A. MARINO

CERBONE, ANNA MARIA

DI CAPUA, MIRKO

DI MINNO, GIOVANNI

G. DI LORENZO

M. DI PALO

M. LIVIA BURZO

MESOLELLA, MASSIMO

R. MORMILE

Archivio della ricerca - Università degli studi di Napoli Federico II

in two Tunisian families with combined fac-tor V and factor VIII deficiency. Haemo-philia 2010; 16(5): 801–4.4 Ivaskevicius V, Windyga J, Baran B et al. Thefirst case of combined coagulation factor Vand coagulation factor VIII deficiency inPoland due to a novel p.Tyr135Asn missensemutation in the MCFD2 gene. Blood CoagulFibrinolysis 2008; 19(6): 531–4.5 Zheng C, Liu HH, Yuan S, Zhou J,Zhang B. Molecular basis of LMAN1 incoordinating LMAN1-MCFD2 cargoreceptor formation and ER-to-Golgi trans-port of FV/FVIII. Blood 2010; 116(25):5698–706.6 Zhang B, Cunningham MA, Nichols WCet al. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex.Nat Genet 2003; 34: 220–5.7 Zheng C, Liu HH, Zhou J, Zhang B. EF-hand domains of MCFD2 mediate interac-tions with both LMAN1 and coagulationfactor V or VIII. Blood 2010; 115(5): 1081–7.8 Ge J, Xue F, Gu DS et al. Combined defi-ciency of factors V and VIII caused by anovel compound heterozygous mutation ofgene Lman1. Zhongguo Shi Yan Xue YeXue Za Zhi. 2010; 18(1):185–90.9 Chapin J, Cardi D, Gibb C, Laurence J.Combined factor V and factor VIII defi-ciency: a report of a case, genetic analysis,and response to desmopressin acetate. ClinAdv Hematol Oncol. 2012; 10(7): 472–4.10 Di Marzio I, Iuliani O, Malizia R et al.Successful use of recombinant FVIIa incombined factor V and FVIII deficiencywith surgical bleeding resistant to substitu-tive treatment. A case report. Haemophilia.2011; 17(1): 160–1.Predicting early and delayed bleedings in children whoundergo adeno-tonsillectomy surgery. Is it really possible?M. DI CAPUA,* M. LIVIA BURZO,* M. DI PALO,* A. MARINO,† G. DI LORENZO,†M. MESOLELLA,† R. MORMILE,* G. DI MINNO* and A. M. CERBONE**Regional Reference Center for Coagulation Disorders and †Department of Otolaryngology, “Federico II” UniversityHospital – Naples, Naples, ItalyAdenoidectomy and tonsillectomy (AT) are two of themost commonly performed paediatric surgical proce-dures. Even if surgery-related bleedings in paediatricpatients are considered uncommon events, AT surgeryhas a non-negligible incidence of bleeding complica-tions which occur in about 2–7% of cases, both earlyand delayed, and range from mild to life threatening[1]. The causes generally recognized are surgicaltrauma, ineffective local haemostasis or local infec-tions. An inherited bleeding disorder can be responsi-ble of these complications only in a minority of casesand, if this circumstance occurs, the diagnosis is chal-lenging for the physicians. Several studies haveaddressed the issue concerning the definition of thebest strategy to screen paediatric patients at potentialrisk of bleeding during or after surgery. Currently, anapproach based on the personal bleeding history isconsidered more cost-effective than a complete haemo-static screening. Several researchers have worked inorder to obtain a standardization in collecting thehaemorrhagic tendency; so a variety of bleeding ques-tionnaires have been described for adults and the mostcommon used is the bleeding score (BS) validated byRodeghiero et al. as screening tool in adults with sus-pected type 1 Von Willebrand disease (VWD) [2].Recently the BS used in the adults has been adaptedfor use in children. A group of specific paediatricsymptoms were added: postcircumcision bleeding,cephalohaematoma, macroscopic haematuria, bleedingfrom the umbilical stump, conjunctival haemorrhage,postvenepuncture bleeding [3]. The resulting Paediat-ric Bleeding Questionnaire (PBQ), with its scoring sys-tem, has been evaluated by Bowman et al. in term ofdiagnostic accuracy for VWD and has revealed a sen-sitivity of 83% and a specificity of 79%, with a posi-tive predictive value and negative predictive value of0.14 and 0.99 respectively [4]. The efficacy of thesescores was also been evaluated in