Guideline for the diagnosis and management of the rare coagulation disorders

The objective of this document is to guide diagnosis and management of patients with rare coagulation disorders (RCD). This document replaces the 2004 UK Haemophilia Centre Doctors' Organization (UKHCDO) rare coagulation disorders guideline (Bolton-Maggs et al, 2004a). The RCD are here defined as monogenic bleeding disorders caused by deficiency of a soluble coagulation factor or factors, other than von Willebrand disease (VWD), Haemophilia A or Haemophilia B. The RCD described in this document include heritable deficiencies of fibrinogen, prothrombin, factor (F) V, FVII, FX, FXI and FXIII, combined FV and FVIII deficiency and vitamin K-dependent coagulation factor deficiency. RCD are usually caused by recessive inheritance of unique or rare nucleotide variations in the genes encoding the coagulation factors or in proteins necessary for their post-translational processing. RCD are more common in ethnic groups in which consanguineous partnerships are common, because of the higher likelihood of homozygosity. Dysfibrinogenaemia and FXI deficiency may show autosomal dominant or recessive inheritance (Table 1). Heterozygous carriers of variations in other classically 'recessive' RCDs sometimes display bleeding symptoms. 1:1 million (AR) Unknown (AD) 1:1 million (AR) 1:30 000 (AD) The writing group was representative of UK experts in RCD. Evidence was gathered from primary English language publications identified in PubMed from 1990 using the disorder names and synonyms as index terms. Relevant reviews and other guidelines were also searched for informative primary publications. The writing group produced a draft guideline that was revised by consensus by the UKHCDO Advisory Group and the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH) and the BCSH Executive Committee. The guideline was then reviewed by a sounding board of 50 members of the British Society for Haematology (BSH) who have commented on its content and applicability in the UK setting. The strength of recommendations and quality of evidence are presented in GRADE format http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. Published descriptions of the RCD have historically comprised case reports or short series. However, initiatives, such as the European Network of Rare Bleeding Disorders (EN-RBD; Peyvandi et al, 2012a), the North American Rare Bleeding Disorders Registry (Acharya et al, 2004) and several disease-specific registries (Herrmann et al, 2006, 2009; Ivaskevicius et al, 2007; Bernardi et al, 2009) have improved understanding of the RCD. This has enabled the EN-RBD, under the auspices of the International Society of Thrombosis and Haemostasis to propose laboratory criteria of disease severity for most RCD (Table 1; Peyvandi et al, 2012a). Despite this progress, the clinical characteristics of many RCD remain incompletely documented and management is informed by open label observational studies and not randomized controlled trials. Therefore, the quality of most evidence considered in this guideline is moderate (B) or low (C) and most recommendations are weak (2). This document is intended to guide factor replacement or other therapies for most clinical scenarios. However, clinicians are expected to modify treatment plans according to the severity of individual bleeds or procedures and to the background bleeding phenotype of each case. Further guidance about laboratory evaluation, selection of therapeutic products and the management of women with RCD, including regional anaesthesia, is provided in previous UKHCDO or BCSH guidelines (Lee et al, 2006; Keeling et al, 2008). In common with other heritable bleeding disorders, the treatment and prevention of bleeding in the RCD requires general measures, such as avoiding high bleeding risk activities, selecting invasive procedures with the minimum bleeding risk and ensuring adequate communication of treatment plans developed by haemophilia centres with appropriate expertise. Consideration should be given to adjunctive treatments, such as topical pro-haemostatic agents and endocrine therapy for heavy menstrual bleeding (HMB; Keeling et al, 2008; Peyvandi et al, 2013). Tranexamic acid or other anti-fibrinolytics may be sufficient for HMB and for minor bleeds, particularly at sites such as the oropharyngeal mucosa. Tranexamic acid may also be a useful adjunct to factor replacement, but