Objective To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. Design A randomised placebo-controlled trial. Setting Thirteen maternal-fetal medicine units across New Zealand and Australia. Population Women with singleton pregnancies affected by fetal growth restriction at 22(+0) to 29(+6) weeks. Methods Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32(+0) weeks, birth or fetal death (whichever occurred first). Main Outcome Measures The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. Results Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75). Conclusions Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. Tweetable abstract Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

BackgroundWomen with gestational diabetes mellitus (GDM) are at increased risk for maternal and fetal complications including delivery of large for gestational age (LGA) infants. Maternal body mass index (BMI) and excessive weight gain during pregnancy are associated with delivery of LGA infants. However, whether maternal BMI and weight gain are associated with LGA infants in women with GDM is unclear.Basic proceduresData on 1049 pregnant women who developed GDM were collected from a university teaching hospital in China and retrospectively analyzed. Data included maternal BMI, weight gain, incidence of LGA and gestational week at diagnosis.Main findingsThe incidence of LGA infants was significantly associated with maternal BMI (p=0.0002) in women with GDM. The odds of delivery of LGA for obese or overweight pregnant women are 3.8 or 2 times more than normal weight pregnant women. The incidence of LGA infants was also significantly associated with maternal weight gain in women with GDM. The odds ratio of delivery of LGA for pregnant women with excessive weight gain was 3.3 times more than pregnant women with normal weight gain. The effect of weight gain was not significantly different between different maternal BMI.Principal conclusionThe incidence of delivery of LGA infants in Chinese women with GDM who were overweight or obese is higher than Caucasians, Hispanic, and Asian-Americans. The effects of maternal BMI and weight gain on the delivery of LGA infants by women with GDM are additive.

The coagulation system of the foetus is markedly different from that of adults. To assess the influence of maternal age, mode of delivery and intrapartum events, and foetal gender and weight on the foetal coagulation system. Cord blood was collected from 154 healthy pregnant women, with gestational age 37 - 42 weeks at birth. Mann-Whitney test was used for analysis of binary data and continuous variables were analysed using Pearson's correlation coefficient. Mean cord blood levels of FVIII:C, VWF:Ag, VWF:CB, FIX, FXI, FXII and plasminogen were significantly higher in babies delivered after labour, compared to those delivered after an elective caesarean. Mean cord blood levels of FII (P = 0.003), FV (P = 0.009), FVII (P = 0.0004) and FX (P = 0.0009) were significantly lower in the babies with meconium stained liquor in labour, compared with those with clear liquor. Augmentation with oxytocin, instrumental delivery, did not affect any of the factor levels and duration of labour did not have an effect on the level of coagulation proteins in cord blood. This study provides valuable information about effect of labour on the coagulation system of the foetus. It is concluded that, in cord blood, the results of coagulation parameters in the newborn baby should be considered in light of mode of delivery and events of labour.

