Bleeding disorders How to assess the bleeding phenotype in children and adults: epitomes from inherited bleeding disorders and immune thrombocytopenia F. Rodeghiero, ABSTRACT A. Tosetto The vast amount of information on the pathophysiology and molecular basis of congenital bleeding Department of Cell Therapy and disorders contrasts with the paucity of data on their clinical phenotype and natural history. Recent Hematology, San Bortolo Hospital, efforts have paved the way to a standardized collection and a quantitative evaluation of the different Vicenza, Italy bleeding manifestations. These aspects are of critical importance for mild bleeding disorders (MBD) of which von Willebrand disease, mainly type 1, is the most relevant and frequent epitome. In fact, the clinician needs a clinical-based approach guided by the patients’ symptoms in order to start a specific Hematology Education: diagnostic process in the “right” patient, aiming not just at putting the patient into a nosographic cat - the education program for the egory, producing a permanent stigma, but at providing him/her with a clinically useful information. annual congress of the European In acquired disorders, a systematic approach to the standardization of the description of bleeding phe - Hematology Association notype has so far never been systematically investigated and no consensus on bleeding assessment tool (BAT) is available for this scope. The epitome of these conditions could be represented by immune 2012;6:57-64 thrombocytopenia (ITP). Even if the primary management goal in this disorder should be to avoid or reduce bleeding while maintaining a satisfactory quality of life, platelet count remains the best sur - rogate endpoint for assessing the severity of the disease and for evaluating the response to treatment. Acknowledgements: This article provides a synthetic review of the critical issues in the construction of a comprehensive The project for a consensus BAT in and reliable BAT. These aspects have proven instrumental for the establishment of the first BAT for ITP has been made possible thanks MBD and will form the basis of a proposal for a distinct tool for acquired bleeding disorders, like ITP. to the contribution of the other members of the International Working Group on ITP: Donald Arnold, Victor Blanchette, George Buchanan, James B. Bussel, Doug Cines, Nichola Cooper, Terry Introduction The second condition is immune thrombo - Gernsheimer, Bertrand Godeau, Paul Bleeding is a particularly alarming symp - cytopenia (ITP), chosen as the epitome to Imbach, Mehdi Khellaf, Rob tom for both patients and clinicians. Major illustrate the critical role that a standardized Klaassen, Thomas Kühne, Howard Liebman, Maria Gabriella bleeding episodes might be life-threatening bleeding assessment could have in improving Mazzucconi, Marc Michel, Cindy and fatal, but also minor bleedings may the management of an acquired bleeding dis - Neunert, Ingrid Pabinger, Marco severely impair the quality of life. order. Ruggeri, Roberto Stasi. In contrast with the enormous scientific For the sake of simplicity, in this paper the The development of the BATs work that has been devoted to the understand - term symptom refers also to bleeding signs. presented in this paper was ing of the pathophysiology of congenital or supported by the Fondazione acquired bleeding disorders in the last Progetto Ematologia (Hematology decades, much less attention has been devoted Von Willebrand’s disease as an Project Foundation, Vicenza, Italy). to the description of the different bleeding epitome of MBD: when to start a manifestations. The lack of standardization in diagnostic process this field is a major cause for the insufficient description of the clinical phenotype of many Considering the ever-increasing quest for congenital and acquired diseases especially higher wellbeing standards in affluent soci - those in which the hemorrhagic manifesta - eties, and the physicians’ desire to avoid even tions are not of such immediate clinical appre - minor risks concerning their liability, it is not ciation. surprising that even conditions carrying an In this review, we will discuss two different intermediate or low bleeding risk are increas - conditions to exemplify the need for an ade - ingly searched and diagnosed. Furthermore, quate approach to the description of bleeding well informed population is less prone to tol - phenotype. The first is represented by von erate even minor symptoms and is increasing - Willebrand disease, the most frequent congen - ly looking for medical remedies. Therefore, ital bleeding condition. This disorder, particu - while the clinical hematologist was once larly type 1, can be assumed as the epitome of required to