The Use of Factor XI Concentrates (Hemoleven, LFB) in Patients with Congenital Factor XI Deficiency and a Known Bleeding Tendency.

Abstract Traditional treatment modalities for FXI deficiency (UK prevalence 400 cases) include antifibrinolytics, desmopressin, fresh frozen plasma (FFP) and FXI concentrates but there has been reluctance to use FXI concentrates because of reported incidence rates of thrombosis up to 10%. Concerns over the safety and efficacy of FFP, with additional viral inactivation steps possibly leading to reduced FXI recoveries, have led us to increase our use of FXI concentrates. We aimed to assess the indications, dosage, recovery, efficacy and safety of Hemoleven, a plasma derived, purified and virally inactivated FXI concentrate, which also contains heparin and antithrombin, in patients with congenital factor XI deficiency. A retrospective study was performed using hospital notes and laboratory records of all patients who had received Hemoleven over a 2-year period. Eleven patients (6 male, 5 female) had been treated with a median age of 38 years (range 7–74) and mean baseline FXI:C levels of 25.4U/dl (3–50). All patients received Hemoleven as prophylaxis for surgery or dental work and had all previously had excess bleeding when surgically challenged. One patient died of a condition unrelated to FXI treatment. Pre- and post-FXI:C levels were available for a total of 60 treatment episodes of which 25 were 1000-unit doses and 35 were 2000-unit doses. The mean increase in FXI:C per 1000-unit dose was 25.4 U/dl (12.4–43.9) while the mean increase in FXI:C per 2000-unit dose was 50.5 U/dl (11.8–106.5). This is consistent with the manufacturer’s data. Ten minute post infusion FXI:C levels were above the normal range (73–133 U/kg) in 8% of patients given 1000 units and 11% of patients given 2000 units but below the normal range in 24% of patients who received 1000 units and 20% of patients who received 2000 units. 90% of treatment episodes led to FXI:C levels above the usual treatment target of 65 U/dl. Genetic analysis of 9/11 patients showed that 2 were homozygous (one type II and one type III), 6 were heterozygous for other recognised mutations and one had no mutation identified but apparent absence of RNA from one allele demonstrated in a relative by qRT-PCR. No excess bleeding or inhibitor development was recorded even in one patient who had had a poor haemostatic response with FFP. There were no episodes of arterial or venous thrombotic complications within this group and no clinical or laboratory evidence of DIC following treatment. In summary, treatment with factor XI concentrates gave consistent increments in FXI:C at the doses given and achieved good haemostasis with no episodes of thrombosis in this study, even in patients over the age of 60y. While the risk of prion transmission is still unknown, use of FXI concentrates is not associated with the risks of fluid overload and TRALI that are seen with FFP. We acknowledge that the study includes small numbers of patients however the cohort of patients with a bleeding diathesis in this condition is small. We conclude that Hemoleven appears to be an effective and reliable treatment for patients with FXI:C deficiency but should be given in the context of FXI:C level monitoring in order to detect those patients who may develop high levels and possible thrombosis.

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Production and Therapeutic Use of a Factor XI Concentrate from Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648439 ◽

1992 ◽

Vol 67 (03) ◽

pp. 314-319 ◽

Cited By ~ 50

Author(s):

P H B Bolton-Maggs ◽

R T Wensley ◽

P B A Kernoff ◽

C K Kasper ◽

L Winkelman ◽

...

Keyword(s):