Rare bleeding disorders (RBDs) include the inherited deficiencies of coagulation factors, fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, FXI and FXIII, and are usually transmitted as autosomal recessive disorders [1Tuddenham E.G.D. Cooper D.N. The Molecular Genetics of Haemostasis and its Inherited Disorders. Oxford University Press, 1994Google Scholar]. Due to their rarity, they sometimes present significant challenges in diagnosis and treatment [2Peyvandi F. Palla R. Menegatti M. Mannucci P.M. Introduction. Rare bleeding disorders: general aspects of clinical features, diagnosis, and management.Semin Thromb Hemost. 2009; 35: 349-55Crossref PubMed Scopus (94) Google Scholar]. The development of guidelines for classification and treatment of these disorders has been hampered by a lack of sufficient knowledge about epidemiology and clinical outcomes, the difficulty in recognizing affected patients and collecting longitudinal clinical data, the limits of laboratory assays, and a lack of consensus concerning the criteria by which these disorders are classified. A collaboration among experts on RBDs was therefore proposed. Over the past 5 years, the Rare Bleeding Disorders Working Group, under the umbrella of the Factor VIII and Factor IX Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis, has started to focus on the need for comprehensive data collection regarding laboratory phenotype and clinical manifestations in RBDs. Different networks and registries, established in Europe (European network of Rare Bleeding Disorders – (EN‐RBD)) [3Peyvandi F. Palla R. Menegatti M. Siboni S.M. Halimeh S. Faeser B. Pergantou H. Platokouki H. Giangrande P. Peerlinck K. Celkan T. Ozdemir N. Bidlingmaier C. Ingerslev J. Giansily‐Blaizot M. Schved J.F. Gilmore R. Gadisseur A. Benedik‐Dolnicar M. Kitanovski L. et al.Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.J Thromb Haemost. 2012; 10: 615-21Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar], the United Kingdom (United Kingdom Haemophilia Centre Doctors’ Organisation registry (UKHCDO)) [4Bolton‐Maggs P.H. Perry D.J. Chalmers E.A. Parapia L.A. Wilde J.T. Williams M.D. Collins P.W. Kitchen S. Dolan G. Mumford A.D. The rare coagulation disorders‐‐review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation.Haemophilia. 2004; 10: 593-628Crossref PubMed Scopus (439) Google Scholar], the USA (The North American Rare Bleeding Disorders Registry (NARBDR) [5Acharya S.S. Coughlin A. Dimichele D.M. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.J Thromb Haemost. 2004; 2: 248-56Crossref PubMed Scopus (241) Google Scholar] and the American Thrombosis Hemostasis Network (ATHN) Rare Coagulation Disorder database (http://www.athn.org)) and India [6Viswabandya A. Baidya S. Nair S.C. Abraham A. George B. Mathews V. Chandy M. Srivastava A. Correlating clinical manifestations with factor levels in rare bleeding disorders: a report from Southern India.Haemophilia. 2012; 18: e195-200Crossref PubMed Scopus (27) Google Scholar] started to collaborate with an initial task of understanding what data are currently available through each system. Here, we report the results of a preliminary review of available data that explored the association between residual plasma coagulant factor activity and the clinical bleeding profile for each of the RBDs. Combined vitamin K‐dependent clotting factor deficiencies are not included in this analysis. The results are based on two different sets of data. 1A detailed review of the available literature. We searched Medline and PubMed for articles published in English between January 1990 and March 2012, with the following search terms: ‘clinical manifestations’ OR ‘bleeding symptoms’ OR ‘genotype phenotype’ OR ‘outcomes’ in combination with the specific type of deficiency OR ‘rare bleeding disorder’. We excluded articles on the basis of their titles or abstracts and included remaining articles and those identified from reference lists of relevant reports that reported data on the association between the laboratory phenotype and clinical bleeding characteristics for at least five patients. We identified 51 relevant original articles (Table S1) and 39 review articles (Table S2).2Overview of data on the association between the laboratory phenotype and clinical bleeding characteristics from the EN‐RBD, UKHCDO, NARBDR and Indian registries for a total of 4359 patients affected with RBDs (592, 3192, 294 and 281, respectively). The following classification systems were identified in the original resources and used to interpret the association between the residual plasma coagulant factor activity and the clinical bleeding severity. 1Residual plasma coagulant factor activity was classified as mild, moderate or severe in the UKHCDO, NARBDR and Indian registries as described in Table 1. Classification of clinical bleeding severity was based on site and frequency of bleeding.Table 1Laboratory phenotype classifications according to the four registries, compared with the laboratory classification of hemophiliaSevereModerateMildUKHCDO*< 5% (subdivided into 0 and 1–5%) Fibrinogen: < 0.1 g L−15–10% Fibrinogen: 0.1–0.5 g L−1> 10% (subdivided into 10–20% and > 20%) Fibrinogen: > 0.5 g L−1NARBDR†< 1% Afibrinogenemia: < 0.5 g L−1 FXIII: abnormal clot lysis assay1–19% Hypofibrinogenemia: 0.5 g L−1 ‐ LLN (lower limit of normal range in local)> 20%INDIA‡Afibrinogenemia: no detectable clot FV, FVII, and FX: < 1% FXI: < 2% FXIII: abnormal clot lysis assayHypofibrinogenemia: < 1 g L−1Dysfibrinogenemia: > 1 g L−1 FV + FVIII: < 40–45%§ Hemophilia< 1%1–5%> 5%*UKHCDO data analysed in this manner for this study only. Definitions have not been agreed for the database and are not used currently by the reporting clinicians. †The original publication [5Acharya S.S. Coughlin A. Dimichele D.M. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.J Thromb Haemost. 2004; 2: 248-56Crossref PubMed Scopus (241) Google Scholar] defined severe RBDs (exclusive of fibrinogen and FXIII) by levels of < 20%. The classification depicted here was used in a secondary post‐publication analyses performed for this project. Clinical and laboratory correlation analyses were also performed using the hemophilia classification of severity. ‡All patients who presented with FII deficiency had coagulant activity < 20% associated with significant bleeding. The analysis, carried out by the Indian registry, did not divide patients with FII deficiency into mild, moderate or severe deficiency as the aim was to show the clinical manifestations of patients who presented with FII deficiency. §When analysis of data taking the factor level < 10% or both levels > 10% or both factor levels < 10% was carried out, there was no difference in symptoms. Open table in a new tab 2Residual plasma coagulant factor activity was considered as a continuous variable in the EN‐RBD, while clinical bleeding severity was classified as described in Table 2.Table 2Assigned categories of clinical bleeding severity in the EN‐RBD [3Peyvandi F. Palla R. Menegatti M. Siboni S.M. Halimeh S. Faeser B. Pergantou H. Platokouki H. Giangrande P. Peerlinck K. Celkan T. Ozdemir N. Bidlingmaier C. Ingerslev J. Giansily‐Blaizot M. Schved J.F. Gilmore R. Gadisseur A. Benedik‐Dolnicar M. Kitanovski L. et al.Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.J Thromb Haemost. 2012; 10: 615-21Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]Clinical bleeding severityDefinitionAsymptomaticNo documented bleeding episodesGrade I bleedingBleeding that occurred after trauma or drug ingestion (antiplatelet or anticoagulant therapy)Grade II bleeding Spontaneous minor bleeding: bruising, ecchymosis, minor wounds, oral cavity bleeding, epistaxis and menorrhagiaGrade III bleeding Spontaneous major bleeding: hematomas*, hemarthrosis, CNS, GI and umbilical cord bleedingCNS = central nervous system, GI = gastrointestinal. *Intramuscular requiring hospitalization. Open table in a new tab 3For data retrieved from the literature (Tables S1 and S2), residual plasma coagulant factor activity was classified differently by different references, and these are described in Tables S1 and S2. For clinical bleeding severity, we relied on the authors’ original classification of severity, and in cases where that was not provided we used the classification system described in Table 2. *UKHCDO data analysed in this manner for this study only. Definitions have not been agreed for the database and are not used currently by the reporting clinicians. †The original publication [5Acharya S.S. Coughlin A. Dimichele D.M. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.J Thromb Haemost. 2004; 2: 248-56Crossref PubMed Scopus (241) Google Scholar] defined severe RBDs (exclusive of fibrinogen and FXIII) by levels of < 20%. The classification depicted here was used in a secondary post‐publication analyses performed for this project. Clinical and laboratory correlation analyses were also performed using the hemophilia classification of severity. ‡All patients who presented with FII deficiency had coagulant activity < 20% associated with significant bleeding. The analysis, carried out by the Indian registry, did not divide patients with FII deficiency into mild, moderate or severe deficiency as the aim was to show the clinical manifestations of patients who presented with FII deficiency. §When analysis of data taking the factor level < 10% or both levels > 10% or both factor levels < 10% was carried out, there was no difference in symptoms. CNS = central nervous system, GI = gastrointestinal. *Intramuscular requiring hospitalization. Based on the interpretation of published data and the experiences from the networks and registries, it is evident that: 1there is a heterogeneous association between residual plasma coagulant factor activity and clinical bleeding severity in different RBDs (these data indicate that a more detailed evaluation on each single factor deficiency is required for future planning of optimal diagnosis and management); and2it is not appropriate to use a single criterion of classification for all types of RBDs. Despite the heterogeneity of the data available in the literature or collected through the different networks and registries, a general picture of each single deficiency is reported in the following sections. Information from the literature (Tables S1 and S2) shows that patients with afibrinogenemia have a bleeding tendency of variable severity. The typical symptoms include umbilical cord, mucosal, gastrointestinal tract (GI), genitourinary or central nervous system (CNS) bleeding. Other relatively frequent symptoms include hemarthroses and hematomas. First trimester abortion is common in afibrinogenemic women. Both arterial and venous thromboembolic complications were also recorded in some cases. The bleeding pattern of patients with hypofbrinogenemia is similar but appears milder; however, patients may bleed when exposed to trauma (Tables S1 and S2). The bleeding tendency of patients with dysfibrinogenemia is unpredictable, and hemorrhages occur often after trauma or surgery or in the post‐partum period. Thrombosis may also occur. Patients with a fibrinogen level around 1.0 g L−1 are usually asymptomatic (Tables S1 and S2). Despite different classifications used in the four registries, there is general agreement on clinical manifestations and a good association between laboratory phenotype and clinical severity (and also age at diagnosis) was observed in patients affected with fibrinogen deficiency. The lack of standardization of the available assays makes it difficult to reach conclusions regarding the minimal amount of fibrinogen that could significantly reduce bleeding symptoms. However, EN‐RBD data show that there is a strong association between fibrinogen level and clinical bleeding severity, with patients having undetectable levels being more likely to experience major spontaneous bleeding while those with levels > 0.1 g L−1 are mostly asymptomatic. It is to be mentioned that sometimes the quantification of a low fibrinogen concentration using the Clauss or PT‐derived methods, routinely used in the clinical laboratories to measure plasma levels of the protein, may vary significantly and this phenomenon could generate uncertainty in assigning the severity grade of the hypofibrinogenemia. The relative mismatch between the levels measured by different assays and clinical severity of the hypofibrinogenemia may stem also from this phenomenon. The recommendation should be that the Clauss method remains the reference method because it can be performed on all instruments (not the case for the PT‐derived method). Due to the small number of reported cases, any association between bleeding manifestations and residual FII coagulant activity in plasma is very difficult to ascertain. However, FII coagulant activity < 10% is usually reported to be associated with severe bleeding manifestations (Tables S1 and S2), and only a few cases with < 5% of coagulant activity associated with a low level of antigen (type II deficiency) have been reported (Tables S1 and S2). In the NARBDR, a weak direct correlation between laboratory severity and the age at first bleed was noted. Furthermore, an inverse correlation between laboratory severity and mean lifetime number of trauma‐induced and musculoskeletal bleedings was noted, with both NARBDR and hemophilia classification (Table 1). Significant symptoms reported in Indian patients with FII coagulant level < 20% were prolonged post‐injury bleeding, mucosal bleeding and subcutaneous and muscle hematoma, while GI bleeding was seen only in a few cases. Results of the literature review suggest that the severity of symptoms is variable and correlates poorly with laboratory phenotype (Tables S1 and S2). Data from the registries confirmed this heterogeneity, showing a weak association between laboratory phenotype and clinical severity (including the age of patients at diagnosis or at first bleed). Analysis of the EN‐RBD registry demonstrated that undetectable residual coagulant activity was associated with spontaneous major bleeding, while patients with activity levels > 10% seem to remain asymptomatic. Data from India showed that the most common symptoms in patients with severe FV deficiency were prolonged bleeding post‐injury and mucosal bleeding, followed by hematoma, hemarthrosis and GI bleeding. Intracranial and umbilical cord bleeding were recorded in only 10% of patients with severe deficiency. Platelets provide a concentrated supply of FV: although most FV is present in plasma, approximately 20–25% of the circulating FV is found within platelet α‐granules [7Mann K.G. Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde.Blood. 2003; 101: 20-30Crossref PubMed Scopus (176) Google Scholar]. After α‐granule release upon platelet activation, FV can presumably bind immediately to surface receptors optimizing prothrombinase complex activity [7Mann K.G. Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde.Blood. 2003; 101: 20-30Crossref PubMed Scopus (176) Google Scholar]. This probably protects some patients with FV deficiency from severe life‐threatening bleeding, and may explain the weak association between laboratory phenotype and clinical severity. According to the literature, patients usually present with a wide range of clinical symptoms, ranging from spontaneous hematomas and mucosal/oral bleeding to post‐traumatic bleeding (Tables S1 and S2). Patients with mild or moderate compound FV + VIII deficiency usually experience minor bleeding; however, few patients with major bleeding were also recorded (Tables S1 and S2). The same data have been confirmed by the registries that tracked this disorder, and no strong association between laboratory phenotype and clinical manifestations has been observed. In the EN‐RBD, patients with activity levels < 20% were most likely to experience spontaneous major bleeding, while those with levels > 40% remained largely asymptomatic. Data from the literature suggest that hemorrhagic manifestations cannot be easily predicted by the coagulant activity level, and patients with similar coagulant activities can vary greatly in their bleeding symptoms (Tables S1 and S2). Similarly to FV deficiency, data from the registries confirmed a poor association between laboratory phenotype and clinical severity. Even for this deficiency, data from the EN‐RBD registry showed that < 10% of residual coagulant activity seems to be associated with major spontaneous bleedings. It is to be considered that the choice of the reagents used in FVII assays is really important: the diagnostic efficiency of the FVII coagulant activity assays is highly dependent on the thromboplastin sensitivity. In general, thromboplastin of human origin or recombinant thromboplastins structurally identical to the human type should be used [8Mariani G. Bernardi F. Factor VII Deficiency.Semin Thromb Hemost. 2009; 35: 400-6Crossref PubMed Scopus (152) Google Scholar]. The most common symptoms reported in the Indian registry were prolonged bleeding post‐injury and mucosal bleeding, followed by hematoma, hemarthrosis and GI bleeding. Intracranial and umbilical cord bleeding were recorded in few patients with severe deficiency. Data from the literature (Tables S1 and S2) show that patients with undetectable FX coagulant activity have severe bleeding manifestations, such as CNS, GI or umbilical cord bleeding, or recurrent hemarthroses and hematomas. These symptoms are uncommon in patients with moderate and mild deficiency, who usually only manifest mucocutaneous bleeding or remain asymptomatic throughout their lifetime. Similar results were found after analyzing data from the registries: a strong inverse association between FX coagulant level and bleeding severity was noted. In particular, analysis of the EN‐RBD registry demonstrated that patients with activity levels < 10% of FX had a high risk of major spontaneous bleeding, such as CNS and GI bleeding, suggesting this as a target level for prophylaxis. However, patients with levels > 40% remained largely asymptomatic and those having levels between 10 and 40% only suffered minor spontaneous or triggered bleeding. The literature reports that clinical bleeding tendency appears not to be associated with FXI coagulant activity. Spontaneous hemorrhage is uncommon in patients with FXI activity levels < 15–20%, who, on the contrary, have a high probability of postoperative hemorrhage (Tables S1 and S2). Patients with levels between 20 and 65% of FXI coagulant activity usually remain asymptomatic or have a low risk of postoperative bleeding (Tables S1 and S2). Data from registries that tracked this disorder confirmed this finding and did not show any association between clinical bleeding tendency and residual FXI coagulant activity, both when undetectable or moderately reduced (< 20%). Patients with undetectable FXIII coagulant activity have severe bleeding manifestations, such as CNS or umbilical cord bleeding, or recurrent hemarthroses and hematomas. Miscarriages are very common in women with severe deficiency. Patients with moderate and mild deficiency can have only mucocutaneous bleeding or may be completely asymptomatic (Tables S1 and S2). Data from the registries indicate that the severity of the FXIII laboratory phenotype correlates well with the age at diagnosis, the clinical symptoms and the amount of replacement therapy required for treatment. However, this association in patients with severe FXIII deficiency (< 5%) is particularly difficult to interpret and may not be accurate, because most of the available data are based on the clot solubility test. This is a qualitative test that is poorly standardized and insensitive in the range of values 1–5% of FXIII coagulant activity. In any case, EN‐RBD data showed that patients with undetectable FXIII coagulant activity were most likely to experience major spontaneous bleeding, while those with levels ≥ 30% remained primarily asymptomatic, although with wide confidence intervals (10–50%). In conclusion, although the sources used in this report may be inadequate to provide a basis for evidence‐based recommendations for treatment of patients with RBDs, the collection and interpretation of these data allowed us to reach the following classification on the basis of the observed associations between clinical and laboratory severity. 1Fibrinogen, FII, FX and FXIII deficiencies are RBDs with a strong association between clinical severity and coagulant activity level, with a few exceptions.2FV and FVII deficiencies are RBDs with a poor association between clinical severity and coagulant activity level.3FXI deficiency shows no association between clinical severity and coagulant activity level, both when undetectable or moderately reduced (< 20%).4Compound FV + FVIII deficiency is mainly associated with mild or moderate clinical symptoms and patients rarely experience severe bleeding. Therefore for most of the RBDs, except FXI deficiency, the following severity classification could be proposed (Table 3).Table 3Proposal of the project on RBDsCoagulant factorLaboratory phenotypeCoagulant activitySevereModerateMildFibrinogenUndetectable clot0.1−1g L−1> 1 g L−1FIIUndetectable activity≤ 10%> 10%FVUndetectable activity< 10%≥ 10%FV + FVIII< 20%20–40%> 40%FVII< 10%10–20%> 20%FX< 10%10–40%> 40%FXIIIUndetectable activity< 30%≥ 30% Open table in a new tab 1Severe deficiency: coagulant activity associated with spontaneous major bleeding.2Moderate deficiency: coagulant activity associated with mild spontaneous or triggered bleeding.3Mild deficiency: coagulant activity associated with a mostly asymptomatic disease course. This classification is based primarily on the EN‐RBD data but without significant contradictions from the analyses of the other registries. It has to be mentioned that a proposed classification by Lapecorella et al. [9Lapecorella M. Mariani G. Factor VII deficiency: defining the clinical picture and optimizing therapeutic options.Haemophilia. 2008; 14: 1170-5Crossref PubMed Scopus (89) Google Scholar] for FVII deficiency based on symptoms and not on activity levels may be taken into consideration for the disorders with poor association between clinical severity and coagulant activity (Table 4).Table 4Severity classification of FVII deficiency, as reported in table 1 of reference [9Lapecorella M. Mariani G. Factor VII deficiency: defining the clinical picture and optimizing therapeutic options.Haemophilia. 2008; 14: 1170-5Crossref PubMed Scopus (89) Google Scholar]SevereThey had at least one of the following symptoms: GI or CNS bleeding or hemarthrosis with or without other bleedsModerateThose who had three or more symptoms with the exception of GI CNS bleeding or hemarthrosisMildThose who had one or two symptoms with the exception of GI CNS bleeding or hemarthrosisCNS, central nervous system; FVIIc, factor VII coagulation activity; GI, gastrointestinal. Open table in a new tab CNS, central nervous system; FVIIc, factor VII coagulation activity; GI, gastrointestinal. The antigen level is usually not mandatory for routine diagnostic laboratory investigations, except for fibrinogen and FII deficiencies, in which the antigen measurement could help to differentiate hypo‐ or dys‐prothrombinemia and hypo‐ or dys‐fibrinogenemia, especially because a normal antigen level in plasma could increase the risk of thrombosis. Despite the large number of patients evaluated in this overview (both from the literature and the aforementioned registries), there is a large heterogeneity in the pre‐assigned severity definitions for both coagulant activity and bleeding symptoms. We interpreted the reported associations and derived conclusions from common observations in different resources. Moreover, inherited and acquired hemostatic defects apart from the given disorder have not been ruled out, and thus laboratory versus clinical phenotypes may be misleading. These limitations underline the future need to develop an accurate data collection tool, available to hemophilia centres around the world. Achieving common definitions between different parties alongside longitudinal data collection would help determine the hemostatic level of each single factor to prevent spontaneous and post‐trauma/surgery/delivery hemorrhage for each type of RBD. In fact, such efforts are ongoing and two large longitudinal data collection projects (PRO‐RBDD) for patients affected with congenital fibrinogen and FXIII deficiency are underway. Moreover, the heterogeneous nature of the association between the laboratory phenotype and clinical manifestations in some RBDs indicates that other disease modifiers may be in play, which merit further study. It also points out the inadequacy of the available assays to evaluate the minimum residual level of coagulation factor to prevent the risk of bleeding. The assays used to measure plasma levels of the coagulation factor and the choice of the reagents are also really important to consider, because there are usually significant inter‐laboratory differences in the results of factor assays. Some consensus on factor assay methodology is important so that values from different laboratories/centres can be compared. This conclusion should pave the way to define the role of other global measurements such as thrombin generation and/or thromboelastography in the definition of hemorrhagic risk. Global assay standardization and application in RBDs should represent the next step to be undertaken by the working group in organising centralized laboratory assessment. F. Peyvandi designed the study, supervised the data collection and wrote the manuscript; D. Di Michele provided data obtained by the NARBDR and revised the manuscript; P. H. B. Bolton‐Maggs provided and analysed data from the UKHCDO registry and revised the manuscript; C. A. Lee revised the progress of this work and critically revised the manuscript; A. Tripodi critically revised the manuscript; A. Srivastava provided data obtained in India, and critically revised the results and the manuscript. All authors approved the final version of the manuscript. The authors state that they have no conflict of interest. The authors thank: A. Shapiro (Indiana Hemophilia and Thrombosis Centre, Indianapolis, IN, USA) and C. Negrier (Unité d’Hémostase Clinique, Hôpital Edouard Herriot, Lyon, France) for being members of the Project on Consensus Definitions in Rare Bleeding Disorders of the Factor VIII/Factor IX Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis; K. M. Musallam, I. Garagiola and A. Cairo (U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Milan, Italy) for the accurate revision of data available in the scientific literature; R. Palla and M. Menegatti (U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano and Luigi Villa Foundation, Milan, Italy) for performing statistical analysis, and interpretation of the data collected by the EN‐RBD network; L. Dewhurst (Administrator Assistant to the UKHCDO database, Ardwick, Manchester, UK); S. Acharya, co‐author of the NARBDR and participant in the secondary data analyses of that registry; A. Viswabandya and S. Chandran Nair (Christian Medical College, Vellore, India) for the data from India; F. Bernardi (Department of Biochemistry and Molecular Biology, University of Ferrara, Italy), R. De Cristofaro (Institute of Internal Medicine and Geriatrics and Hemostasis Research Center, Catholic University School of Medicine, Rome, Italy), P. De Moerloose (Division of Angiology and Haemostasis, University Hospital, Geneva, Switzerland), L. Muszbek (Clinical Research Center, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary), D. Perry (Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK) and U. Selighson (The Amalia Biron Research Instistute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Isreal), for their comments and critical revision of the manuscript; and all the collaborating partners involved in the EN‐RBD project (http://www.rbdd.eu/partners.htm): 1Hemofilie Centrum Leuven, Katholieke Universiteit, Leuven, Belgium (K. Peerlink);2Antwerp University Hospital UZA, Edegem, Belgium (A. Gadisseur);3Centre for Hemophilia and Thrombosis, Department of Clinical Biochemistry, University Hospital Skejbi, Aarhus, Denmark (J. Ingerslev);4Hopital Saint Eloi, Montpellier, France (J.F. Schved and M. Giansily–Blaizot) and associated centres;5Pediatric Hemophilia and Thrombosis Centre, Dr. von Hauner’s Children’s University Hospital, Munich, Germany (C. Bidlingmaier);6MVZ Labor Duisburg GmbH – Duisburg, Germany (S. Halimeh);7Haemophillia Center, Haemostasis Unit, Agia Sofia Children’s Hospital, Athens, Greece (H. Platokouki, H. Pergantou);8First Regional Transfusion and Haemophilia Center, Hippocration Hospital, Athens, Greece (G. Theodossiades);9‘Laiko’ General Hospital – 2nd Blood Transfusion Center and Haemophilia Center, Athens, Greece (O. Katsarou);10Hippoktrateion Hospital, Tessalonike, Greece (V. Economou);11National Centre for Hereditary Coagulation Disorders, St James’s Hospital, Dublin, Ireland (R. Gilmore);12Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università degli Studi di Milano, Milan, Italy (S.M. Siboni);13Haemostasis Department and Haemophilia Center, Blood Transfusion Institute of Serbia, Belgrade, Serbia (D. Mikovic);14National Haemophilia Center, University Children’s Hospital, Ljubljiana, Slovenia (M. Benedik‐Dolnicar and L. Kitanovski);15Department of Pediatric Hematology‐Oncology, Cerrahpasa Medical Faculty of Istanbul University, Istanbul, Turkey (T. Celkan and N. Özdemir);16Oxford Haemophilia & Thrombosis Centre, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom (P. Giangrande);17Royal Free Hampstead NHS Trust, London, United Kingdom (E.G.D. Tuddenham and P. Morjaria). Table S1. Patients, laboratory phenotype and clinical severity described in 51 original publications. Table S2. Patients, laboratory phenotype and correlation between laboratory phenotype and clinical severity described in 39 review articles. 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. The risk of variant Creutzfeldt-Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed-up for 1020 years through the UK Haemophilia Centre Doctors Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 implicated clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch-manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is =1% for 595, =50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty-one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow-up of this cohort is needed.

Summary. This review describes the background for the development of recombinant FVIIa (rFVIIa; NovoSeven) for use in haemophilic patients with inhibitors. The first proof of principle for using pharmacological doses of FVIIa as a haemostatic agent was obtained by producing small amounts of pure plasma‐derived FVIIa, which showed encouraging effect in two patients with haemophilia A and inhibitors. To make pure FVIIa available for use in a larger number of patients, rFVIIa was produced that was approved for use in patients with inhibitors against coagulation factors (congenital haemophilia and acquired haemophilia) in 1996 (EU), 1999 (USA) and 2000 (Japan). The efficacy rate in severe bleedings and in major surgery including major orthopaedic surgery has been found to be around 90% in controlled studies, and no serious safety concerns have been demonstrated. The availability of rFVIIa has facilitated the performance of elective major surgery in haemophilia patients with inhibitors. Further steps along the vision of providing a treatment for inhibitor patients similar to non‐inhibitor patients have been the efficacy of rFVIIa in home‐treatment and recently the encouraging experience in prophylaxis. The concept of using pharmacological doses of rFVIIa as a haemostatic agent is a new one, which has caused difficulties in finding the correct dose. A step forward has been the demonstration that similar efficacy can be achieved after one single dose of 270 μg kg −1 instead of three injections of a dose of 90 μg kg −1 . The higher clearance rate in children suggests that higher doses may be beneficial in children. The availability of rFVIIa has made advances in the understanding of coagulation processes possible. In a cell‐based in vitro model, it has been shown that rFVIIa binds to preactivated platelets if present in concentrations of 30 n m or higher. By doing so, it activates FX into FXa and enhances the thrombin generation on the activated platelet surface in the absence of FVIII/FIX. Through the increased thrombin generation, a firm, well‐structured fibrin haemostatic plug, which is resistant to premature lysis, is formed. By exploiting this mechanism of action, rFVIIa may also be effective in situations other than haemophilia, characterized by an impaired thrombin generation.