is relatively contraindicated for renal tract bleeding and in cases with high thrombotic risk. For the prevention of surgical or obstetric bleeding, oral or intravenous tranexamic acid should be administered no later than 2 h before surgery or delivery to ensure peak plasma levels at the time of haemostatic challenge. Tranexamic acid should be used cautiously with prothrombin complex concentrate (PCC) or FXI concentrate because of thrombosis risk (Bolton-Maggs et al, 1994; Kohler, 1999), although more recent experience of tranexamic acid in combination with activated PCC in haemophilia inhibitor patients suggests that thrombosis risk may be low (Tran et al, 2014). Tranexamic acid is not licensed for use in children and should be used with caution in neonates. Replacement therapies for the RCD include recombinant factor concentrates of FXIII A-subunit and activated FVII (FVIIa) and plasma-derived factor concentrates of fibrinogen, FVII, FX, FXI and FXIII (Table 2). If available, specific recombinant or virally inactivated plasma-derived factor concentrates should be used in preference to fresh frozen plasma (FFP) or cryoprecipitate. Riastap (Fibrinogen) CSL Behring NovoSeven (rFVIIa) NovoNordisk Factor X (FX) Bioproducts laboratories (Elstree, UK) Factor XI concentrate (FXI) Bioproducts laboratories Hemoleven (Factor XI) LFB (Les Ulis, France) NovoThirteen (rFXIII-A) NovoNordisk Fibrogammin (FXIII) CSL Behring PCC are plasma-derived concentrates that are available as 'four factor' products containing FII, FVII, FIX and FX and as 'three factor' products without FVII (Table 3; Keeling et al, 2008). PCC may be useful in prothrombin deficiency, vitamin K-dependent clotting factor deficiency and in FX and FVII deficiency if a specific factor concentrate is unavailable. The potency of most PCC is expressed as FIX activity units, but the activities of the other constituent coagulation factors may vary between products and product batches (Table 3). High or repeated doses of PCC have been associated with arterial and venous thrombosis, usually in cases with pre-existing risk factors (Kohler, 1999). Beriplex P/N PCC (FII, VII, IX and X) CSL Behring Octaplex PCC (FII, VII, IX and X) Octapharma Standard fresh frozen plasma NHS Blood and Transplant (Watford, UK) OctaplasLG Pathogen-reduced plasma Octapharma Pathogen reduced cryoprecipitate NHS Blood and Transplant FFP is the only currently available replacement therapy for FV deficiency and combined deficiency of FV and FVIII, but may be effective in other RCD in emergencies if a more specific replacement therapy is unavailable or if diagnosis is uncertain. Cryoprecipitate may be effective in fibrinogen or FXIII deficiency if a single factor concentrate is unavailable (O'Shaughnessy et al, 2004). Should FFP or cryoprecipitate be necessary, it is currently recommended that all cases with heritable bleeding disorders receive pathogen-reduced products (Keeling et al, 2008). This requires virus inactivation either by methylene blue and light (MB-FFP) or solvent detergent (SD-FFP) treatments during manufacture, which may reduce FV, FVIII, FXI and fibrinogen content (Table 3; Williamson et al, 2003). Single donor MB-FFP supplied by UK NHS Blood and Transplant (NHS-BT) is currently quality controlled for FVIII activity (Williamson et al, 2003). The SD-FFP product Octaplas LG® (CSL Behring, Marburg, Germany) has mean FV, FVIII and FXI activities of 0·7–0·9 iu/ml and is quality controlled to ensure activities exceed 0·5 iu/ml (Table 3). The activities of other coagulation factors in SD-FFP are 0·8–1·0 iu/ml. As SD-FFP is prepared from pooled plasma donations, there is less variation in factor activities compared to single donor MB-FFP. MB-cryoprecipitate supplied by NHS-BT has an average fibrinogen content of 250 mg/unit and a minimum of 140 mg/unit. There are limited data describing the pharmacokinetics of coagulation factors administered via FFP or cryoprecipitate (Inbal et al, 1993; Horowitz & Pehta, 1998). Achieving therapeutic levels of coagulation factors, particularly with FFP, may be practically difficult because of the low starting concentration of factors in this product. Fibrinogen deficiency (F1D; MIM #202400) is an autosomal recessive or dominant disorder in which quantitative (afibrinogenaemia or hypofibrinogenaemia) or qualitative (dysfibrinogenaemia) defects in the fibrinogen Aα, Bβ or γ protein chains lead to reduced functional