Parvovirus B19 ◽

Virus Transmission ◽

Liver Function Tests ◽

Fresh Frozen Plasma ◽

Bleeding Tendency ◽

Factor Xi ◽

Excessive Bleeding ◽

Human Donor ◽

Factor Xi Deficiency ◽

The Mean

SummaryFactor XI deficiency is an uncommon bleeding disorder usually manifested by excessive bleeding after surgery or trauma. Until recently the only effective therapy has been fresh-frozen plasma (FFP) infusion. We describe the efficacy and safety of a new factor XI concentrate produced from human donor plasma by a modification of the method used for antithrombin III concentrate. The mean recovery of factor XI in the circulation measured on 62 occasions was approximately 91% of the injected dose, and the mean half-disappearance-time was 52 h. The concentrate was used for 31 invasive procedures in 30 patients, including 16 patients who had a definite bleeding tendency on previous occasions, with normal haemostasis being achieved in all but 1. Only 1 patient (previously experiencing allergy to FFP) experienced adverse effects during infusion. Monitoring of liver function tests and viral antibody status in suitable patients has shown no evidence of transmission of hepatitis viruses, HIV-1 or parvovirus B19.We conclude that this concentrate provides effective treatment for patients with factor XI deficiency. Preliminary results suggest safety from virus transmission, but this needs to be established in further studies of previously untreated patients.

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Clinical and Biological Determinants of Bleeding Manifestation in Congenital Factor XI Deficiency; A Systematic Review

Blood ◽

10.1182/blood.v128.22.1407.1407 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1407-1407 ◽

Cited By ~ 1

Author(s):

Milana Drakulic ◽

Chatree Chai-Adisaksopha ◽

Alfonso Iorio

Keyword(s):

Gene Mutation ◽

Bleeding Tendency ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Risk Of Bleeding ◽

History Of ◽

Surgical Bleeding ◽

Bleeding Manifestation ◽

Baseline Factor ◽

Congenital Factor

Abstract Background: Congenital factor XI (FXI) deficiency is a rare inherited bleeding disorder caused by mutation of the FXI gene. Clinical manifestation and bleeding severity of FXI deficiency are varied. To our best knowledge, there are no studies investigating the predictors of bleeding in these patient population. Our study aims to investigate the clinical presentation of congenital FXI deficiency and to identify clinical, biological, and genetic determinants of bleeding. Methods: We conducted a systematic search in MEDLINE and EMBASE databases from inception to March 2016. We included the studies of congenital FXI deficiency. In terms of study design, we included prospective or retrospective studies as well as case series and case reports. We collected clinical characteristics of the patients including age, sex, family history of FXI deficiency, family history of bleeding, and site of bleeding. We also collected the laboratories including baseline aPTT, FXI level, and genetic test results. Results: There were 141 studies included in this review, involving 728 patients with reported congenital FXI deficiency. Forty-three percent of the patients were male. Clinical characteristics of the patients was demonstrated in Table 1. Of these, 421 (51.84%) patients had bleeding tendency. Surgical bleeding was the most common bleeding manifestation (31.88%), following bymucocutaneous bleeding (13.35%) and hypermenorrhea (9.11%). Factor XI gene mutation was found in 422 patients (57.97%). Type II mutation was the most common reported mutation (45.19%). With regards tozygosity of patients with gene mutation, 43.94% of patients had heterozygosity of factor XI gene mutation. Univariate analysis revealed that patients with baseline factor XI level less than 25% were associated with higher risk of bleeding (odd ratio 1.48 (95% confidence interval [CI]; 1.05 to 2.09). In addition, patients with combined mutation were at higher risk of bleeding when compared to patients with single mutation (odd ratio 2.83 (95% CI; 1.09-7.39). Conclusion: Our study found that patients with factor XI deficiency has mild bleeding manifestation. Half of the patients do not experience bleeding tendency. Surgical bleeding is the most common presentation in these patient population and likely to be the first bleeding symptom. Baseline factor XI level less than 25% is the predictor of bleeders as well as combined gene mutation. Table 1 Characteristics of patients with congenital factor XI deficiency Table 1. Characteristics of patients with congenital factor XI deficiency Disclosures No relevant conflicts of interest to declare.

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A Relatively Low Frequency of Bleeding in Patients with Severe Factor XI Deficiency Who Undergo Surgery Involving Tissues with Low Fibrinolytic Activity Supports on Demand Rather Than Prophylactic Use of Plasma.

