FXI Deficiency Research Articles

Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study

AbstractPatients with hereditary rare bleeding disorders (RBDs) present with diverse hemorrhagic symptoms. Correlation between factor activity levels and clinical bleeding severity is poor for most RBDs. Threshold factor activity levels have been previously described in relation to bleeding severity but have not yet been validated. The Rare Bleeding Disorders in the Netherlands (RBiN) study is a nationwide cross-sectional study of patients registered in all 6 Dutch Haemophilia Treatment Centers with a known RBD and who are age 1 to 99 years. Bleeding scores were determined, and laboratory and clinical data were extracted from patient files. In all, 263 patients were included, of whom 202 (77%) attended the scheduled study visit. The median International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) score was 9. Correlations between baseline factor activity levels and ISTH BAT scores were strong for deficiencies in factor II (FII) (r = –0.792) and FX (r = –0.838) and were moderate for deficiencies of fibrinogen (r = –0.683), FV (r = –0.623), FVII (r = –0.516), FXIII (r = –0.516), and α2-antiplasmin (r = –0.594). There was no correlation for FXI deficiency (r = –0.218). The RBD BAT identified more women (94% vs 83%) and children (100% vs 71%) with an RBD than the ISTH BAT did. Importantly, 48% of patients had more severe bleeding than predicted for their baseline factor activity level. In addition, 34% of patients were predicted to be asymptomatic, but they actually had grade 2 (31%) or 3 (3%) bleeding. Bleeding severity in patients with RBDs is more pronounced than previously anticipated. The previously determined threshold factor activity levels to ensure no (spontaneous) bleeding in patients with an RBD are inaccurate. This trial was registered at www.clinicaltrials.gov as #NCT03347591.

How to Capture the Bleeding Phenotype in FXI-Deficient Patients.

Factor XI (FXI) is a serine protease involved in the propagation phase of coagulation and in providing clot stability. Several mutations in the F11 gene lead to FXI deficiency, a rare mild bleeding disorder. Current laboratory methods are unable to assess bleeding risk in FXI-deficient patients, because the degree of bleeding tendency does not correlate with plasma FXI activity as measured by routine coagulometric aPTT-based assays. Bleeding manifestations are highly variable among FXI-deficient patients and FXI replacement therapy can be associated with an increased thrombotic risk. A correct evaluation of the patient hemostatic potential is crucial to prevent under- or overtreatment. In recent years, different research groups have investigated the use of global coagulation assays as alternative for studying the role of FXI in hemostasis and identifying the clinical phenotype of FXI deficiency. This brief review article summarizes the main features of coagulation factor XI and its deficiency and resumes the principle axes of research and methods used to investigate FXI functions.

Postpartum haemorrhage in women with mild factor XI deficiency.

With the advent of direct-to-consumer genetic testing, mild factor XI deficiency is increasingly recognized. There are limited data regarding the risk of postpartum haemorrhage (PPH) among women with mild FXI deficiency following obstetrical delivery. To assess the risk of PPH among women with mild FXI deficiency undergoing vaginal or caesarean delivery. We conducted a retrospective, case-control study, in women with FXI levels between 20% and 70% of normal. For a control population, delivery outcomes were analysed in 200 women (between 2016 and 2018) without known bleeding disorders. There was no PPH among 45 vaginal deliveries in women with mild FXI deficiency compared with one PPH among 125 vaginal deliveries in the control cohort. The rate of PPH was significantly higher among the 26 caesarean deliveries in women with mild FXI deficiency relative to 75 control caesarean deliveries (odds ratio 2.73, 95% CI 1.02-7.26, P=.04). Prior history of haemorrhage was a strong predictor of PPH following caesarean delivery. All women who developed PPH following caesarean delivery had either a history of haemorrhage or independent risk factor for PPH. Due to the low rates of postpartum haemorrhage following vaginal delivery, routine prophylaxis to prevent postpartum haemorrhage in the setting of mild FXI deficiency does not appear warranted, especially in the absence of a bleeding history. Mild FXI deficiency is associated with an increased risk of PPH following caesarean delivery.

Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor

AbstractThe intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa–initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI−/− mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX−/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI−/− mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa–mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.

Inherited coagulation disorders in Turkish children: A retrospective, single-center cohort study

ObjectiveThis study aims to investigate the distribution, clinical characteristics and outcome of inherited coagulation disorders (ICD) in Turkish children. Subjects and methodsData from all children (age<18 years) with ICD examined in our center were retrospectively reviewed. ResultsThere were 403 children with ICD (233 males and 170 females) with a median age of four years at diagnosis. The percentages of von Willebrand disease (vWd), hemophilia and rare bleeding disorders (RBD) were 40 %, 34 % and 26 %, type-1, type-2 and type-3 vWd were 63 % 17 % and 20 %, hemophilia A and B were 84 % and 16 %, and severe, moderate and mild hemophilia were 48 %, 30 % and 22 %, respectively. Factor VII and FXI deficiencies were the most prevalent, comprising 56 % and 22 % of all children with RBD, respectively. Parental consanguinity rates were 72 % in type-3 vWd and 61 % in severe RBD. The overall prevalence of gastrointestinal bleedings was 4.5 % (18/403), intracranial bleeding (ICB) was 4.96 % (20/403), mortality from ICB was 30 % (6/20) and the overall mortality rate was 1.49 % (6/403). No life-threatening bleeding was seen during regular prophylaxis. Chronic arthropathy prevalence in severe hemophilia was 8 % with primary prophylaxis and 53 % with demand therap. Inhibitor prevalence was 14 % in hemophilia-A and 5 % in hemophilia-B. ConclusionsThese data show that vWd is the most common ICD, type-3 vWd and RBD are prevalent due to frequent consanguineous marriages and diagnosis of ICD is substantially delayed in Turkish children. Prophylactic replacement therapy prevents occurrence of life-threatening bleedings and reduces the development of hemophilic arthropathy.

Bleeding characteristics and management of minor surgeries in rare bleeding disorders: report from a Turkish Pediatric Hematology Center.

In this retrospective report the aim was to present the experience about bleeding characteristics and management of minor surgeries in rare bleeding disorders (RBDs). Twenty-six patients were included; with Factor (F) V, FV+VIII, VII, FXI deficiency and afibrinogenemia. Six of the patients were asymptomatic. Fifty-three percent of the patients suffered from mucosal bleeding. Life-threatening bleedings were observed only in the patients with afibrinogenemia and good hemostatic control could only be provided with plasma-derived (pd)-fibrinogen concentrate. Twelve of the patients had undergone 17 minor surgeries. In the patients with FVII and FXI deficiencies with plasma F:C activity between 20-47%, there was a history of uneventful tooth extractions, circumcisions and a pilonidal sinus operation performed without any replacement treatment, whereas one patient with plasma F:C activity of FVII 47% had a history of poor hemostatic control during an adeno-tonsillectomy operation. Although some of these patients were asymptomatic to be on the safe side, minor operations were performed with preoperative administration of one dose of (pd)-fibrinogen concentrate to one afibrinogenemia patient, recombinant active FVII (rFVIIa) to 2 FVII deficient patients and fresh frozen plasma (FFP) to 3 FXI deficient and 1 FVII deficient patients plus postoperatively tranexamic acid (TXA) for 5-7 days. Only with one dose of the replacement therapy just before surgeries good hemostatic control was achieved and none of them had bleeding neither during nor after the surgeries. We suggest that minor operations must be performed with preoperative replacement therapies plus 5-7 days of antifibrinolytics under close observation of the hematologist and the surgeon.

