“Trending Issues in Rare Bleeding Disorders”

"Trending Issues in Rare Bleeding Disorders"

Rare bleeding disorders (RBDs), deficiencies of fibrinogen, factors (F) I, II, V/VIII, VII, X, XI, XIII, and PAI-1 and α2-antiplasmin, have long been considered orphan diseases because of their rarity in the general population. They have an estimated worldwide prevalence of 1:500,000 to 1:1-2 million.1, 2, 3 As such, they have posed challenges to clinicians in terms of symptom recognition, difficulty with laboratory testing, and either a paucity or a lack of specific replacement therapy.1, 4  However, with increasing knowledge of RBDs, including a greater understanding of their genetic and molecular basis and clinical phenotype, as well as improved laboratory assay capabilities and better-established treatment strategies, the outlook is improving for patients with these disorders.5, 6 

To promote awareness among clinicians about the latest developments in RBDs, this activity presents insights gleaned from the 2012 American Society of Pediatric Hematology/Oncology (ASPHO) symposium, at which 6 Blood CME Center faculty, with expertise in RBDs, shared with an audience of their peers the most recent scientific findings and empirical data in this therapeutic area.

RBDs: Regional and Cultural Barriers to Care
Individuals with bleeding disorders confront physical, psychological, financial, and employment challenges due to the chronic nature of their illness.7  The hardships and restrictions imposed by these diseases can take an emotional toll, and for the approximately 30% of individuals in the United States with a bleeding disorder who receive no care or substandard care, the challenges are even more imposing.7,8  These individuals, categorized as unserved or underserved, typically receive care through non—hemophilia treatment center (HTC)-affiliated physicians, private hematologists, hospital emergency departments, or clinics.8 

The National Hemophilia Foundation (NHF) defines unserved or underserved as "any person with a bleeding disorder for whom the recognition, diagnosis, and care of his or her condition and complications are delayed or inadequate." 9  It has been found that culturally diverse groups with bleeding disorders fall into this category, with racial and ethnic minorities in the United States (a growing population, according to US Census data [as cited in Clay 201110 ]) receiving a lower quality of healthcare than nonminorities.9 

Several barriers contribute to the lack of care a specific population receives, including income and inability to afford quality care, limited literacy, and inability to speak English.8  According to US Census Bureau estimates for 2007, 1 in 5 US residents speaks a language other than English at home (as cited in Clay 201110 ). Correspondingly, 1 in 5 Spanish-speaking Latinos reports not seeking medical care because of language barriers.9   Other barriers to care include rural isolation and distance to the HTC, transportation costs, child care concerns, and cultural differences.8  Provider response to patients’ cultural beliefs may also create barriers and add to the feeling of isolation patients may already have.8,10 

Education is key to reaching unserved and underserved populations and bringing them into the fold of adequate medical care. Clinicians need to be educated on the signs and symptoms of RBDs to more readily recognize them. Clinicians should also be cognizant about how patients from different cultures view their bleeding disorder and its treatment. Patients, too, need to be educated about the disease they have. If language is a barrier, an interpreter should be provided during interactions with healthcare staff.10 Education should also be tailored to the literacy level of the patient for greater comprehension.

Genetics and Prenatal Counseling for RBDs
Recent discoveries in 2 disorders, Quebec platelet disorder and pulmonary fibrosis, highlight the importance of genetics for understanding the basis of a disease.11, 12  Knowledge of the genetic and molecular basis for most RBDs has increased over the past 10 years.5  Genetic screening and counseling are important for all affected individuals and their family members to determine the molecular defect within affected kindred, thereby enabling comparison with affected individuals from other reported kindreds.13  Such screening, however, has implications for future offspring of affected families, especially those born of consanguineous marriages (RBDs are prevalent in countries with this practice).14  One recent study of hemophilia in 7 generations of a Pakistani tribe revealed that autosomal recessive genes can be hidden for generations within a family and only surface phenotypically in offspring following new consanguineous marriages.14  Nevertheless, while genetic screening and counseling are important in theory, they are difficult to implement in practice.6 

Besides potentially disturbing the cultural and religious roots in the custom of consanguineous marriage, implementation of genetic testing is technically demanding and expensive—the entire coding region of a given gene needs to be sequenced to locate the causative mutation in most kindreds with RBDs.6  Additionally, no information exists on genotype and phenotype correlates in all RBDs, because genetic testing facilities are extremely limited. As a result, very few patients worldwide have undergone this type of testing.15  Chances are, however, that even if genetic testing were more readily available, it would not be very helpful in screening for a bleeding disorder.16  Nevertheless, several of the RBDs do have a specific identifiable defect that can be used in family studies (Table 1).16

The World Health Organization has issued recommendations for minimizing the negative effects of consanguinity on children’s health (as cited in Borhany et al 2010 14):
  • Identify families at high risk of a genetic disease and provide genetic counseling