Blood ◽

10.1182/blood.v106.11.4036.4036 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4036-4036

Author(s):

Ophira Salomon ◽

David M. Steinberg ◽

Uri Seligsohn

Keyword(s):

Fibrinolytic Activity ◽

Oral Surgery ◽

Low Frequency ◽

Fresh Frozen Plasma ◽

Bleeding Tendency ◽

Factor Xi ◽

Factor Xi Deficiency ◽

On Demand ◽

Number Of Patients ◽

Fresh Frozen

Abstract Severe factor XI (FXI) deficiency is an injury related bleeding tendency. Fresh frozen plasma (FFP) or FXI concentrate are usually used for achieving hemostasis in such patients undergoing surgery but this can lead to inhibitor formation in 33% of patients with FXI level <1 U/dL (Blood101:4783, 2002). Based on observations in a limited number of patients with severe FXI deficiency, we previously suggested that surgery at tissues with known fibrinolytic activity is accompanied by bleeding more frequently than in other sites (NEJM325:153, 1991). In this study we retrospectively assessed the frequency of post surgical bleeding in 165 unrelated patients with severe FXI deficiency who were not treated by hemostatic means. Criteria for bleeding included local hematoma, need for surgical arrest of bleeding, or use of blood components. Bleeding occurred in 7/57 (12.3%) patients operated at tisues with low fibrinolytic activity, and in 29/48 (60.4%) patients operated at fibrinolytic sites (Table). Bleeding following circumcision (a non-fibrinolytic site) was accompanied by bleeding only in 1/64 (1.6%) and following oral surgery in 55/110 patients (50%). The relatively low frequency of bleeding following surgery at non-fibrinolytic sites advocates on demand rather than prophylactic replacement therapy when such surgery is performed. SITE OF SURGERY N BLEEDERS % BLEEDERS Non-fibrinolytic Appendicectomy 22 1 1.6 Gastric 3 0 0 Cholecystectomy 5 1 20 Herniotomy 13 3 23 Hysterectomy 5 2 40 Orthopedic 9 0 0 Fibrinolytic Tonsillectomy 33 20 60.6 Nose 12 7 58.3 Prostatectomy 3 2 66.6 Circumcision 64 1 1.6 Oral Tooth extractions 100 49 49 Gum 10 6 60

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Thrombin Generation Test Can Predict Bleeding Tendency In Patients With Severe Factor XI Deficiency

Blood ◽

10.1182/blood.v122.21.3600.3600 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3600-3600 ◽

Cited By ~ 2

Author(s):

Tami Livnat ◽

Uriel Martinowitz ◽

Rachel Mansharov ◽

Zivelin Ariella ◽

Ophira Salomon

Keyword(s):