Spectrum of Bleeding Disorders In Pakistan: A Cross-Sectional Study

Abstract This is a cross-sectional study conducted to determine the frequency and spectrum of bleeding disorders in different regions of Pakistan and to improve facilities to cure them. Samples were collected from different regions of Pakistan. There bleeding presentation and history of the family were recorded. 435 patients were selected from the different regions of Pakistan; 318 male (73%) and 117 female (26%). Laboratory analysis included Prothrombin time, Activated partial thromboplastin time, Bleeding time, platelet counts and fibrinogen assay were performed. According to their results, vWF:Ag, vWF:RCo, inhibitor screening, Bethesda test, urea clot solubility test, and platelet aggregation test were performed to diagnosed bleeding disorders in patients. Out of 435 patients, 283 constitute CBD, 80 diagnosed with RBD, and 72 remain undiagnosed. Patients diagnosed with 52% hemophilia A, 1.4% with its inhibitor, 8.4% with hemophilia B, 0.35% with its inhibitor, 3.88% with VWD, 33.5%with its type III. A rare bleeding disorder is diagnosed in 80 subjects with 20% fibrinogen, 16.25% FXIII, 15% FVII, 11.25% FV, 10% vitamin k dependent factors, 8.25% GT, 5% FXII and epinephrine, 2.5% FII and FX and 1.25% FV + FVIII, BSS and FXI deficiencies. Clinical bleeding episodes varied in patients with respect to its deficiencies include gum bleeding, menorrhagia, hematoma, bruises, umbilical cord bleeding, hemorrhagia, and hemarthrosis. Study shows that hemophilia A is more frequent than hemophilia B. vWD type III has a higher prevalence. In RBD, fibrinogen deficiency is the most common, followed by FXIII, FVII, and FV respectively.

Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX.

FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

High Molecular Weight Kininogen but Not Factor XII Deficiency Attenuates Acetaminophen-Induced Liver Injury in Mice

Acetaminophen (APAP) toxicity is a common cause of acute liver failure (ALF). Dysregulation of coagulation is well documented in ALF patients. Recent reports indicate that small subset of ALF patients (~10%) exhibit spontaneous bleeding, while thrombotic complications are more frequent. Animal studies demonstrated that the inhibition of tissue factor-initiated thrombin generation attenuates APAP-induced liver injury in mice via both fibrin- and protease activated receptor 1-dependent mechanisms. Activation of FXII leads to two events: propagation of coagulation by activation of FXI (intrinsic pathway) and activation of plasma prekallikrein to kallikrein, with subsequent cleavage of high molecular weight kininogen (HK) into bradykinin (BK) and cleaved HK fragments (contact pathway). There is a growing interest in therapeutic targeting of FXII or FXI to prevent thrombosis, primarily because this goal may be attainable without incurring a significant bleeding risk. In this study, we evaluated if the intrinsic coagulation pathway contributes to the activation of coagulation and liver injury in a mouse model of APAP-induced ALF. We postulated that targeting FXII would attenuate coagulation and reduce liver injury without affecting hemostasis. In addition, FXII deficiency could provide a further protection by preventing activation of contact pathway and subsequent reduction of inflammatory response. We used 12 weeks old FXII, FXI, prekallkrein and HK deficient male mice and their respective WT controls. Mice were fasted for 16 hours followed by a single intraperitoneal injection of APAP (400 mg/kg) or sterile saline. Livers and plasma samples were collected 6 and 24 hours after injections. Hepatocellular necrosis was determined on liver sections stained with H&amp;E. Plasma levels of alanine transaminase (ALT- marker of liver injury), thrombin-antithrombin (TAT) complexes, plasmin-α2 antiplasmin (PAP) complexes and interleukin-6 were analyzed using commercially available assays. HK cleavage was determined using BK ELISA, Western blot, and mass spectrometry analysis. Consistently with previously published data, plasma levels of ALT, TAT and IL-6, as well as liver injury scores were significantly elevated in APAP-challenged mice compared to saline-injected WT mice at both 6 and 24 hours. Surprisingly, neither FXII, FXI, nor prekallikrein deficiency had statistically significant effects on any of these parameters in APAP-challenged mice at either time point. Interestingly, however, plasma levels of ALT were significantly attenuated in HK-/- mice (n=23-34) compared to HK+/+ (n=19-31) controls at both 6 (1278 ± 184 vs. 1850 ± 235 U/L; p&amp;lt;0.05) and 24 hours (1546 ± 302 vs. 3857 ± 493 U/L; p&amp;lt;0.01) after injection of APAP. The attenuation of liver injury was observed despite the lack of a significant effect on APAP-induced coagulation activation (plasma TAT levels [mean±SEM]: 72.9 ± 8.2 μg/L in HK+/+ vs. 70.8 ± 4.3 μg/L in HK-/-). HK deficiency also reduced plasma levels of IL-6 (75.8%; p&amp;lt;0.001), number of infiltrating neutrophils in liver (59.8%; p&amp;lt;0.001) and liver necrotic area (28.1%; p&amp;lt;0.001) 24 hours after APAP challenge. Importantly, the protective effects of HK deficiency were completely reversed by the injection of HK protein into APAP-treated HK-/- mice. It has been previously shown that plasminogen deficiency protects against APAP-induced liver injury. Indeed, APAP administration activated the fibrinolytic system in WT mice as demonstrated by increased plasma levels of active tissue plasminogen activator (19.5 fold; p&amp;lt;0.01) and PAP complexes (64.4 fold; p&amp;lt;0.01). Using Western blotting analysis, BK ELISA, and mass spectrometry analysis we demonstrated that plasmin efficiently cleaves HK in a buffer system as well as in mouse and human plasma. Importantly, plasmin mediated cleavage of HK resulted in the release of BK and generation of cleaved HK fragments. In summary, our data indicate that the extrinsic but not the intrinsic coagulation pathway drives the coagulation-mediated pathologies associated with APAP-induced liver injury in mice. HK contributes to the liver injury independently of thrombin generation. We propose that in APAP-challenged mice, HK cleavage and downstream hepatotoxicity, are mediated by plasmin rather than FXIIa-dependent generation of kallikrein. Disclosures McCrae: Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Key:Uniqure BV: Research Funding.

