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disorders How to assess the bleeding phenotype in children and adults: epitomes from inherited bleeding disorders and immune

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 , 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, 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 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 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 bleeding risk and Immune Thrombocytopenia as an epitome of consequently the cost-benefit ratio of such a diagnosis acquired bleeding disorders: can bleeding remains uncertain. Only in patients with moderate bleed - assessment become a useful tool for patient ing severity, as usually are those having VWD, it seems management? that a diagnosis could be of some benefit, but for very mild conditions this remains unsettled. In a recent analy - Differently from MBD, assessment of bleeding mani - sis of a cohort of type 1 VWD patients (the European festations is not required for the diagnosis of ITP. In a MCMDM Study), patients that received the diagnosis of consensus report by an International Working Group VWD appeared to have a constant bleeding risk in their (IWG) the previous denomination of the disease lifetime, in contrast with normal controls or subjects clas - (Idiopathic/immune Thrombocytopenic , ITP), sified as unaffected that have a substantially absent risk of which included the term “purpura”, has recently been bleedings during their life. 11 replaced by Immune ThrombocytoPenia, maintaining the Therefore, it seems likely that an appropriate identifica - same acronym, 13 considering that up to 30% of cases tion of patients may spare some bleeding episodes in present without bleeding and are diagnosed incidental - VWD patients. When a patient should be considered for ly. 14 In this report, primary ITP is defined as an autoim - evaluation of a MBD remains still incompletely defined, mune disorder characterized by isolated thrombocytope - although some scenarios could be broadly considered. nia (platelet count <100 ¥10 9/L) in the absence of other causes or disorders that may be associated with thrombo - The patient with bleeding symptoms cytopenia. Thus, primary ITP remains a diagnosis of A patient with a significant history ( e.g. , having a exclusion and no robust clinical and laboratory parame - bleeding score above 3, see below) could be generally ters are currently available to establish the diagnosis. All considered as suggestive of a bleeding diathesis, 10 and other forms of immune thrombocytopenia are classified worth of evaluation with laboratory tests exploring the as secondary and their natural history may be influenced clotting and hemostatic systems. If an abnormality is by the underlying disorder. All patients with ITP have an