  • Advise families with segregating autosomal recessive conditions to limit further intermarriages among high-risk carriers, if carrier testing is unavailable

Supplemental Information

Global Assay Technology for RBDs
Laboratory assays for RBDs have gone high-tech, with the use of such measures as thromboelastography (TEG) and microfluidics—also known as "lab-on-a-chip." Standard coagulation assays, including those most commonly used for RBDs—the 1-stage aPTT and PT—do not reflect overall in vivo biology and have other limitations specific to these disorders.17, 18  For instance, the aPTT and PT only provide information on the initial stage of clot formation. Although they do provide a specific biochemical diagnosis, results do not necessarily correlate with the clinical phenotypes of some RBDs.18  With FVII deficiency, only the PT is prolonged. Other tests are normal.19 With FX deficiency, there can be varying test results, depending on the source of thromboplastin used.19  The aPTT may miss a FXI defect, because the lower limit of the normal range is between 60 and 70 IU/dL. Finally, with FXIII deficiency, all standard coagulation assays provide normal results.19

TEG and microfluidics offer alternative approaches for monitoring RBDs. TEG provides a global picture of the coagulation process.20  First described in 1948, its use has increased recently in point-of-care management for perioperative bleeding in cardiac and liver transplantation. For inherited bleeding disorders, it is primarily
used for monitoring response to therapeutic interventions (eg, fibrinogen).20, 21

TEG provides information on clot formation rate, propagation kinetics, fibrin-platelet interaction, and clot firmness and fibrinolysis.20  To date, it has been used to understand the mechanism of action of whole blood clot formation, making it especially useful for investigating the RBDs.18  During standard TEG tracking, the dynamic changes occurring until maximum amplitude of clot formation are of special interest. By calculating the slope at each time point of the coagulation course, a velocity profile of clot formation is achieved (see Figure 1).18

Microfluidics, another alternative testing approach, has an application for the diagnosis of RBDs. In broad terms, it is the science concerned with the design and construction of microminiaturized devices containing chambers and tunnels through which fluids flow in a controlled manner.17  Small platforms provide the possibility to isolate, purify, manipulate, and transport particles, biomolecules, bacteriophages, cells, or organisms for a simplified, parallel analysis. The goal of this technology is to improve and extend the possibilities of bioassays, cell biology, and biomedical research. The miniaturization process allows for more accurate modeling of physiological situations.

With applications in drug discovery, cell biology, and tissue engineering, microfluidic systems in development can model biological environments and physically mimic biological tissues and organs.17  Its use in diagnosing RBDs is still in its nascency, and its efficacy remains to be seen.

Clinical Phenotype of FVII Deficiency:
Unraveling the Mystery

For most RBDs, the correlation between factor level and disease severity is clear. With FVII deficiency, however, this correlation is cloudy.22  While bleeding episodes in the most severe cases occur within the first 6 months of age, it is not uncommon to see a lack of symptoms in patients with a FVIIc of less than 1%. Conversely, in patients with FVIIc levels less than 5%, severe symptoms may be observed.22 

Factor VII deficiency has a diverse clinical heterogeneity, ranging from lethal to mild or asymptomatic.23, 24  Standard coagulation assays do not shed any light on bleeding tendency based on factor levels, because they are generally not predictive of inherent bleeding risk.25  Indeed, standard coagulation assays are normal, with the exception of
the PT.19 

For some time, Dr. Guglielmo Mariani and his colleagues have been analyzing data from 2 FVII registries—the retrospectively designed International Registry on Congenital FVII Deficiency (IRF7) and the prospectively designed Seven Treatment Evaluation Registry (STER)—to corroborate some early findings regarding bleeding manifestations and age at presenting symptom. These registries combined have more than 750 evaluable cases of FVII deficiency and provide investigators with the opportunity to learn more about this bleeding disorder.26 

Based on data analysis of 687 individuals enrolled in the registries and an evaluation of whether the type of symptom at disease presentation could help predict other symptoms of FVII deficiency, Di Minno and colleagues identified 3 bleeding phenotypes.27  The most prevalent is mucocutaneous bleeding, or platelet-like bleeding, which was experienced by nearly half of the evaluated patients (49.2%). A small percentage of patients (11.2%) experienced hemophilia-like symptoms consisting of life- or limb-threatening hemorrhage. In a third phenotype classification, just over one-third of patients (39.6%) were asymptomatic, and most within this category (87.1%) tended to remain so.27  From these observations, investigators concluded that bleeding symptoms at disease presentation predict bleeding phenotype. With this observation, some light has been shed on the clinical phenotype of FVII deficiency.

