within joints affected at the time of transplantation, suggesting MSC homed to sites of ongoing injury/inflammation to release FVIII, explaining the dramatic improvement in hemarthrotic joints. In summary, this novel, non-ablative MSC transplantation was straightforward, safe, and converted life-threatening, debilitating HA to a moderate phenotype in a large animal model.
Hemophilia A; large animal model; mesenchymal stem cells; gene therapy; non-ablative transplant
The development of inhibitors against administered clotting factors may render replacement therapy ineffective for some hemophilia patients. Such patients are therefore at the highest risk of developing arthropathy. Elective orthopedic surgery (EOS) in hemophilic patients having such inhibitors remains a rare, expensive, and difficult surgery, whose management represents a significant challenge. We report the case of a 35-year-old man with a severe form of hemophilia A (factor VIII < 1%), who was suffering from repetitive spontaneous hemarthrosis, especially in his knee joints that had consequently become more susceptible to bleeding. The patient had a history of high levels of factor VIII inhibitor (> 5.0 Bethesda Unit [BU]/ml) as shown by the factor VIII inhibitor assay; therefore, we began treatment with factor VIIa for his mild-to-moderate bleeding (90 µg/kg intravenous bolus injections). The interval between injections varied with the severity of the hemorrhage in each bleeding episode. The inhibitor level reduced to 3.1 BU/ml after three months, to 1.6 BU/ml after six months, and disappeared completely after one year of treatment. We administered factor VIII at a dose of 50 IU/kg every eight hours during the first three post-operative days, then continued administration with a dose of 40 IU/kg every 12 hours for another four days, and observed a very good response to treatment with no bleeding. Recombinant activated factor VII (rFVIIa) is not an inhibitor-removal strategy, but an inhibitor-bypassing product. However, in our patient, the treatment of mild-to-moderate bleeding with short-term use of rFVIIa and no exposure to factor VIII caused a gradual reduction in the inhibitor level over a period of 1 year.
Orthopedics; Hemophilia A; Hemophilia B; Inhibitor
Hemophilia is a potentially disabling condition as hemophilic arthropathy develops early in life and is progressive, especially in patients treated in an on-demand regime.
This study aimed to describe the structural joint status and the functional independence score of hemophiliac adults and correlate structural damage with the functional deficits found in these patients.
Hemophiliacs at the Juiz de Fora Regional Blood Center - HEMOMINAS Foundation, aged 18 years and over and treated in an on-demand regime, were clinically evaluated in respect to structural joint damage using the World Federation of Hemophilia Physical Examination Scale (WFH-PE) and functional deficits using the Functional Independence Score in Hemophilia (FISH). The Spearman rank test was used to evaluate the correlation between the two scores.
Thirty-nine patients were evaluated. The mean age was 36.8 years. Target joints were detected in 69.2% of patients studied. The mean Physical Examination Scale and Functional Independence Score were 16.87 and 25.64, respectively. Patients with mild hemophilia showed no significant joint involvement. Patients with severe or moderate hemophilia had similar results regarding structural damage (p-value < 0.001) and functional deficits (p-value = 0.001). There was statistical significance in the correlation between the two scores (r = -0.850; p-value = 0.01).
The World Federation of Hemophilia Physical Examination Scale and Functional Independence Score in Hemophilia may be useful to clinically assess structural joint damage and functional deficits in hemophiliacs as the tools are inexpensive and easy to administer and may be able to detect hemophilic arthropathy, which results from recurrent hemarthrosis and is common in the population studied.
Hemophilia A; Hemophilia B; Joint diseases; Disability evaluation; Hemarthrosis
Classically, a swollen, painful joint in a patient with hemophilia has been considered to be due to a hemarthrosis until otherwise proven, and treated immediately with appropriate coagulation factor replacement. Two cases of human immunodeficiency virus (hiv)-infected hemophiliacs presenting with an initial apparent hemarthrosis, complicated subsequently by numerous pyarthroses and sepsis are described. In light of the prevalence of hiv infection in the adult hemophiliac population with arthropathy, a reappraisal of the clinical caveat of immediate infusion without joint aspiration is required.
