Hrev_master [page 66] [Emergency Care Journal 2013; 9:e22] Mild to moderate bleeding: diagnostic and therapeutic paths Caterina Cenci,1 Elena Silvestri,2 Alberto Marchi,1 Giacomo Emmi,2 Domenico Prisco2 1Medical Pathology Department, Careggi University Hospital, Florence; 2Experimental and Clinical Medicine Department, University of Florence, Florence, Italy Abstract We consider mild to moderate bleedings all bleeding events that do not meet the criteria proposed by the International Society of Thrombosis and Haemostasis (ISTH) for the definition of major bleeding. As regards the approach to the bleeding patient, the first step is undoubtedly an accurate collection of clini- cal history and overall physical examination. Then, the etiological diagnosis of a bleeding disorder uses a series of laboratory investiga- tions, divided into first level tests, which are intended to identify the altered phase of the hemostatic process, and second level ones, i.e. more specific tests used if screening tests are negative or to better characterize the alter- ation identified by them. For the treatment of a bleeding disorder there are several approach- es, all strictly dependent on the etiologic diag- nosis of this disorder. Introduction We consider mild to moderate bleedings all bleeding events that do not meet the International Society of Thrombosis and Haemostasis (ISTH) criteria1 according to which major bleeding is defined: i) fatal bleed- ing; and/or ii) symptomatic bleeding in a criti- cal area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra- articular or pericardial, or intramuscular with compartment syndrome; and /or iii) bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfu- sion of two or more units of whole blood or red cells. Differently from previous definitions, ISTH experts did not include in major bleeding bleeding resulting in surgical intervention as a separate criterion as, if no other criteria for major bleeding have been satisfied, perform- ance of surgical interventions will often be minor and not justify categorization as a major bleed.1 Thus, many bleedings resulting in sur- gical procedures have to be considered mild to moderate. Bleeding disorders defined as mild to moderate refer to those conditions in which there is an increased tendency to bleeding, in particular associated with trauma and surgery, but in which life-threatening bleeding does not generally occur. Therefore, the discrimination between normal and a pathological tendency to bleed is often challenging,2 because most symptoms may occur in healthy subjects, but it is of pivotal importance to identify patients with hemostatic disorders who need investiga- tions and specific treatments. The International Society of Thrombosis and Haemostasis questionnaire The first step of the approach to a bleeding patient is undoubtedly the collection of person- al and family medical history as accurately as possible in order to ascertain the type of bleed- ing disorder and its characteristics, the age of onset of symptoms, the presence of similar events in other family members, the recent exposure to medications, the concomitant presence of other diseases. In this regard, some questionnaires that provide more effec- tive criteria for the formulation of questions and the evaluation of the related answers have been produced. In particular, the ISTH ques- tionnaire consists of two stages: the first is the collection of a bleeding history following encoded criteria (Table 1) and the second is the attribution of a predetermined value to each symptom based on its severity according to a bleeding score (Table 2). The use of such questionnaires is actually much debated as they are not applicable in all the conditions; however, they have been demonstrated to be effective in identifying, among patients with a probable bleeding diathesis, those with a real clinical problem that require further diagnos- tic investigations.3 In particular, although the use of this bleeding score has been formally validated only for von Willebrand’s disease patients but not for those with other bleeding disorders, a score greater than 3 in males and more than 5 in females can be considered highly suggestive of the real existence of a bleeding diathesis.4 Secondly, it should not be overlooked an accurate general physical examination that must include an assessment of the overall sta- tus (vital signs, state of the skin and mucous membranes, any associated sign, conscious- ness) and the search for specific patterns that may direct the physician to the correct diagno- sis.5 For example, the detection of petechiae can evoke the suspicion of thrombocytopenia, bleeding from the mucous membranes can ori- ent towards the von Willebrand’s disease or a pathology of platelets, while a muscular hematoma may point to a lack of coagulation factors. The definitive diagnosis of a specific bleed- ing disorder also employs a series of laborato- ry tests, divided into first level tests (screening tests), which are intended to identify the altered phase of the haemostatic process, and second level tests, or more specific surveys useful in the case in which screening tests are normal or to better characterize the alter- ation(s) identified. In the case of altered