Abstract A nurse at Israel’s National Hemophilia Center for over 35 years, Dalia reflects on lifelong relationships with patients and the ‘family approach’ to care in the context of her experience of caring for a woman with severe haemophilia A. Having cared for the patient since she was a young child, Dalia describes the difficulties she has faced and the importance of ongoing conversations about her life in shaping her care, including risks around pregnancy and having a child. The patient went on to have a son by caesarean section, covered by factor VIII and tranexamic acid; her son was diagnosed with severe haemophilia A at birth and Dalia now sees them both in clinic. The patient also contributes her view on the importance of the close therapeutic relationships she has with Dalia. While acknowledging the importance of setting boundaries, Dalia reflects on the role of the haemophilia centre as an extension of the patient’s family and the nurse as a ‘mother’ figure. She feels the centre’s family approach is reflected not only in the care team’s knowledge of their patients but also through close and effective working relationships between staff, built on experience sharing, discussion and mutual support. Dalia believes it is this combination that has made her centre so successful in its involvement in clinical trials.

Introduction Emicizumab (Hemlibra (TM)) is approved for prophylaxis of Haemophilia A (HA) patients with and without inhibitors. However, real-world data on emicizumab use in the elderly HA patients with concomitant cardiovascular risk factors are lacking. Aim To evaluate the safety and efficacy of emicizumab in a real-world cohort of elderly HA patients. Methods A prospective longitudinal observational study on HA patients over 50 years old treated, followed and monitored during emicizumab prophylaxis was conducted. We documented any bleeding or adverse events and collected plasma samples for emicizumab levels, aPTT and thrombin generation (TG). Results Seventeen HA patients (2 with inhibitor), whose median age was 62.4 years (range: 51.5-77.1) composed the cohort, including 9/17 with multiple cardiovascular risk factors (high risk group). Seven patients had chronic HIV infection. The median follow-up of our cohort was 400 days (range 89-805, IQR 211-479 days). The median annualized bleeding rate (ABR) significantly decreased for all patients. Among patients who displayed significant bleeding tendencies, emicizumab steady state levels as well as TG were lower as compared with the group. The ABR of four patients concomitantly treated by antiplatelet agents was significantly higher compared with the rest of the cohort. Neither thrombosis nor thrombotic microangiopathy (TMA) was encountered. Conclusions Emicizumab prophylaxis for HA patients older than 50 years including those with cardiovascular risk factors was well tolerated. As lower emicizumab and TG levels were observed among bleeding patients, we suggest that monitoring laboratory assays could be of value within this age group.

Introduction: Real-world data on prophylaxis of severe haemophilia A (HA) patients treated by emicizumab are scarce. Aim: To study the efficacy and safety of longitudinal emicizumab prophylaxis and assess laboratory monitoring correlations in a large patient cohort. Methods: HA patients with and without FVIII inhibitors, initiating emicizumab prophylaxis, were prospectively enrolled. Bleeding, adverse events and surgeries were documented. FVIII inhibitors, emicizumab levels and thrombin generation ( TG) were sequentially measured. Results: A total of 107 patients, including 58 children (whose median (IQR) age was 6 (1-11) years) with severe HA, composed the study cohort. Twenty-nine per cent (31/107) of our HA patients had FVIII inhibitors. Patients were followed for a median of 67 weeks (up to 144 weeks). Fifty-three patients, whose median follow-up was 53 weeks, experienced zero bleeds. Most bleeds (94%) among children were trauma-related, whereas 61% of adults sustained spontaneous joint bleeds. Four patients experienced major bleeds, with a fatal outcome in one infant, who also presented with central venous line thrombosis. No other serious adverse events were encountered. Seven patients have decided to stop emicizumab treatment for various reasons. Emicizumab plasma levels increased after emicizumab prophylaxis initiation, and values were maintained during follow-up, in all but one patient, suspected of anti-drug antibodies. A significant reduction of FVIII inhibitor levels was noted among inhibitor patients. TG was increased and sustained yet could not prognosticate bleeding risk. Conclusion: Emicizumab prophylaxis was mostly well tolerated, although 50% of patients experienced breakthrough bleeds. Routine TG monitoring is not obligatory, and further studies are warranted in selected patient populations.

Aim Very little is known regarding reproductive choices, pregnancy, and delivery of women with moderate to severe hemophilia. Our aim was to describe our experience with three hemophiliac women and their journey to achieve motherhood. Methods Medical charts of women with moderate to severe hemophilia A treated at our center were evaluated. Data regarding choices of conception, pregnancy course, mode of delivery, and pregnancy outcomes were obtained. Results Three women are presented. Whereas patient 1 chose to adopt her first child and later had twins through egg donations and a surrogate mother, patient 2 underwent spontaneous pregnancy and delivered via cesarean section. Patient 3 preferred in vitro fertilization and preimplantation genetic diagnosis to avoid hemophilia and hemophilia carriership in her offspring. Conclusion The appropriate means to achieve parenthood for women with moderate to severe hemophilia should be individualized and requires support of a comprehensive multidisciplinary team.