C. A . LEE ,* A . HUBBARD, C. A . SAB IN , U. BUDDE ,§ G . CA STAMA N,– E . J . FAVALORO,** K . D . FR IEDMAN, and A . B . FE DER I C I ON BEHALF OF THE ISTH-SSC SUBCOMMITTEE ON VWF *University of London, London; Biotherapeutics Group, NIBSC, Hertfordshire; UCL Medical School, Royal Free Campus, London, UK; §Coagulation Laboratory, Aescularbor, Hamburg, Germany; –Division of Hematology, S. Bortolo Hospital, Vicenza, Italy; **Hematology, ICPMR Westmead Hospital, Westmead, NSW, Australia; Blood Center of Wisconsin, Milwaukee, WI, USA; and Division of Hematology and Transfusion Medicine, L. Sacco University Hospital and Department of Internal Medicine, University of Milan, Milan, Italy

Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.

Haemophilia is an x-linked inherited bleeding disorder which can cause severe arthropathy. We have reviewed the results of 70 primary total knee replacements (TKR) performed in 57 haemophilic patients between 1983 and 2007. The functional results were assessed using the Hospital for Special Surgery (HSS) knee scoring system and Kaplan-Meier survivorship analysis. Six patients died. HSS scores were available for 60 TKRs at a mean follow-up of 9.2 years (2 to 23); 57 (95%) had good or excellent results. Deep infection was recorded in one patient. Kaplan-Meier analysis using infection and aseptic loosening as endpoints showed the survival rate at 20 years to be 94.0%. A reduction in infection, spontaneous haemarthrosis and improvement in the quality of life were noted to justify surgery in our series of patients with a mean age of 43 (25 to 70). We have found that using the latest techniques of continuous infusion of clotting Factor have significantly helped to reduce the complication rates and have achieved results which match those of the non-haemophilic population undergoing TKR.

Summary. The appearance and rapid evolution of BSE in UK cattle in the mid 1980s, with compelling data supporting variant Creutzfeldt–Jakob disease (vCJD) as its human manifestation, pose a potentially severe threat to public health. Three clinical cases and one asymptomatic case of vCJD infection have been reported in UK recipients of non‐leucodepleted red cell transfusions from donors subsequently diagnosed with vCJD. Plasma from both these and other donors who later developed vCJD has contributed towards plasma pools used to manufacture clotting factor concentrate. The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) Surveillance Study has detected asymptomatic vCJD postmortem in a haemophilic patient treated with UK plasma products including two batches of clotting factor linked to a donor who subsequently developed vCJD. Over 4000 bleeding disorder patients treated with UK plasma products are recorded on the UKHCDO National Haemophilia Database. The risk of vCJD transmission by plasma products is not known. However, public health precautions have been implemented since 2004 in all UK inherited bleeding disorder patients who received UK‐sourced plasma products between 1980 and 2001 to minimize the possible risk of onward vCJD transmission. We evaluate vCJD surveillance and risk management measures taken for UK inherited bleeding disorder patients, report current data and discuss resultant challenges and future directions.

The hip is considered to be one of the main load bearing joints of the body. In the haemophilic patient joint bleeds can be catastrophic, leading to long-term joint degeneration and accompanying arthritis. In this review we explore the mechanisms of joint destruction, with particular consideration of the anatomy of the hip and how it may influence disease progression. We also review current strategies for treatment including hip replacement in the haemophilic patient and describe our experiences as a unit. Finally we evaluate future prospects in the management of hip disease in haemophilia.