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

IntroductionFactor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. ObjectiveTo describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. Material and methodsA retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994–2014) without clinical selection. ResultsWe identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. ConclusionWomen with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects.

Potential of the Community Counts registry to characterize rare bleeding disorders.

Rare bleeding disorders (RBDs) comprise of heterogeneous coagulation factor deficiencies and platelet disorders that are underreported worldwide. First report on RBD data from United States haemophilia treatment center network (USHTCN). A national surveillance system for the federally recognized USHTCN developed in collaboration with the Centers for Disease Control and Prevention (CDC) and American Thrombosis and Haemostasis Network (ATHN) was queried for patients with RBDs. Patient counts were extracted from the HTC Population Profile (HTC PP) component including limited data on patients followed through the USHTCN, and from the Registry component, including patient authorized, detailed clinical data. The prevalence of RBDs in the United States was estimated based on the HTC PP data and compared to the expected national prevalence based on data extrapolated from Orphanet, an international registry. Based on the estimated prevalence of RBD in the overall 2017 US population, the cases in the HTC network were lower than expected for FI, FII, FX, and FV+FVIII deficiencies by 36%, 61%, 75% and 94%, respectively, and higher than expected for FXIII, FV, FVII, and FXI deficiencies by 7%, 14%, 33% and 185%, respectively. The proportion of RBD patients reported in the HTC PP, enrolled in the Registry, was 10.8%. There is a clear need to identify individuals with RBDs who could benefit from the comprehensive care provided in the USHTCN. In addition, increased enrolment of people with all RBDs in the Registry is needed to improve knowledge of treatment outcomes of patients with RBDs in the United States.

Impact of Deficiency of Intrinsic Coagulation Factors XI and XII on Ex Vivo Thrombus Formation and Clot Lysis.

