Prophylaxis with Once, Twice or Three-Times Weekly Dosing of rFVIII-FS prevents Joint Bleeds in a Previously Treated Pediatric Population with Moderate/Severe Hemophilia A

ABSTRACT

PURPOSE

This prospective study evaluated three different prophylaxis regimens for preventing joint bleeds and preserving the joint status in previously treated children with severe or moderate hemophilia A.

METHODS

Previously treated children (>20 exposure days [ED], on-demand or prophylaxis) with severe or moderate hemophilia A were allocated to receive one of three treatment regimens – regimen 1: subjects received 70 IU/kg once per week; regimen 2: subjects received two doses per week (30 IU/kg plus 40 IU/kg); and regimen 3: subjects received 25 IU/kg three times per week; with option for escalation for regimen 1 and 2 in the event of a joint bleed. The primary efficacy variable was the proportion of patients with <2 joint bleeds during the 9-month treatment period.

RESULTS

A total of 32 children, aged between 1 and 13 years, participated in this study, and all of them were included in the efficacy and safety analysis. Overall, 78.1% of subjects achieved the primary efficacy endpoint. All three regimens reduced the bleeding rate compared to 6 months prior to study entry. This was accompanied by a stabilized or even improving joint status and an improved quality of life. Dose escalation was required in seven patients. All regimens were well tolerated, and the incidence of adverse events (AEs) during the study period was as expected for children in this age group. One case of transient low titer FVIII inhibitor development in a previously untreated child was reported. The results indicated a higher effectiveness of regimen 3.

CONCLUSION

This study demonstrated that prophylaxis with once, twice, and especially three-times weekly rFVIII-FS dosing protects children from bleeding events, in particular from joint bleeds.

Current Practice in Clinical Thrombosis and Hemostasis

ABSTRACT

Clinical thrombosis and hemostasis is emerging as a growing subspecialty area characterized by an increasing interaction between clinical and laboratory medicine and many other disciplines. The impact of these changes on the activity and workload of specialized hemostasis and thrombosis clinics has so far not been analyzed.

Reasons for referral, final diagnoses, and results of hemostatic evaluations in all out-patients referred over a 24-month period to the Haemostasis and Thrombosis Unit and Haemophilia Center of the Cliniques Universitaires Saint-Luc, Brussels, were reviewed.

In total, 4502 out-patient consultations were analyzed representing 23% of the total activity of the hematology division. A majority of patients (63.6%) were referred for venous or arterial thromboembolic diseases including venous thromboembolic events (30.8%), thrombophilia screening for complicated pregnancy and monitoring of anticoagulation during pregnancy (12.2%), primary or secondary venous insufficiency (10.9%), arterial thrombosis (6.3%), or family screening for thrombophilia (3.4%). A smaller group (23.7%) was referred for evaluation of bleeding symptoms (14.2%) or follow-up of inherited bleeding disorders (hemophilia, 7.0% and von Willebrand disease, 1.3%). A thrombophilic trait was found among 28% of patients referred for thrombophilia testing. Among patients with bleeding symptoms, a biological abnormality was found in 32.6% of patients using routine tests.

Since the conclusions of this study largely reflect the local set-up and patterns of referral to a single thrombosis and hemostasis clinic, they cannot be generalized and extrapolated to other centers. They, however, provide valuable and original information on the wide spectrum of clinical hemostasis and thrombosis and highlight the competences and skills needed by specialists in coagulation disorders.

