e436
LETTERS TO THE EDITORS
Combined FV and FVIII deficiency (F5F8D) in a Chinese family with a novel missense mutation in MCFD2 gene A . W A N G , X . L I U , J . W U , X . C A I , W . Z H U and Z . S U N Department of Hematology, Anhui Medical University Affiliated Anhui Provincial Hospital and Anhui Provincial Hemophilia Treatment Center, Anhui Provincial Hospital, Hefei, Anhui, China
Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare bleeding disease first reported in 1954 [1]. F5F8D are most reported in these families originated from the Mediterranean, Middle Eastern, in which regions consanguineous marriages are common. F5F8D, characterized with simultaneous decreases of FV and FVIII activity to 5 to 30% of normal plasma and mild-to-moderate bleeding tendency, have excessive bleeding symptoms like easy bruising, epistaxis, gum bleeding, menorrhagia, dental extraction, postpartum haemorrhage, haemarthroses, gastrointestinal bleeding and haematuria [2]. Mutations in LMAN1 and MCFD2 genes which involved in the transport of FV and FVIII from the endoplasmic reticulum to the Golgi, are responsible for this disease. LMAN1 and MCFD2 contain 13 exons and 4 exons respectively, which localized to chromosomes 18 (18p21) and 2(2p21). At least 36 LMAN1 mutations and 18 MCFD2 mutations have been reported [2], while most of the mutations are nonsense, insertion/deletion or splice site mutations. In the paper, one novel missense mutation, namely Asp81Ala in exon 3 of MCFD2 gene, is firstly reported and described as a cause of combined FV and FVIII deficiency in a Chinese family. The patient and his five unaffected family members from a Chinese family were studied. The patient was a 30-yearold male, who had been previously without clinical bleeding tendency, and firstly diagnosed on the basis of excessive bleeding during and after trauma, a prolonged activated partial thromboplastin time (78.7 s, normal 20–40 s) and prolonged prothrombin time (21.1 s, normal 9.5–14.5 s) due to reduced levels of FV(6%) and FVIII(23.8%) activities. To identify the genetic defect, the genomic DNA from the peripheral blood samples of the family’s members was isolated using standard procedure. All the exons of LMAN1 and MCFD2 genes were PCR amplified as the literature [3,4]. We sequenced the amplicons in both direcCorrespondence: Anyou Wang, Jingsheng Wu, Department of Hematology, Anhui Medical University Affiliated Anhui Provincial Hospital, No.17, Lujiang Road, Hefei, Anhui 230001, China. Tel.: +551 62283863; fax: +551 62283863 e-mail: [email protected] (A. WANG) and [email protected] (J. WU) Accepted after revision 15 August 2014 DOI: 10.1111/hae.12549 Haemophilia (2014), 20, e399--e443
tions by using ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction [Sangon Biotech (Shanghai) Co, Ltd. Shanghai City, China] and analysed using the Seqman software to Sequencing Analysis. For the patient, direct sequencing of all amplified fragments allowed us to identify one novel genetic defect in exon 3 in MCFD2 gene, whereas no mutation was identified in LMAN1 gene. The mutation was: g.242 A>C, leading to the Asp81Ala missense substitution (GAT fi GCT). The Asp81Ala mutation was found in the homozygous state in the patient, while heterozygous for his father and one of his sisters, and without defect for his other two sisters and his nephew. The parents of the patient were consanguineous marriage. The father was found in the heterozygous state with Asp81Ala, so the died mother was also to be infer heterozygote for the Asp81Ala mutation (Fig. 1). We also had a genotype analysis of the exon 3 in MCFD2 gene in 50 healthy controls, which were revealed only the wild-type sequence. F5F8D is a rare autosomal recessive disease in which most patients hold low activities of FV and FVIII between 5% and 30%. Mutations defect in the LMAN1 gene or MCFD2 gene attributed to the disease. The most mutations described are nonsense mutations. Missense mutations often provide important clues to study for functional domains of proteins. Only eight of the 18 MCFD2 mutations (Asp81Tyr, Asp81His, Asp89Ala, Asp89Asn, Asp122Val, Asp129Glu, Tyr135Asn and Ile136Thr) identified to date are missense mutations [2,3]. We reported one novel missense mutation, namely Asp81Ala in exon 3 of MCFD2 gene in a Chinese family. The Asp81 missense mutations reported in MCFD2 to date was carried out from the many patients, like Asp81Tyr and Asp81Asn, while the novel