Old and New Challenges in Hemophilia Management

Welcome to the latest issue of Seminars in Thrombosis & Hemostasis, dealing with some “old” and some “new” hot topics in the field of hemophilia. Thanks to the advances in replacement treatment and in their comprehensive care over the last few decades, persons with hemophilia presently achieve a highly satisfactory quality of life and a life expectancy approaching that of the general male population.[1] Further improvements are confidently awaited from emerging factor concentrates with extended half-life on clinical trials and favorable developments in gene therapy that are overcoming previously disappointing results.[1] [2] Meanwhile, research and clinical efforts are focused on clarifying recognized issues (determinants of bleeding phenotype, assessment of efficacy and safety of treatment in long-term outcomes), facing emerging challenges (age-related comorbidities), and on the whole, optimizing hemophilia management. In this scenario, the 14 hemophilia-related articles in this theme-based issue represent a “bumper issue” that addresses original perspectives and provides recent updates or data, thus renewing interest about such topics.

In the first article, Santagostino and Fasulo deal with the debate about differences between hemophilia A and hemophilia B, traditionally considered clinically indistinguishable.[3] Except the well-known differences in terms of prevalence and inhibitor development, increasing data suggest that bleeding tendency associated with factor IX (FIX) deficiency may be less severe, with consequent better long-term outcomes. A biological plausibility behind such different clinical expression might be found in the genetic background of the two forms of congenital hemophilia, with predominance of null mutations in hemophilia A and of missense mutations in hemophilia B.

Pavlova and Oldenburg then address another intriguing and disputed issue, that is, the relationship between bleeding phenotype and residual factor VIII (FVIII)/IX activity, which also “defines” the severity of hemophilia.[4] The relatively high heterogeneity of phenotype in hemophilia patients with the same factor levels is well recognized. As herein reviewed, a series of genetic and environmental “modifiers” of clinical phenotype have been investigated and may also influence treatment decisions.

Recent years have witnessed the recognition of prophylaxis, the long-term regular regimen of factor concentrate infusion aimed at preventing bleeding episodes and, in particular, their deleterious effects on joint health, as the evidence-based treatment of choice in children with severe hemophilia.[5] However, to overcome problems of venous access and adherence to treatment, and to optimize regimens according to individual bleeding phenotype and/or pharmacokinetic profile, a series of modifications of the standard full-dose weight-based regimens have been proposed. Such “tailored” approaches, potentially able to reduce factor concentrate consumption and cost (a major barrier to the wider international diffusion of prophylaxis), are reviewed by Santoro et al.[6] The authors also discuss the different outcome measures needed to validate the efficacy and safety of prophylactic regimens in the long term. Hemophilic arthropathy being the main determinant of morbidity and of the impaired quality of life in these patients; the assessment of joint status is crucial for monitoring arthropathy prevention or progression as part of clinical care as well as an outcome for clinical trials. The next article by Di Minno and colleagues deals in greater detail with hemophilic arthropathy, reporting a systematic review of literature regarding the prevalence and severity of joint damage, the degree of quality-of-life impairment, and the need for orthopedic care or aids in patients with moderate hemophilia.[7] These patients usually experience fewer joint bleeds than those with the severe form of hemophilia and are thought to rarely develop significant degree of arthropathy. However, few studies, reviewed here, have been devoted specifically to patients with this form of hemophilia and available data show a wide heterogeneity, with approximately 30% of patients receiving prophylaxis regimens, usually after diagnosis of clinically overt arthropathy. Again, these data highlight that severity of hemophilia should not only be defined according to FVIII/FIX levels; and that even in nonsevere patients, “tailored” approaches of treatment should be considered. Completing the discussion on different severities of hemophilia, Di Perna et al report an interesting study regarding desmopressin (DDAVP) responsiveness and treatment in 75 patients with mild hemophilia A followed at a single center.[8] They found that 76% of patients had complete or partial response after a dose-test of DDAVP, which was correlated with age (higher age in DDAVP responders) and type of causative mutations (all 10 patients with mutations in the promoter were DDAVP nonresponders). Among responder patients, over a median follow-up period of 12 years, 50 received DDAVP for trauma/invasive procedures (142 events) or bleeding episodes (82 in 23 patients), with high hemostatic efficacy (96 and 92%, respectively) and no significant adverse event, in most cases as home treatment.