The ankle joint is well known to show early involvement in severe haemophilia. We describe a novel operative technique developed by the senior author. This combines a medial approach to the ankle, medial malleolar osteotomy, bone graft and compression with staples. All patients had excellent pain relief and improvement in function with 100% achieving bony union. There was a significant improvement in Mazur ankle scores following ankle fusion (P < 0.01). This surgical technique gives good results which are reproducible in this patient population.

HIV associated thrombocytopenia occurs in 5-10% of asymptomatic individuals, and 25-45% of people with AIDS. A variety of treatments are available but the inherited bleeding disorder in addition to the thrombocytopenia makes management in haemophiliacs a special problem. The management of this double coagulopathy is described in seven patients. IV gammaglobulin and steroids were useful only in the short term; zidovudine produced a good response, could be taken orally, had anti-HIV activity and was well tolerated in asymptomatic HIV positive patients. Interferon was an alternative when zidovudine was ineffective or produced intolerable side-effects. Splenectomy was considered only after failure of other treatments because of the increased risks of bleeding.

One hundred and eleven men with haemophilia at the Royal Free Hospital Haemophilia Centre, London, became infected with HIV between October 1979 and July 1985. This paper describes the incidence of HIV-related disease in this cohort in the absence of pre-AIDS treatment and assesses the effect of antiretroviral and prophylactic therapies on this. In particular the relationship between the CD4 count and the development of HIV-related disease is investigated. Before the introduction of pre-AIDS treatment in November 1988, 60 patients (54%) had developed some type of HIV-related pre-AIDS condition or AIDS, a cumulative incidence of 77% (95% Confidence Interval 63% to 91%) by nine years after seroconversion. The probability of developing such conditions was associated with falling CD4 lymphocyte counts and an estimated 51% of patients (95% Confidence Interval 38% to 63%) would be expected to develop some manifestation of HIV-related disease before their CD4 count has fallen to 0.2 x 10(9)/1. Consequently, only conditions which develop later in HIV infection (AIDS, oral candida, herpes tester) are likely to be influenced by treatment. Since November 1988, there has been a reduction in these conditions, although the reduction in the rate of new AIDS cases was small (P=0.16). The risk of developing oral candida has been reduced at low CD4 counts from 12 cases in 76 years of experience below 0.2 x 10(9)/1, prior to November 1988, to two cases in 81 years after November 1988, (P=0.005). Similarly, since that date no herpes tester infections were observed in our cohort.

Factor XI (FXI) deficiency is associated with bleeding after invasive procedures. Risks of human plasma-derived FXI replacement products include transfusion transmitted infection, thrombosis and fluid overload. This study was designed to test the hypothesis that recombinant factor VIIa (rFVIIa) is an effective haemostatic agent in patients with FXI deficiency undergoing surgery. Fourteen FXI deficient patients [five severely deficient (FXI:C <20 U dL(-1)) and nine partially deficient (FXI:C 20-70 U dL(-1)] received rFVIIa to prevent surgical bleeding during five major, four minor and six dental procedures. Minor surgical and dental procedures were covered with two doses of rFVIIa (90 microg kg(-1) i.v.), the first pre-operatively and the second 4 h postoperatively. Major surgery was covered with 90 microg kg(-1) i.v. two hourly for the first 24 h and four hourly for the second 24 h. Oral tranexamic acid was given for 7 days postoperatively. Effective haemostasis was observed in all cases and no alternative haemostatic agents or blood transfusions were required. Three adverse events were recorded; an acute cerebrovascular accident in a patient with a history of cardiovascular disease, an allergic reaction and local phlebitis. In this study, rFVIIa was an effective alternative to plasma-derived FXI replacement for the prevention of surgical bleeding in FXI deficient patients but rFVIIa may not be suitable for patients with pre-existing risk factors for thrombosis.

Twenty haemophiliacs (17 CDC group IV and 3 CDC group II) were treated with zidovudine for a median of 37 weeks (range 10-66). Eight (40%) tolerated zidovudine without a dose change. Two patients died and five patients (29%) developed opportunist infections. Haematological toxicity occurred in ten CDC IV patients (59%) but only one case of sepsis occurred in 101 episodes of documented granulocytopenia. Thrombocytopenia responded to treatment with zidovudine in four of five patients. It is concluded that zidovudine is beneficial for symptomatic haemophiliacs and although the haematological toxicity is high, it is mostly asymptomatic, reversible and well tolerated. Two of the three CDC II patients treated with zidovudine progressed to CDC IV, but had low initial T4 lymphocyte counts and were P24 antigen positive.

In the past, there were only minimal studies aimed at establishing the dose of concentrate required for treating an acute joint bleed in patients without inhibitors. The cost of treatment with bypassing agents consumes huge economic resources and therefore it is important to have rigorous studies to establish rational dosing. Both the FEIBA NovoSeven Comparative study and the comparative dosing study have been bold attempts to clarify treatment regimens for managing joint bleeds in patients with inhibitors. As a very challenging situation in which to conduct research, it is important that such endeavour continues.