| 58 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012 increased risk of bleeding which becomes more evident when platelet count falls below a certain threshold. Most Differences and common issues in clinicians agree that without additional risk factors, con - establishing a bleeding assessment tool genital or acquired, and in absence of severe hemostatic A systematic approach to the development of tools for challenges, a platelet count of 30 ¥10 9/L could be rela - an appropriate and standardized assessment of bleeding tively safe. 15,16 However platelet count alone is not a good symptoms is advisable (Table 1), keeping however in indication of the bleeding phenotype of ITP in the indi - mind the profound differences between congenital and vidual patient. First, the relationship between platelet acquired bleeding disorders (Table 2). First, data must be count and bleeding is not so strict to be used as a reliable collected using stringent criteria and clinical judgment. surrogate of the bleeding phenotype in the individual This step requires the physician to interview the patient patient, suffice it to say that same individuals do tolerate about both the presence and the absence of bleeding 9 symptoms and has been already reviewed extensively profound thrombocytopenia (<5 ¥10 /L), whereas others 21-23 may show severe or life-threatening bleeding at higher (see for instance refs). A structured, written questionnaire could be helpful to platelet levels (5-30 ¥10 9/L). In particular, small children seem to tolerate profound thrombocytopenia for long improve the quality of data collection and to reduce both intra- and inter-observer variability. Second, collected periods without major bleeding at variance with older data must be interpreted to verify if the bleeding history people. 17,18 Thus, the concept of a platelet count as a is compatible with a bleeding disease, and for this pur - threshold sufficient to avoid or defer treatment (a con - pose a bleeding score (BS), accounting for both the num - cept often referred to as “safe platelet count”) appears ber and the severity of the bleeding symptoms, may be arbitrary and prone to lead to over or under treatment. useful. The BS is generated by summing the severity of Second, platelet count cannot substitute for bleeding all bleeding symptoms reported by a subject, and graded phenotype if one wants to explore how bleeding or fear according to an arbitrary scale. For each symptom, the of bleeding interfere with the quality of life (QoL) of grades of bleeding severity were designed “a priori” to be patients or the attitude of patients or doctors to treat the meaningful for each bleeding symptom in a given patient, disease on the basis of platelet count or the presence of only the most severe symptom before diagnosis is scored. bleeding manifestations. It has to be remembered that the Recently, the International Society of and primary aim of treating ITP should be to avoid or prevent Haemostasis (ISTH) has endorsed the development of a bleeding and not to simply correct platelet count. In this consensus questionnaire to collect and interpret clinically regard the statement by a recent report of the Cochrane relevant bleeding symptoms in patients with congenital Collaboration is of particular importance. 19 This bleeding disorders, along with a bleeding scale that could Cochrane review shows that the thrombopoietin receptor be used to compute a bleeding score (see http://www.isth. agonists (romiplostim and eltrombopag), recently org/default/index.cfm/ssc1/collaborations/ for the ISTH approved for clinical use, have failed to demonstrate a consensus questionnaire). 24 Most importantly, the panel of significant reduction of severe bleedings (WHO grade III and IV) when prospectively compared to patients ran - domized to placebo or standard of care, despite a remark - Table 1. Steps required for a systematic approach to bleed - able increase of platelet counts. Unfortunately, all these ing history. studies adopted a rough bleeding scale based on or Step Action derived from the WHO scale introduced in 1981 to record the toxicity of cancer treatment. 20 Definition of bleeding Selection and precise definition of bleeding symptoms. In principle, a standardized bleeding assessment specif - Design of a standardized questionnaire to gather ically developed for patients with ITP could be of major information for each bleeding symptom. utility providing a more exact definition of clinically Validation in terms of content and face validity by an meaningful bleeding events and for the purpose of making expert-consensus panel correlations of bleeding with QoL or other bleeding deter - minants or risk factors, like associated congenital or Data collection Collection of the patient bleeding history using a acquired bleeding disorders that may be present in the standardized questionnaire, by an appropriately trained physician patients. Exploring the correlation between bleeding severity and the actual platelet count over the course of the Data storage Possibly as electronic database disease and the different treatments, could also be of par - ticular interest, both intra and inter-patients. So far a sys - Data interpretation From stored data, unambiguous quantification of the tematic investigation of these correlations has been ham - severity of bleeding using a pre-specified grading scale pered by the lack of a sensitive, objective and reliable (e.g. , bleeding score for each symptom and total bleeding scale. A clear definition of the different bleeding bleeding score) manifestation is required as for the MBD, however, sepa - rating true pathological bleeding from bleedings often Recalibration/Validation The performance of the proposed questionnaire, recorded by normal people, a daunting task in the context definitions and bleeding scale should be assessed and of MBD, is a much more easy one in patients with ITP. In re-calibrated if not satisfactory in terms of content and face validity fact these patients can immediately compare their actual Prognostic value of any proposed bleeding score bleeding manifestations with those (if any) occurring requires independent validation in prospective ad hoc before the onset of the disease. Thus the category of trivial studies bleeding can be omitted (see below).