results, it is necessary to evaluate the accura- cy of data, which depends on a correct prepara- tion and manipulation of the sample, and, in any case, confirm it with a repetition of the test on a new sample. First level tests (Table 3)6 include blood count with platelet count, bleeding time and/or the more recent platelet function analyzer (PFA)-100, which explore primary haemosta- sis, prothrombin time (PT), activated partial thromboplastin time (aPTT) and the dosage of fibrinogen, which explore the coagulation cas- cade. According to some, also the determina- tion of AB0 blood group and the tests that explore liver function belong to first level tests, since it is known that group 0 subjects are more prone to develop a bleeding diathesis compared to subjects of other blood groups.7 Moreover, given the high prevalence in the population of von Willebrand disease, many centers include the immunoassay of von Willebrand factor (VWF:Ag) associated with the specific assay of the VWF activity on platelet agglutination in the presence of risto- Emergency Care Journal; volume 9:e22 Correspondence: Caterina Cenci, Medical Pathology Department, Careggi University Hospital, largo Brambilla 3, 50134 Florence, Italy. Tel. +39.347.1662592 - Fax: +39.055.794.6455. E-mail: caterinacenci@gmail.com Key words: mild bleeding, moderate bleeding, ISTH questionnaire. Contributions: the authors contributed equally. Conflict of interests: the authors declare no potential conflict of interests. Received for publication: 15 March 2013. Revision received: 2 September 2013. Accepted for publication: 5 September 2013. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright C. Cenci et al., 2013 Licensee PAGEPress, Italy Emergency Care Journal 2013; 9:e22 doi:10.4081/ecj.2013.e22 No n- co mm er cia l u se on ly [Emergency Care Journal 2013; 9:e22] [page 67] cetin (ristocetinic cofactor activity, VWF:RCo) and factor VIII coagulant activity (FVIII:C) in the group of first level tests. Second level tests (Table 4) include mixing tests, platelet aggregation test, the dosage of individual coagulation factors, and possibly the tests exploring the fibrinolytic cascade. In the case of a patient with bleeding diathe- sis, first level tests help to determine whether the defect is to be referred to primary haemostasis (vascular phase/platelets) or sec- ondary haemostasis (coagulation phase). Platelet count allows to identify a thrombocy- topenia while, in the case of platelet normal values, the PFA-100, able to reproduce in vitro platelet adhesion and aggregation, and the much more operator-dependent bleeding time according to Mielke method are able to identi- fy the existence of a platelet dysfunction or von Willebrand disease. In the case of positive results of these tests, it is indicated to start specific diagnostics for von Willebrand dis- ease, the most common bleeding disorder, and to carry out, if this diagnosis is excluded, platelet aggregation tests. It should be noted that the characterization of a congenital thrombocytopathy requires highly specialized centers; moreover, we must remember the need for a careful drug history in the interpre- tation of an altered result of tests exploring platelet function. PT is defined as the time in seconds an aliquot of platelet-poor plasma takes to clot fol- lowing the addition of an extract of tissue fac- tor of human or animal origin (thromboplas- tin) and calcium ions at 37°C. This test explores the extrinsic and common pathway of coagulation and it is prolonged in case of fac- tor II, V, VII, X, and fibrinogen deficiency, as well as during treatment with antagonists of vitamin K. It should be noted that the test is commonly altered in advanced liver disease and vitamin K deficiencies. aPTT, instead, is the time in seconds an aliquot of platelet-poor plasma takes to clot following the addition of an activator of the contact phase (kaolin, ellag- ic acid, silica, etc.), of phospholipids and calci- um ions at 37°C. This test explores the intrin- sic and common coagulation pathway and it is prolonged in case of factors II, V, VIII, IX, X, XI and fibrinogen deficiency as well as during therapy with unfractionated heparin, and often with antagonists of vitamin K. The presence of antiphospholipid antibodies and factor XII ArticleOpinion Report Table 1. The International Society of Thrombosis and Haemostasis questionnaire. Symptom Relevant features Questions Epistaxis Frequent (at least once a week); How many episodes/year? Duration>5’; How long they last? Not only pre-puberal; Are they spontaneous or after drug assumption? Complicated What was the age of maximum frequency? Did they require medical attention? If yes, please specify Cutaneous symptoms Spontaneous bruising or hematoma>3 cm Which kind of manifestation? Where? After trauma? If yes, which kind of trauma? Did they require medical attention? If yes, please specify Bleeding from minor wounds Duration>5’ How many episodes/year? At least 1 episode/year due to superficial cuts How long they last? Did they require medical attention? If yes, please specify Bleeding in the oral cavity Spontaneous gingival bleeding lasting>1' Where? characterized by the presence of blood in the In which occasion? sputum or resulting from brushing; Did