Haemostasis: Normal Physiology, Disorders of Haemostasis and Thrombosis
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
One of the better known bleeding disorders is haemophilia. The genetic forms of this are grouped as haemophilia A (deficiency of factor VIII) or haemophilia B – Christmas disease (deficiency of factor IX). These are then classified as mild, moderate or severe depending on the patient’s baseline factor level (mild is factor level < 30%, moderate < 5% and severe < 1%). In most haemophilias the genetic defect ‘runs true’ within the family, therefore the severity of haemophilia also runs true within families. Haemophilia A and B are X-linked genetic disorders and as such classically affect males. However, there are rare instances of female carriers presenting with increased bleeding tendency related to a low factor level (i.e. carriers of severe haemophilia). There are also instances of affected females with very low factor levels due to other complicated inheritance genetics (extreme X chromosome lyonization and mosaicism). Lastly it should be remembered that there are rare families who have two completely separate bleeding disorders, which can lead to some individuals having a much more severe bleeding phenotype than would be normally expected because they have inherited both. This means the patient’s personal history and bleeding manifestations are of vital importance in treatment decision-making. Severe and moderate haemophilias are usually diagnosed in childhood with many cases having been suspected antenatally when family history is known. Milder cases may present in adulthood. Spontaneous new mutations occur in approximately 20% of cases (therefore there is no family history). People with severe haemophilias have increased bruising but this does not usually cause a problem. The main issues for these patients are spontaneous joint and muscle bleeds and excessive bleeding following even minor procedures. All patients with a diagnosis of or suspected haemophilia should have surgery managed in a centre with specialist haematology experience.
Patient-reported outcome measures: Clinical applications in the field of chronic pain self-management
Francis Guillemin, Alain Leplège, Serge Briançon, Elisabeth Spitz, Joël Coste in Perceived Health and Adaptation in Chronic Disease, 2017
Hemophilia is an inherited bleeding disorder caused by deficiencies of blood clotting factors. Hemophilia A (caused by factor VIII deficiency) and hemophilia B (caused by factor IX deficiency) are both sex-linked recessive disorders in which the classic pattern of transmission is from carrier mother to affected son. Hemophilia A affects about 1 in 5000 males and hemophilia B about 1 in 30,000 males (Kliegman, 2011). Prevalence rates vary considerably between countries and over time (Stonebraker et al., 2010), but in 2012 there were 6742 people identified with hemophilia in the United Kingdom, 6035 in France, 4660 in Germany, and 18,628 in the United States (World Federation of Hemophilia, 2013). People with hemophilia are susceptible to hemarthroses (joint bleeds), which happen when small blood vessels in the joint are ruptured and the joint space fills with blood, causing severe acute pain. Recurrent joint bleeds damage the joints, leading to arthropathy and severe chronic pain (Acharya, 2012). Bleeds and arthropathy can be prevented or minimized by early prophylactic (preventative) clotting factor treatment (Rodriguez-Merchan, 2012). A survey of over 5000 adults with hemophilia in Europe showed that 67% had arthropathy and 35% had chronic pain (Holstein et al., 2012), and one in the United States showed that 39% of people with hemophilia believed their pain was not well treated (Witkop et al., 2012). In hemophilia, there has been considerable use of PROMs such as the SF36, which is a very widely used measure of HRQoL that meets most of the minimum standards criteria for PROM measures (Reeve et al., 2013). Studies have shown that people with hemophilia have poorer physical HRQoL than the general population (Fischer et al., 2003; Szende et al., 2003) and that physical HRQoL is poorer among people with hemophilia who have more joint damage or are not receiving prophylactic clotting factor treatment (Fischer et al., 2005; Royal et al., 2002; Solovieva, 2001). However, mental QoL is less affected by hemophilia and is less closely associated with joint status (Poon et al., 2012; Zhou et al., 2011).
