Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

How do we optimally utilize factor concentrates in persons with hemophilia?

The current mainstay of therapy for hemophilia is to replace the deficient clotting factor with the intravenous administration of exogenous clotting factor concentrates. Prophylaxis factor replacement therapy is now considered the standard of care in both pediatric and adult patients with hemophilia with a severe phenotype to protect musculoskeletal health and improve quality of life. Heterogeneity in bleeding presentation among patients with hemophilia due to genetic, environmental, and treatment-related factors has been well described. Accordingly, the World Federation of Hemophilia recommends an individualized prophylaxis regimen that considers the factors mentioned above to meet the clinical needs of the patient, which can vary over time. This review focuses on the practical points of choosing the type of factor concentrate, dose, and interval while evaluating appropriate target trough factor levels and bleeding triggers such as level of physical activity and joint status. We also discuss the use of a pharmacokinetics assessment and its incorporation in the clinic for a tailored approach toward individualized management. Overall, adopting an individualized prophylaxis regimen leads to an optimal utilization of factor concentrates with maximum efficacy and minimum waste.

Reduced cardiovascular morbidity in patients with hemophilia: results of a 5-year multinational prospective study

Hemophilia is a congenital bleeding disorder caused by low clotting factor VIII or IX levels. Life expectancy of people with hemophilia (PWH) has increased with the availability of clotting factor concentrates. At the same time, the incidence of cardiovascular disease (CVD) has increased. In retrospective studies there are conflicting data if, despite this increase, the incidence is still lower than in the general population. We prospectively compared the incidence of CVD in PWH with the predicted incidence. This prospective, multicenter, observational study included adult PWH (>30y) from the Netherlands and United Kingdom (UK). They were followed for a 5-year period and CVD incidence was compared with a predicted event rate based on the QRISK2-2011 CVD risk model. The primary endpoint was the observed fatal and nonfatal CVD incidence after 5 years compared to the estimated events and in relation to severity of hemophilia. The study included 709 patients, of whom 687 (96.9%) completed 5 years follow up or reached an endpoint. For 108 patients the QRISK score could not be calculated at inclusion. For the remaining 579 fewer CVD events were observed than predicted: 9 versus 24 (RR 0.38; 95% CI: 0.18 - 0.80 p=0.01), corresponding with an absolute risk reduction of 2.4%. Severe hemophilia treated on demand had the highest risk reduction. There was no statistical significant relation between severity of hemophilia and incidence of CVD. In hemophilia a lower than predicted CVD incidence was found, supporting the theory that hemophilia protects against CVD. The study is registered at www.clinicaltrials.gov (identification number NCT01303900).

Thermolability of factor VIII in donor fresh frozen blood plasma

A criterion of the quality of fresh frozen blood plasma (FFP) is the activity of clotting factor VIII (FVIII).Aim — to identify technological barriers in the study of FVIII thermolability and to describe the requirements for experiments, providing new knowledge about the thermolability of this factor.Basic information. An analysis of domestic and foreign publications devoted to the study of the mechanisms responsible for reducing the value of FVIII activity in donor blood plasma from the moment of donation to the moment of transfusion was carried out. Data on the decrease in FVIII activity at various stages of work with blood plasma are presented. An analysis of methods for preparing samples for studying changes in the values of FVIII in donor blood plasma was performed. The existence of contradictory conclusions about the infl uence on the change in FVIII at the thawing stage of various values of the effects on FFP and poor knowledge of the change in the indicator at the stage of heating to the transfusion temperature after the end of the phase transition in the samples was established. The fundamental differences in the methods of preparing and conducting experiments in previous works are determined. Methods for increasing the reliability of experimental results for studying the thermal lability of FVIII are proposed.

Impact of pharmacokinetics to reduce bleeding in a cohort of patients with severe hemophilia A in a personalized comprehensive management program

Introduction: In recent decades, hemophilia A treatment has been focused on body weight, without taking pharmacokinetic parameters into account. Previous research has shown that the individual pharmacokinetic response is more effective in predicting the required dose of clotting factor. We want to evaluate the impact on reducing the frequency of bleeding in patients treated with recombinant factor VIII, based on a personalized comprehensive management program. Objective: Our aim was to compare the results of a standard comprehensive treatment program (stage I) vs. a personalized pharmacokinetic - based treatment program (stage II) in a cohort of 60 patients with severe hemophilia without inhibitors. Results:The median age was 15.5 years (3 - 68). The ABR was 1.03 (62 episodes) in the first stage and 0.58 (35 episodes) in the second one, (p = 0.004). By type of bleeding, the impact of the intervention differs significantly in spontaneous bleeding (p = 0.007) and a 73% reduction in the first stage. There were no significant differences in traumatic bleeding. Conclusions: The use of pharmacokinetics for personalized dosing of patients with severe hemophilia A, significantly reduces ABR and spontaneous bleeding, improving the patient's quality of life and costs for the health system.

Von Willebrand disease in pregnancy: a case report

Von Willebrand disease (VWD) is a hereditary bleeding disorder that can be severe and potentially life-threatening, particularly in pregnant women during labor and subsequently during early puerperium. There is no optimal treatment or management for this disorder. Hence, all efforts aim at early diagnosis and the focus is mainly on minimising and controlling blood loss. We described the case of a woman in the post-partum period with severe VWD, admitted in the obstetrics and gynaecology ward at Rajarajeswari Medical College and Hospital, Bangalore. Prompt diagnosis, initiation of pre-partum and intra-partum Von Willebrand factor (VWF)/clotting factor replacement therapy, vigilant post-partum monitoring of blood loss and systematic follow up will help expedite recovery and prevent adverse outcomes.