they require medical attention? If yes, please specify Bleeding of labial, buccal, or lingual mucosa>5' or that causes swelling of the tongue or mouth; Any bleeding after dental eruption that requires medical attention Gastrointestinal bleeding Any How many episodes/year? Which kind of manifestation? Is it associated to local diseases? Did they require medical attention? If yes, please specify Post-dental extraction bleeding Any bleeding that occurs during or post dental What is the ratio between number of dental extraction and extraction that complicated it those complicated? At what age and what type of tooth? kind of therapeutic measure was needed? Post-surgery bleeding Any bleeding considered excessive by the surgeon What is the ratio between total number of surgery and those or that has determined a delay in the discharge from complicated? the hospital delayed or that made it necessary any What is the type of surgery? supportive treatment What kind of therapeutic measure was needed? Menorrhagia None What is the duration of average menstruation (days)? What is the duration of heavy menstruation (days)? What is the age of onset and when has it reached the maximum intensity? Did it require medical attention? If yes, please specify Post-partum hemorrhage None What is the ratio between number of deliveries and those complicated? What kind of therapeutic measure was needed? Muscle ematoma or hemarthrosis None Where? Spontaneous or traumatic? No n- co mm er cia l u se on ly [page 68] [Emergency Care Journal 2013; 9:e22] deficiency explain those cases in which aPTT is prolonged in the absence of a hemorrhagic syndrome. PT and aPTT, therefore, investigate the function of several coagulation factors while each one is sensitive to a more limited group of factors. Their values allow not only to confirm or rule out an alteration of secondary haemostasis but also to orient toward the pos- sible defect: for example, the isolated prolon- gation of PT is suggestive for factor VII defi- ciency, while the alteration of both tests occurs in factor II, V, X and fibrinogen deficiency as well as during antagonists of vitamin K treat- ment, in advanced liver disease and dissemi- nated intravascular coagulation. The deficien- cy of one or more factors or the presence of an inhibitor of coagulation is determined by repeating the test on a mixture prepared with the patient plasma and a normal plasma in a 1:1 ratio. If the coagulation time performed on the mixture results closer to that of normal plasma we can conclude for a factor deficiency and we will proceed with the dosage of the individual related coagulation factors; instead, if the clotting time of the mixture turns out to be closer to that obtained on patient plasma we will likely be in the presence of an inhibitor of coagulation. Another situation, although not very fre- quent, is the presence of an abnormal fibrino- gen (dysfibrinogenemia)8 in patient plasma and in this case PT and aPTT tests are not very sensitive. This condition, whose consequence can be both a bleeding or a thrombotic event (depending on the type of defect), is diagnosed thanks to the functional and immunological assay of fibrinogen or using the thrombin time and the reptilase time. These last two tests directly explore the conversion reaction of fib- rinogen to fibrin: thrombin time, however, is also affected by the therapy with heparin so, by using the two tests together, we can identify those situations in which both tests are altered due to a dysfibrinogenemia. If the results of the tests are normal, but the patient’s medical history is positive for bleed- ing, the dosage of factor XIII, whose deficiency can lead to a rare hemorrhagic syndrome, and the exploration of the fibrinolytic system with the dosages of antiplasmin, tissue plasmino- gen activator (t-PA) and plasminogen activator inhibitor (PAI-1),9,10 may be useful. Principles of therapy It is difficult to give an appropriate treat- ment algorithm for patients with mild to mod- erate bleeding disorders since the treatment depends critically on the specific diagnosis and it has been shown by a recent study that in 54% of those patients with family and personal history of mucocutaneous bleeding a cause cannot be identified.11 In addition, before start- ing a treatment a balance between its risks and benefits should be evaluated: in fact, on one hand, the use of specific drugs active on the haemostatic cascade is able to block the process by reducing hemorrhagic complica- tions, but, on the other hand, these drugs may increase the risk of thrombotic events.11 In case of bleeding during antiplatelet or antico- agulant therapy, the first decision is to stop the antithrombotic drug. For the treatment of bleeding disorders, in addition to the use of concentrates of coagulation factors in the case of specific factors deficiencies, a possible option are the inhibitors of the fibrinolytic cas- cade such as tranexamic acid that is normally used with success both in the prevention of bleeding events in patients at risk before sur- gical procedures, and in the therapy of acute mucocutaneous bleeding (for example in case of menorrhagia).12,13 It is also known that desmopressin, a synthetic analogue of vaso- pressin, is effective in