The contributions of coagulation factor XI (FXI) and FXII to human clot formation is not fully known. Patients with deficiency in FXI have a variable mild bleeding risk, whereas FXII deficiency is not associated with bleeding. These phenotypes make FXII and FXI attractive target proteins in anticoagulant therapy. Here, we studied the mechanisms of fibrin clot formation, stability, and fibrinolytic degradation in patients with severe FXI or FXII deficiency. Thrombin generation was triggered in platelet-poor (PPP) and platelet-rich plasma (PRP) with the biological FXII trigger sulfatides. Intrinsic and extrinsic thrombus formation and degradation in whole blood were determined with rotational thromboelastometry (ROTEM). Clot formation under flow was assessed by perfusion of whole blood over collagen microspots with(out) tissue factor (TF). Thrombin generation and clot formation were delayed in FXII- and FXI-deficient patients triggered with sulfatides. In FXI-deficient plasma, this delay was more pronounced in PRP compared to PPP. In whole blood of FXII-deficient patients, clots were smaller but resistance to fibrinolysis was normal. In whole blood of FXI-deficient patients, clot formation was normal but the time to complete fibrinolysis was prolonged. In flow chamber experiments triggered with collagen/TF, platelet coverage was reduced in severe compared with moderate FXI deficiency, and fibrin formation was impaired. We conclude that quantitative defects in FXII and FXI have a substantial impact on contact activation-triggered coagulation. Furthermore, FXI deficiency has a dose-dependent suppressing effect on flow-mediated and platelet/TF-dependent clot formation. These last data highlight the contribution of particularly FXI to hemostasis.

PF334 EPIDURAL/SPINAL ANESTHESIA IN PREGNANT JEWISH ASHKENAZI WOMEN HETEROZYGOTES FOR FACTOR XI DEFICIENCY, A SINGLE CENTER PROSPECTIVE STUDY

Background:Factor XI deficiency is a rare bleeding disorder worldwide. The prevalence of heterozygous and homozygotes among Ashkenazi Jews is 8–9% and 0.22–0.53%, respectively. The severity of bleeding does not always correlate with plasma factor XI levels and many heterozygotes patients, with factor XI levels of 20–70 IU dl−1 are undiagnosed. Data regarding bleeding phenotype is scarce. Likewise, there is no consensus regarding safety of neuro‐axial anesthesia (epidural/spinal) in these women. During pregnancy, aPTT is shortened due to physiological changes of pregnancy such as elevation in factor VIII, while the level of factor XI remains stable. Thus, in Ashkenazi Jews there is no indication to test aPTT or factor XI levels before neuro‐axial anesthesia. We assume that up to 10% of the Ashkenazi Jewish women who had neuro‐axial anesthesia in our center each year undergo neuro axial anesthesia without knowing factor XI deficiency status.Aims:1. Assess the incidence of Jewish Ashkenazi women heterozygotes for factor XI deficiency who underwent neuro‐axial anesthesia in our center. 2. Asses the bleeding tendency, aPTT and thrombin generation in Jewish women of Ashkenazi descent with/without factor XI deficiency.Methods:Jewish women from Ashkenazi origin who underwent neuro‐axial anesthesia during labor in our center were recruited. After labor and signing an informed consent form, women were asked to complete the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for PT, aPTT, fibrinogen, factor XI and thrombin generation. Thrombin generation was tested on a fully automated coagulation analyzer using low concentration of tissue factor 0.3pM. Reduced factor XI was defined as below 70 IU dl−1. Patients were divided according to factor XI levels; group A &lt;70 IU dl−1 and group B ≥ 70 IU dl−1.Results:Between August 2017 and October 2018, 248 women were recruited. Of them 81% were of full Ashkenazi ethnicity. Group A included 39 (16%) women with median factor levels of 63 IU dl−1 (range: 32–69.6 IU dl−1) and group B included 209 women with a median of 96 IU dl−1 (range: 70.1–270 IU dl−1). Among group A, 20 women (51%) underwent neuro‐axial anesthesia in previous labors and 17 women (44%) underwent amniocentesis in the current pregnancy. No bleeding complications were noted in these procedures as well as in the present neuro‐axial anesthesia. Only 1 patient (group B) reported a family history of FXI deficiency. 240 women (97%) completed the BAT. There was no difference in bleeding history as reported in BAT between the 2 groups. 9 women (23%) from group A reported any bleeding complications (2 epistaxis, 1 menorrhagia, 6 postpartum hemorrhages (PPH);1 in the present labor) compared to 48 (23%) women from group B (including 13 women with PPH). Thrombin generation did not differ between the groups (Table 1). Although aPTT was within the normal range in all women, aPTT levels were significantly lower in group A compared to group B.Summary/Conclusion:A significant number of Jewish Ashkenazi women with undiagnosed partial FXI deficiency undergo neuro‐axial anesthesia. Bleeding phenotype does not differ between women with or without partial factor XI deficiency. Thrombin generation at delivery does not differ between women with or without factor XI deficiency, suggesting that hypercoagulability of pregnancy may compensate for factor XI deficiency and neuro‐axial anesthesia may be safe in these women.image