paediatric patientswith inherited platelets disorders [5].The diagnostic accuracy of PBQ in identifyingbleeding tendencies has been tested recently in chil-dren undergoing AT surgery [6]. The PBQ hasrevealed to have a low positive predicting value (PPV)and a low sensitivity against a high specificity andnegative predicting value (NPV) (97% and 98%respectively) in identifying patients at high risk ofbleeding after elective surgery but was not indicatedas an effective screening tool due to the limited popu-lation size. Moreover, in other precedent surveys, boththe clinical history and laboratory tests, such as plate-lets count (PLT), prothrombin time (PT), activatedpartial thromboplastin time (APTT), failed to suggestan increased bleeding risk or to reveal a mild bleedingdisorder (MBD) [1,7,8].Different AT-surgery techniques and antibiotic pro-phylaxis have widely reduced the risk of bleeding [9]Correspondence: Mirko Di Capua, Regional Reference Centerfor Coagulation Disorders, Federico II University Hospital, ViaS. Pansini, 5 – 80131 Naples, Italy.Tel.: +39 0817462317; fax: +39 0815466152;e-mail: mirdica@hotmail.comAccepted after revision 26 August 2014DOI: 10.1111/hae.12552Haemophilia (2014), 20, e399--e443 © 2014 John Wiley & Sons Ltde438 LETTERS TO THE EDITORSbut it is still uncertain if a latent MBD could beresponsible of some surgery-related bleeds. The aim ofour study was to evaluate the efficacy of PBQ, stan-dard laboratory tests (PLT, PT and APTT) and bleed-ing time (BT) in predicting the bleeding risk in apopulation of children undergoing AT surgery. Wealso evaluated the bleeding history in parents (throughthe administration of BS) to find out if a positiveresult could suggest an increased risk of bleedingsamong children, given the inherited nature of the mostpart of coagulation disorders.We prospectively enrolled 72 consecutive childrencandidate to AT surgery. Seven patients were lost dur-ing follow-up. The final group consisted in 65 chil-dren, 44 males (67.7%) and 21 females (32.3%), aged3–13 (mean age 6.32 yrs  1.96). We took a personalbleeding history in every child through administrationof PBQ. PBQ was considered abnormal if higher than2. We performed a complete haemostasis laboratorytesting that consisted of PT-ratio, APTT-ratio, PLTand BT. The latter was performed with a paediatricSurgicutt(ITC, Edison (New Jersey), USA) devicefollowing the Ivy method modified. The BT waspreferred to other techniques (such as PFA-100) as thededicated laboratory staff was not available every dayand because the BT is a test worldwide available andnot requires technical personnel in the field of coagu-lation for its execution. PLT was considered abnormalat less than 100.000/mm3. BT was considered pro-longed if it lasted more than 7 mins. BS was consid-ered abnormal if higher than three in fathers andhigher than five in mothers. Irrespective of PBQ, BTand BS results, children underwent AT surgery. Thesame surgical staff performed all adeno-tonsillecto-mies. Each child received intra-operatively antifibrino-lytic prophylaxis with tranexamic acid 500 mg andantibiotic prophylaxis with amoxicillin-clavulanate(875 +125 mg) bid, according to local protocol. Post-operative observation was achieved for at least 48 hand, in case of delayed bleeds, the patient was invitedto return immediately at observation.The main population characteristics are showed inTable 1. Thirty-eight adeno-tonsillectomies and 27adenoidectomies were performed. In three childrenAPTT-r were altered at a first laboratory determina-tion, probably due to the presence of transitory inhib-itors. They resulted normal after 3 weeks and afternormalization of inflammation parameters (C-reactiveprotein and WBC count). Four patients out of 65(6.15%) had a PBQ ≥ 2 and seven (5.38%) out of130 BSs were abnormal. Sixty-one BT were per-formed, of these nine (14.75%) were prolonged.There was not a statistical correlation between theprolonged BTs and the abnormal PBQs or BSs (p notsignificant). Only