Review of the Literature of FEIBA Administration in Patients with Hemophilia B and Inhibitors

ABSTRACT

During the last three decades, the use of FEIBA (Factor Eight Inhibitor Bypassing Activity, Baxter AG, Vienna, Austria) has steadily increased in the management of patients with hemophilia A and inhibitors. This literature review focuses on the reported use of FEIBA in hemophilia B patients with inhibitors, as these rare individuals present with unique management challenges. We have identified and described a total of 37 reports (1979–2010) on the use of FEIBA in 46 hemophilia B patients aged 2–70 years with inhibitors. FEIBA effectively and safely controlled a range of acute soft tissue and joint hemorrhages including several severe and life-threatening bleeding episodes. When used to cover surgery, FEIBA provided appropriate hemostatic control, enabling even major surgeries to be completed successfully. FEIBA also provided effective bleed prevention, allowing several individuals to undergo intensive rehabilitation with good long-term clinical outcomes. FEIBA was well tolerated in the majority of cases reported, although anaphylaxis to factor IX (FIX) was reported in six patients. There were no reports of nephrotic syndrome, but three thrombotic complications were potentially related to FEIBA administration. This review demonstrates that over recent years, anti-inhibitor treatment strategies have been extended to hemophilia B patients with inhibitors including prophylaxis, immune tolerance induction (ITI), and surgery. Although accepting the limitations of using a case series approach to evaluate the efficacy and safety of FEIBA in hemophilia B patients with inhibitors, the findings reported suggest that FEIBA represents an essential treatment option for these rare but clinically challenging individuals.

Decreased Bone Mineral Density in Adult Patients with Hemophilia: Clinical Significance, Prevalence and Risk Factors

ABSTRACT

Osteoporosis is widely recognized as a major health problem, and considerable resources are spent screening, diagnosing, and treating this disease in postmenopausal women. Adults with hemophilia have unique factors that place them at an increased risk for developing osteoporosis including periods of immobilization after bleeds, impaired joint mobility that may limit weight bearing physical activity, and infection with Hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV). Several publications report the prevalence of osteoporosis in adults with hemophilia to be in the range of 25% and 50%. The severity of hemophilic joint arthropathy appears to be the strongest predictor of significant bone loss in patients with hemophilia. The relative contribution of other risk factors, including HIV and HCV infection are less well defined. The clinical significance of decreased bone mineral density as measured by dual energy X-ray absorptiometry (DXA) to fracture risk in men, and in particular younger men, is also unclear. We recommend screening adult patients with hemophilia with documented fragility fractures, in those with severe joint arthropathy, and in those patients >50 years of age with additional risk factors such as HIV/HCV infection or low BMI. Adequate vitamin D and calcium intake, weight bearing physical activity, and interventions to maintain joint mobility are recommended for all hemophilia patients. The role of pharmacologic agents, including bisphosphonates, is untested, and they should be reserved for those with documented osteoporosis and fragility fractures or additional risk factors that place them at high risk for developing fragility fractures.

Safety of Recombinant Factor VIII Therapy: Focus on Inhibitor Development

ABSTRACT

INTRODUCTION

Pathogen transmission and inhibitor development are the principal safety concerns when treating hemophilia A with factor VIII (FVIII) replacement therapy. The availability of recombinant FVIII (rFVIII) products, which are manufactured using little or no plasma-derived proteins, has minimized the risk of pathogen transmission but has not eliminated the possibility of FVIII inhibitor development.

OBJECTIVES

To review the safety issues related to use of second- and third-generation rFVIII products with a focus on incidence of inhibitor development.

METHODS

A Medline search was conducted using the search terms “recombinant factor VIII” and “safety.” Articles from this search were selected based on their relevance to the topic and supplemented with papers identified by reviewing the reference lists of published work.

RESULTS

The manufacture of rFVIII products differs from that of plasma-derived FVIII products in that plasma-derived proteins are used only in the culture medium (second-generation rFVIII products) or not at all (third-generation rFVIII products), limiting the risk of blood-borne pathogen transmission. In clinical trials involving previously untreated patients (PUPs), the incidence of inhibitor development for the second-generation rFVIII product formulated with sucrose (rFVIII-FS) was 15%, which compares favorably with the incidence range reported for clinical trials in PUPs receiving other rFVIII products (19%–35%).

CONCLUSION

Differences in study design and patient populations complicate comparisons of inhibitor formation among rFVIII products, but the incidence of inhibitor development with rFVIII products generally appears to be low.