Hereditary Plasma Protein Disorders
Genesio Murano, Rodger L. Bick in Basic Concepts of Hemostasis and Thrombosis, 2019
Much less is known about the pathophysiology of this disorder in comparison to hemophilia A. It is known, however, that variants of hemophilia B do exist. The first variants were discovered using Ox brain thromboplastin times. Previous work revealed that some patients with Factor IX deficiency had a prolonged Ox brain thromboplastin time, while others had normal times. These patients with a prolonged Ox brain thromboplastin time have been designated hemophilia B the “m” being derived from the surname of the first family found with this disorder. It has been established that some patients with Factor IX deficiency resemble classical hemophilia in that Factor IX-like antigen or nonfunctioning Factor IX protein is present. Thus these patients are cross-reacting material (CRM) positive. The majority of patients with hemophilia B, however, have no detectable Factor IX levels by currently available immunologic techniques. Thus there are hemophilia B patients who are CRM and CRM. Therefore, at least four genetic variants of hemophilia B exist. These are delineated in Table 3. The clinical significance of these variances is not known. Evidence suggests that patients who are CRM have a milder form of the disease.
The benefits of prophylaxis in patients with hemophilia B
Published in Expert Review of Hematology, 2018
Introduction: The health benefits of prophylactic dosing regimens for clotting factor therapy in patients with hemophilia include reduced joint damage and improved quality of life; as such, prophylaxis is recommended in treatment guidelines. However, many patients with hemophilia B are treated on demand, and prophylaxis has been utilized less frequently than in hemophilia A. Areas covered: This review discusses the opportunities and evidence for prophylaxis in hemophilia B, in the context of treatment guidelines and with regard to factor IX (FIX) replacement therapies, including long-acting recombinant FIX (rFIX). Expert commentary: Long-acting rFIX concentrates may increase uptake of and adherence to prophylaxis regimens through attainment of higher trough levels with longer dosing intervals. In this new era of hemophilia B treatment, physicians may be able to achieve better clinical outcomes for their patients and reconsider treatment goals. Maintaining higher FIX trough levels will undoubtedly have long-term benefits for patients, such as preserving joint function. The long-acting rFIX concentrates support robust prophylaxis regimens and offer physician’s flexibility in treating patients to best suit their needs, whether to enable an active lifestyle, to achieve higher trough levels for better bleed protection, or simply to decrease the burden of treatment by reducing injection frequency.
Current management of hemophilia B: recommendations, complications and emerging issues
Published in Expert Review of Hematology, 2014
Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild-to-severe bleeding complications according to the degree of FIX defect. The mainstay of treatment of hemophilia B consists of replacement therapy and nowadays several plasma-derived and recombinant FIX products are commercially available. This article reviews the current management of hemophilia B patients analyzing the results of the most important clinical trials. In addition, it will focus on the more recent advances in the production of new FIX molecules aimed at the improvement of the clinical management of such patients.
Trenonacog alfa for prophylaxis, on-demand and perioperative management of hemophilia B
Published in Expert Opinion on Biological Therapy, 2018
Yvonne Brennan, Jennifer Curnow, Emmanuel J. Favaloro
Introduction: Current treatment for hemophilia B involves replacing the missing coagulation factor IX (FIX) with either plasma-derived or recombinant (r) FIX. Trenonacog alfa is the third normal half-life rFIX that has been granted FDA approval. Area covered: In this review, the authors examine trenonacog alfa for the treatment of hemophilia B including prophylaxis, on-demand and perioperative hemostasis. They compare the PK profile to nonacog alfa and evaluate the drug’s efficacy and safety from published studies. Expert opinion: Trenonacog alfa appears to be an effective and safe treatment option for patients with hemophilia B with a PK profile similar to that of nonacog alfa. Despite the advent of extended half-life rFIX and other novel therapeutic approaches, normal half-life rFIX products, including trenonacog alfa, are likely to continue to have a place in hemophilia B treatment for at least the immediate future while the new landscape takes shape, particularly in countries that cannot afford the newer treatments.
Related Knowledge Centers
- Hemostatic Disorders
- Inherited Blood Coagulation Disorders
- Chromosome
- Blood Coagulation Disorders
- X-Linked Genetic Diseases
- Hemorrhagic Disorders
- Coagulation Protein Disorders