Influence of factor XII deficiency on activated partial thromboplastin time (aPTT) in critically ill patients

FXII deficiency results in spontaneous prolongation of activated partial thromboplastin time (aPTT), which is widely used to monitor thromboprophylaxis. Misinterpretation of spontaneously prolonged aPTT may result in omission of thromboembolic treatment or even unnecessary transfusion of blood products. This retrospective analysis was performed to calculate a threshold level of FXII resulting in aPTT prolongation. 79 critically ill patients with spontaneous prolongation of aPTT were included. A correlation analysis and a ROC curve for aPTT prolongation predicted by FXII level were created to find the FXII threshold level. Prolongation of aPTT was associated with disease severity. A significant inverse proportionality between FXII and aPTT was seen. A ROC curve for aPTT prolongation, predicted by FXII level (AUC 0.85; CI 0.76–0.93), revealed a FXII threshold level of 42.5%. Of our patients 50.6% experienced a FXII deficiency, in 80.0% of whom we found aPTT to be prolonged without a significantly higher bleeding rate. The FXII deficiency was more common in patients with higher SAPS3 scores, septic shock, transfusion of red blood cells and platelet concentrates as well as in patients receiving renal replacement therapy. Patients with a FXII deficiency and prolonged aPTT less often received anticoagulatory therapy although they were more severely ill. The rate of thromboembolic events was higher in these patients although the difference was not statistically significant. Of all patients with spontaneous aPTT prolongation 50.6% had a FXII level of 42.5% or less. Those patients received insufficient thromboembolic prophylaxis.

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

IntroductionFactor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. ObjectiveTo describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. Material and methodsA retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994–2014) without clinical selection. ResultsWe identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. ConclusionWomen with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects.

Heterozygous FXII deficiency is not associated with an increased incidence of thrombotic events: Results of a long term study

ObjectiveTo investigate the incidence of thrombotic events in patients heterozygous for FXII deficiency during a long observation period. Patients and methods103 heterozygotes for FXII deficiency, 49 female and 54 male were followed for 19.6 years (range 5–32 years). As controls 103 unaffected family members of same sex and similar age (±5 years) were enrolled. The thrombotic end points were: myocardial infarction, deep vein thrombosis and ischemic stroke.The mean Factor XII level in the heterozygotes was 48.5%: range (35–60%) that of control was 96.5% (range 70–155%).The heterozygotes showed one myocardial infarction, two deep vein thromboses and no ischemic stroke. The unaffected family members observed 2 myocardial infarctions, one deep vein thrombosis and one ischemic stroke.There were seven deliveries (five women) among the heterozygotes and six (five women) among the controls. Furthermore, four and five surgical procedures were carried out in the patient and in the control group, respectively.Immobilization times for surgical procedures or pregnancies were 50 days and 57 days for the heterozygotes and the unaffected family members, respectively.Heterozygotes for FXII deficiency did not show an increased incidence of thrombotic events as compared with unaffected family members during a long follow up.