mutations ‘Asp81Ala’ have not previously been reported. Therefore, It seems most likely that the mutation in the Asp 81 is a hot region, which change highly conserved amino acids in the first EF-hand domains, thus affecting the binding between LMAN1 and MCFD2 [2,5–7]. To confirm this interpretation, more studies about mutated protein expression are required to be done. The family’s members of the patient are healthy, clinical data of other affected family’s members are shown in Table 1. The presence of consanguineous marriage in the family played an important role in the cause of this disease. There was not obvious bleeding © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e437
(a)
(b)
Fig. 1. Pedigree of the family (a) and mutation of exon 3 in MCFD2 gene in the family (b). Table 1. Clinical data. Members
Years
PT
APTT
Symptoms
Mutation type
Patient
30
21.1 s
78.7 s
Homozygous(C/C)
Father Sister 1 Sister 2 Sister 3 Nephew Mother
68 47 41 41 18 ND
12.3 s 14 s 12.6 s 11.7 s 14.3 s ND
28.9 s 25.3 s 29.1 s 28.2 s 32.5 s ND
Intracranial bleeding after trauma Asymptomatic Asymptomatic Asymptomatic Asymptomatic Asymptomatic ND
Heterozygous(A/C) Heterozygous(A/C) Wild type(A/A) Wild type(A/A) Wild type(A/A) Heterozygous (A/C) ?
more than 1 week), while the correction of the prolonged activated partial thromboplastin time and prothrombin time were not obvious. Substitutive therapy had failed to control and stop the bleeding by head CT scan. We also tried to use desmopressin infusions (0.3 ug kg1 per day) as reports [9], which finally stopped after one times application due to intolerance headache. Recombinant FVIIa might be good choice as reported in the literature [10], but not be implemented because of patient discharge automatically.
ND, no data; ?, to be infer.
tendency to be found in the family, which is in agreement with features of autosomal recessive heredity. Currently, novel missense mutation in MCFD2 gene has not been reported to date in Chinese population [8]. We report here the first case of Asp81Ala in Chinese family. We also observed the treatment for the patient. The patient was treated with combined FFP and FVIII concentrate infusions (200–400 mL FFP and 10–20 IU kg1 FVIII concentrate per day
References 1 Oeri J, Matter M, Isenschmid H, Hauser F, Koller F. Congenital factor V deficiency (pa-
© 2014 John Wiley & Sons Ltd
Acknowledgements The authors thank Zheng Nan, Xu Xiucai for their help in samples processing. The study is supported by the Foundation of Anhui Provincial Natural Science (no. 1308085QH129, no. KJ2013Z133) and the Foundation of Anhui Medical University (no. 2012xkj048)
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
rahemophilia) with true hemophilia in two brothers. Bibl Paediatr. 1954; 58: 575–88. 2 Zheng C, Zhang B. Combined deficiency of coagulation factors V and VIII: an update.
Semin Thromb Hemost 2013; 39(6): 613– 20. 3 Abdallah HE, Gouider E, Amor MB, Jlizi A, Meddeb B, Elgaaied A. Molecular analysis
Haemophilia (2014), 20, e399--e443
e438
LETTERS TO THE EDITORS
in two Tunisian families with combined factor V and factor VIII deficiency. Haemophilia 2010; 16(5): 801–4. 4 Ivaskevicius V, Windyga J, Baran B et al. The first case of combined coagulation factor V and coagulation factor VIII deficiency in Poland due to a novel p.Tyr135Asn missense mutation in the MCFD2 gene. Blood Coagul Fibrinolysis 2008; 19(6): 531–4. 5 Zheng C, Liu HH, Yuan S, Zhou J, Zhang B. Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi trans-
port of FV/FVIII. Blood 2010; 116(25): 5698–706. 6 Zhang B, Cunningham MA, Nichols WC et al. Bleeding due to disruption of a cargospecific ER-to-Golgi transport complex. Nat Genet 2003; 34: 220–5. 7 Zheng C, Liu HH, Zhou J, Zhang B. EFhand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII. Blood 2010; 115(5): 1081–7. 8 Ge J, Xue F, Gu DS et al. Combined deficiency of factors V and VIII caused by a novel compound heterozygous mutation of
gene Lman1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18(1):185–90. 9 Chapin J, Cardi D, Gibb C, Laurence J. Combined factor V and factor VIII deficiency: a report of a case, genetic analysis, and response to desmopressin acetate. Clin Adv Hematol Oncol. 2012; 10(7): 472–4. 10 Di Marzio I, Iuliani O, Malizia R et al. Successful use of recombinant FVIIa in combined factor V and FVIII deficiency with surgical bleeding resistant to substitutive treatment. A case report. Haemophilia. 2011; 17(1): 160–1.