The four subsequent articles focus on the current major challenge in hemophilia management, that is, the development of alloantibodies against the infused factor concentrates, which may render replacement treatment no longer effective and prophylaxis unfeasible. These inhibitors, occurring in approximately 30% of patients with severe hemophilia A, expose patients to an increased risk of developing target joints, severe arthropathy, and an impaired quality of life.[9] Inhibitor development results from a complex multifactorial interaction between genetic and nongenetic risk factors.[10] On a susceptible genetic background, nongenetic risk factors modify the risk of inhibitor development. In particular, the identification of treatment-related factors would offer the possibility to modify treatment strategies, particularly in those patients with high “genetic” risk. Gouw and Fijnvandraat have evaluated the research findings on such nongenetic risk factors, with special focus on those treatment-related factors, including intensity and modality of treatment and type of FVIII products.[11] The latter controversial issue (i.e., the different inhibitor risk associated with FVIII products—plasma-derived vs. recombinant products; different generations of recombinant products), further debated following the recent publication of the large observational RODIN study,[12] is addressed in the systematic review and meta-analysis of prospective studies performed by an ad hoc Italian working group of hemophilia experts.[13] In this analysis, updated to March 2013 and using restrictive criteria and an original assessment of methodological quality of the included studies, no significant differences were observed in the incidence of all and high-titer inhibitors either between plasma-derived and recombinant FVIII concentrates or comparing different classes of recombinant products.

Knowledge about inhibitor development is much more limited in hemophilia B because of the lower prevalence of such complication (2–3% of patients) in this less frequent disorder. However, unlike hemophilia A, inhibitors in hemophilia B are associated in a high proportion of patients (∼60%) with further morbidity due to severe allergic reactions following the administration of FIX, up to the development of nephrotic syndrome. Such an allergic phenotype makes it difficult to attempt and successfully conduct induction of immune tolerance induction (ITI), for which reported success rates are in a low range of 13 to 33%.[14] Therefore, a series of desensitization and immunomodulation protocols have been used as part of ITI, but there is no clear consensus on how to effectively and safely treat hemophilia B with inhibitors and recommendations for ITI in this setting are substantially lacking. These challenges are reviewed within the presentation of a successful inhibitor eradication in a boy with severe hemophilia B by Batorova et al.[15]

Given higher success rates (60–80%) with the possibility of restoring factor VIII replacement and prophylaxis, ITI is the treatment of choice in patients with hemophilia A and inhibitors, particularly in children.[14] However, in patients awaiting this therapeutic approach or when this fails, bleeding episodes are treated (or prevented) with bypassing agents, recombinant-activated factor VII or activated prothrombin complex concentrates. Franchini et al summarize the main characteristics of these bypassing agents and briefly discuss available literature data, in particular focusing on the few comparative studies.[16]

Although substantial improvements in the safety of blood and plasma products for the management of patients with bleeding disorders have been achieved and no cases of major blood–borne infections have been reported in the last two decades, elimination of all microbes from blood remains potentially impossible and there are always threats from emerging pathogens. Moreover, pathogen testing is not all-inclusive, and manufacturing and purification techniques are often not standardized. An international panel of infectious disease and hematology specialists therefore analyze literature data and discuss these eternal hot topics in the subsequent review in this issue of the Seminars in Thrombosis & Hemostasis.[17] Evolving risk from emerging pathogens in this context is highlighted, including viruses (particularly parvovirus B19 and human parvovirus 4), prions, and protozoa.