one patient (1.54%) experiencedearly postoperative bleeding that required readmissionto the operating room. This 3-years-old girl had aPBQ value of 0. She had never been subjected to anyhaemostatic challenge before AT surgery. Her BTwas 8 mins, while her father BS was 4. Coagulationassessment has resulted in upper borderline value forAPTT-r, which was 1.13. Her parents refused anysecond level investigation. In one patient the abnor-mal PBQ was correlated with an abnormal BS in theparents. Nor the BT nor the laboratory assessment ofthis child was altered. He did not experienced peri-or postoperative haemorrhage. In our setting, PBQhas revealed a poor ability in selecting children atrisk of bleeding after surgery. Similarly, performanceof BS in the parents and of the BT proved to bepoor. Although these markers of bleeding were corre-lated with the single haemorrhage we observed, in allthe other cases the abnormal PBQ, the abnormal BSor the prolonged BT did not identify a bleeding phe-notype. Even if we cannot exclude that the adminis-tration of antifibrinolytic therapy has reduced thebleeding incidence in our population, we assumedthat if a symptomatic bleeding disorder was present,this prophylaxis would not be able to effectivelyreduce the risk of bleeding. In our case series, PBQshowed a very low PPV and sensitivity against agood specificity and NPV (93.3% and 98.3% respec-tively), similarly to outcomes reported by Sim et al.[6]. Although these specificity and the NPV are desir-able for a screening tool, our observation is not con-clusive due to the limited sample size of ourpopulation and larger studies are required to confirmthese data. No significant alteration in the laboratoryassessment was found in our case series, even in thesingle case of bleeding we observed. According toprevious surveys that did not identify in the labora-tory screening an effective tool to detect children atrisk of bleeding, in our study laboratory assessmentfailed to suggest an increased bleeding tendency inchildren [1,7,8]. Anyhow, in our institution, the rou-tine coagulation assessment maintains its mandatoryuse before surgery, adhering to the recommendationsof the Italian society of haemostasis and thrombosisTable 1. This table illustrates the main population characteristics (sex dis-tribution, mean and median age) and the frequencies of normal and patho-logical paediatric bleeding questionnaire (PBQ), bleeding time (BT) andbleeding score (BS). SD= Standard DeviationTotal Normal PathologicalPopulation, n 65Male, n (%) 44 (67.7) – –Female, n (%) 21 (32.3)Mean age,years  SD6.32  1.96 – –Median age, years 6PBQ, n (%) 65 (100) 61 (93.85) 4 (6.15)BT, n (%) 61 (100) 52 (85.25) 9 (14.75)BS, n (%) 130 (100) 123 (94.62) 7 (5.38)Fathers, n (%) 65 (100) 61 (93.85) 4 (6.15)Mothers, n (%) 65 (100) 62 (95.38) 3 (4.62)© 2014 John Wiley & Sons Ltd Haemophilia (2014), 20, e399--e443LETTERS TO THE EDITORS e439[10], to detect a bleeding disorder even in absence ofan history suggestive for bleeding tendencies and torespond to the need of obtaining a baseline test incase of peri and postoperative bleeding complications.Considering the results of this study, the failure ofthe PBQ, BS and BT in identifying an increasedbleeding risk in paediatric patients could be relatedto their the poor sensitivity combined with the lowprevalence in absolute of bleeding disorders and theresulting low probability that latent MBDs areresponsible of AT surgery-related bleeds. Therefore,peri and postoperative haemorrhages seems to beunpredictable events, even if the small size of ourpopulation does not allow us to give any conclusiveconsideration as larger surveys are required. The useof BT as a screening tool showed similar results inour population. Moreover, it should be taken intoaccount that, even if the BT was executed alwayswith the same technique, due to its inter-operatordependency the results could be confounded in partby this variable. As to the BS, it did not demonstratea