fibrinogen. Hypodysfibrinogenaemia describes F1D with both quantitative and qualitative fibrinogen defects. Afibrinogenaemia has an estimated prevalence of one in 1 000 000 (Mannucci et al, 2004). There are no reliable estimates of the prevalence of dysfibrinogenaemia. Fibrinogen is a complex glycoprotein comprising pairs of Aα, Bβ and γ chains and is the major ligand for the platelet αIIBβ3 integrin during platelet aggregation. Partial proteolysis of fibrinogen by thrombin enables polymerization to form fibrin clot (Weisel & Litvinov, 2013). Fibrinogen also has an anticoagulant effect, possibly by sequestering free thrombin, and contributes to fetal implantation and wound healing. Afibrinogenaemia is caused by variations in the FGA, FGB and FGG genes, which encode the fibrinogen Aα, Bβ and γ chains, respectively. Afibrinogenaemia is associated with homozygous or compound heterozygous mutations and hypofibrinogenaemia is usually linked with heterozygous mutations (de Moerloose et al, 2013). Dysfibrinogenaemia is usually associated with heterozygous mutations in FGA, FGB or FGG, clustered within specific functional domains (Haverkate & Samama, 1995; Miesbach et al, 2010; Shapiro et al, 2013). Some FGA variations cause hereditary renal amyloidosis, which is not associated with abnormal haemostasis (Gillmore et al, 2009). In 106 cases with afibrinogenaemia or hypofibrinogenaemia in US, Iranian and Indian registries, the most common symptoms were mucocutaneous, soft-tissue, joint, genitourinary, traumatic and surgical bleeding and HMB (Peyvandi & Mannucci, 1999; Acharya et al, 2004; Viswabandya et al, 2012). Intracranial bleeding was reported in 5% of registry cases. Similar symptoms and frequent umbilical bleeding were reported in 65 cases in Iranian and Palestinian case series (Fried & Kaufman, 1980; Lak et al, 1999) and in an international survey of 100 cases (Peyvandi et al, 2006). Arterial and venous thrombosis, poor wound healing and splenic rupture are rare features of afibrinogenaemia and hypofibrinogenaemia (de Moerloose et al, 2013). Some types of hypofibrinogenaemia are associated with liver disease because of retention of abnormal fibrinogen in hepatocytes (Brennan et al, 2000). In 26 cases with afibrinogenaemia or hypofibrinogenaemia in the EN-RBD registry, cases with severe bleeding had fibrinogen activity <0·9 g/l and asymptomatic cases had fibrinogen activity 0·2–2·0 g/l determined by the Clauss assay (Peyvandi et al, 2012a). Afibrinogenaemia and usually hypofibrinogenaemia manifest as prolonged prothrombin (PT), activated partial thromboplastin (APTT) and thrombin clotting (TCT) times and absent or reduced fibrinogen activity determined by the Clauss assay. There is a concordant reduction in fibrinogen antigen determined by immunoassay, gravimetric assays or by measurement of dry clot weight (Cunningham et al, 2002; Mackie et al, 2003). Assays that measure total clottable fibrinogen are an alternative that may assist diagnosis of F1D subtypes (Mackie et al, 2003). Acquired hypofibrinogenaemia is a feature of many acquired coagulopathies and can usually be distinguished from F1D on clinical grounds. Fibrinogen replacement with plasma-derived fibrinogen concentrate (Table 2) may be required to treat or prevent bleeding in F1D. In afibrinogenaemia, the recovery of fibrinogen activity after infusion of fibrinogen concentrate was 0·018 g/l per mg/kg and the half-life was 80 h, but it was shorter in children aged <16 years (Manco-Johnson et al, 2009). Therefore, a typical dose of fibrinogen concentrate of 4–6 g is expected to increase plasma fibrinogen activity by 1·0–1·5 g/l in a 70 kg adult. In a review of case reports (Bornikova et al, 2011) and in a questionnaire survey of physicians treating F1D (Peyvandi et al, 2006), fibrinogen concentrate 50–100 mg/kg every 2–4 d, to achieve fibrinogen activity >1·0–1·5 g/l was usually sufficient to treat or prevent spontaneous or surgical bleeding. Higher and more frequent dosing was required in children and in cases with severe bleeds or having major surgery (Peyvandi et al, 2006; Bornikova et al, 2011). Venous or arterial thrombosis occurred in 30% of cases in the case report series, most with afibrinogenaemia (Bornikova et al, 2011). In an open label prospective study, fibrinogen concentrate was effective in 26 bleeds and 11 surgical procedures in 12 cases with F1D. Venous thrombosis occurred in one case with other thrombotic risk factors (Kreuz et al, 2005). Fibrinogen isoantibody formation has not been reported in F1D. Pathogen-reduced cryoprecipitate has greater variation in fibrinogen content than fibrinogen concentrate and may be associated with transfusion reactions or volume overload (Table 3: O'Shaughnessy et al, 2004). A typical dose of 10–20 units (500–1000 ml) of MB-cryoprecipitate is expected to increase fibrinogen activity by 0·6–1·2 g/l in a 70 kg adult. The efficacy of cryoprecipitate is similar to that of fibrinogen concentrate (Peyvandi et al, 2006). Afibrinogenaemia may present with intracranial haemorrhage and umbilical bleeding (Lak et al, 1999; Peyvandi & Mannucci, 1999). Fibrinogen activity determined by the Clauss assay was reduced and the TCT prolonged in the healthy newborn compared to adults in some (Reverdiau-Moalic et al, 1996) but not other (Andrew et al, 1987) studies. This may be because the high sialic acid content of fetal fibrinogen affects some fibrinogen activity and TCT tests (Barr, 1978; Ignjatovic et al, 2011). Although diagnosis of afibrinogenaemia is straightforward on cord or neonatal blood samples, diagnosis of hypofibrinogenaemia requires comparison of test results with neonatal reference intervals and on re-testing at 3–6 months. Successful long-term prophylaxis with cryoprecipitate (Rodriguez et al, 1988; Peyvandi et al, 2006) or fibrinogen concentrate (Parameswaran et al, 2000; Kreuz et al, 2005; Peyvandi et al, 2006) has been reported in cases with afibrinogenaemia associated with intracranial bleeding. Typical regimens comprised fibrinogen concentrate 18–120 mg/kg, once per week to give trough fibrinogen activity of 0·5–1·0 g/l (Parameswaran et al, 2000; Peyvandi et al, 2006). Fibrinogen activity increases during normal pregnancy (Stirling et al, 1984). However, this does not prevent potential complications such as venous thrombosis, pregnancy loss, ante-partum haemorrhage (APH) and post-partum haemorrhage (PPH) in women with afibrinogenaemia and hypofibrinogenaemia (Goodwin, 1989; Dupuy et al, 2001; Roque et al, 2004; Kadir et al, 2009). Fibrinogen replacement helps maintain pregnancy and reduces bleeding. However, reports indicate that fibrinogen concentrate 5–30 g per week in 2–3 divided doses to maintain fibrinogen activity >0·6–1·0 and >1·5 g/l at delivery and post-partum does not prevent all pregnancy complications (Bornikova et al, 2011), possibly because these trough levels are inadequate. Higher doses of fibrinogen concentrate are required to maintain fibrinogen activity as pregnancy progresses (Roque et al, 2004). In a review of 250 reported cases with dysfibrinogenaemia, 53% were asymptomatic and 26% had bleeding that was typically mucocutaneous, traumatic or surgical (Haverkate & Samama, 1995). The remaining 21% of cases had venous or arterial thrombosis (Haverkate & Samama, 1995). Similar symptoms were reported in a series of 93 cases with dysfibrinogenaemia in which incidental diagnosis after routine coagulation tests or thrombophilia screens was also common (Miesbach et al, 2010; Shapiro et al, 2013). Thrombosis and bleeding may co-exist in the same case (Haverkate & Samama, 1995). Dysfibrinogenaemia may manifest as a prolonged PT and/or APTT depending on test reagent and methodology. The TCT and reptilase time are usually prolonged and there is a reduction in the Clauss fibrinogen activity, typically to 0·1–0·8 g/l. Some rare variants are associated with a shortened TCT (Cunningham et al, 2002; Mackie et al, 2003). As dysfibrinogenaemia is associated with a selective functional defect in fibrinogen activity, fibrinogen antigen or total clottable fibrinogen are not reduced. There is no association between fibrinogen activity and clinical phenotype in dysfibrinogenaemia, but some genotypes correlate with either bleeding or thrombosis (Haverkate & Samama, 1995). The PT-derived fibrinogen assay is not suitable for evaluation of dysfibrinogenaemia (Mackie et al, 2003). There are individual reports of cases with haemorrhagic dysfibrinogenaemia receiving fibrinogen concentrate (Kreuz et al, 2005). Thrombotic dysfibrinogenaemia has been managed with low molecular weight heparin for thromboprophylaxis and with coumarin anticoagulation for long-term prevention of thrombosis. Fibrinogen concentrate may have an anti-thrombotic effect by increasing the proportion of normal circulating fibrinogen molecules compared to endogenous thrombotic variant molecules. However, any