The next article focuses on the emerging challenges of the aging persons with hemophilia. Because of their currently prolonged life expectancy, these patients are experiencing age-related comorbidities, such as cardiovascular diseases, renal diseases, sexuality issues, malignancies, and neurologic problems, until recently rarely seen and managed by hemophilia caretakers. Evidence-based recommendations for the management of such conditions are probably unfeasible and literature data remain scarce. In this evolving clinical scenario, the comprehensive care of aging patients should be updated, including new diagnostic and consultancy facilities. In this perspective, a panel of Italian hemophilia specialists briefly reported the current knowledge on the aging patient with hemophilia, along with the clinical approaches that may be integrated at the hemophilia treatment centers for preventing, diagnosing, and monitoring age-related comorbidities.[18]

The last review on hemophilia clinical issues in this bumper volume of Seminars in Thrombosis & Hemostasis, by Coppola et al, deals with the available strategies for noninvasive assessment of liver fibrosis in patients with chronic hepatitis C (CHC).[19] The impact of such an “old” comorbidity in hemophilia patients is still very pervasive, with high proportions of adult patients showing progressive CHC, co-infected with HIV in 15% of cases or more. The assessment and monitoring of liver fibrosis is crucial in the management and definition of prognosis of these patients. Recognized limitations of liver biopsy (invasive nature, sampling errors, interobserver variability, nondynamic evaluation of liver fibrosis), but traditionally considered the reference standard, stimulated the search for noninvasive approaches, which are particularly attractive in patients with congenital bleeding disorders. A series of biomarkers, often combined in scores or algorithms, and, more recently, instrumental techniques evaluating liver stiffness (in particular transient elastography) have been validated and routinely employed in CHC patients. Performances of such approaches and their clinical implementation in general populations of CHC patients are summarized in this article, together with recent studies extending the use of noninvasive methods (particularly transient elastography) in patients with congenital bleeding disorders.

Two articles in this issue of Seminars in Thrombosis & Hemostasis then address laboratory issues, which are crucial in hemophilia care, for enabling correct diagnosis, patient management, including therapeutic choices, and follow-up of complications, particularly inhibitor development. These aspects are comprehensively reviewed by Favaloro et al, who highlight problems in hemophilia diagnosis or inhibitor detection that can occur at any stage in the clinical diagnosis/laboratory interface, from the “pre-preanalytical” to the “preanalytical,” the “analytical,” the “postanalytical” and the “post-postanalytical” phases.[20] A series of general and hemophilia-specific strategies to overcome these challenges are available, but, together with the adoption of best practice by all involved, including clinicians, phlebotomists, and laboratorians, the key remains the recognition that such errors may occur and a careful assessment of laboratory test results in the context of patient's clinical history, with testing repetition on fresh samples when needed. One such “preanalytical” aspect is further and specifically evaluated in the study presented by Lippi et al, who evaluated the impact of postcentrifugation platelet count in postfreeze-thawed samples on activated partial thromboplastin time, prothrombin time (PT), fibrinogen, FVIII, and FIX activity testing.[21] Indeed, because of increasing economic constraints and organizational issues, most specialized hemostasis tests are now performed on postfreeze-thawed samples and rarely on fresh centrifuged plasma. An appropriate plasma matrix, with a very low platelet count (which is also influenced by sample centrifugation, where 1500g is the recommended speed), is necessary to generate unbiased results of both first and second line coagulation tests in these postfreeze-thawed samples. In this study, results of PT and fibrinogen were consistently altered in samples centrifuged at 1,000 or 500g, although the correlation with the reference measures remained clinically acceptable. Data obtained for FVIII and FIX activities revealed a positive bias in all postfreeze-thawed plasmas, achieving statistical significance in samples centrifuged at 3,000g.

Finally, in line with the recent tendency of Seminars in Thrombosis & Hemostasis to occasionally include theme-unrelated but nevertheless “hot topic” material, the last article of this issue, by Di Minno et al,[22] provides a literature analysis on laboratory monitoring of new direct oral anticoagulant drugs rivaroxaban, apixaban, edoxaban, and dabigatran. Because their anticoagulant effect is dose-predictable, steady, and little influenced by diet and drugs, laboratory monitoring was “deemed” unnecessary in trials on venous and arterial thromboprophylaxis with such new drugs. However, there are special clinical settings in which the anticoagulant effect of the new direct anticoagulant agents should be measured,[23] [24] [25] and both the available laboratory methods and the clinical judgment required while employing the results of such tests to make clinical decisions are discussed in this review.[22]

In conclusion, we thank all the authors for their original and comprehensive contributions, and we believe that the various articles of this issue of Seminars in Thrombosis & Hemostasis that focused on well-recognized, evolving, and emerging challenges in hemophilia management will be of particular interest for the readership.