Coagulopathies in Intensive Care Medicine: Balancing Act between Thrombosis and Bleeding

Patient Blood Management advocates an individualized treatment approach, tailored to each patient’s needs, in order to reduce unnecessary exposure to allogeneic blood products. The optimization of hemostasis and minimization of blood loss is of high importance when it comes to critical care patients, as coagulopathies are a common phenomenon among them and may significantly impact morbidity and mortality. Treating coagulopathies is complex as thrombotic and hemorrhagic conditions may coexist and the medications at hand to modulate hemostasis can be powerful. The cornerstones of coagulation management are an appropriate patient evaluation, including the individual risk of bleeding weighed against the risk of thrombosis, a proper diagnostic work-up of the coagulopathy’s etiology, treatment with targeted therapies, and transfusion of blood product components when clinically indicated in a goal-directed manner. In this article, we will outline various reasons for coagulopathy in critical care patients to highlight the aspects that need special consideration. The treatment options outlined in this article include anticoagulation, anticoagulant reversal, clotting factor concentrates, antifibrinolytic agents, desmopressin, fresh frozen plasma, and platelets. This article outlines concepts with the aim of the minimization of complications associated with coagulopathies in critically ill patients. Hereditary coagulopathies will be omitted in this review.

Acquired Factor VIII Deficiency Presenting as Gross Hematuria in a Hispanic, Pregnant Patient with Previously Undiagnosed Connective Tissue Disease

Acquired factor VIII deficiency is a bleeding disorder caused by the presence of autoantibodies against clotting factor VIII. We report a case of a 24-year-old pregnant woman who presented with gross hematuria secondary to acquired factor VIII deficiency in the presence of a previously undiagnosed connective tissue disease. This article includes a literature review of pregnancy-related cases of acquired factor VIII deficiency. We also reviewed various therapeutic approaches for the management of the acquired factor inhibitor which include achieving hemostasis and elimination of the inhibitor via immunosuppressive agents. This case report describes the rare presentation of acquired factor VIII deficiency related to pregnancy and highlights the importance of considering a factor VIII inhibitor in the differential diagnosis of patients who present with bleeding and prolonged PTT during the peripartum and postpartum periods.

Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

Introduction Complications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration. Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB. Methods Data from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses. Results A total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001). Conclusions The results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. Disclosures Ali: UniQure: Current Employment. Li: UniQure: Current Employment. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony: BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe: Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.

Factor VIII Level Comparison in Patients with Severe Hemophilia a on Emicizumab with Inhibitors with One Stage, Bovine and Human Chromogenic Assays and the Factor VIII Equivalency of Emicizumab Using In Vivo Global Hemostasis Assays

Introduction Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with hemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to compare the current available laboratory methods in clinical practice; one-stage clotting factor assays (OSCA), bovine and human chromogenic FVIII activity (bovCHR and humCHR, respectively) and FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). Aims The aim of this study is to address the differences of FVIII activity with different techniques in patients with severe HA with inhibitors on emicizumab. Materials and Methods Factor VIII levels are determined with an activated partial thromboplastin time (aPTT), OSCA using SynthASil on the ACL TOP 500 (Instrumentation Laboratory, Bedford, MA). Factor VIII activity is also determined photometrically via the Chromogenix Coatest® SP4 FVIII chromogenic assay kit (bovCHR, Diapharma Group, West Chester, OH) and the Biophen FVIII:C chromogenic assay kit (humCHR, Aniara Diagnostica, West Chester, OH). For F8EmT, linear regression was utilized to model the FVIII levels as a function of the endogenous thrombin potential (ETP) and peak thrombin values for patients with mild/moderate hemophilia. Then, we used the ETP and peak thrombin results of the severe HA patients on emicizumab with the calibration curve to calculate their F8EmT. Association between patient weight and their F8EmT were also examined and evaluated by linear regression. Results Data is presented for eight patients with severe HA with inhibitors on emicizumab in the non-bleeding state (Table-1). All patients' FVIII levels measured with OSCA are in or above the normal range (94.0-289.1). Bovine chromogenic FVIII activity is in the severe hemophilia range for five out of eight patients, for the rest it is in the moderate hemophilia range. Human chromogenic FVIII activity ranged between 12.5-49.8%. Factor VIII Equivalency of Emicizumab by Thrombin Generation is either in the mild hemophilia or normal range in all participants of the study. Conclusion One-stage clotting factor assays demonstrated falsely high results as expected since it is activated partial thromboplastin time based. Bovine chromogenic FVIII activity results were consistent with the severe HA range of the patients though a few had results slightly above that level. Previous literature has stated that the humCHR in patients on emicizumab results in FVIII levels of ∼30% when emicizumab is at its therapeutic concentration (∼50 mcg/ml). This study also demonstrated similar results with 5/8 patients having levels 30-50%. F8EMT levels were mostly consistent with the humCHR. In conclusion, understanding the degree to which emicizumab corrects the coagulation defect of is an important goal as it has clinical implications.Certainly, additional studies with higher participant numbers are needed to confirm these findings. Figure 1 Figure 1. Disclosures Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding.