Diagnosis and treatment of inherited factor X deficiency

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1 Haemophilia (2008), 14, DOI: /j x ORIGINAL ARTICLE Diagnosis and treatment of inherited factor X deficiency D. L. BROWN* and P. A. KOUIDES *Department of Pediatrics, University of Texas Health Science Center in Houston, Houston, TX; and Mary M. Gooley Hemophilia Treatment Center and the Rochester General Hospital, Rochester, NY, USA Summary. Factor X is a vitamin K-dependent, liverproduced serine protease that serves a pivotal role in coagulation as the first enzyme in the common pathway to fibrin formation. Inherited factor X deficiency is a rare autosomal recessive bleeding disorder that is estimated to occur in 1: individuals up to 1:500 carriers. Several international registries of FX-deficient patients have greatly expanded the knowledge of clinical phenotype. A proposed classification of severity is based on FX:C activity measurements: an FX:C measurement <1% is severe, an FX:C measurement of 1 5% is moderate and an FX:C measurement of 6 10% is mild. Levels above 20% are infrequently associated with bleeding and heterozygotes are usually asymptomatic. Among patients with FX:C levels <10%, unlike moderate or severe haemophilia A and B, mucocutaneous bleeding symptoms such as epistaxis and menorrhagia occur in the majority. In addition, patients with moderate severe deficiency may have symptoms similar to that of haemophilia A and B, including haemarthrosis, intracranial haemorrhage, and gastrointestinal bleeding. Genotype characterization may offer important clues about clinical prognosis. More than 80 mutations of the F10 gene have been identified, most of which are missense mutations. There is no specific FX replacement product yet readily available, but fresh frozen plasma and prothrombin complex concentrates can be used for treatment of bleeding symptoms and preparation for surgery. Keywords: deficiency, diagnosis, factor X, gene, haemophilia, treatment Introduction Morawitz may have been the first to isolate factor (F)X in 1905 when he identified a factor named ÔthromboplastinÕ that interacted with ÔthrombogenÕ to form thrombin [1]. For many years, the terms FVII, proconvertin and serum prothrombin conversion accelerator were used to describe a relatively heat-stable factor adsorbable by barium sulphate and reduced in dicoumarol plasma, which probably included FX. In 1955, Duckert reported a factor deficiency distinct from FVII and FIX in patients receiving coumarins and named the new factor, FX [2]. Inherited FX deficiency was subsequently identified by two independent groups. In 1956, Telfer Correspondence: Deborah L. Brown, MD, University of Texas Health Science Center in Houston, 6655 Travis St, Suite 400, Houston, TX 77006, USA. Tel.: ; fax: ; Accepted after revision 21 July 2008 et al. [3] described a 22-year-old woman named Miss Prower with a bleeding diathesis who had an abnormal thromboplastin generation test result and a prolonged prothrombin time that was corrected with the addition of plasma from two patients taking coumarin analogues. In 1957, Hougie et al. [4] described a 36-year-old man named Mr Stuart thought to have FVII deficiency until it was found that his plasma could correct the prolonged prothrombin time of another FVII-deficient patient. FX became known as the Stuart-Prower factor until it was given its official nomenclature of FX in Materials and methods A MEDLINE search from 1965 to July 2007 was performed using the search heading Ôfactor X deficiencyõ. Only studies in English were selected. Eightytwo key publications were selected for review and an additional 27 publications were identified through citation cross-checking Journal compilation Ó 2008 Blackwell Publishing Ltd

2 FACTOR X DEFICIENCY 1177 Incidence, racial/ethnic predilection Severe FX deficiency (homozygous) is a rare bleeding disorder that is estimated to have a worldwide incidence of 1: [5], although it is more common in populations in which consanguineous marriage is common, such as Iran, where the frequency is reported to be 1: [6]. FX deficiency accounts for 1.3% of patients with inherited coagulation deficiencies in Iran, 0.4% in Italy and 0.5% in the UK [5]. The prevalence of heterozygous FX deficiency (carrier state) may be as high as 1:500 [7]. Pathophysiology Role of the clotting factor in coagulation. Factor X synthesis occurs in the liver and similar to other vitamin K-dependent proteins requires post-translational carboxylation of 11 glutamic acid (Gla) residues. The Gla residues allow Ca ++ -dependent binding of FX to negatively charged phospholipid membranes. Glycosylation of 2 Asn residues and B-hydroxylation must occur before FX can be activated. The mature 2- chain form of FX consists of a light chain of 139 amino acids and heavy chain linked by a disulphide bond. The light chain contains the Gla domain and two epidermal growth factor domains; the heavy chain contains the catalytic serine protease domain. The 59- kda 2-chain protein circulates in the plasma at a concentration of 10 lg ml )1. The active form (FXa) is a catalytic serine protease that is produced when the zymogen is cleaved in the heavy chain, releasing the 52-residue activation peptide that contains the His236, Asp228 and Ser379 catalytic site. Activation can occur through the extrinsic or intrinsic pathway and is considered to be the first step in the Ôcommon pathwayõ to fibrin conversion. Activation occurs through the extrinsic pathway via tissue factor:fviia complex with calcium ions on a phospholipid surface. Intrinsic pathway activation occurs most efficiently in the ÔtenaseÕ complex, which contains the serine protease FIXa and its cofactor FVIIIa in the presence of calcium ions on a phospholipid surface. Factor Xa is the most important activator of prothrombin, cleaving prothrombin to generate thrombin in complex with FVa, Ca ++ and phospholipids. FXa can also activate FV and FVIII and hydrolyses FVII to FVIIa, completing a FVII FX feedback loop. FXa is inactivated by antithrombin, which forms a complex that is rapidly cleared from the circulation. FXa also binds to tissue factor pathway inhibitor to form a quaternary complex with tissue factor: FVIIa, blocking the extrinsic pathway to thrombin generation. FXa is also inactivated by protein Z-dependent protease inhibitor, a serine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence of protein Z [8]. Defects in protein Z lead to increased FXa activity and a possible increased risk of thrombosis [9]. Levels associated with severity of bleeding. Factor X deficiency produces a variable bleeding tendency, but patients with severe FX deficiency tend to have the most severe symptoms of the rare coagulation disorders, similar to those of FVIII and FIX deficiency. On the basis of the plasma levels of FX coagulant activity (FX:C) measured with a prothrombin time-based assay using rabbit thromboplastin and FX-deficient plasma, patients have been classified into three groups: severe (FX:C, <1%), moderate (FX:C, 1% 5%) and mild (FX:C, 6% 10%) [10]. Severe clinical symptoms, such as intracranial haemorrhage (ICH), gastrointestinal bleeding and haemarthrosis, are uncommon in patients with FX:C levels >2%. In the Greifswald Factor X Deficiency Registry, the median level of FX:C in symptomatic patients was 13.3%. Patients genetically proven to be heterozygotes are usually asymptomatic but may have minor mucocutaneous bleeding symptoms. Types of disorder if more than one. The classification of FX deficiency is based on the results of both immunological and functional laboratory assays. In type I deficiency, both functional activity and antigen level are proportionally decreased, as proved to be the case in the original patient (Mr Stuart). In type II deficiency, represented by Miss Prower, a dysfunctional FX protein results in a near-normal antigenic level, whereas the FX activity is reduced. Genetics/molecular basis of disorder The FX gene (F10) is 22 kb long and is located at 13q34-ter, 2.8 kb downstream of the F7 gene. The coding sequence is homologous to the other vitamin K-dependent proteins and is divided into eight exons, each of which encodes a specific domain within the protein: exon 1 encodes the signal peptide, exon 2 encodes the propeptide and Gla domain, exon 3 encodes the aromatic amino acid stack domain, exons 4 and 5 each code for the epidermal growth factor-like regions, exon 6 encodes the activation domain, and exons 7 and 8 encode the catalytic domain. The F10 cdna consists of 1474 bp coding for the pre-proleader sequence, the 488 amino acid mature protein, a Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14,

3 1178 D. L. BROWN and P. A. KOUIDES short 3 untranslated region and the poly (A) tail. No TATA box has been identified in the 5 region, allowing for multiple transcription initiation sites. Severe (homozygous) FX deficiency is inherited as an autosomal recessive disorder and is more prevalent in populations in which consanguineous marriage is common. The earliest reported molecular abnormality affecting the F10 gene was reported by Scambler and Williamson in 1985, who described a female who was monosomic for 13q34 and was deficient in both FVII and FX [11]. Her brother was trisomic for 13q34 and had increased levels of both FVII and FX. The FX knockout mouse with an 18-kb deletion of the F10 gene died of bleeding complications in utero or within the first 30 days of life [12], suggesting that a complete absence of FX is incompatible with life, perhaps explaining why severe FX deficiency is one of the rarest of the known bleeding disorders. Most of the F10 gene mutations responsible for human disease are single base pair substitutions [5]. To date, more than 80 different mutations of the F10 gene have been identified among individuals with FX deficiency [4,5,13,14]. Most of these mutations are private (i.e., unique to a particular patient or family). Among 102 patients with confirmed F10 gene mutations in the Greifswald Factor X Deficiency Registry, 29 different mutations from 45 families were identified. Twenty-six of these were missense mutations, two were microdeletions and one was a splice site mutation. The most common sites of mutations have been localized to the Gla domain (exon 2) and the catalytic site (exons 7 and 8) [15] (Fig. 1). Clinical manifestations Related to level of deficiency Clinical information about FX deficiency has improved as several important registries have been developed, including the Greifswald Registry of Factor X Deficiency in Europe and Latin America [14], the Rare Bleeding Disorder Registry in North America [16] and population registries of inherited bleeding disorders from the UK Hemophilia Centre Directors Organization [17] and the Hemophilia Surveillance System in Iran [6]. The bleeding symptoms reported from these registries are summarized in Table 1. In contrast to FVIII and FIX deficiency, the most frequent bleeding symptoms are mucocutaneous: easy bruising, epistaxis and gum bleeding. Menorrhagia has been reported in 10 75% of women with severe FX deficiency [9,14,18]. FX levels increase in pregnancy of non-affected women [19], but FXdeficient women have been described to have uterine bleeding, foetal loss and postpartum haemorrhage. Among 14 reported pregnancies in women with homozygous FX, there were two instances of miscarriage and two of postpartum haemorrhage [20]. Haemarthrosis occurred in 69% of Iranian patients with FX levels <10% [10]. Several patients with moderate to severe FX deficiency have been described to have recurrent haemarthrosis with development of haemophiliac arthropathy. Intracranial haemorrhage is reported in 9 26% patients and is most common during the neonatal period. One in utero subdural haemorrhage occurring at 35 weeks of gestation in an affected foetus has been reported. Umbilical cord bleeding is also a common bleeding symptom in the neonatal period, having been reported in 28% patients with FX levels <10% [10]. Phenotypic genotypic relationships have been described in several of the registries. Several homozygous mutations [Leu()32)Pro, Glu102Lys,- Gly114Arg] are associated with higher levels of FX:C, and these patients describe mild or no bleeding symptoms [14]. Twenty-six of 28 homozygous individuals from the Greifswald Factor X Deficiency Registry [15] were symptomatic for spontaneous bleeding symptoms. Of the 42 symptomatic patients, 26 were found to be homozygous, whereas seven were compound heterozygotes and nine had a mutation identified in one allele only. The seven compound-heterozygous patients had FX:C activities of <1 3% and all had a severe bleeding phenotype. Severe bleeding complications in the homozygous and compound heterozygous patients were similar to those of severe FVIII and FIX deficiencies, including haemarthrosis, ICH and gastrointestinal bleeding. Haemarthrosis appears to be particularly common among patients with the Gly()20)Arg and Gly94Arg mutations. Five of the seven patients with ICH in the Fig. 1. Location of factor X mutations projected on functional protein domains. Haemophilia (2008), 14, Journal compilation Ó 2008 Blackwell Publishing Ltd

4 FACTOR X DEFICIENCY 1179 Table 1. Frequency of bleeding symptoms in patients with factor X deficiency. Symptoms Herrmann et al [13] (n = 35)* Acharya et al [15] (n = 19) Peyvandi et al [5] (n = 32) à Anwar et al [17] (n = 20) Easy bruising 18 (51%) (45%) NR 9 (45%) Epistaxis 12 (34%) 23 (72%) 7 (35%) Gum bleeding 12 (34%) NR 7 (35%) Menorrhagia 9/12 (75%) (4 9)% 4/8 (50%) 1/10 (10%) GI bleeding 4 (14%) 12 (38%) 2 (10%) Haematuria 3 (9%) 8 (25%) 1 (5%) Haematomas 16 (46%) (27%) 21 (66%) NR Haemarthrosis 14 (40%) 22 (69%) 1 (5%) ICH 9 (26%) 15% 3 (9%) NR Umbilical cord NR NR 9 (28%) 3 (15%) Circumcision NR NR NR 3/10 (30%) GI, gastrointestinal; ICH, intracranial haemorrhage; NR, not reported. *Includes 28 homozygous and seven compound heterozygous patients. Includes homozygous patients with factor X levels of 0 13%. à All patients have factor X levels <10%. Factor X levels were not reported. Greifswald Factor X Deficiency Registry were homozygous for the Gly380Arg mutation, found only in subjects enrolled from Costa Rica. Several kindreds have been described in which heterozygotes (carriers) have mucocutaneous bleeding symptoms, including gastrointestinal bleeding. The Stuart kindred included several family members who were obligate carriers who had prolonged prothrombin times and a mild bleeding tendency [7]. Registry data suggest that most heterozygotes are asymptomatic, however. In the Greifswald Factor X Deficiency Registry, 9 of 67 heterozygotes (13%) described mucocutaneous bleeding symptoms, such as epistaxis, easy bruising and menorrhagia. One female had postpartum bleeding. The nine symptomatic heterozygotes had FX:C levels similar to the asymptomatic heterozygotes (50.7% vs. 52%). Symptomatic carriers may have F10 gene mutations, which result in a mutant protein that exerts an inhibitory effect on the normal protein [21], or there may be other extragenic modifiers in heterozygotes with bleeding manifestations. Timing of presentation Patients with severe FX deficiency may present in the neonatal period with bleeding with circumcision, umbilical stump bleeding (usually when the stump falls off at 7 14 days), ICH or gastrointestinal haemorrhage. Moderately affected patients may be recognized only after haemostatic challenge, such as surgery, trauma or menses. Mild FX deficiency may be diagnosed during routine screening or because of a positive family history. Diagnosis Laboratory The diagnosis of FX is usually suspected when both the prothrombin time (PT) and activated partial thromboplastin time (APTT) are abnormal and correct with a 1:1 mix with normal plasma. FX functional activity (FX:C) is quantified by performing serial dilutions with FX-deficient plasma. PT reagents may vary in sensitivity to FX deficiency and congenital variants have been identified in which both the PT and PTT are normal [21]. Additional assays which are available for protein characterization include the russell viper venom (RVV) time. RVV is a metalloproteinase that will activate FX (as well as FV, prothrombin and fibrinogen) directly and will detect deficiency of FX if FX-deficient plasma is used as substrate. Immunological assays, such as enzyme-linked immunosorbent assay, measure FX antigen. Chromogenic assays use a FXa-sensitive chromophoric substrate that can be detected spectrophotometrically. Immunological and chromogenic assays may miss cases of dysfunctional FX and therefore should not be used as screening tests for FX deficiency. Factor X levels are low at birth and should be compared with age- and gestational age-matched normal ranges before a deficiency is diagnosed in the neonate. FX levels in healthy full-term infants average 0.40 (SD, 0.14) IU ml )1 and do not approximate adult values until after 6 months of age [22]. Because FX is synthesized in the liver, liver disease will result in low levels of FX, along with the other liver-produced factors prothrombin, FV, FVII and FIX. Vitamin K deficiency and warfarin use also result in low levels of FX, FVII and FIX. Acquired FX deficiency occurs in up to 5% of patients with amyloidosis as a result of adsorption into amyloid fibrils in the spleen [23]. There have been reports of acquired FX deficiency with cancer, myeloma, infection and use of sodium valproate. Acquired inhibitors to FX have been identified in burns, respiratory infections and exposure to topical thrombin [24]. Molecular where can it be done? Currently, no clinical laboratory in the US offers genetic mutation analysis or prenatal diagnosis for FX deficiency. Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14,

5 1180 D. L. BROWN and P. A. KOUIDES Management Treatments currently available Because of the rarity of FX deficiency, evidencebased management guidelines are lacking. Guidelines for management of FX deficiency and other rare coagulation disorders based on literature and extensive clinical experience have been published by the United Kingdom Haemophilia Centre DoctorsÕ Organisation [17]. For minor bleeding symptoms, topical therapies and antifibrinolytic agents may be sufficient treatment. Nosebleeds Quick ReleaseÔ powder, which is a hydrophilic polymer (Biolife; LLC, Sarasota, FL, USA), may be helpful in the treatment of nosebleeds and fibrin glue preparations can be used at surgical sites to achieve local haemostasis. Aminocaproic acid (Amicar; Xanodyne Pharmaceuticals Inc, Newport, KY, USA) can be used as a mouthwash (15 ml every 6 h) or taken orally ( mg kg )1, maximum of 3 g every 6 h) for mouth bleeding or recurrent nosebleeds. Aminocaproic acid is also reported to be effective in the treatment of idiopathic menorrhagia and is used with generally good results in women with bleeding disorders. Tranexamic acid is a better-tolerated and more potent antifibrinolytic agent [25] (oral dose is 15 mg kg )1 or 1 g every 6 8 h). Although an oral preparation is not currently available in the US, there are on-going trials in the US studying a sustained release formulation of tranexamic acid (XP12B; Xanodyne Pharmaceuticals Inc) in healthy women with menorrhagia [http://clinical- Trials.gov; Efficacy and Safety Study of XP12B in Women With Menorrhagia, 2007 (http://clinicaltrials.gov/ct/show/nct )]. Factor X replacement therapy can be accomplished with fresh frozen plasma (FFP) or plasma-derived FIX concentrates [prothrombin complex concentrates (PCC)]. No purified FX concentrate is available in the US. FFP has been associated with allergic reactions and transfusion-associated lung injury. PCC is a plasma-derived concentrate which has undergone viral inactivation procedures to lessen the risk of viral transmission. The use of PCC in high doses has been associated with thrombosis in haemophilia patients, but the precise frequency is unknown. There have been no reported cases of inhibitory antibodies to FX in patients with congenital FX deficiency in patients treated with FFP or PCC. The biological half-life of infused FX is h, but varies among individuals and with repeated dosing [1]. A loading dose of ml kg )1 of FFP, followed by 3 6 ml kg )1 twice daily, will usually achieve trough levels above 10 20% [18]. PCC or highly purified FIX concentrates may contain therapeutic amounts of FX as well (Table 2). PCC products with a FX: FIX ratio of 1:1 will increase plasma levels approximately 1.5% for every 1IUkg )1 BW given. Because of the long half-life, daily treatment may result in increasing levels and is not usually required [16]. Monitoring FX and FIX levels is required during long-term treatment or in the postoperative period to avoid overtreatment and risk of thrombosis. Adjuvant use of antifibrinolytic therapy should be avoided during treatment with PCCs because of an increased risk of thrombosis. Targeted levels for treatment and surgery are not well established. Patients with FIX levels >10% and no significant bleeding history may not require treatment [16]. In a single case report from 1985, FX levels of 9 17% achieved with FFP were sufficient to control minor bleeding [26]. Emergency surgery for haemoperitoneum was safely performed with the use of PCC to achieve a level of 35%, followed by FFP to maintain levels of 10 20% for 6 days in the postoperative period [26]. A subdural haematoma was evacuated in an infant after treatment with 10 ml kg )1 of plasma every 8 h for 10 days [27]. A central venous catheter was placed without bleeding complications using PCC Table 2. Commercial clotting factor products that contain factor X*. Factor units/100 U of factor IX Product name Manufacturer II VII IX X Factor X P CSL Behring, King of Prussia, PA, USA à Factor IX HS CSL Behring, King of Prussia, PA, USA Profilnine SD Grifols USA, Biocience Division, Los Angeles, CA, USA Proplex T Baxter Pharmaceuticals, Deerfield, IL, USA Bebulin VH Baxter Pharmaceuticals, Deerfield, IL, USA FEIBA Baxter Pharmaceuticals, Deerfield, IL, USA Variable amounts of activated factors *Modified from Roberts and Bingham [1]. Licensed in Switzerland. à Actual factor X content is included on the product label. Haemophilia (2008), 14, Journal compilation Ó 2008 Blackwell Publishing Ltd

6 FACTOR X DEFICIENCY IU kg )1 given on alternate days, maintaining a FX level >50% [17]. Thirteen pregnancies among women homozygous for FX deficiency have been reported in the literature, and all of these women have been treated with FFP, PCC or plasmapheresis prior to delivery and some have received additional dosing postdelivery [20]. In spite of this treatment, the complication rate was relatively high, including two cases of postpartum haemorrhage. None of the women were reported to have had thrombosis. Although prophylactic replacement therapy has been used by FVIII- and FIX-deficient patients to prevent recurrent haemarthrosis and ICH, these strategies have only recently been attempted for FX-deficient patients. Kouides and Kulzer report on a patient with recurrent haemarthrosis treated with Profilnine-SD (Grifols USA, Bioscience Division, Los Angeles, CA, USA; FX: FIX ratio of ), 30 FIX Ukg )1 twice weekly, who had only a single traumainduced bleeding episode during the 23-month follow-up period [28]. A trough FX level drawn 48 h after infusion was 30% and the patient had no thrombotic complications. Seven patients in the Greifswald Factor X Deficiency Registry have been initiated with prophylaxis for joint disease and were treated with FX U kg )1 (FIX HS; CSL Behring, King of Prussia, PA, USA) once weekly [29]. Dosing was increased to 2 3 times weekly to prevent breakthrough bleeding and two patients have required every other day treatment. A 21-month-old child with recurrent intracranial haemorrhage was given 40 FIX U kg )1 of PCC twice weekly and had a preinfusion level of 7% and a postinfusion of 85% with no further bleeding while following this regimen [27]. However, in two other young children with ICH, PCC given weekly or twice weekly was insufficient to prevent recurrent ICH [30]. Four Irish children with severe FX deficiency and history of bleeding symptoms who were treated with PCC (Bpl 9A; Bio Products Laboratory, Elstree, Herts, UK and Prothromplex; Baxter, Vienna, Austria), FIX U kg )1 1 2 times per week, had no breakthrough bleeding when FX levels were maintained over 5% [31]. Survival studies on two of the children found a half-life of h and the authors suggest that dosing could be based on pharmacokinetics. Activated recombinant factor VII (rviia) has been reported to be effective in treating persistent skin and muscle bleeding in a patient with acquired FX deficiency as a result of amyloidosis [23]. Because FX is a substrate for rviia, it has been suggested that it may prove to be ineffective in cases of severe FX deficiency [17]. Research/investigational new drug treatment protocols (IND) The Centers for Disease Control Universal Data Collection study of patients with haemophilia that involves longitudinal study, including serial range of motion assessment and infectious disease testing, is an on-going protocol available for US FX-deficient patients. A parallel study compiling obstetrical and gynaecological data points for women with inherited coagulation disorders, including FX deficiency, is also planned. Prognosis With early recognition and diagnosis of severe FX deficiency, bleeding symptoms can be effectively treated and managed. Home treatment with FX-containing concentrates allows for prompt resolution of bleeding symptoms and patients with severe bleeding tendencies may benefit from prophylactic therapy. Certain genotypes appear to be associated with a high rate of haemarthrosis and ICH, and this information could influence the decision to start prophylactic therapy. Women with mild FX deficiency who have menorrhagia may benefit from visiting a comprehensive haemophilia treatment centre with coordinated services to manage menses and pregnancy issues. Heterozygotes of FX deficiency are most likely to be identified by abnormal coagulation screening tests or family history and may benefit from genetic counselling and haematology consultation during surgical procedures. Individuals with interest in area Individuals holding INDs for treatment Currently, no individuals in the US are holding INDs for treatment of inherited FX deficiency. FX P Behring by CSL Behring is available in Switzerland. Individuals doing research in pathophysiology, molecular basis, etc. Currently, Dr Flora Peyvandi, Milan, Italy and Dr Karin Wulff, Greifswald, Germany, are performing epidemiological, clinical presentation and genetic studies on FX deficiency. Dr James Uprichard and David Perry, Cambridge, England, are researching the pathophysiology of FX deficiency. Disclosures D. L. Brown has acted as a paid consultant and has received funds for research. P. A. Kouides has stated Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14,