• References

• 1 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
• 2 Viiala NO, Larsen SR, Rasko JE. Gene therapy for hemophilia: clinical trials and technical tribulations. Semin Thromb Hemost 2009; 35 (1) 81-92
• 3 Santagostino E, Fasulo MR. Hemophilia A and hemophilia B: different types of diseases?. Semin Thromb Hemost 2013; 39 (7) 697-701
• 4 Pavlova A, Oldenburg J. Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost 2013; 39 (7) 702-710
• 5 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38 (1) 79-94
• 6 Santoro C, Baldacci E, Mercanti C, Mazzucconi MG. Tailored versus standard dose prophylaxis in children with hemophilia. Semin Thromb Hemost 2013; 39 (7) 711-722
• 7 Di Minno MND, Ambrosino P, Franchini M, Coppola A, Di Minno G. Arthropathy in patients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost 2013; 39 (7) 723-731
• 8 Di Perna C, Riccardi F, Franchini M, Rivolta GF, Pattacini C, Tagliaferri A. Clinical efficacy and determinants of response to treatment with desmopressin in patients with mild hemophilia A. Semin Thromb Hemost 2013; 39 (7) 732-739
• 9 Gringeri A, Mantovani LG, Scalone L, Mannucci PM ; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102 (7) 2358-2363
• 10 Gouw SC, van den Berg HM. The multifactorial etiology of inhibitor development in hemophilia: genetics and environment. Semin Thromb Hemost 2009; 35 (8) 723-734
• 11 Gouw SC, Fijnvandraat K. Identifying nongenetic risk factors for inhibitor development in severe hemophilia A. Semin Thromb Hemost 2013; 39 (7) 740-751
• 12 Gouw SC, van der Bom JG, Ljung R , et al; PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368 (3) 231-239
• 13 Franchini M, Coppola A, Rocino A , et al; Italian Association of Hemophilia Centers (AICE) Working Group. Systematic review of the role of FVIII concentrates in inhibitor development in previously untreated patients with severe hemophilia A: a 2013 update. Semin Thromb Hemost 2013; 39 (7) 752-766
• 14 DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 (Suppl. 01) 1-22
• 15 Batorova A, Morongova A, Tagariello G, Jankovicova D, Prigancova T, Horakova J. Challenges of the management of hemophilia B with inhibitor. Semin Thromb Hemost 2013; 39 (7) 767-771
• 16 Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39 (7) 772-778
• 17 Di Minno G, Canaro M, Ironside JW , et al. Pathogen safety of long-term treatments for bleeding disorders: (un)predictable risks and evolving threats. Semin Thromb Hemost 2013; 39 (7) 779-793
• 18 Coppola A, Santoro C, Franchini M , et al. Emerging issues on comprehensive hemophilia care: preventing, identifying, and monitoring age-related comorbidities. Semin Thromb Hemost 2013; 39 (7) 794-802
• 19 Coppola A, Di Capua M, Conca P , et al. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis C (and congenital bleeding disorders): where do we stand?. Semin Thromb Hemost 2013; 39 (7) 803-815
• 20 Favaloro EJ, Meijer P, Jennings I , et al. Problems and solutions in laboratory testing for hemophilia. Semin Thromb Hemost 2013; 39 (7) 816-833
• 21 Lippi G, Rossi R, Ippolito L , et al. Influence of residual platelet count on routine coagulation, factor VIII, and factor IX testing in postfreeze-thaw samples. Semin Thromb Hemost 2013; 39 (7) 834-839
• 22 Di Minno A, Spadarella G, Prisco D, Franchini M, Lupoli R, Di Minno MND. Clinical judgment when using coagulation tests during direct oral anticoagulant treatment: a concise review. Semin Thromb Hemost 2013; 39 (7) 840-846
• 23 Favaloro EJ, Lippi G, Koutts J. Laboratory testing of anticoagulants: the present and the future. Pathology 2011; 43 (7) 682-692
• 24 Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb) 2012; 22 (3) 329-341
• 25 Favaloro EJ, Lippi G. Laboratory testing and/or monitoring of the new oral anticoagulants/antithrombotics: for and against?. Clin Chem Lab Med 2011; 49 (5) 755-757