Bone Marrow Transplantation Related Thrombotic and Hemorrhagic Complications: An Updated Review

ABSTRACT

Thrombotic and hemorrhagic complications are common in bone marrow transplantation (BMT) recipients. Endothelial cell injuries due to chemotherapy, growth factors, intravenous catheter, graft versus host disease, as well as profound thrombocytopenia are major components involved in the hemostatic complications. Common thrombotic manifestations include veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA). Diffuse alveolar hemorrhage and hemorrhagic cystitis are severe bleeding manifestations in BMT recipients with high morbidity and mortality rate and no effective treatment. More intensive conditioning regimens and mismatched donors increase the risk of hemostatic complications. Management of thrombotic and bleeding complications is discussed including current data on the role of recombinant factor VIIa for severe hemorrhage and defibrotide for VOD.

Risk for Cardiovascular Disease in Pregnant Women with Familial Hypercholesterolemia: A Review on the Endothelial and Hemostatic Balance in a Clinical Perspective

ABSTRACT

OBJECTIVES

Familial hypercholesterolemia leads to a markedly increased risk for atherosclerotic disease with a more pronounced increase in relative risk in young middle aged patients versus older. Women with FH need to stop treatment with virtually all types of lipid lowering medication during pregnancy and lactation. The aim of the study was to review the literature to examine if pregnancy increases the risk for vascular disease in women with FH.

METHODS

A search in PubMed for “acute myocardial infarction AND pregnancy” resulted in 433 references on which the present paper is based. These studies were interpreted based on nearly 20 years of clinical experience with the treatment of FH in a large lipid clinic.

RESULTS

Pregnancy increases vascular stress, alters the hemostatic balance, and activates the endothelium, but there is almost no data on clinical vascular disease regarding pregnant women with FH.

CONCLUSION

Several important risk factors for arterial vascular disease are negatively influenced by pregnancy, but current literature is too sparse to allow any conclusion on the risk for major cardiovascular outcomes in women with FH during pregnancy.

Disseminated Intravascular Coagulation

ABSTRACT

OBJECTIVES

To review the current knowledge on the clinical manifestation, pathogenesis, diagnosis, and management of disseminated intravascular coagulation (DIC).

DATA SOURCES

Selected articles from the Medline database.

RESULTS

DIC may complicate a variety of disorders and can cause significant morbidity (in particular related to organ dysfunction and bleeding) and may contribute to mortality. The pathogenesis of DIC is based on tissue factor-mediated initiation of systemic coagulation activation, insufficiently contained by physiological anticoagulant pathways, and amplified by impaired endogenous fibrinolysis. The diagnosis of DIC can be made using routinely available laboratory tests and scoring algorithms. Supportive treatment of DIC may be aimed at replacement of platelets and coagulation factors, anticoagulant treatment, and restoration of anticoagulant pathways.

CONCLUSION

Insight into the pathogenesis of DIC has resulted in better strategies for clinical management including straightforward diagnostic criteria and potentially beneficial supportive treatment options.

Prevention of Venous Thromboembolism in Patients With Cancer in Spain

ABSTRACT

BACKGROUND

There is scarce information on the strategies for preventing venous thromboembolism (VTE) in patients with cancer.

PATIENTS AND METHODS

We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) database to retrospectively assess the clinical characteristics, prophylactic details, and 3-month mortality of all Spanish patients with active cancer.