7 1182 D. L. BROWN and P. A. KOUIDES that he has no interests that might be perceived as posing a conflict or bias. References 1 Roberts HR, Bingham MD. Other Coagulation Factor Deficiencies. Thrombosis and Hemorrhage, 2nd edn. Baltimore, MD: Williams & Wilkins, 1998: Duckert F, Fluckinger P, Matter M, Koller F. Clotting factor X; physiologic and physico-chemical properties. Proc Soc Exp Biol Med 1955; 90: Telfer TP, Denson KW, Wright DR. A new coagulation defect. Brit J Haematol, 1956; 2: Hougie C, Barrow EM, Graham JB. Stuart clotting defect. I. Segregation of an hereditary hemorrhagic state from the heterogeneous group heretofore called stable factor (SPCA, proconvertin, factor VII) deficiency. J Clin Invest 1957; 36: Peyvandi F, Duga S, Akhavan S, Mannucci PM. Rare coagulation deficiencies. Haemophilia 2002; 8: Karimi M, Yarmohammadi H, Ardeshiri R, Yarmohammadi H. Inherited coagulation disorders in sourthern Iran. Haemophilia 2002; 8: Graham JB, Barrow EM, Hougie C. Stuart clotting defect. II. Genetic aspects of a new hemorrhagic state. J Clin Invest 1956; 36: Rezaie A, Manithody C, Yang L. Identification of factor Xa residues critical for interactin with protein Z-dependent protease inhibitor: both active site and exosite interactions are required for inhibition. J Biol Chem 2005; 280: Razzari C, Martinelli I, Bucciarelli P, Viscardi Y, Biguzzi E. Polymorphisms of the protein Z-dependent protease inhibitor (ZPI) gene and the risk of thromboembolism. Thromb Haemost 2006; 95: Peyvandi F, Mannucci PM, Lak M et al. Congenital factor X deficiency: spectrum of bleeding symptoms in 32 Iranian patients. Brit J Haematol 1998; 102: Scambler PJ, Williamson R. The structural gene for human coagulation factor X is located on chromosone 13q34. Cytogenet Cell Genet 1985; 39: Dewerchin M, Liang Z, Moons L et al. Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice. Thromb Haemost 2000; 83: Millar DS, Elliston L, Deex P et al. Molecular analysis of the genotype phenotype relationship in factor X deficiency. Hum Genet 2000; 106: Herrmann FH, Auerswald G, Ruiz-Saez A et al. Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene. Haemophilia 2006; 12: Mannucci PM. Recessively inherited coagulation disorders. Blood 2004; 104: Acharya SS, Coughlin A, DiMichele DM, T.N.A.R. B.D.S. Group. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2003; 2: Bolton-Maggs PHB, Perry DJ, Chalmers EA et al. The rare coagulation disorders review with guidelines for management from the United Kingdom Haemophilia Centre DoctorsÕ Organisation. Haemophilia 2004; 10: Anwar M, Hamdani SNR, Ayyub M, Ali W. Factor X deficiency in North Pakistan. J Ayub Med Coll 2004; 16: Condie RG. A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by pre-eclampsia. Brit J OB Gyn 1976; 83: Romagnolo C, Burati S, Ciaffoni S et al. Severe factor X deficiency in pregnancy: case report and review of the literature. Haemophilia 2004; 10: Perry DJ. Factor X and its deficiency states. Haemophilia 1997; 3: Andrew M, Paes B, Milner R et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: Boggio L, Green D. Recombinant human factor VIIa in the management of amyloid-associated factor X deficiency. Brit J Haematol 2001; 112: Uprichard J, Perry DJ. Factor X deficiency. Blood Rev 2002; 16: Fraser IS, Lukes AS, Kouides PA. A benefit-risk review of systemic haemostatic agents in surgery and gynaecology. Drug Saf 2008; 31: Knight RD, Barr CF, Alving BM. Replacement therapy for congenital factor X deficiency. Transfusion 1985; 25: Sandler E, Gross S. Prevention of recurrent intracranial hemorrhage in a factor X-deficient infant. Am J Pediatr Hematol Oncol 1992; 14: Kouides PA, Kulzer L. Prophylactic treatment of severe factor X deficiency with prothrombin complex concentrate. Haemophilia 2001; 7: Auerswald G. Prophylaxis in rare coagulation disorders factor X deficiency. Thromb Res 2006; 118S1: S Sumer T, Ahmad M, Sumer NK, Al-Mouzan MI. Severe congenital factor X deficiency with intracranial haemorrhage. Eur J Pediatr 1986; 145: McMahon C, Smith J, Goonan C, Byrne M, Smith OP. The role of primary prophylactic factor replacement therapy in children with severe factor X deficiency. Brit J Haematol 2002; 119: Links to organizations professional, lay National Hemophilia Foundation: philia.org/nhfweb/mainpgs/mainnhf.aspx?menu id=188&contentid=52&rptname=bleeding Canadian Hemophilia Society: National Library of Medicine and National Institutes of Health Medline Plus: gov/medlineplus/ency/article/ htm Haemophilia (2008), 14, Journal compilation Ó 2008 Blackwell Publishing Ltd

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