Despite the worldwide prevalence of rare bleeding disorders (RBDs), knowledge of these conditions and their management is suboptimal; health care professionals often have little diagnostic and ...treatment experience with variable access to diagnostic modalities required for accurate identification. Therefore, patients often experience morbidity and mortality due to delayed diagnosis. As RBDs represent a small potential commercial market, few, if any, specific therapies exist for these conditions. As a result, affected individuals commonly face delayed diagnosis, incomplete laboratory evaluation, and limited treatment options. Standardization and customization of coagulation assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with RBDs. In addition, new therapeutic modalities, both recombinant and plasma derived, are emerging, at least in developed countries. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are appropriately diagnosed and properly treated. Expansion and harmonization of international registries has been initiated to correlate genotype, laboratory, and clinical phenotypes including bleeding severity to improve the diagnosis and therapeutic approach. This review focuses on the latest advances in our understanding, diagnosis, and treatment of RBDs.
Modern haemophilia care Berntorp, Erik, Prof; Shapiro, Amy D, MD
The Lancet (British edition),
04/2012, Letnik:
379, Številka:
9824
Journal Article
Recenzirano
Haemophilia care has undergone substantial improvements during the past 40–50 years. Early clotting factor concentrates were not sufficiently refined to enable self-administered treatment at home ...until the 1970s. Unfortunately, these advances led to transmission of viral diseases including HIV and hepatitis, resulting in an increased burden of morbidity and mortality, especially during the 1980s. Throughout the past two decades, product development, including the advent of recombinant concentrates, has greatly improved the safety and availability of therapy and the focus of care is shifting towards prevention and management of disease sequelae. Long-term substitution therapy (prophylaxis) of the missing clotting factor is the recommended treatment in severe haemophilia, but several research issues remain to be elucidated such as when to start and how to optimise these regimens, and when or whether to stop this expensive treatment. The major side-effect of treatment, development of inhibitors to the infused concentrate, is the main threat to the health of patients and consequently the goal of intense research. Development of new products with improved pharmacokinetics is the next step to improved therapy.
Introduction
Recent technological innovations in haemophilia have advanced at an astounding pace, including gene therapy programmes and bioengineered molecules for prophylaxis, products that reduce ...treatment burden through half‐life extension, unique mechanisms of action, and subcutaneous administration. Additional technological advancements have emerged that are anticipated to further transform haemophilia care.
Aim
Review new and emerging haemophilia therapies, including replacement and bypassing products, digital applications, utilisation of big data, and personalised medicine.
Methods
Data were obtained from peer‐reviewed presentations/publications, and ongoing studies in haemophilia, ultrasonography, and artificial intelligence (AI).
Results
Available treatments include new recombinant factors VIII (FVIII) and IX (FIX), extended half‐life FVIII/IX products, a new FVIIa product for inhibitor patients, and a FVIIIa‐mimetic. Several novel therapeutics are in clinical trials, including FVIIIa mimetics and inhibitors of naturally‐occurring anticoagulants. Ongoing gene therapy trials suggest that a single vector infusion using an optimised construct can produce factor activity that reduces bleeding to near zero for years. Today, persons with haemophilia (PwH) approach a lifespan comparable to that of the general population, presenting treatment challenges for age‐related co‐morbidities. Technological innovations have broadened beyond therapeutics to include large database analyses utilising remote data collection with handheld devices, and to tailor AI applications. Current development efforts include patient‐performed ultrasonography, algorithms for scan interpretation, and point‐of‐care haemostatic testing devices.
Conclusions
We have entered a golden age for haemophilia treatment and care with wide‐ranging advancements targeting improved quality of life (QoL). Future‐focused efforts by clinical and patient communities may provide equitable access and care for people impacted by haemophilia worldwide.
Current hemophilia B treatment guidelines recommend routine prophylaxis with factor IX (FIX) replacement products, tailored to maintain plasma activity at levels that will prevent bleeds. However, ...plasma FIX activity may not be the primary determinant or best indicator of hemostatic efficacy due to its extravascular distribution. FIX replacement therapy has evolved to include extended half-life (EHL) products that provide effective bleed protection when administered at intervals of 7 days or longer. rFIXFc is a recombinant fusion protein with an extended circulation time. rFIXFc has a biodistribution profile consistent with distribution into extravascular space, where it may support hemostasis at sites of vessel injury independent of circulating plasma activity levels. The safety and efficacy of rFIXFc prophylaxis is well established in adults, adolescents and children including previously untreated patients with hemophilia B, with substantial evidence from clinical trials and real-world clinical practice. This review describes the pharmacokinetic characteristics of rFIXFc, summarizes available safety and efficacy data, and evaluates the use of rFIXFc in special populations. Current hemophilia B treatment challenges, including target FIX plasma levels, perioperative use, and management of patients with comorbidities, are discussed together with the potential role of EHL products in the future treatment landscape of hemophilia B.