Thrombin Generation ◽

Prophylactic Treatment ◽

Conflicts Of Interest ◽

Peak Height ◽

Activity Level ◽

Bleeding Tendency ◽

Bleeding Disorders ◽

Normal Range ◽

Factor Xi ◽

Factor Xi Deficiency

Abstract Introduction Factor XI (FXI) is a rare bleeding disorder defined as severe deficiency when FXI activity level is less than 20IU/dL. Unlike hemophilia A or B, patients with severe FXI deficiency do not bleed spontaneously and their bleeding tendency is unpredictable and poorly correlated with FXI level. Therefore, almost all patients with severe FXI deficiency are being treated similarly unrelated to their inert bleeding tendency. Lately there is a growing interest in introducing global coagulation tests to assess the risk of bleeding in trauma patients as well as in patients with congenital bleeding disorders. Thrombin generation (TG) test is a global assay that can provide information regarding hemostasis in healthy individuals or in patients with congenital and acquired bleeding disorders. Our group had previously shown that recalcification induced TG is a useful tool to determine the optimal dose of recombinant factor VIIa for patients with severe FXI deficiency and inhibitors going through major surgery (Livnat et al. Thromb Haemost 2009). Aim In the present study we aimed to characterize the capability of TG to serve as an ideal tool to define upfront bleeders and non-bleeders among FXI deficient patients and find the optimal conditions of TG that could distinguish between bleeders and non-bleeders thus eventually leading to efficient personalized treatment. Methods Case control study composed of 16 unrelated patients with FXI levels range >1-8dL-1and 14 healthy controls. For TG assay blood was taken from all participants simultaneously in both buffered citrate and corn trypsin inhibitor (CTI) tubes after obtaining informed consent. TG was performed in platelet poor plasma (PPP) in the presence of 4 µM phospholipids and initiated by recalcification in the presence and absence of 1pM tissue factor (TF). Three TG parameters were analyzed: lag time, thrombin peak and endogenous thrombin potential (ETP). Results Table 1 summarizes FXI activity, FXI genotype, thrombin peak height and bleeding status (i.e, bleeding following challenges when prophylactic treatment was not given) of patients in the study group. As expected, FXI levels poorly correlated with bleeding tendency. Good correlation between FXI levels, bleeding tendency and TG peak height was found when blood was taken in citrated tubes and not in CTI containing tubes. While the normal range of peak height in recalcification-induced TG (without TF) was 421±161 nM, no TG was initiated with recalcification in PPP of FXI patients with less than 1%. FXI levels 2-4% were sufficient to induce TG with recalcification but thrombin peak height was remarkable lower in comparison to controls. In FXI levels above 5%, the thrombin peak height induced by recalcification varied between low to normal range. Interestingly, when TG was initiated by 1pM TF the TG peak of non-bleeders reached normal values (normal peak height in the presence of 1pM TF=411±121), while in the bleeders the peak was reduced unrelated to FXI levels (range 74-205). Conclusions In summary TG induced by recalcification in the presence of low TF but not when performed in CTI tubes may efficiently distinguish between bleeders and non-bleeders in FXI deficient patients going through major trauma unrelated to patients' FXI level. This observation permits to consider less aggressive prophylactic treatment to patients with reduced risk for bleeding thus lowering the risk of thrombosis due to over treatment. Disclosures: No relevant conflicts of interest to declare.

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Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study

Medicina Clínica ◽

10.1016/j.medcli.2019.01.029 ◽

2019 ◽

Vol 153 (10) ◽

pp. 373-379

Author(s):

Carlos Bravo-Perez ◽

Teresa Ródenas ◽

Julio Esteban ◽

Maria Eugenia de la Morena-Barrio ◽

Salam Salloum-Asfar ◽

...

Keyword(s):

Observational Study ◽

Retrospective Observational Study ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Caucasian Women ◽

Congenital Factor

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Congenital Factor XI Deficiency

Congenital Bleeding Disorders ◽

10.1007/978-3-319-76723-9_12 ◽

2018 ◽

pp. 291-306

Author(s):

Tahere Tabatabaei ◽

Akbar Dorgalaleh

Keyword(s):

Factor Xi ◽

Factor Xi Deficiency ◽

Congenital Factor

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Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study

Medicina Clínica (English Edition) ◽

10.1016/j.medcle.2019.01.042 ◽

2019 ◽

Vol 153 (10) ◽

pp. 373-379

Author(s):

Carlos Bravo-Perez ◽

Teresa Ródenas ◽

Julio Esteban ◽

Maria Eugenia de la Morena-Barrio ◽

Salam Salloum-Asfar ◽

...

Keyword(s):

Observational Study ◽

Retrospective Observational Study ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Caucasian Women ◽

Congenital Factor

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A G>A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.

Blood ◽

10.1182/blood.v106.11.1788.1788 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1788-1788

Author(s):

Michael J. Mitchell ◽

Letian Dai ◽

Anwar Alhaq ◽

Geoffrey F. Savidge

Keyword(s):

Base Change ◽

Clinical Severity ◽

Molecular Defect ◽

Polymorphism Analysis ◽

Bleeding Tendency ◽

Translation Efficiency ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Plasma Factor ◽

Exon 1

Abstract Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1. In a study of >120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G>A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G>T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C>G polymorphism. Analysis of >50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels. Purine-rich sequences, such as that in exon 1 affected by the −53 G>A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G>A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G>A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation. We speculate that the -53 G>A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.