Predicting early and delayed bleedings in children who undergo adeno-tonsillectomy surgery. Is it really possible? M. DI CAPUA,* M. LIVIA BURZO,* M. DI PALO,* A. MARINO,† G. DI LORENZO,† M . M E S O L E L L A , † R . M O R M I L E , * G . D I M I N N O * and A . M . C E R B O N E * *Regional Reference Center for Coagulation Disorders and †Department of Otolaryngology, “Federico II” University Hospital – Naples, Naples, Italy
Adenoidectomy and tonsillectomy (AT) are two of the most commonly performed paediatric surgical procedures. Even if surgery-related bleedings in paediatric patients are considered uncommon events, AT surgery has a non-negligible incidence of bleeding complications which occur in about 2–7% of cases, both early and delayed, and range from mild to life threatening [1]. The causes generally recognized are surgical trauma, ineffective local haemostasis or local infections. An inherited bleeding disorder can be responsible of these complications only in a minority of cases and, if this circumstance occurs, the diagnosis is challenging for the physicians. Several studies have addressed the issue concerning the definition of the best strategy to screen paediatric patients at potential risk of bleeding during or after surgery. Currently, an approach based on the personal bleeding history is considered more cost-effective than a complete haemostatic screening. Several researchers have worked in order to obtain a standardization in collecting the haemorrhagic tendency; so a variety of bleeding questionnaires have been described for adults and the most common used is the bleeding score (BS) validated by Rodeghiero et al. as screening tool in adults with susCorrespondence: Mirko Di Capua, Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Via S. Pansini, 5 – 80131 Naples, Italy. Tel.: +39 0817462317; fax: +39 0815466152; e-mail: [email protected] Accepted after revision 26 August 2014 DOI: 10.1111/hae.12552 Haemophilia (2014), 20, e399--e443
pected type 1 Von Willebrand disease (VWD) [2]. Recently the BS used in the adults has been adapted for use in children. A group of specific paediatric symptoms were added: postcircumcision bleeding, cephalohaematoma, macroscopic haematuria, bleeding from the umbilical stump, conjunctival haemorrhage, postvenepuncture bleeding [3]. The resulting Paediatric Bleeding Questionnaire (PBQ), with its scoring system, has been evaluated by Bowman et al. in term of diagnostic accuracy for VWD and has revealed a sensitivity of 83% and a specificity of 79%, with a positive predictive value and negative predictive value of 0.14 and 0.99 respectively [4]. The efficacy of these scores was also been evaluated in paediatric patients with inherited platelets disorders [5]. The diagnostic accuracy of PBQ in identifying bleeding tendencies has been tested recently in children undergoing AT surgery [6]. The PBQ has revealed to have a low positive predicting value (PPV) and a low sensitivity against a high specificity and negative predicting value (NPV) (97% and 98% respectively) in identifying patients at high risk of bleeding after elective surgery but was not indicated as an effective screening tool due to the limited population size. Moreover, in other precedent surveys, both the clinical history and laboratory tests, such as platelets count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), failed to suggest an increased bleeding risk or to reveal a mild bleeding disorder (MBD) [1,7,8]. Different AT-surgery techniques and antibiotic prophylaxis have widely reduced the risk of bleeding [9]
© 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
Combined FV and FVIII deficiency (F5F8D) in a Chinese family with a novel missense mutation in MCFD2 gene A . W A N G , X . L I U , J . W U , X . C A I , W . Z H U and Z . S U N Department of Hematology, Anhui Medical University Affiliated Anhui Provincial Hospital and Anhui Provincial Hemophilia Treatment Center, Anhui Provincial Hospital, Hefei, Anhui, China
Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare bleeding disease first reported in 1954 [1]. F5F8D are most reported in these families originated from the Mediterranean, Middle Eastern, in which regions consanguineous marriages are common. F5F8D, characterized with simultaneous decreases of FV and FVIII activity to 5 to 30% of normal plasma and mild-to-moderate bleeding tendency, have excessive bleeding symptoms like easy bruising, epistaxis, gum bleeding, menorrhagia, dental extraction, postpartum haemorrhage, haemarthroses, gastrointestinal bleeding and haematuria [2]. Mutations in LMAN1 and MCFD2 genes which involved in the transport of FV and FVIII from the endoplasmic reticulum to the Golgi, are responsible for this disease. LMAN1 and MCFD2 contain 13 exons and 4 exons respectively, which localized to chromosomes 18 (18p21) and 2(2p21). At least 36 LMAN1 mutations and 18 MCFD2 mutations have been reported [2], while most of the mutations are nonsense, insertion/deletion or splice site mutations. In the paper, one novel missense mutation, namely Asp81Ala in exon 3 of MCFD2 gene, is firstly reported and described as a cause of combined FV and FVIII deficiency in a Chinese family. The patient and his five unaffected family members from a Chinese family were studied. The patient was a 30-yearold male, who had been previously without clinical bleeding tendency, and firstly diagnosed on the basis of excessive bleeding during and after trauma, a prolonged activated partial thromboplastin time (78.7 s, normal 20–40 s) and prolonged prothrombin time (21.1 s, normal 9.5–14.5 s) due to reduced levels of FV(6%) and FVIII(23.8%) activities. To identify the genetic defect, the genomic DNA from the peripheral blood samples of the family’s members was isolated using standard procedure. All the exons of LMAN1 and MCFD2 genes were PCR amplified as the literature [3,4]. We sequenced the amplicons in both direcCorrespondence: Anyou Wang, Jingsheng Wu, Department of Hematology, Anhui Medical University Affiliated Anhui Provincial Hospital, No.17, Lujiang Road, Hefei, Anhui 230001, China. Tel.: +551 62283863; fax: +551 62283863 e-mail: [email protected] (A. WANG) and [email protected] (J. WU) Accepted after revision 15 August 2014 DOI: 10.1111/hae.12549 Haemophilia (2014), 20, e399--e443
tions by using ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction [Sangon Biotech (Shanghai) Co, Ltd. Shanghai City, China] and analysed using the Seqman software to Sequencing Analysis. For the patient, direct sequencing of all amplified fragments allowed us to identify one novel genetic defect in exon 3 in MCFD2 gene, whereas no mutation was identified in LMAN1 gene. The mutation was: g.242 A>C, leading to the Asp81Ala missense substitution (GAT fi GCT). The Asp81Ala mutation was found in the homozygous state in the patient, while heterozygous for his father and one of his sisters, and without defect for his other two sisters and his nephew. The parents of the patient were consanguineous marriage. The father was found in the heterozygous state with Asp81Ala, so the died mother was also to be infer heterozygote for the Asp81Ala mutation (Fig. 1). We also had a genotype analysis of the exon 3 in MCFD2 gene in 50 healthy controls, which were revealed only the wild-type sequence. F5F8D is a rare autosomal recessive disease in which most patients hold low activities of FV and FVIII between 5% and 30%. Mutations defect in the LMAN1 gene or MCFD2 gene attributed to the disease. The most mutations described are nonsense mutations. Missense mutations often provide important clues to study for functional domains of proteins. Only eight of the 18 MCFD2 mutations (Asp81Tyr, Asp81His, Asp89Ala, Asp89Asn, Asp122Val, Asp129Glu, Tyr135Asn and Ile136Thr) identified to date are missense mutations [2,3]. We reported one novel missense mutation, namely Asp81Ala in exon 3 of MCFD2 gene in a Chinese family. The Asp81 missense mutations reported in MCFD2 to date was carried out from the many patients, like Asp81Tyr and Asp81Asn, while the novel mutations ‘Asp81Ala’ have not previously been reported. Therefore, It seems most likely that the mutation in the Asp 81 is a hot region, which change highly conserved amino acids in the first EF-hand domains, thus affecting the binding between LMAN1 and MCFD2 [2,5–7]. To confirm this interpretation, more studies about mutated protein expression are required to be done. The family’s members of the patient are healthy, clinical data of other affected family’s members are shown in Table 1. The presence of consanguineous marriage in the family played an important role in the cause of this disease. There was not obvious bleeding © 2014 John Wiley & Sons Ltd