In a study involving patients with severe hemophilia A, an injection of the novel fusion protein BIVV001 resulted in a duration of factor VIII activity that was up to four times as long as that for ...recombinant factor VIII, an increase that may signal the possibility of weekly therapy.
Introduction
Surgery is frequently required in persons with haemophilia A (PwHA). Emicizumab, a bispecific, humanized monoclonal antibody, bridges activated factor (F) IX and FX. Management of ...patients undergoing surgery while receiving emicizumab is of clinical interest due to paucity of data.
Aim
Review real‐world experience of PwHA with/without FVIII inhibitors who required surgery while receiving emicizumab prophylaxis.
Methods
Data regarding peri‐operative management, including type of surgery, haemostatic agent use and bleeding complications, were collected for PwHA receiving emicizumab undergoing surgery between 25/10/18 and 31/12/19 at the Indiana Hemophilia and Thrombosis Center. Analyses were exploratory and descriptive.
Results
Twenty minor and five major surgeries were performed in 17 and five patients, respectively. Overall, 9/20 minor surgeries were planned to occur with emicizumab as the sole haemostatic agent; of these, four required additional coagulation factor (2 due to haematomas following port removals, 1 due to oozing at port removal site, 1 due to bleeding following squamous cell carcinoma removal). Three of the 11 minor surgeries with planned additional coagulation factor resulted in non‐major bleeds; all were safely managed with additional coagulation factor. All five major surgeries were planned with additional haemostatic agents; there was 1 bleed in a patient undergoing elbow synovectomy with nerve transposition, likely triggered by physical/occupational therapy. There were no major bleeds, thrombotic events or deaths.
Conclusions
Additional haemostatic agent use is safe in PwHA undergoing surgery while receiving emicizumab. Additional data are needed to determine the optimal dosing/length of treatment of additional haemostatic agents to lower bleeding risk.
Concizumab is a novel subcutaneous prophylactic therapy for hemophilia. It is a hemostatic rebalancing agent that binds to the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI), one of the ...molecules that contributes to downregulation of coagulation thereby preventing TFPI from binding to and blocking the factor Xa (FXa) active site. When the TFPI inhibitory activity is decreased, sufficient FXa is produced by the FVIIa-tissue factor complex to achieve hemostasis. On the basis of this mechanism of action, concizumab is expected to be equally effective in hemophilia A and B, regardless of inhibitor status. Moreover, the concizumab mechanism of action does not interfere with the regulation of coagulation downstream of TFPI. Results from 2 phase 2 trials in patients with hemophilia A or B with and without inhibitors demonstrated that concizumab had a favorable safety profile, with no deaths, no thromboembolic events, and no adverse events leading to withdrawal. Clinical proof of concept in prevention of bleeding episodes was confirmed in both concizumab phase 2 trials across all hemophilia subtypes assessed, with a statistically significant and clinically relevant reduction in annualized bleeding rates observed in inhibitor patients compared to those who received on-demand treatment. On the basis of phase 2 results, the US Food and Drug Administration granted concizumab Breakthrough Therapy designation for hemophilia B with inhibitor patients, a rare and vulnerable patient subgroup that currently has the highest unmet medical need. In the ongoing concizumab phase 3 trials, an optimized dosing regimen will be administered in patients with hemophilia A or B with and without inhibitors.
Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to ...evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate ABR at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events AEs and antidrug antibodies ADAs). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval CI, 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.
•Concizumab was safe and well tolerated in HA and HAwI/HBwI, including with breakthrough bleed treatment.•Clinical proof of concept in terms of preventing bleeds was demonstrated in 2 concizumab phase 2 trials across hemophilia subtypes.
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Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study ...(HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.
•The data demonstrate the complexity of the genetic contribution to inhibitor development in people with hemophilia A.•Potentially decisive markers have been identified, indicating the importance of further evaluation of intracellular signaling pathways.
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