Severe Von Willebrand's disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. In severe VWD, factor VIII (FVIII) levels are low due to rapid clearness. Emicizumab is a humanized bispecific antibody which mimics the function of coagulation factor VIII (FVIII). It has been approved for prophylaxis in hemophilia A. This is the first study assessing the potential role of emicizumab as an alternative prophylactic treatment in a cohort of patients with severe VWD. We present a TG model evaluating patients' hemostasis following ex vivo spiking of their plasma samples with emicizumab. We also report 24 weeks of successful emicizumab prophylaxis in a child with severe VWD and repeated hemarthroses. A cohort of twenty-four VWD patients were included in the study. Fifty-four percent of our patients were males and the cohort consisted of 14 children (≤18 years) and 10 adults. The majority of patients (96%) were of Caucasian origin. Hemarthrosis was encountered in most type 3 VWD patients, whereas none of the type 2 VWD patients had any joint bleeds. Prophylactic treatment was administered in the majority of type 3 VWD patients, whereas type 2 VWD patients largely required only intermittent on demand therapy applied for bleeding episodes or any surgical interventions. Thrombin generation analysis was carried out blindly in plasma obtained from thirteen type 3 VWD patients and eleven type 2 VWD patients. Seventeen healthy volunteers served as a control group. In plasma from type 3 VWD patients, TG was substantially lower than in plasma from type 2 VWD patients, with ETP of 765 nM×min (596-962) vs. 1954 nM×min (1483-2008) (P = 0•001) and peak height of 47 nM (36-65) vs. 262 nM (142-318) (P = 0•002) In order to examine the potential use of emicizumab as an alternative treatment option for type 3 VWD patients, an ex vivo spiking analysis comparing the effect of Haemate P and emicizumab on TG was performed. An improvement in peak height was demonstrated following spiking with both Haemate P concentrations (P = 0•001 for both) and with the higher emicizumab concentration (P = 0•011). Notably, whereas spiking with both Haemate P concentrations increased peak height to near-normal level, spiking with higher emicizumab concentration increased it to a lesser extent (the median was still lower than in normal controls (P = 0•005). Following the decision to treat our impetus patient with emicizumab prophylaxis, TG analyses were performed in the patient's plasma before and during emicizumab loading and maintenance (Figure 3). As expected, patient's initial TG was extremely low and improved following the first administration of emicizumab loading dose (at week 2 after therapy initiation), at which time emicizumab level was 21 µg/mL. Further significant improvement of TG was noted following loading period completion while emicizumab level was 62 µg/mL. Our patient has been treated with emicizumab for more than six months altogether and did not encounter any joint bleeds since the commencement of therapy. During this period, a single dose of Haemate P was administered following tooth exfoliation. Our study contributes towards a better understanding of TG as a surrogate marker of VWD patients' hemostasis. Our data suggests that some severe VWD patients could be safely and efficiently treated with emicizumab. The successful prophylaxis of our patient and our ex vivo laboratory findings should set the ground for further collaborative multicenter studies to examine the efficacy and safety of emicizumab prophylaxis in type 3 VWD patients. Disclosures Barg: roshe: Honoraria, Speakers Bureau. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The use of Emicizumab in sever Von Willebrand disease

Real-world data on emicizumab use and monitoring in paediatric severe haemophilia A (HA) patients are scarce. We therefore sought to evaluate safety, efficacy, and laboratory monitoring of emicizumab prophylaxis in a cohort of 40 children with severe HA, including 22 non-inhibitor patients and nine infants younger than one year. Bleeding, trauma, adverse events, and surgeries were documented during a median follow-up of 45 weeks. Emicizumab levels, activated partial thromboplastin time (aPTT) values, and thrombin generation were measured before and during therapy. Twenty patients experienced zero bleeds. All bleeding was trauma-related, and bleeding risk was positively correlated with the length of emicizumab prophylaxis. Sixteen surgical interventions were performed in 12 patients, with no thrombotic complications or thrombotic microangiopathy. Prolonged aPTT values normalised after emicizumab initiation, correlating with an increase in emicizumab plasma levels. Elevation in the thrombin generation was observed following emicizumab prophylaxis, with lower values recorded in younger infants. Emicizumab prophylaxis was safe and well tolerated. As all bleedings were trauma-related, laboratory monitoring could not predict bleeding risk. Our results do not support routine thrombin generation monitoring in children treated by emicizumab, yet further studies are warranted in the context of surgical procedures.