LETTERS TO THE EDITORS
e437
(a)
(b)
Fig. 1. Pedigree of the family (a) and mutation of exon 3 in MCFD2 gene in the family (b). Table 1. Clinical data. Members
Years
PT
APTT
Symptoms
Mutation type
Patient
30
21.1 s
78.7 s
Homozygous(C/C)
Father Sister 1 Sister 2 Sister 3 Nephew Mother
68 47 41 41 18 ND
12.3 s 14 s 12.6 s 11.7 s 14.3 s ND
28.9 s 25.3 s 29.1 s 28.2 s 32.5 s ND
Intracranial bleeding after trauma Asymptomatic Asymptomatic Asymptomatic Asymptomatic Asymptomatic ND
Heterozygous(A/C) Heterozygous(A/C) Wild type(A/A) Wild type(A/A) Wild type(A/A) Heterozygous (A/C) ?
more than 1 week), while the correction of the prolonged activated partial thromboplastin time and prothrombin time were not obvious. Substitutive therapy had failed to control and stop the bleeding by head CT scan. We also tried to use desmopressin infusions (0.3 ug kg1 per day) as reports [9], which finally stopped after one times application due to intolerance headache. Recombinant FVIIa might be good choice as reported in the literature [10], but not be implemented because of patient discharge automatically.
ND, no data; ?, to be infer.
tendency to be found in the family, which is in agreement with features of autosomal recessive heredity. Currently, novel missense mutation in MCFD2 gene has not been reported to date in Chinese population [8]. We report here the first case of Asp81Ala in Chinese family. We also observed the treatment for the patient. The patient was treated with combined FFP and FVIII concentrate infusions (200–400 mL FFP and 10–20 IU kg1 FVIII concentrate per day
References 1 Oeri J, Matter M, Isenschmid H, Hauser F, Koller F. Congenital factor V deficiency (pa-
© 2014 John Wiley & Sons Ltd
Acknowledgements The authors thank Zheng Nan, Xu Xiucai for their help in samples processing. The study is supported by the Foundation of Anhui Provincial Natural Science (no. 1308085QH129, no. KJ2013Z133) and the Foundation of Anhui Medical University (no. 2012xkj048)
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
rahemophilia) with true hemophilia in two brothers. Bibl Paediatr. 1954; 58: 575–88. 2 Zheng C, Zhang B. Combined deficiency of coagulation factors V and VIII: an update.
Semin Thromb Hemost 2013; 39(6): 613– 20. 3 Abdallah HE, Gouider E, Amor MB, Jlizi A, Meddeb B, Elgaaied A. Molecular analysis
Haemophilia (2014), 20, e399--e443
e438
LETTERS TO THE EDITORS
in two Tunisian families with combined factor V and factor VIII deficiency. Haemophilia 2010; 16(5): 801–4. 4 Ivaskevicius V, Windyga J, Baran B et al. The first case of combined coagulation factor V and coagulation factor VIII deficiency in Poland due to a novel p.Tyr135Asn missense mutation in the MCFD2 gene. Blood Coagul Fibrinolysis 2008; 19(6): 531–4. 5 Zheng C, Liu HH, Yuan S, Zhou J, Zhang B. Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi trans-
port of FV/FVIII. Blood 2010; 116(25): 5698–706. 6 Zhang B, Cunningham MA, Nichols WC et al. Bleeding due to disruption of a cargospecific ER-to-Golgi transport complex. Nat Genet 2003; 34: 220–5. 7 Zheng C, Liu HH, Zhou J, Zhang B. EFhand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII. Blood 2010; 115(5): 1081–7. 8 Ge J, Xue F, Gu DS et al. Combined deficiency of factors V and VIII caused by a novel compound heterozygous mutation of
gene Lman1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18(1):185–90. 9 Chapin J, Cardi D, Gibb C, Laurence J. Combined factor V and factor VIII deficiency: a report of a case, genetic analysis, and response to desmopressin acetate. Clin Adv Hematol Oncol. 2012; 10(7): 472–4. 10 Di Marzio I, Iuliani O, Malizia R et al. Successful use of recombinant FVIIa in combined factor V and FVIII deficiency with surgical bleeding resistant to substitutive treatment. A case report. Haemophilia. 2011; 17(1): 160–1.