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 59 | 17 th Congress of the European Hematology Association experts did reach a consensus on the minimal criteria to sis of type 1 VWD was higher than that obtained using a classify a symptom as clinically relevant: criteria based on the presence of more than two bleeding – Epistaxis : Any that causes interference or symptoms (sensitivity, 64.3%). One of the benefits of distress with daily or social activities. using the BS lies however in the possibility of establish - – Cutaneous bleeding: are considered significant ing likelihood ratios of VWD for each level of BS. By when 5 or more (>1cm) in exposed areas. using likelihood ratios, one could quantify the increase in – Minor cutaneous : Any bleeding episode caused the probability of a person having VWD rather than of by superficial cuts ( e.g. , by shaving razor, knife, or scis - being a normal subject given his/ her BS 27 and could also sors) or that requires frequent bandage changes . integrate the information coming from the bleeding histo - – Oral cavity bleeding: Gum bleeding should be consid - ry with that obtained from other independent data, such as ered significant when it causes frankly bloody sputum VWF measurement. Such data have been provided by the and lasts for 10 minutes or longer on more than one European MCMDM-1VWD study, and demonstrate that occasion. Tooth eruption or spontaneous tooth loss the likelihood of VWD increases approximately in an bleeding should be considered significant when it exponential way with each unit increase of BS, 22 resulting requires assistance or supervision by a physician, or in a very unlikely VWD diagnosis for a BS below 0 but a lasts at least 10 minutes. Bleeding occurring after bites very likely VWD diagnosis for a BS above 4. Very recent - to lips, cheek, and tongue should be considered signifi - ly, our group tried to integrate information coming from cant when it lasts at least 10 minutes or causes a clinical, laboratory and family data into a single value swollen tongue or mouth. (the final probability of having VWD. 28 – Tooth extraction: Any bleeding occurring after leaving With this approach, the physician collects data about the dentist’s office and requiring a new, unscheduled the bleeding history in the patient (summarized in a BS) visit or prolonged bleeding at the dentist’s office caus - and measures VWF level in the patients and in as many ing a delay in the procedure or discharge. first relatives as possible (to detect relatives with VWF – Surgical bleeding: Any bleeding judged by the surgeon levels below the normal range). This information is trans - to be abnormally prolonged, that causes a delay in dis - lated into likelihood ratios for bleeding history, VWF charge, or requires some supportive treatment. level and family data, respectively, and then used to com - – Menorrhagia: Any bleeding that interferes with daily pute the final probability of having VWD. For instance, activities such as work, housework, exercise or social the presence of VWF levels below 40 IU/dL in at least activities during most menstrual periods. two family members (including the proband) and of a BS at least of 1 in the proband resulted in a final odd of VWD of 2.0 (or a final probability of VWD of 66%). Therefore, Mild bleeding disorders: where we stand rather than using fixed criteria with unknown sensitivity or specificity, physicians may compute the probability of Several investigators have described the use of bleed - VWD for each given subjects of a particular family. This ing questionnaires, mainly for the purpose of predicting approach appears to be more flexible, but it still requires bleeding before surgery, 25,26 but until recently no attempt further validation before being proposed for a widespread has been made to quantitatively describe bleeding disor - use. ders. Two recent experiences of such an approach to The BS has been prospectively tested for the diagnosis MBD have been recently reported, one in type 1 VWD of patients referred for evaluation of bleeding symptoms and one in a platelet function deficiency, the Quebec and/or abnormal laboratory screening tests in a secondary platelet disorder. 10,12 setting, 29 and it was found that a clinical prediction guide In the International Multicenter Study, normal males based on BAT and aPTT could be useful to exclude showed a BS below 3 and normal females a BS below 5. 10 patients with suspected MBD in a low-prevalence Using this cut-off, the sensitivity of the BS in the diagno - (screening) setting. Assuming a prevalence for MBD in the general population around 1%, a normal BS (<=3) had a very high negative predictive value (99.2%). The posi - Table 2. Differences between congenital and acquired tive predictive value in patients referred for hemostatic or bleeding disorders. familial evaluation at second level clinics was estimated Congenital ( e.g. , VWD) Acquired ( e.g. , ITP) to be 71.0 and 77.5% (assuming a MDB prevalence of 20% and 50%, respectively, in these settings). Bleeding history Usually lifelong Usually silent

Background bleeding Critical Irrelevant ITP: where we stand reported by healthy people In addition to the often misused WHO scale (0=no Time-span of collection From birth to diagnosis At diagnosis or bleeding; 1=petechiae; 2=mild loss; 3=gross blood of bleeding symptoms subsequently loss; 4=debilitating blood loss), 20 several bleeding scales have been proposed for children and adults with ITP. 30-37 Patient recall bias May be relevant Irrelevant Table 3 summarizes main examples. These scales are very heterogeneous for what concerns the reporting of the dif - Often uninformative Required ferent bleeding symptoms and the assigned grades of severity, usually encompassing 3 to 5 points. 38 Main purpose of bleeding Diagnostic Descriptive, 35 quantification Prognostic Buchanan and Adix proposed an instrument to allow semiquantitative assessment of hemorrhage in children.