INTRODUCTION:Hemophilia is a hereditary congenital hemorrhagic diathesis caused by mutations in blood coagulation factor VIII (FVIII) or IX (FIX) genes, causing hemophilia A and B, respectively. Most cases are familial but a significant minority is sporadic.OBJECTIVES:To examine the presenting symptoms of patients with hemophilia in Israel and identify causes for delay in diagnosis.METHODS:Retrospective analysis of data from medical files of newly diagnosed patients with hemophilia during the period from 1st January 2010 to 31s December 2017.RESULTS:During the study period 104 children had been diagnosed with hemophilia. Fifteen percent were diagnosed with hemophilia B and 85% with hemophilia A. In most familial cases the diagnosis was established by examination of aPTT and the level of the relevant clotting factor shortly after birth. Diagnosis of sporadic cases (40 cases) was performed due to suggestive clinical symptoms. Perinatal complications were observed in 6 newborns. The most common presenting symptom was disproportionate bleeding following circumcision. In 6/21 patients who experienced excessive bleeding following circumcision there was a delay in diagnosis. Severe bleeding requiring intensive care admission was observed in twelve neonates.DISCUSSION:Diagnosis of hemophilia in Israel is made at an earlier age than in Europe. This is probably due to the performance of ritual circumcision during the neonatal period. In recent years a reduction in familial cases of severe hemophilia has been noted due to genetic counseling of hemophilia carriers. In cases of excessive bleeding following circumcision aPTT and PT should be examined promptly.

Heparin-induced thrombocytopenia (HIT) is the most important non-hemorrhagic complication of heparin treatment. We report a case of a major thromboembolic event accompanied by thrombocytopenia following heparin exposure during coronary artery bypass graft surgery. Thrombocytopenia was documented one month after the surgery, and a major thromboembolic event which led to the patient’s death diagnosed 6 weeks after heparin exposure. We discuss the pathophysiology and clinical aspects of heparin-induced thrombocytopenia, focusing on the unique features of this patient, including late persistent thrombocytopenia. •

Abstract Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products. Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity. Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration. Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic. Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.

Background/Purpose. Hepatitis C (HCV) is a major cause of morbidity and mortality in haemophilia patients who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Recently, it has been suggested that anti-HCV treated patients, particularly those achieving a sustained virological response (SVR) have an improved outcome. We sought to examine the survival of treated and untreated HCV-infected haemophilia patients.Material and methods. We studied overall and liver-related survival of patients with haemophilia and other congenital bleeding disorders between 2000 and 2010. The outcome was compared in 3 sub-groups: HCV mono-infected (N = 127), HCV/HIV co-infected (N = 28), and patients with either HCV-antibodies negative or persistent HCV RNA-negative (referred to as non-infected) (N = 45). Sixty-two (40%) (HCV and HCV/HIV) patients underwent anti-HCV treatment with an SVR rate of 40.3%.Results. Overall and liver-related 10-year survival were: 82.1 and 89.3%, 95.3 and 99.2 and 100% for HCV/HIV co-infected, HCV mono-infected and non-infected haemophilia patients, respectively (p = 0.015 and 0.023 for comparisons of HCV/HIV vs. HCV; p = 0.003 for comparison of HCV/HIV and non-infected). One HCV mono-infected and 3 co-infected patients died of end-stage liver disease (2 underwent liver transplantation). There was no survival benefit from anti-HCV treatment or from attaining of an SVR. Only clinically suspected cirrhosis remained as an independent predictor of survival.Conclusion. The prognosis of haemophilia patients who acquired HCV/HIV co-infection is worse than that of HCV mono-infected or non-infected or haemophiliacs. This is mainly due to liver-related mortality. Anti-HCV treatment or SVR had no observable impact on survival rate.

Summary. Non‐invasive modalities to estimate fibrosis stage are desirable in hepatitis C‐infected haemophilia patients. Previous studies found a high rate of significant fibrosis both by Fibrotest (FT) and Fibroscan (FS) in these patients. To estimate liver fibrosis and to assess the concordance between FT and FS in hepatitis C‐infected haemophilia patients. FT and FS were performed at different laboratories and were unaware of the results of the alternative test. Three successive liver stiffness measurements (LSM) were performed at different sites on the liver. Two‐validated algorithms were used to improve evaluation of fibrosis by non‐invasive methods. Fifty‐seven hepatitis C‐infected haemophilia patients were evaluated by FT and FS. Acquisition of LSMs was not feasible in two patients: obesity – one, surgical scars – one. Fibrosis stage ≥F2, ≥F3 or =F4 were estimated in about a half, about a third and in 15–20% of the evaluated patients by FS and FT respectively. The corresponding concordance rates and κ score for fibrosis stage ≥F2, ≥F3 or =F4 between FT and FS were 62%, 69%, 85% and 0.24, 0.32, 0.44 respectively. Using the two aforementioned algorithms, additional 14 patients could be reliably estimated for fibrosis stage ≥F2. High proportion hepatitis C‐infected haemophilia patients were estimated with significant or advanced stages of liver fibrosis using both tests. Nevertheless, the agreement between modalities was only fair and improved with more advanced stages of fibrosis. Practical algorithms for the accuracy of FT and FS may improve reliable evaluation of fibrosis in this population.