therapeutic effect may be offset by the increased absolute fibrinogen concentration after concentrate infusion. There are no available data to guide optimum dosing of fibrinogen concentrate in thrombotic dysfibrinogenaemia. Women with dysfibrinogenaemia experience similar pregnancy complications to women with hypofibrinogenaemia. There are isolated case reports suggesting that these may be prevented by fibrinogen replacement throughout pregnancy (Yamanaka et al, 2003). Prothrombin (FII) deficiency (F2D; MIM #613679) is an autosomal recessive disorder in which reduced plasma prothrombin activity is caused by quantitative (hypoprothrominaemia) or qualitative (dysprothrombinaemia) defects in the FII protein. F2D has an estimated prevalence of one in 2 000 000 (Mannucci et al, 2004). FII is activated to the serine protease thrombin by activated FX in the initiation phase of coagulation, and by the prothrombinase complex in the amplification phase. Thrombin back-activates other coagulation factors and platelets and enables fibrin generation (Roberts et al, 2006). F2D is caused by variations in the F2 gene which encodes FII. There is a poor association between F2 genotype and clinical phenotype (Lancellotti et al, 2013). In 43 cases with F2D in the US, Iranian and Indian registries, the most common symptoms were mucocutaneous, soft tissue, joint and surgical bleeding and HMB. Less common symptoms were gastrointestinal, obstetric and umbilical bleeding. Intracranial haemorrhage was reported in of registry cases (Peyvandi & Mannucci, 1999; Acharya et al, 2004). Similar symptoms were reported in a survey of 26 case reports et al, 1998). Bleeding caused by F2D in was more severe in cases with FII activity iu/ml than in with FII activity iu/ml who typically bleeding (Acharya et al, 2004). In there is a poor association between clinical and laboratory et al, 2000). Heterozygous F2D carriers have FII activities of iu/ml and are typically asymptomatic et al, 1998). F2D as of the PT and APTT and reduced FII activity determined by although test results may vary by FII determined by immunoassay, is necessary to and et al, et al, 2000). assays that and may some variants et al, Acquired FII deficiency may in which is distinguished from F2D on clinical PT and APTT studies and the of et al, 2012). FII replacement with PCC may be required to treat or prevent bleeding in PCC FIX and FII activities and show FII activity recovery of iu/ml per and a half-life of h (Table 1; et al, Therefore, a typical therapeutic dose of PCC is expected to increase plasma FII activity by iu/ml. Similar doses at 2–3 intervals may be necessary for treatment 1999). If PCC is pathogen-reduced FFP is expected to increase plasma FII activity by FII have not been reported in Intracranial and umbilical bleeding may be features of F2D et al, 1999; et al, 2000). FII activity is iu/ml in healthy and at (Andrew et al, Therefore, diagnosis of F2D at delivery requires comparison of test results with neonatal reference intervals or after routine of vitamin and at re-testing There is limited experience of prophylaxis in PCC every has been reported as effective in case reports & FII activity does not during normal pregnancy (Stirling et al, and usually for delivery in women with severe pregnancy and were identified in case series of in women with F2D et al, Peyvandi & Mannucci, 1999). had comprised PCC during et al, Factor deficiency MIM is an autosomal recessive disorder in which reduced plasma FV activity is caused by quantitative qualitative defects in the FV protein. has an estimated prevalence of one in 1 000 000 (Mannucci et al, 2004). FV is in hepatocytes and in plasma and in platelet FV is activated by thrombin or activated FX to form a for activated FX in the prothrombinase complex (Roberts et al, 2006). is associated with variations in the gene that encodes FV, which usually FV & 2013). There is a poor between genotype and the clinical phenotype of In cases with in the US, Iranian and Indian registries, the most common symptoms were mucocutaneous, soft-tissue, surgical and traumatic bleeding and HMB. Less common symptoms were joint, genitourinary, and umbilical bleeding (Lak et al, Peyvandi & Mannucci, 1999; Acharya et al, 2004; Viswabandya et al, 2012). Similar symptoms were reported in series of cases et al, 2009; et al, 2011). Intracranial bleeding occurred in of registry cases and may be a feature of et al, 2000; et al, 