Hemophilia; HIV infection; Pyarthrosis
To assess whether viscosupplementation with hyaluronic acid in patients with severe hemophilic arthropathy associated with triamcinolone after washing with saline improves joint pain, stiffness, function and quality of life.
Eleven patients with hemophilic arthritis of the knee with and without involvement of other joints (elbows and ankles) underwent joint lavage with saline and subsequent injection of Hylan and triamcinolone in all affected joints. The patients answered the algo-functional (Lequesne and WOMAC), visual analog scale for pain (VAS) and SF-36 (quality of life) questionnaires preoperatively, and at one and three months postoperatively.
Pain (VAS and WOMAC pain) and stiffness (WOMAC stiffness) did not show significant improvement (p = 0.3, p = 0.2, p = 0.1, respectively). However function had significant improvement given by WOMAC total and function (averaging 11 points, p = 0.04 and p = 0.001). There was no significant variation in scores in Lequesne's questionnaire (p = 0.1), yet both mental and physical components of SF-36 presented clinically relevant and significant improvements (p = 0.002).
Joint lavage with saline followed by injection of corticosteroids and Hylan is effective in the treatment of hemophilic arthropathy, especially in functional improvement and quality of life. Level of Evidence IV, Case series.
Hemophilia; Osteoarthritis; Knee; Hyaluronic acid/ administration & dosage; Hyaluronic acid/therapeutic use
Pyogenic arthritis in patients with hemophilia is predominantly monoarticular, usually involving the knee, is associated with hemophilic arthropathy and other predisposing factors for infection, is mainly due to Staphylococcus aureus and carries serious morbidity. In patients with hemophilia, it is associated significantly with fever, an increased leukocyte count, knee joint involvement and possible predisposing factors for infection. Such patients presenting with unexplained fever of more than 1°C(1.8°F) and acute symptoms of joint inflammation should have an arthrocentesis.
Objective: We aimed to assess the role of Magnetic Resonance Imaging (MRI) and X-Ray in the evaluation of response to radiosynovectomy (RS) in patients with hemophilic arthropathy.
Material and Methods: Eleven patients who suffered from hemophilic arthropathy with a mean age of 11.7 (range between 7-15) were included in this study. 148-185 MBq Yttrium 90 silicate (Y-90) was administered intraarticularly to ten knee joints and one patient was treated with intraarticular 74 MBq Rhenium 186 (Re-186) injection into his ankle. Before radiosynovectomy, plain anteroposterior and lateral X-rays of the target joints were obtained by standard technique. The follow-up MRI and X-ray studies of the patients were done 6 months after RS. Pettersson hemophilic arthropathy scales were utilized to stage the condition of the joints on plain X-ray and classification of the investigated joints on MRI were done according to Denver score. The clinical assessment of the efficacy of the RS was made with the comparison of the average bleedings before and after the intervention.
Results: During the 6-month follow-up period after RS, an improvement in number of hemarthrosis 75% or greater compared with the prior six months occurred in six joints (54.5%). The Pettersson scores worsened in 1/11 (9%), remained unchanged in 9/11 (81.8%), and improved in 1/11 (9%) joints. At the 6-month follow-up, the MRI score worsened in one (9%) and was unchanged in 10/11 joints (90.9%).
Conclusion: MRI is a more sensitive tool than plain radiography for evaluating and follow-up of joint disease in persons with hemophilia, but both methods don’t show correlation with the therapeutic response
Conflict of interest:None declared.
Radiosynovectomy; hemophilic arthropathy; magnetic resonance imaging; therapy response
Objective: To present the case of a collegiate soccer player who suffered from a traumatic knee hemarthrosis secondary to hemophilia A. This case presents an opportunity to discuss the participation status of athletes with hemophilia.
Background: Hemophilia is a hereditary blood disease characterized by impaired coagulability of the blood. Hemophilia A is the most common of the severe, inherited bleeding disorders. This type, also called classic hemophilia, is due to a deficiency of clotting factor VIII. The athlete with hemophilia A reported pain and loss of function of his knee during a soccer game despite the absence of injury.
Differential Diagnosis: Anterior cruciate ligament tear, intra-articular fracture, meniscus tear, capsular tear, hemarthrosis.
Treatment: After the injury, the athlete was admitted to the hospital, where his knee joint was aspirated and he was infused with factor VIII. Later, he participated in traditional knee rehabilitation and was returned to play at the discretion of the orthopaedist and the hematologist.
Uniqueness: In past participation guidelines, individuals with bleeding disorders were disqualified from athletic participation; however, with advances in medical care, these individuals may be permitted to participate in accordance with the law.
Conclusions: Individuals with hemophilia participate in athletics; therefore, team physicians and athletic trainers must be prepared to care for these individuals.
Americans with Disabilities Act; desmopressin acetate; factor VIII; preparticipation physical examination; blood coagulation
Radisosynovectomy (RS) is a local form of radionuclide therapy used in various forms of arthritis characterized by synovitis. In hemophilic arthropathy, RS provides removal of inflamed synovium and prevents further joint damage. This review focuses on the practical aspects of radionuclide synovectomy in hemophilic patients and describes the issues both related to the methodology and post-therapeutic follow-up.
Conflict of interest:None declared.
radioisotope therapy; Hemophilia; synovitis
Over the past forty years the availability of coagulation factor replacement therapy has greatly contributed to the improved care of people with hemophilia. Following the blood-borne viral infections in the late 1970s and early 1980, caused by coagulation factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer treatment became crucial to the hemophilia community. The introduction of virus inactivated plasma-derived coagulation factors and then of recombinant products has revolutionized the care of these people. These therapeutic weapons have improved their quality of life and that of their families and permitted home treatment, i.e., factor replacement therapy at regular intervals in order to prevent both bleeding and the resultant joint damage (i.e. primary prophylaxis). Accordingly, a near normal lifestyle and life-expectancy have been achieved. The main current problem in hemophilia is the onset of alloantibodies inactivating the infused coagulation factor, even though immune tolerance regimens based on long-term daily injections of large dosages of coagulation factors are able to eradicate inhibitors in approximately two-thirds of affected patients. In addition availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of this complication. The major challenges of current treatment regimens, such the short half life of hemophilia therapeutics with need for frequent intravenous injections, encourage the current efforts to produce coagulation factors with more prolonged bioavailability. Finally, intensive research is devoted to gene transfer therapy, the only way to ultimately obtain cure in hemophilia.
FVIII; FIX; Plasma-derived factor concentrates; Recombinant factor concentrates; Gene therapy
The aim of this study was to investigate prophylactic treatment effects in Korean patients with severe hemophilia A.
A prospective study of 32 severe hemophilia A patients was conducted with the approval of the Institutional Review Board at the Eulji University Hospital. Two patients received primary prophylaxis; whereas, the other 30 patients were divided into 2 groups-secondary prophylaxis (n=15) and on-demand (n=15)-on the basis of their consent for secondary prophylaxis. A 20-25 IU/kg dose of factor VIII concentrate was administered to the primary and secondary prophylaxis group patients every 3 days for 1 year. The prophylactic effect was evaluated by observing changes in the Pettersson scores, annual number of total and joint bleeds, and factor VIII consumption for 1 year.
No moderate or severe bleeding was observed, and the Pettersson scores remained unchanged during the prophylaxis period in the patients who received primary prophylactic treatment. After the treatment was changed from on-demand to secondary prophylaxis, the annual number of total and joint bleeds in the secondary prophylaxis group decreased by 64.4%±13.0% and 70.0%±15.2%, respectively. The average increase in Pettersson scores within 1 year was 0.5±0.8 and 1.3±1.1 in the secondary prophylaxis and on-demand groups, respectively. Prophylactic effects were also observed in patients >17 years who had nearly the same initial Pettersson scores.