RESULTS

Of 24 382 patients enrolled as of October 2009, 4664 (19%) had active cancer, of whom 736 (16%) had recent surgery, and 909 (19%) had recent immobility for ≥4 days. Of these, 68% of the surgical (95% CI: 65–71) and 29% of the immobilized patients (95% CI: 26–32) had received VTE prophylaxis. The 3-month incidence rate of fatal bleeding, fatal pulmonary embolism (PE), and overall death were: 0.68% (95% CI: 0.25–1.45), 1.36% (95% CI: 0.69–2.41), and 13.7% (95% CI: 11.4–16.4), respectively, in the surgical patients. In VTE patients after immobility for ≥4 days, the incidence rates were: 3.52% (95% CI: 2.46–4.87), 5.06% (95% CI: 3.77–6.64), and 44.4% (95% CI: 41.2–47.7), respectively. In the 3019 patients with no recent surgery or immobilization the incidence rates were: 1.32% (95% CI: 0.96–1.78), 3.05% (2.48–3.71), and 23.0% (95% CI: 21.6–24.5), respectively.

CONCLUSIONS

In RIETE, we found a substantial underuse of VTE prophylaxis in at-risk patients, particularly in cancer patients with immobility ≥4 days. This is important because their 3-month outcome is much worse.

Isolated Recurrent Lower Limb Deep Vein Thrombosis: A Rare Presentation of Paroxysmal Nocturnal Hemoglobinuria

ABSTRACT

Paroxysmal nocturnal hemoglobinuria(PNH) is an uncommon disease. Overall estimated prevalence of PNH is less than 1 in 100000. It is acquired stem cell disorder characterized by chronic hemolytic anemia due to intravascular hemolysis, nocturnal hemoglobinuria, thrombosis and pancytopenia-Non malignant clonal expansion of hematopoetic stem cells having acquired mutation of phosphatidylinositol glycan complementation class A gene (PIG-A) is the basic molecular defect.Thrombosis of visceral veins is common in PNH. Hepatic veins are commonly involved presenting as Budd Chiari Syndrome. Arterial thrombosis can also occur that lead to cerebral infarct. We evaluated a patient who was suffering from recurrent deep vein thrombosis (DVT) of left lower limb which is a rarely reported presentation of PNH.

Combined Protein C and Protein S Deficiency Presenting as Deep Vein Thrombosis

ABSTRACT

Vitamin K dependent factors protein C and protein S act as anticoagulants by degrading the activated factors V and VIII. Deficiency of these factors, acquired or hereditary, are associated with increased risk of venous thrombosis. A patient having combined deficiency of both factors protein C and protein S is very rare. Here, we report a 59-year-old Asian female who presented with pain and swelling of the right lower extremities. Venous Doppler showed deep venous thrombus in the right femoral vein and further evaluation of coagulation profile showed combined deficiency of protein C and S. She was then started on long-term anticoagulant therapy. In conclusion, combined deficiency of protein C and protein S is extremely rare. Anticoagulation therapy is the cornerstone in the management of patients with inherited coagulation defects.

Home Versus Hospital Treatment With Bypassing Agent: An Economic Analysis

ABSTRACT

Treatment of acute bleeding episodes in patients with hemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing agents such as activated prothrombin complex concentrate (aPCC) or recombinant factor VIIa (rFVIIa).

Home treatment of acute bleeding in patients with inhibitors provides clinical advantages, increased convenience, and time saved for the patient. The time between the first symptom of bleeding and initiation of treatment is reduced compared to hospital treatment, minimizing the potential damages caused by the hemorrhage. Although home treatment with bypassing products is an option today, documentation of safety, efficacy, and cost-effectiveness is rather scarce.

We conducted a cost-minimization analysis from a societal perspective with the objective to compare the economic consequences of home treatment versus hospital treatment with a bypassing product. The analysis was based on the prospective, single-center study on long-term home treatment with bypassing agents in inhibitor patients ¹. The cost per bleeding episode for home treatment was estimated by assessing the resource use of the 10 patients followed for 7.5 years in the study.

Our cost-minimization analysis demonstrates that the total average societal costs per bleeding episode associated with hospital treatment is noticeably higher than the costs associated with home treatment in a centralized hemophilia care setting as in our study performed in Norway. However, the results of the scenario analysis demonstrated that home treatment would still be preferential both from a clinical and economic perspective also in countries with a more decentralized care of hemophilia patients.