Predicting early and delayed bleedings in children who undergo adeno-tonsillectomy surgery. Is it really possible? M. DI CAPUA,* M. LIVIA BURZO,* M. DI PALO,* A. MARINO,† G. DI LORENZO,† M . M E S O L E L L A , † R . M O R M I L E , * G . D I M I N N O * and A . M . C E R B O N E * *Regional Reference Center for Coagulation Disorders and †Department of Otolaryngology, “Federico II” University Hospital – Naples, Naples, Italy
Adenoidectomy and tonsillectomy (AT) are two of the most commonly performed paediatric surgical procedures. Even if surgery-related bleedings in paediatric patients are considered uncommon events, AT surgery has a non-negligible incidence of bleeding complications which occur in about 2–7% of cases, both early and delayed, and range from mild to life threatening [1]. The causes generally recognized are surgical trauma, ineffective local haemostasis or local infections. An inherited bleeding disorder can be responsible of these complications only in a minority of cases and, if this circumstance occurs, the diagnosis is challenging for the physicians. Several studies have addressed the issue concerning the definition of the best strategy to screen paediatric patients at potential risk of bleeding during or after surgery. Currently, an approach based on the personal bleeding history is considered more cost-effective than a complete haemostatic screening. Several researchers have worked in order to obtain a standardization in collecting the haemorrhagic tendency; so a variety of bleeding questionnaires have been described for adults and the most common used is the bleeding score (BS) validated by Rodeghiero et al. as screening tool in adults with susCorrespondence: Mirko Di Capua, Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Via S. Pansini, 5 – 80131 Naples, Italy. Tel.: +39 0817462317; fax: +39 0815466152; e-mail: [email protected] Accepted after revision 26 August 2014 DOI: 10.1111/hae.12552 Haemophilia (2014), 20, e399--e443
pected type 1 Von Willebrand disease (VWD) [2]. Recently the BS used in the adults has been adapted for use in children. A group of specific paediatric symptoms were added: postcircumcision bleeding, cephalohaematoma, macroscopic haematuria, bleeding from the umbilical stump, conjunctival haemorrhage, postvenepuncture bleeding [3]. The resulting Paediatric Bleeding Questionnaire (PBQ), with its scoring system, has been evaluated by Bowman et al. in term of diagnostic accuracy for VWD and has revealed a sensitivity of 83% and a specificity of 79%, with a positive predictive value and negative predictive value of 0.14 and 0.99 respectively [4]. The efficacy of these scores was also been evaluated in paediatric patients with inherited platelets disorders [5]. The diagnostic accuracy of PBQ in identifying bleeding tendencies has been tested recently in children undergoing AT surgery [6]. The PBQ has revealed to have a low positive predicting value (PPV) and a low sensitivity against a high specificity and negative predicting value (NPV) (97% and 98% respectively) in identifying patients at high risk of bleeding after elective surgery but was not indicated as an effective screening tool due to the limited population size. Moreover, in other precedent surveys, both the clinical history and laboratory tests, such as platelets count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), failed to suggest an increased bleeding risk or to reveal a mild bleeding disorder (MBD) [1,7,8]. Different AT-surgery techniques and antibiotic prophylaxis have widely reduced the risk of bleeding [9]
© 2014 John Wiley & Sons Ltd