Intermediate-dose prophylactic treatment may delay hemarthropathy progression and prevent its occurrence in Korean severe hemophilia A patients.
Hemophilia A; Factor VIII; Prophylaxis
The bypassing agent recombinant factor VIIa (rFVIIa) is efficacious in treating bleeding in hemophilia patients with inhibitors. Efforts have focused on the rational engineering of rFVIIa variants with increased hemostatic potential. One rFVIIa analog (V158D/E296V/M298Q-FVIIa, NN1731) improves thrombin generation and clotting in purified systems, whole blood from hemophilic patients and factor VIII-deficient mice.
We used calibrated automated thrombography and plasma clotting assays to compare effects of bypassing agents (rFVIIa, NN1731) on hemophilic clot formation, structure, and ability to resist fibrinolysis.
Both rFVIIa and NN1731 shortened the clotting onset and increased the maximum rate of fibrin formation and fibrin network density in hemophilic plasma clots. In the presence of tissue plasminogen activator, both rFVIIa and NN1731 shortened the time to peak turbidity (TTPeaktPA) and increased the area under the clot formation curve (AUCtPA). Phospholipids increased both rFVIIa and NN1731 activity in a lipid concentration-dependent manner. Estimated geometric mean concentrations of rFVIIa and NN1731 producing similar onset, rate, TTPeaktPA, and AUCtPA as seen with 100% factors VIII and IX were: 24.5, 74.3, 29.7, and 37.1 nM rFVIIa, and 8.6, 31.2, 9.0, and 11.3 nM NN1731, respectively. In each case, the NN1731 concentration was significantly lower than rFVIIa.
These findings suggest that like rFVIIa, NN1731 improves the formation, structure, and stability of hemophilic clots. Higher lipid concentrations may facilitate assessment of both rFVIIa and NN1731 activity. NN1731 appears likely to support rapid clot formation in tissues with high endogenous fibrinolytic activity.
hemophilia; recombinant factor VIIa; fibrinogen; fibrinolysis; NN1731
A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A. I hypothesize that adults with mature cartilage and joints are less susceptible to joint bleeds and joint damage, and that once-weekly recombinant factor VIII prophylaxis, with up to two rescue doses per week, is as effective as thrice-weekly prophylaxis in reducing bleeding frequency, but less costly and more acceptable, with higher quality of life. The ultimate goal of this project is to determine whether once-weekly prophylaxis is any worse than thrice-weekly prophylaxis in reducing joint bleeding frequency, while potentially utilizing less factor, at lower cost, leading to a better quality of life. This is an innovative concept, as it challenges the current paradigm of thrice-weekly prophylaxis in adults, which is based on dosing in children. Furthermore, this trial will assess interdose thrombin generation, a novel tissue factor-based assay of hemostasis, to determine if individualized thrombin generation can predict more individualized prophylaxis dosing, which would be practice changing.
factor VIII; hemophilia; joint bleeds; prophylaxis; thrombin generation
In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients’ physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life.
hemophilia; quality of life; factor VIII inhibitors; hemophilia treatment center; early treatment; bypassing agent
Hemophilia is uncommon in females and there is little knowledge about the clinical manifestation.
We report here an unusual case of three hemophilic females diagnosed as factor IX deficient. Normal reports of ultrasonography (USG) and relevant endocrine investigations conducted in two adult females ruled out any usual gynecological and endocrinal causes of bleeding. Complete coagulation profiles were conducted and diagnosed these female bleeders to be hemophiliacs suffering from factor IX deficiency.
Females presenting with menorrhagia and bleeding from other sites without any discernable cause require proper evaluation for congenital coagulation disorders. In the present case series, females are diagnosed factor IX deficient (Hemophilia B).