| 60 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012

Bleeding was recorded for oral, and epistaxis with 5 bleeding manifestation of the patient at the time of exami - grades for severity (no bleeding, minor, mild, moderate, nation, giving major emphasis to the distinction between severe). An overall bleeding scale with 6 grades was also minor/moderate symptoms from more alarming bleeding proposed. The same weight was assigned to history and manifestations. The score was not linear for each symptom physical examination. Inter-rater agreement was accept - but mainly based on the clinical a priori intuition that some able but only for oral bleeding and epistaxis. This scale manifestations call for immediate interventions. This sys - was not widely adopted in subsequent studies. tem, with some modifications, was used in a countrywide Another often referenced pediatric scale is that pro - study investigating the efficacy of compassionate use of posed by Bolton-Maggs and Moon 30 which is very simple romiplostim in 72 adult patients with ITP not responsive to encompassing 3 grades of bleeding. Mild, in case of no or several treatment lines. Interestingly, patients with a high minimal interference with daily living; moderate and bleeding score at baseline were the less responsive. This severe when symptoms require hospital admission or study shows for the first time a prognostic value of bleeding blood transfusion or seriously interfere with quality of symptoms, independent from platelet count. 33 life. This scale appears based on broad criteria and open Recognizing the existing limitation plaguing bleeding to subjective interpretation and to be sensitive only to rel - assessment in patients with ITP and that none of the BATs atively large clinical changes. 38 developed for congenital hemostatic disorders was suit - Unfortunately, in all randomized trials on the efficacy able for ITP, the IWG on ITP has promoted during the last and safety of thrombopoietin receptor agonists in adults 2 years several meetings of expert international clinicians poor attention has been paid to the reporting and analysis in order to propose a consensus Bleeding Assessment of bleeding symptoms. In the romiplostim registrative Tool (BAT) based on a standardized questionnaire and a study comparing the investigational agent versus place - grading system harmonized to this questionnaire bo 39 and in a subsequent study of romiplostim versus stan - (Rodeghiero personal communication, EHA 2012, sub - dard of care in patient not splenectomized and followed mitted). for 1 year, 40 bleeding events were considered only as One of the main aims of this project is to provide a ter - adverse events and each bleeding was graded into an ill- minology for hemorrhagic manifestations in ITP that inte - defined 5 point scale apparently derived from an expand - grates and is consistent with the terminology already ed WHO scale (mild, moderate, severe, life threatening adopted for other bleeding disorders and that may be rel - and fatal) by investigator judgment. A post hoc analysis evant for the purposes of developing an ITP-specific based on the limited data obtained from these studies and bleeding assessment. Bleeding signs/symptoms are from additional open label extension studies 41 was carried grouped according to three major groups: Skin (S), visible out 42 without providing conclusive evidence on the reduc - Mucosae (M) and Organ (O). tion of bleeding symptoms. The IWG recognized that standard medicine textbooks In the two main trials comparing eltrombopag versus may offer different descriptions particularly for skin and placebo 43,44 bleeding events were recorded both at enroll - mucosal domains, and that adherence to standard defini - ment and during the study and bleeding reduction was tion is often limited and thus decided to recapitulate main included among the secondary endpoints of the studies. definitions of the principal symptoms in these districts WHO scale, not originally proposed for this scope, was and how to identify them (Table 4). Organ domain includ - adopted without further guidance for symptoms classifi - ed the following types of bleeding: GI bleeding cation, thus sapping any definite conclusion. (hematemesis, melena, hematochezia, rectorrhagia); Recently Khellaf 45 proposed a standardized bleeding Lung bleeding (); Hematuria; Menorrhagia; score based on the immediate clinical appreciation of the Muscle ; ; Ocular bleeding;

Table 3. Main characteristics of different bleeding scores.

Studies Bleeding grading Site specific Patients and type of study Aim

Bolton-Maggs 30 Yes, 5 grades No Pediatric ITP, retrospective Descriptive

Godeau 31 Yes, not linear Yes Adult ITP, first line therapy; prospective Descriptive Identification of major hemorrhages at presentation

Page 32 Yes, 3 grades Yes Adult ITP, retrospective Descriptive

Khellaf 33 Yes, not linear Yes Adult ITP treated with TPO receptor Identification of major hemorrhages at presentation agonist, prospective Prognostic value

Buchanan 34 Yes, 5 grades No Pediatric ITP, first line therapy, prospective Efficacy of therapy

Buchanan 35 Yes, 5 grades Yes Pedriatics ITP, retrospective Descriptive

Medeiros 36 No, criteria for major hemorrages No Pediatric ITP, retrospective Descriptive

Mazzucconi 37 Yes, 5 grades No Adult ITP, first line therapy; prospective Descriptive

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 61 | 17 th Congress of the European Hematology Association

Table 4. Definition of bleeding signs based on physical examination.