superior ability in detecting children at risk ofbleeding than the same PBQ.The AT surgery-related bleedings remain unpredict-able events. The in vitro (coagulation assessment) andin vivo (bleeding time) tests we performed did notincrease the rate of prediction of bleeding complica-tions. The PBQ has shown an elevated specificity andNPV, so it could find a role as support tool to the pre-operative bleeding risk assessment but these data needto be confirmed in larger surveys, given the small sizeof our population.AcknowlegementsMirko Di Capua designed the study, enrolled the patients, administeredpaediatric bleeding questionnaires and bleeding scores, performedbleeding times and statistical analysis, wrote the article; Maria Livia Bur-zo designed the study, enrolled the patients, administered paediatricbleeding questionnaires and bleeding scores, performed bleeding timesand statistical analysis, wrote the article; Mariagiovanna Di Palo enrolledpatients, administered paediatric bleeding questionnaires and bleedingscores, performed bleeding times; Anna Marino enrolled patients, per-formed adenotonsillectomies; Giuseppe Di Lorenzo enrolled patients,performed adenotonsillectomies; Massimo Mesolella enrolled patients,performed adenotonsillectomies; Rosaria Mormile contributed Surgicuttbleeding time kits; Giovanni Di Minno designed the study; Anna MariaCerbone designed the study.DisclosuresThe authors stated that they had no interests which might be perceived asposing a conflict or bias.References1 Burk CD, Miller L, Handler SD, CohenAR. Preoperative history and coagulationscreening in children undergoing tonsillec-tomy. Pediatrics 1992; 89: 691–5.2 Rodeghiero F1, Tosetto A, Abshire T et al.ISTH/SSC joint VWF and Perinatal/Pediat-ric Hemostasis Subcommittees WorkingGroup. ISTH/SSC bleeding assessment tool:a standardized questionnaire and a proposalfor a new bleeding score for inherited bleed-ing disorders. J Thromb Haemost 2010; 8:2063–5.3 Biss TT, Blanchette VS, Clark DS, BowmanM, Wakefield CD, Silva M. Quantitationof bleeding symptoms in children with vonWillebrand Disease: use of a standardizedpediatric bleeding questionnaire. J ThrombHaemost. 2010; 8: 950–6.4 Bowman M, Riddel J, Rand ML, TosettoA, Silva M, James PD. Evaluation of thediagnostic utility for von Willebrand dis-ease of a pediatric bleeding questionnaire.J Thromb Haemost 2009; 7: 1418–21.5 Biss TT, Blanchette VS, Clark DS, Wake-field CD, James PD, Rand ML. Use of aquantitative pediatric bleeding question-naire to assess mucocutaneous bleedingsymptoms in children with a platelet func-tion disorder. J Thromb Haemost 2010; 8:1416–19.6 Sim AY, Bowman M, Hopman W, EngenD, Silva M, James P Predicting operativebleeding in elective pediatric surgeries usingthe Pediatric Bleeding Questionnaire (PBQ).J Pediatr Hematol Oncol 2014; 36:e246–7.7 Howells RC, Wax MK, Ramadan HH.Value of preoperative prothrombintime/partial thromboplastin time as apredictor of postoperative hemorrhage inpediatric patients undergoing tonsillectomy.Otolaryngol Head Neck Surg 1997; 117:628–32.8 Zwack GC, Derkay CS. The utility ofpreoperative hemostatic assessment inadenotonsillectomy. Int J Pediatr Otorhino-laryngol 1997; 39: 67–76.9 Prasad KC. Prasad SC assessment of opera-tive blood loss and the factors affecting itin tonsillectomy and adenotonsillectomy.Indian J Otolaryngol Head Neck Surg2011; 63: 343–8.10 Cosmi B1, Alatri A, Cattaneo M et al. Tad-dei Assessment of the risk of bleeding inpatients undergoing surgery or invasiveprocedures: guidelines of the Italian Societyfor Haemostasis and Thrombosis (SISET).Thromb Res 2009; 124: e6–12.Haemophilia (2014), 20, e399--e443 © 2014 John Wiley & Sons Ltde440 LETTERS TO THE EDITORS

Predicting early and delayed bleedings in children who
undergo adeno-tonsillectomy surgery. Is it really possible?

Predicting early and delayed bleedings in children who undergo adeno-tonsillectomy surgery. Is it really possible?

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