investigate and manage only many congenital bleeding diseases, collec - patients with severe bleeding disorders, such tively identified as mild bleeding disorders as hemophilia, he/she is now increasingly (MBD), in contrast to severe hemostatic asked to exclude the presence of a, purported - defects (like hemophilia A or B, or ly mild, bleeding disorder. He or she should Glanzmann’s thromboasthenia or Bernard- be aware of the wide availability of drugs Soulier disease) that usually present with a (such as desmopressin, antifibrinolytics) that clear-cut bleeding phenotype. may safely improve the bleeding diathesis in Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 57 | 17 th Congress of the European Hematology Association patients having a MBD but should also avoid medicaliza - identified, it is likely that the patient has a significant tion of otherwise healthy people. For instance, mild VWD bleeding tendency that may benefit from treatment ( e.g. , could be diagnosed in up to 20% of women with menor - antihemorrhagic prophylaxis before surgery or tooth rhagia, 1,2 and the severity of this bleeding symptom is extraction). If no abnormalities are found even in the improved by the use of subcutaneous desmopressin. 3 presence of a significant bleeding score, the presence of MBD (particularly Type 1 VWD and platelet secretion other disorders ( e.g. , Rendu-Weber-Osler, Ehlers- disorders) are prevalent in the general population, being Danlos, Cushing disease) should be sought. It should be present in up to 1% of normal subjects, thus being an also remembered that one limitation of the bleeding interesting target for specific interventions. However, score is that it is influenced by the age of the patient, and considering that menorrhagia could be well managed therefore it could be of limited value in young patients without a specific diagnosis, such a simplistic approach (see below). could in itself be devoid of any clinical utility unless the patient has a risk of significant bleeding in case of hemo - The asymptomatic patient with a family history static challenges. On the contrary, it might unwillingly of bleeding result in the stigma of labeling the patient with a congen - Counseling an asymptomatic relative of a patient with ital disease. known MBD (the proband) could be particularly difficult. Distinguishing a patient having a MBD, for whom a Even if the same type of deficiency observed in the specific diagnosis would be useful, from an otherwise proband is identified, there are no clues that may be used normal subject having casual bleeding is a formidable to predict bleeding in such patients. Selection bias, pres - issue, however. Whereas the boundary between severe ence of circumstantial factors ( e.g. , aspirin use), co-inher - bleeding disorders (such as hemophilia A, type 3 VWD or itance of other MBD may have worsened the bleeding homozygous FVII deficiency) and mild hemorrhagic dis - diathesis in the proband, and extreme caution should be order may be considered to be clinically well-defined, the used before labeling an asymptomatic patient as “affect - distinction between normal subjects and patients with ed”. Therefore, even before evaluating for a specific lab - mild-bleeding disorders (MBD) is often unclear since oratory defect, reassurance of the asymptomatic patient is even normal subjects, when questioned about their histo - always advisable. ry, refer hemorrhagic symptoms quite frequently, in up to more than 20% of cases. 4-8 The number of symptoms The pediatric patient reported by a patient may be influenced by his/her educa - The pediatric patient with bleeding symptoms should tion, family setting ( e.g. , some symptoms may be under - be carefully evaluated because he/she is usually referred reported by subjects belonging to a bleeding family) and for only scarce manifestations that would be otherwise personality, but also by the type of data ascertainment. dismissed as “trivial” in an adult. Data from other family For instance, using a self-reported questionnaire Friberg members should always be collected, since bleeding in et al reported that as much as 23% of Swedish girls other relatives may be frequently reported for autosomal reported three or more hemorrhagic symptoms, 9 whereas dominant disorders. 12 The family history may be however using a questionnaire guided by a physician, Rodeghiero negative for recessive disorders, and a complete evalua - et al observed three or more hemorrhagic symptoms in tion of the pediatric patient should be performed in doubt - less than 1% of normal controls. 10 ful cases. Given these clinical complexities, is it worthwhile to pursue the diagnosis of MBD at all? For most MBD we do not have clinical data on the lifelong