Low endoscopy bleeding risk in patients with congenital bleeding disorders.

Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor (VWD) or recombinant factor (haemophilia A and haemophilia B), desmopressin and/or tranexamic acid. Our primary outcome was the 72-hour postendoscopy bleeding rate. One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders.

Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, potentiates coagulation function in factor XI‐deficient plasma in vitro

Essentials Emicizumab mimics factor (F)VIIIa cofactor function, augments the intrinsic tenase activity. We assessed the emicizumab-driven hemostatic function in FXI-deficient plasmas. Emicizumab improved the coagulation potentials in severe FXI-deficient plasma. Emicizumab may provide a possibility for clinical application in patients with FXI deficiency. SUMMARY: Background Patients with factor (F)XI deficiency commonly present with markedly prolonged activated partial thromboplastin times (APTT), although bleeding phenotypes are heterogeneous. Emicizumab, a bispecific monoclonal antibody to FIX/FIXa and FX/FXa, mimics FVIIIa cofactor function on phospholipid (PL) surfaces. Antibody reactions were designed, therefore, to augment mechanisms during the propagation phase of blood coagulation. Aim To assess emicizumab-driven hemostatic function in FXI-deficient plasmas. Methods and Results Standard ellagic acid (Elg)/PL-based APTTs of different FXI-deficient plasmas (n=13; FXI activity, <1IUdl-1 ) were markedly shortened dose dependently by the presence of emicizumab. To further analyze the effects of emicizumab, clot waveform analysis (CWA) in FXI-deficient plasmas with emicizumab, triggered by tissue factor (TF)/Elg demonstrated improvements in both clot times, reflecting the initiation phase, and coagulation velocity, which represents the propagation phase. Emicizumab also enhanced the TF/Elg-triggered thrombin generation in FXI-deficient plasmas dose-dependently although the degree of enhancement varied in individual cases. Thrombin generation with either FVII-deficient plasma or FIX-deficient plasma treated with anti-FXI antibody showed little or no increase by the co-presence of emicizumab, suggesting that the accelerated thrombin generation in FXI-deficient plasmas by emicizumab should depend on the FIXa-involved coagulation propagation initially triggered by FVIIa/TF. The exvivo addition of emicizumab to whole blood from three patients with severe FXI deficiency demonstrated modest, dose-dependent improvements in Ca2+ -triggered thromboelastograms (NATEM mode). Conclusion Emicizumab appeared to improve coagulation function in severe FXI-deficient plasma, and might provide possibilities for clinical application in patients with FXI deficiency.

906: FXI deficiency found on expanded carrier screening: A quandary in routine obstetric management

906: FXI deficiency found on expanded carrier screening: A quandary in routine obstetric management

Phenotypic and genetic analysis of two pedigrees affected with hereditary coagulation FXII deficiency

To carry out phenotypic and genotypic analysis for two Chinese pedigrees affected with coagulation factor XII (F XII) deficiency. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), and blood coagulation factor VIII, IX, XI, XII activity (FVIII:C, FIX:C, FXI:C, FXII:C) were determined with one stage clotting assay on a STAGO coagulation analyzer. FXII antigen was determined with an enzyme linked immunosorbent assay (ELISA). The 14 exons and their flanking sequences of the F12 gene were subjected to PCR amplification and Sanger sequencing. The conservation and structure of mutant protein were analyzed with MegAlign software and PYMOL software. The APTT of the probands was significantly prolonged, while their FXII:C and FXII:Ag were significantly reduced. Genetic analysis of the proband has revealed three novel mutations in the F12 gene, including g.5972G>A splice site mutation in intron 5, g.8810_8814delGTCTA in exon 14, and g.6259G>A (p.Pro182Leu) in exon 7. In addition, a previously known mutation IVS13-1G>A has been found. Four mutations have been identified in the two Chinese pedigrees, among which three were novel. Above mutations probably played a role in the defect of FXII in the two pedigrees.