Rare Bleeding Disorders: Genetic, Laboratory, Clinical, and Molecular Aspects

Welcome to this special issue of Seminars in Thrombosis & Hemostasis. Characteristically, each issue of Seminars in Thrombosis & Hemostasis is theme driven, with each new issue devoted to a particular theme of relevance to thrombosis and hemostasis. The current issue of Seminars in Thrombosis & Hemostasis carries the theme of “Rare Bleeding Disorders” (RBDs) and is an update on a previous issue published in 2009 in this journal.1 In addition to a comprehensive update on the various rare coagulation factor deficiencies or defects (fibrinogen, FII, FV, FV/FVIII, FXI, and FXIII), the current issue also provides updates on a selected group of rare platelet defects. However, some RBDs have not been updated from the 2009 issue, as we believe there is insufficient new significant information to warrant revision. The current issue Seminars in Thrombosis & Hemostasis represents an attempt to enhance the awareness of various RBDs among treating physicians, clinical and research laboratories, as well as research scientists interested in rare disorders. Each article details, for each RBD, the clinical manifestations, the laboratory assays used in the diagnosis (including problems with the laboratory evaluation), as well as the treatment options. Also, there is considerable discussion on some controversial issues related to these diagnoses, and in some articles, on phenotype–genotypic relationships. RBDs comprise bleeding disorders that have low prevalence in the general population. The term often refers to inherited deficiencies or defects in coagulation factors including fibrinogen (FI), prothrombin (FII), FV, FVII, combined FV/ FVIII defects, FX, FXI, and FXIII. These disorders constitute only approximately 3 to 5% of the coagulation disorders.2 The clinical conditions associated with these deficiencies can be very diverse, ranging from mild to severe, and the diagnosis can be quiet challenging. Much less attention is given to RBDs that alter the function of circulating platelets, some of which are not fully characterized and can also pose diagnostic challenges. Impaired platelet-related hemostatic tests may alert to these diagnoses; however, genetic analysis may sometimes be required to confirm diagnosis. Platelet defects can be caused by defective platelet receptors that affect the platelet binding to their ligands, impaired platelet structural elements such as dense and α granules,3 or altered signal transduction pathways. These disorders include Glanzmann thrombasthenia, Bernard–Soulier syndrome, platelet-type von Willebrand disease (PT-VWD), Gray platelet syndrome, and Scott syndrome.3,4 Whether of coagulation factor or platelet origin, the diagnosis and management of patients with RBDs can be difficult. There is little information available about the clinical and laboratory features of some of these diseases and the clinical reports are usually based on single case reports or small case series. In addition, there is a lack of consensus, or lack of awareness regarding expert consensus, with respect to the diagnostic process, which therefore often contributes tomis-/ underdiagnosis. An introduction to this issue by Peyvandi et al provides an overviewof theworldwide efforts for classification, diagnosis, and management of RBDs.5 It updates general information about RBDs published in the 2009 issue,2 discusses the data collection process worldwide, and also discusses the efforts made by the World Federation of Hemophilia (WFH; http:// www.wfh.org) and the International Rare Bleeding Disorders Database (RBDD; www.rbdd.org) in assessing the worldwide prevalence of RBDs. This has more recently been added to by the European Network of the Rare Bleeding Disorders and the Rare Bleeding Disorders Working Group under the umbrella of the FVIII and FIX Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis. This article also discusses efforts to establish a consensus regarding the classification based on clinical severity, issues related to the laboratory diagnosis and consensus (as related to the factor level in making the diagnosis), and also the minimum coagulant activity required to prevent bleeding. The article concludes that prospective large data collection in amulticentermultinational study is required to fill the