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Correlation of a Condensed Bleeding Score with New Diagnosis of a Congenital Bleeding Disorder in Patients Referred to a Tertiary Centre

Blood ◽

10.1182/blood.v118.21.1226.1226 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1226-1226

Author(s):

Deepa Ranjani Jayakody Arachchillage ◽

Tina Biss ◽

John Hanley ◽

Kate Talks

Keyword(s):

Laboratory Tests ◽

Conflicts Of Interest ◽

Bleeding Disorder ◽

Bleeding Tendency ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Number Of Patients ◽

Abnormal Bleeding ◽

Bleeding Score

Abstract Abstract 1226 The performance and utility of a condensed bleeding score (Bowman et al, J Thromb Haemost., 2008;6:2062) in relation to the diagnosis of a congenital bleeding disorder in new referrals to a regional haemostasis clinic over an 8 month period is presented. Between November 2010 and June 2011, 50 patients over the age of 16 (median age, 31 years; range, 16–79), including 32 females, were referred for investigation of a possible congenital bleeding disorder following detection of abnormal coagulation results and/or presentation with a bleeding history. A bleeding score was performed as part of their initial assessment. 12(24%) patients were from local referral and 38(76%) patients were referred from other hospitals in the region for further investigation of a suspected bleeding disorder. Basic coagulation tests (activated partial thromboplastin time (APTT), prothrombin time Clauss fibrinogen and platelet count) were normal in the referred patients from other centres. 50% (6/12) of the local referrals were for investigation of a prolonged APTT detected on routine coagulation screening prior to major surgery. The median bleeding score was 6 with a range of −1 to 14 (Table 1). The presence of a congenital bleeding disorder was confirmed in 31 of the 50 patients (62%), including 19/31 (61%) of the female patients and 12/31(39%) of the males. Correlation of an abnormal bleeding score (score ≥ 4) with diagnosis of a congenital bleeding disorder was only seen for diagnosis of type 1 Von Willebrand Disease (VWD) (Table 2). Analysis of the cases with low scores and abnormal results identified two groups of patients; firstly, those who had not yet had a significant haemostatic challenge, and secondly, those in whom the abnormal coagulation results were explained by a non-haemostatically significant reduction in a coagulation factor level (e.g. FVII, 15%; dysfibrinogenaemia; F XII deficiency). These clinically insignificant laboratory abnormalities explain the discrepancy between the number of patients with abnormal laboratory tests (35) and the number of patients diagnosed with a congenital bleeding disorder (31).Table 1Bleeding score (range)Number of patients with normal lab resultsNumber of patients with abnormal lab results−1 to +1382–44105–74128–102311–1422Total1535Table 2DiagnosisNumber of patientsMedian bleeding scoreAge rangeType 1 VWD116 (4–10)17–51Type 2 VWD48 (5–13)17–36Factor XI123 (1–8)17–76Platelet function defect46 (2–9)17–57 Compared to previous reports the range of scores found with this assessment tool was narrow and could not exclude patients from further laboratory assessment. However the condensed bleeding score has only been validated prospectively for the diagnosis of type 1 VWD and all patients in this cohort who were diagnosed with type 1 VWD had an abnormal bleeding score (≥ 4). This observation supports the role of this scoring system in the assessment of patients for type 1 VWD. The use of the condensed bleeding score in assessing patients with suspected factor XI deficiency is difficult due to the lack of a phenotypic relationship between residual factor XI activity and a bleeding tendency. Furthermore, although factor XI deficiency is a rare congenital bleeding disorder in our cohort of patients 12/31(39%) were diagnosed with factor XI deficiency. This may explain the overall lack of correlation between bleeding score and diagnosis of a congenital bleeding disorder. Patients who have an abnormal bleeding score but normal laboratory tests need consideration of further investigations before concluding they are normal. The possibility of an acquired bleeding disorder should be considered. A thorough drug history is also important as one of the patients with a bleeding score of 14 was taking a non-steroidal anti-inflammatory drug. The use of the condensed bleeding score in the detection of congenital bleeding disorders other than type 1 VWD requires further validation in a larger number of patients. Disclosures: No relevant conflicts of interest to declare.

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