the prevention of bleed- ing in patients with haemophilia A and type 1 von Willebrand disease since it is able to raise by 3-4 times the plasma concentrations of von Willebrand factor and factor VIII. Although there have been few reports of serious side effects, the drug is contraindicated in patients under the age of 2 years, for the risk of hypona- tremia, in adults with symptomatic atheroscle- rosis14 and in women with menorrhagia; in the latter situation desmopressin is used as sec- ond-line therapy or in addition to an anti-fibri- Opinion Report Table 2. Bleeding score. Symptom Score Epistaxis 0=no or trivial 1=present 2=packing or cauterization 3=blood transfusion or replacement therapy Cutaneous 0=no or trivial 1=petechiae or bruises 2=haematomas 3=consultation Bleeding from minor wounds 0=no or trivial 1=present 2=consultation 3=surgical haemostasis Oral cavity 0=no or trivial 1=present 2=consultation only 3=surgical haemostasis or blood transfusion Gastrointestinal bleeding 0=no or trivial 1=present 2=consultation only 3=surgery/ blood transfusion Post-partum haemorrage 0=no or trivial 1=present, iron therapy 2=blood transfusion, dilatation and curettage, suturing 3=hysterectomy Muscle haematomas or haemarthrosis 0=no or trivial 1=present 2=consultation only 3=blood transfusion, surgery Tooth extraction 0=no or trivial 1=present 2=suturing or packing 3=blood transfusion Surgery 0=no or trivial 1=present 2=suturing or resurgery 3=blood transfusion Menorrhagia 0=no or trivial 1=present 2=consultation, contraceptive pill use, iron therapy 3=blood transfusion, hysterectomy, dilatation and curettage No n- co mm er cia l u se on ly [Emergency Care Journal 2013; 9:e22] [page 69] nolytic drug in case of non-remission of haem- orrhagic symptoms.15 Conclusions One of the challenges of the coming years will be the management of bleeding events during therapy with the new oral anticoagu- lants. It must be said, however, that in the con- text of mild to moderate bleeding the manage- ment will be relatively easy and based only on the discontinuation of treatment thanks to the short half-life of these drugs. References 1. Schulman S, Kearon C. Definition of major bleeding in clinical investigations and antihemostatic medicinal products in non- surgical patients. J Thromb Haemost 2005;3:692-4. 2. Rodeghiero F, Tosetto A, Castaman G. How to estimate bleeding risk in mild bleeding disorders. J Thromb Haemost 2007;5:157- 66. 3. Sramek A, Eikenboom JC, Briet E, et al. Usefulness of patient interview in bleed- ing disorders. Arch Intern Med 1995;155:1409-15. 4. Rodeghiero F, Castaman G, Tosetto A, et al. The discriminant power of bleeding histo- ry for the diagnosis of von Willebrand dis- ease type 1: an international, multicenter study. J Thromb Haemost 2005;3:2619-26. 5. Girolami A, Luzzatto G, Varvarikis C, et al. Main clinical manifestations of a bleeding diathesis: an often disregarded aspect of medical and surgical history taking. Haemophilia 2005;11:193-202. 6. De Moerloose P, Levrat E, Fontana P, Boehlen F. Diagnosis of mild bleeding dis- orders. Swiss Med Wkly 2009;139:327-32. 7. O’Donnell J, Laffan MA. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med Rev 2001;11:343-51. 8. Rocha E, Paramo JA, Aranda A, et al. Congenital dysfibrinogenemias. A review. Res Clin Lab 1985;15:205-29. 9. Tripodi A. [Linee guida per lo screening dei pazienti in emergenza emorragica]. [Article in Italian]. Available from: http://www.sisetonline.com/lineeguida/all_ pdf/emergenza1999.pdf 10. Tripodi A. [Linee guida per lo screening dei pazienti con sospetto difetto emorragi- co congenito]. [Article in Italian]. Available from: http://www.sisetonline.com/lineeguida/all_ pdf/difetto.pdf 11. Quiroga T, Goycoolea M, Munoz B, et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004;2:892-8. 12. Hayward CPM. Diagnosis and manage- ment of mild bleeding disorders. Hematology Am Soc Hematol Educ Program 2005:423-8. Available from: http://asheducationbook.hematologyli- brary.org/content/2005/1/423.full.pdf 13. Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising peri- operative allogenic bllod transfusion. Cochrane Db Syst Rev 2001;1:CD001886. 14. Carless PA, Henry DA, Moxey AJ, et al. Desmopressin for minimising periopera- tive allogenic blood transfusion. Cochrane Db Syst Rev 2004;1:CD001884. 15. Lenthagen S. Desmopressin in the treat- ment of women’s bleeding disorders. Haemophilia 1999;5:233-7. Opinion Report Table 3. First level tests (modified from De Moerloose et al., 2009). Basal hematocrit and platelet count Bleeding time/PFA-100 PT aPTT Fibrinogen VWF:Ag, VWF:RCo, FVIII:C PFA, platelet function analyzer; PT, prothrombin time; aPTT, activated partial thromboplastin time; VWF:Ag, immunoassay of von Willebrand factor; VWF:RCo, assay of the VWF activity on platelet agglutination in the presence of ristocetinic cofactor activity; FVIII:C, factor VIII coagu- lant activity. Table 4. Second level tests (modified from De Moerloose et al., 2009). Mixing tests Specific coagulation factors Platelet aggregation test Factor XIII Alpha2-antiplasmin* *A more extensive exploration of fibrinolytic system is not usually recommended except for in specialized centers with specific expertise. No n- co mm er cia l u se on ly