Treatment Advances for RBDs
Plasma-Derived Products

Treatment advances for hemophilia and rarer bleeding disorders have been ongoing. Since the development of viral inactivation methods for plasma-derived clotting factor concentrates, the risk for transmission of HIV, HCV, HBV, and HTLVI and II is low. Nevertheless, with these improvements to the blood supply, some concerns remain, and there is still room for improvements to be made.

Despite the decreased risk for transmission of lipid-enveloped viruses, emerging pathogens can pose potential threats.28, 29  Non—lipid-coated viruses such as encephalomyocarditis and parvovirus B19, as well as prions, can survive the inactivation process and be transmissible.28, 30  Fresh frozen plasma and cryoprecipitate are the mainstays of treatment for inherited bleeding disorders, especially when no specific fractionated product is available, as in the case of FV deficiency. However, there are no pathogen-inactivated cryoprecipitate products available to date,28  thereby placing at risk those patients who must depend on this product.

Efforts are under way to modify currently available clotting factor concentrates by increasing their half-life (the plasma-derived bypassing agent aPCC has a half-life of 4-7 hours), improving ease of delivery, reducing immunogenicity, and increasing potency.31, 32 

Recombinant Products

Recombinant products are safer than plasma-derived products, although first-generation products were manufactured from animal- and human-protein—containing cultures, along with human albumin, with the potential for pathogen transmission.29  Second-generation products, such as the bypassing agent rFVIIa, replaced protein stabilizers such as albumin with sucrose, thereby eliminating the risk for pathogen transmission. Despite the demonstrated efficacy of this agent in hemophilia and congenital FVII deficiency, like aPCC, its half-life is short (2.7 hours in adults and 1.5 hours in children).31, 33 

Products in Development

Third-generation bioengineered recombinant products are in development and should improve upon the limitations of earlier generations.29  Protein modifications in this new generation of product will enhance pharmacokinetic properties or reduce immunogenicity.29  A mutant form of rFVIIa with enhanced activity is in preclinical development.29, 34  One study, conducted by Weimer et al, describes the extended half-life of a recombinant FVIIa molecule based on genetic fusion to human albumin.34  A B-domain—deleted recombinant porcine FVIII molecule is also currently in clinical trials for the treatment of congenital or acquired hemophilia.35, 36  Finally, a recombinant FXIII product has completed clinical trials and is awaiting FDA approval. Inbal and investigators conducted a multinational, open-label, single-arm, multiple-dosing, phase 3 prophylaxis trial, results of which demonstrated the safety and efficacy of this agent for preventing bleeds in patients with congenital FXIII deficiency.37 

Advances continue to be made in the treatment of RBDs. Insights from clinical trials under way and already completed should contribute toward improving the quality of life of individuals with these little-known disorders.

RBD Registries
Because of the low prevalence of RBDs in the general population,2,3  along with their biological heterogeneity and variable disease presentation,38  systematic data collection efforts have been hampered. Although such reporting for several RBDs has been in place in countries such as Iran, where consanguineous marriage is commonplace, it has been historically sketchy for other countries.6

Early registration data collection efforts were undertaken by the World Federation of Hemophilia (www.wfh.org) and the International Rare Bleeding Disorders Database (RBDD) project (www.rbdd.org). These early efforts were not without their limitations. No systematic collection of clinical, phenotypic, genotypic, or treatment features was in place.1  Worldwide distribution of RBDs was not apparent; approximately 50% of data referred to European patients only, resulting in inaccurate epidemiological data (Flora Peyvandi, MD, personal communication). With a scarcity of patient information, no treatment courses could be proposed, and data were not homogeneous, and thus unsuitable for statistical analysis.


Recently, data reporting has become more unified, and the past few years have witnessed the creation of unified registries that span the globe, including registries as diverse as the North American Rare Bleeding Disorders Registry, European Network of Rare Bleeding Disorders, the Greifswald Factor X Deficiency Registry in Europe and Latin America, and the Iranian National Registry of Inherited Bleeding Disorders.

In the past 10 years alone, the RBDD project, one of the largest registries, with a broad reach,1  has investigated more than 400 patients with RBDs from a variety of countries (Figure 2).39  A collaboration with an international network of healthcare providers has fostered dialogue about the prevalence, clinical manifestations, and continuing need for coordinated and consistent data collection.39  Further collaboration will allow for the continued expansion of knowledge and provide a platform on which to focus and develop additional diagnostic and therapeutic research.39 

Since 1996, the RBDD project has proven to be a powerful tool for patient data collection.40  Continued development and improvements will allow for the following:

  • Enable evaluation in large populations
  • Determine efficacy of treatment protocols and monitoring of the natural history of each disease
  • Help establish appropriate use of available resources
  • Plan clinical audit programs
  • Effectively inform patients regarding the disease
  • Identify areas of weakness within the healthcare system in the field of RBDs

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