Site of bleeding Sign Definition

Skin ( and ) Petechiae Red (recent) or purplish (a few days old) spot discoloration in the skin with a diameter between 0.5 mm to 3 mm, not blanching with pressure and not palpable Purpuric macules (purpura) Differentiated from petechiae only for their larger size between 3 to 10 mm. Should be counted as ecchymoses Ecchymosis (bruises or contusions) Flat, rounded or irregular, red, blue, purplish or yellowish green patches, larger than a . If elevated they represent superficial spreading of an underlying hematoma

Skin (subcutaneous tissue) Hematoma Bulging localized accumulation of blood often with discoloration of overlying skin

Visible mucous membranes Petechia, purpuric As for skin macules and ecchymoses Bulla and vescicle (blister) Visible raised, thin-walled, circumscribed lesions containing blood. Bullae are larger than vescicles (<5 mm). They should be counted together as bullae Epistaxis Any bleeding from the nose, may be anterior or posterior and unilateral or bilateral Gingival bleeding Any bleeding from the gingival margins Subconjunctival hemorrhage Bright red discoloration underneath the conjunctiva at onset then same color changes as ecchymoses

Muscles and soft tissues Hematoma Any localized collection of blood visible, or palpable or revealed by imaging. May be dissecting when spreading along fascial spaces

Intracranial (intracerebral, intraventricular, subarach - trained physician may complete a bleeding questionnaire in noidal,subdural, extradural). less than ten minutes, the process of data re-evaluation and Each bleeding manifestation should be assessed at the interpretation may be overwhelming if data is not electron - time of examination. Its severity is graded from 0 to 4. ically stored. Data coming from studies on bleeding Appreciation of bleeding based on history only, without patients is especially precious, since it contains information medical record supplementation, will receive grade 1 any - from series of patients that could be usually studied just way. Grading is harmonized with the questionnaire and once in their lifetime, and should be possibly available to the same grading of the different symptoms within each the entire scientific community if phenotype/genotype cor - domain is assumed to have a similar clinical relevance. relations are to be sought in the coming years. For these For each symptom, the worst ever episode during the reason, the formation and availability of large databases on observation time is scored and then the worst episode bleeding symptoms should be endorsed, and will be a within the domain is recorded. The index produced by major task of the scientific community in the next years. summing the worst ever grade in the 3 domains will rep - Third, a new vision to a systematic approach to bleed - resent the final score for that particular patient. ing symptoms is probably required. An example of such new horizon is possibly given by an ontology approach, in which bleeding symptoms are mapped together with Perspectives anatomic sites and clinical interventions to control bleed - ing (see http://www.bioontology. org/). Such an approach Despite all the advances in the clinical investigation of would allow comparison of the distribution and possibly bleeding symptoms, several actions need to be taken to severity of bleeding manifestations between different further improve the validity and usefulness of such an disease and offers insights on the role of factors modulat - approach in the diagnosis and management of bleeding ing bleeding in humans. An ontology approach to bleed - disorders. ing symptoms has been pioneered by Barry Coller at the First, the validation of the proposed bleeding scales has Rockefeller University (see http://bioportal.bioontol - been achieved only for patients with mild bleeding disor - ogy.org/ ontologies/1116). ders, particularly VWD, but we do not know if bleeding scores could work equally well for the quantitation of bleeding in severe bleeding disorders. Furthermore, References bleeding scores have been used mainly for diagnostic pur - poses, but their prognostic utility in severe and acquire 1. Edlund M, Blomback M, von Schoultz B, Andersson O. On the value of menorrhagia as a predictor for disor - bleeding disorders remains uncertain, requiring appropri - ders. Am J Hematol. 1996 Dec;53(4):234-8. ately designed studies before such a clinical use. 2. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. Second, the use of electronic databases, and possibly of von Willebrand disease in women with menorrhagia: a sys - widely available, web-based instruments, should be tematic review. BJOG. 2004 Jul;111(7):734-40. encouraged and supported. Bleeding questionnaires may 3. Rodeghiero F, Castaman G, Mannucci PM. Prospective multi - contain several items, and although an appropriately center study on subcutaneous concentrated desmopressin for home treatment of patients with von Willebrand disease and

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