Controversies in Inherited Bleeding Disorders.

Abstract

Recent years are witnessing key developments in treatment approaches for congenital bleeding disorders (CBD), in particular the hemophilias, but also other factor deficiencies.1,2 Moreover, cooperative multinational efforts are providing advances in our knowledge of pathophysiological, clinical, and management aspects of these disorders, including the more rare abnormalities.3–6 However, despite being in an era of novel insights and paradigms of treatment, many issues remain controversial or need further research and/or confirmation in clinical practice. Along these lines, the 16 chapters presented in this latest bumper issue of Seminars in Thrombosis and Hemostasis deal with some of these debated or evolving concepts, presenting and discussing the most recent literature information and the available expert recommendations. The assessment of patients with suspected or known CBD is based on accurate and appropriate data from clinical history and laboratory testing. Therefore, two papers at the beginning of the issue focus on these crucial aspects.7,8 Starting from the clinical validation in type 1 von Willebrand disease (VWD), Tosetto reports on the potential clinical usefulness of bleeding assessment tools (BAT), these being first developed essentially as research tools for the quantification of bleeding symptoms and the study of phenotype/ genotype correlations.7 Indeed, although disease-specific implementations should be widely validated in most cases, these tools can provide amain advantage of standardizing the diagnostic process, allowing a rational approach to the laboratory diagnosis, in particular for mild bleeding disorders that may require a complex laboratory work-up. Moreover bleeding severity assessed by these tools has been shown to correlate with the long-term probability of bleeding, thus representing an interesting predictor of disease severity.7 As regards laboratory issues, in viewof the general lack of agreed approaches for the diagnostics of bleeding disorders, Lippi and colleagues provide pragmatic guidance to improve the identification and diagnosis of CBD due to abnormalities of secondary hemostasis, even in nonspecialized laboratories.8 A strategy based on the collection of personal and family history and the results of first-line tests (i.e., prothrombin time, activated partial thromboplastin time, and fibrinogen) is proposed, followed by secondor third-line tests that will definitely establish the specific nature and the severity of the bleeding defect. Indeed, second-line tests (specific factor assays, on the basis of the detected abnormalities in firstline assays) will provide the basis for a preliminary diagnosis, which will then be supported by third-line tests (namely, immunological assays of clotting factors and molecular biology).8 VWD is the most common CBD; however, its identification and management still provides many challenges.9 Three articles in this issue deal with these problems, reflecting a complex and not completely elucidated pathophysiological background. Castaman and Federici review recent evidence regarding one of the most intriguing VWD subtypes, type 2B.10 This rare autosomally dominant inherited variant is due to mutations clustered in exon 28 of the von Willebrand Factor (VWF) gene encoding for the A1 domain, involved in VWF binding to platelet glycoprotein Ib-α. The mutant VWF, normally synthesized and assembled by endothelial cells, shows heightened affinity binding to its platelet receptor. This results in in vivo platelet clumping that is correlatedwith a variable degree of thrombocytopenia, in particular under specific clinical circumstances. However, recent studies show that a true platelet defect is also present in VWD 2B, since morphological and functional defects are detected in these patients, possibly contributing to the clinical and laboratory heterogeneity.10 In the frame of the phenotypical variability in type 2 VWD, the often misdiagnosed subtypes 2A and 2M are being increasingly studied, showing both similarities and differences in various aspects of their presentation to clinicians, researchers, and laboratories. Favaloro and colleagues