2013). Bleeding caused by was more severe in registry cases with FV activity iu/ml than in with FV activity iu/ml who were typically asymptomatic or had mucocutaneous, surgical bleeding and HMB (Acharya et al, 2004; et al, 2009; Viswabandya et al, 2012). In 50 cases with in the EN-RBD registry, cases with severe bleeding had FV activity iu/ml and asymptomatic cases had FV activity iu/ml (Peyvandi et al, There are reports of and intracranial bleeding in cases with FV activity iu/ml (Lak et al, et al, a poor association between clinical and laboratory Heterozygous carriers have FV activity of iu/ml and are typically asymptomatic (Acharya et al, 2004). as of the PT and APTT and reduced FV activity determined by one assay. FV antigen determined by is required to qualitative from quantitative et al, 1995). FV have been reported after FFP treatment in et al, 2000; et al, and after to FV in topical thrombin in cases without & 2011). Acquired FV deficiency may be distinguished from by PT and APTT studies 1999). As there is currently no FV FV replacement with FFP may be required to treat or prevent bleeding in Pathogen-reduced FFP has been recommended for replacement therapy in although FV activity may be than FFP (Keeling et al, 2008). SD-FFP has FV activity of 0·7–0·9 iu/ml and less variation than single donor MB-FFP (Table 3). In an open label of treatment in SD-FFP increased FV activity by iu/ml and was effective for the treatment of spontaneous or traumatic bleeds and the prevention of surgical bleeds & Pehta, 1998). The half-life of FV activity after FFP infusion was h et al, & 2013). concentrates are an alternative of FV that have been used in combination with SD-FFP SD-FFP was et al, recombinant factor (rFVIIa) was effective in cases with to FFP et al, 2005; et al, with FV et al, or to volume overload et al, 2008). FV in have been using of FFP et al, or intravenous et al, transfusion was effective in acquired FV deficiency not to et al, A specific FV concentrate is currently in clinical Intracranial bleeding is reported in with usually with FV activity iu/ml et al, 2013). FV activity has a of in healthy which increases within 1 week (Andrew et al, of at delivery requires comparison of test results with neonatal reference intervals and at re-testing at months. prophylaxis with SD-FFP has been reported in with bleeding or FV activity iu/ml with FFP et al, 2000; et al, 2012). FV prophylaxis is practically difficult and may be limited by and particularly in neonates. In cases with severe it is to maintain trough FV activity using FV activity does not during normal pregnancy (Stirling et al, and is usually for delivery in women with severe was associated with in an Iranian case series (Lak et al, and in a review of in women with et al, of FFP for to maintain FV activity iu/ml and have been reported as effective in bleeding at delivery in women with et al, 2005; et al, Factor deficiency MIM is an autosomal recessive disorder in which reduced plasma FVII activity is caused by quantitative or qualitative defects in the FVII protein. has an estimated prevalence of one in 000 (Mannucci et al, 2004). of FVII as and as activated FVII which factor at sites of blood then from FVII and FX and FIX to low thrombin generation in the initiation phase of coagulation (Roberts et al, 2006). is caused by rare variations in the gene that encodes FVII (Herrmann et al, 2009). variations in the and in 30% of some and FVII activity et al, may cause clinical and laboratory in the phenotype of patients with but are to reduce FVII activity to levels associated with bleeding. In cases in the registry, the most common symptoms were mucocutaneous, soft tissue, joint and bleeding and HMB. Intracranial bleeding was reported in of cases et al, 2009; et al, 2009). Similar symptoms were reported in cases with in US, Iranian and Indian registries, although intracranial bleeding was reported in (Peyvandi & Mannucci, 1999; Acharya et al, 2004; Viswabandya et al, 2012). of cases in the and registries were asymptomatic and were identified after an abnormal PT test (Acharya et al, 2004; et al, 2009). of venous thrombosis in have et al, 2012). bleeding was more in registry cases with FVII activity iu/ml than with FVII activity iu/ml who typically had bleeding or were asymptomatic et al, 2009; Viswabandya et al, 2012). In cases with in the EN-RBD registry, cases with severe bleeding had FVII activity iu/ml and asymptomatic cases had